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CANCER MANAGEMENT IN LATIN AMERICA I

NASOPHARYNGEAL TO RENAL CANCER

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Cancer Management in Latin America Palliative Care: I: Nasopharyngeal to Renal Cancer Oncology Experience from Hong Kong Maurício F Silva, Gustavo Nader Marta, Louisa Cheuk-Yu Lui, Kam-Hung Wong, Luis CM Antunes, Fiona Lim, Rebecca Yeung, Joav Merrick (Editors) Bo Angela Wan, Beatriz Amendola, 2017. ISBN: 978-1-53612-397-5 (Softcover) Joav Merrick (Editors) 2017. ISBN: 978-1-53612-430-9 (eBook) 2020. ISBN: 978-1-53616-733-7 (Hardcover) 2020. ISBN: 978-1-53616-734-4 (eBook) Psychosocial Needs: Success in Life and Career Planning Alternative Medicine Research Daniel TL Shek, Janet TY Leung, Tak Y Lee Yearbook 2017 and Joav Merrick (Editors) Joav Merrick (Editor) 2017. ISBN: 978-1-53611-951-0 (Hardcover) 2018. ISBN: 978-1-53613-726-2 (Hardcover) 2017. ISBN: 978-1-53611-971-8 (eBook) 2018. ISBN: 978-1-53613-727-9 (eBook) Cannabis: Medical Aspects Clinical Art Psychotherapy Blair Henry, Arnav Agarwal, Edward Chow, with War Veterans Hatim A Omar, and Joav Merrick (Editors) Alexander Kopytin and Alexey Lebedev 2017. ISBN: 978-1-53610-510-0 (Hardcover) 2018. ISBN. 978-1-53612-975-5 (Softcover) 2017. ISBN: 978-1-53610-522-3 (eBook) 2017. ISBN: 978-1-53612-976-2 (eBook) Palliative Care: Psychosocial Cancer and Exercise and Ethical Considerations Leila Malek, Fiona Lim, Bo Angela Wan, Blair Henry, Arnav Agarwal, Edward Chow, Patrick L Diaz, Edward Chow, Joav Merrick and Joav Merrick (Editors) (Editors) 2017. ISBN: 978-1-53610-607-7 (Hardcover) 2018. ISBN: 978-1-53612-747-8 (Hardcover) 2017. ISBN: 978-1-53610-611-4 (eBook) 2018. ISBN: 978-1-53612-748-5 (eBook) Oncology: The Promising Future Brennan Healing Science: of Biomarkers An Integrative Approach to Anthony Furfari, George S Charames, Therapeutic Intervention Rachel McDonald, Leigha Rowbottom, Nina Koren, Muriel Moreno Azar Azad, Stephanie Chan, Bo Angela Wan, and Joav Merrick (Editors) Ronald Chow, Carlo DeAngelis, Pearl Zaki, 2018. ISBN: 978-1-53612-825-3 (Hardcover) Edward Chow and Joav Merrick (Editors) 2018. ISBN: 978-1-53612-826-0 (eBook) 2017. ISBN: 978-1-53610-608-4 (Hardcover) 2017. ISBN: 978-1-53610-610-7 (eBook)

Complimentary Contributor Copy Public Health Yearbook 2016 Cancer: Spinal Cord, Lung, Breast, Joav Merrick (Editor) Cervical, Prostate, Head 2017. ISBN: 978-1-53610-947-4 (Hardcover) and Neck Cancer 2017. ISBN: 978-1-53610-956-6 (eBook) Breanne Lechner, Ronald Chow, Natalie Pulenzas, Marko Popovic, Na Zhang, Alternative Medicine Research Xiaojing Zhang, Edward Chow Yearbook 2016 and Joav Merrick (Editors) Joav Merrick (Editor) 2016. ISBN: 978-1-63483-904-4 (Hardcover) 2017. ISBN: 978-1-53610-972-6 (Hardcover) 2015. ISBN: 978-1-63483-911-2 (eBook) 2017. ISBN: 978-1-53611-000-5 (eBook) Cancer: Survival, Quality of Life Pain Management Yearbook 2016 and Ethical Implications Joav Merrick (Editor) Breanne Lechner, Ronald Chow, 2017. ISBN: 978-1-53610-949-8 (Hardcover) Natalie Pulenzas, Marko Popovic, Na Zhang, 2017. ISBN: 978-1-53610-959-7 (eBook) Xiaojing Zhang, Edward Chow and Joav Merrick (Editors) Medical Cannabis: Clinical Practice 2016. ISBN: 978-1-63483-905-1 (Hardcover) Shannon O’Hearn, Alexia Blake, 2015. ISBN: 978-1-63483-912-9 (eBook) Bo Angela Wan, Stephanie Chan, Edward Chow and Joav Merrick (Editors) Cancer: Pain and Symptom 2017. ISBN: 978-1-53611-907-7 (Softcover) Management 2017. ISBN: 978-1-53611-927-5 (eBook) Breanne Lechner, Ronald Chow, Natalie Pulenzas, Marko Popovic, Na Zhang, Cancer: Treatment, Decision Making Xiaojing Zhang, Edward Chow, and Quality of Life and Joav Merrick (Editors) Breanne Lechner, Ronald Chow, 2016. ISBN: 978-1-63483-905-1 (Hardcover) Natalie Pulenzas, Marko Popovic, Na Zhang, 2015. ISBN: 978-1-63483-881-8 (eBook) Xiaojing Zhang, Edward Chow, and Joav Merrick (Editors) Alternative Medicine Research 2016. ISBN: 978-1-63483-863-4 (Hardcover) Yearbook 2015 2015. ISBN: 978-1-63483-882-5 (eBook) Joav Merrick (Editor) 2016. ISBN: 978-1-63484-511-3 (Hardcover) Cancer: Bone Metastases, CNS 2016. ISBN: 978-1-63484-542-7 (eBook) Metastases and Pathological Fractures Breanne Lechner, Ronald Chow, Public Health Yearbook 2015 Natalie Pulenzas, Marko Popovic, Na Zhang, Joav Merrick (Editor) Xiaojing Zhang, Edward Chow, 2016. ISBN: 978-1-63484-511-3 (Hardcover) and Joav Merrick (Editors) 2016. ISBN: 978-1-63484-546-5 (eBook) 2016. ISBN: 978-1-63483-949-5 (Hardcover) 2015. ISBN: 978-1-63483-960-0 (eBook)

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Leadership and Service Learning Textbook on Evidence-Based Holistic Education: Holistic Development Mind-Body Medicine: Holistic Practice for Chinese University Students of Traditional Hippocratic Medicine Daniel TL Shek, Florence KY Wu Søren Ventegodt and Joav Merrick and Joav Merrick (Editors) 2013. ISBN: 978-1-62257-105-5 (Hardcover) 2015. ISBN: 978-1-63483-340-0 (Hardcover) 2012. ISBN: 978-1-62257-174-1 (eBook) 2015. ISBN: 978-1-63483-347-9 (eBook) Textbook on Evidence-Based Holistic Mental and Holistic Health: Mind-Body Medicine: Healing the Mind Some International Perspectives in Traditional Hippocratic Medicine Joseph L Calles Jr, Donald E Greydanus, Søren Ventegodt and Joav Merrick and Joav Merrick (Editors) 2013. ISBN: 978-1-62257-112-3 (Hardcover) 2015. ISBN: 978-1-63483-589-3 (Hardcover) 2012. ISBN: 978-1-62257-175-8 (eBook) 2015. ISBN: 978-1-63483-608-1 (eBook) Complimentary Contributor Copy Textbook on Evidence-Based Holistic Building Community Capacity: Case Mind-Body Medicine: Sexology and Examples from Around the World Traditional Hippocratic Medicine Rosemary M Caron and Joav Merrick Søren Ventegodt and Joav Merrick (Editors) 2013. ISBN: 978-1-62257-130-7 (Hardcover) 2013. ISBN: 978-1-62417-175-8 (Hardcover) 2012. ISBN: 978-1-62257-176-5 (eBook) 2013. ISBN: 978-1-62417-176-5 (eBook)

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Health Risk Communication Human Immunodeficiency Virus (HIV) Marijke Lemal and Joav Merrick (Editors) Research: Social Science Aspects 2012. ISBN: 978-1-62257-544-2 (Hardcover) Hugh Klein and Joav Merrick (Editors) 2012. ISBN: 978-1-62257-552-7 (eBook) 2012. ISBN: 978-1-62081-293-8 (Hardcover) 2012. ISBN: 978-1-62081-346-1 (eBook) Translational Research for Primary Healthcare AIDS and Tuberculosis: Public Erica Bell, Gert P Westert Health Aspects and Joav Merrick (Editors) Daniel Chemtob and Joav Merrick (Editors) 2012. ISBN: 978-1-61324-647-4 (Hardcover) 2012. ISBN: 978-1-62081-382-9 (Softcover) 2012. ISBN: 978-1-62417-409-4 (eBook) 2012. ISBN: 978-1-62081-406-2 (eBook)

Our Search for Meaning in Life: Public Health Yearbook 2011 Quality of Life Philosophy Joav Merrick (Editor) Søren Ventegodt and Joav Merrick 2012. ISBN: 978-1-62081-433-8 (Hardcover) 2012. ISBN: 978-1-61470-494-2 (Hardcover) 2012. ISBN: 978-1-62081-434-5 (eBook) 2011. ISBN: 978-1-61470-519-2 (eBook) Alternative Medicine Research Randomized Clinical Trials Yearbook 2011 and Placebo: Can You Trust Joav Merrick (Editor) the Drugs are Working and Safe? 2012. ISBN: 978-1-62081-476-5 (Hardcover) Søren Ventegodt and Joav Merrick 2012. ISBN: 978-1-62081-477-2 (eBook) 2012. ISBN: 978-1-61470-067-8 (Hardcover) 2011. ISBN: 978-1-61470-151-4 (eBook) Building Community Capacity: Skills and Principles Building Community Capacity: Rosemary M Caron and Joav Merrick Minority and Immigrant Populations (Editors) Rosemary M Caron and Joav Merrick 2012. ISBN: 978-1-61209-331-4 (Hardcover) (Editors) 2012. ISBN: 978-1-62257-238-0 (eBook) 2012. ISBN: 978-1-62081-022-4 (Hardcover) 2012. ISBN: 978-1-62081-032-3 (eBook) Textbook on Evidence-Based Holistic Mind-Body Medicine: Basic Principles Applied Public Health: Examining of Healing in Traditional Hippocratic Multifaceted Social or Ecological Medicine Problems and Child Maltreatment Søren Ventegodt and Joav Merrick John R Lutzker and Joav Merrick (Editors) 2012. ISBN: 978-1-62257-094-2 (Hardcover) 2012. ISBN: 978-1-62081-356-0 (Hardcover) 2012. ISBN: 978-1-62257-172-7 (eBook) 2012. ISBN: 978-1-62081-388-1 (eBook)

Complimentary Contributor Copy Textbook on Evidence-Based Holistic Positive Youth Development: Mind-Body Medicine: Basic Philosophy Evaluation and Future and Ethics of Traditional Hippocratic Directions in a Chinese Context Medicine Daniel TL Shek, Hing Keung Ma Søren Ventegodt and Joav Merrick and Joav Merrick (Editors) 2012. ISBN: 978-1-62257-052-2 (Hardcover) 2011. ISBN: 978-1-60876-830-1 (Hardcover) 2013. ISBN: 978-1-62257-707-1 (eBook) 2011. ISBN: 978-1-62100-175-1 (Softcover) 2010. ISBN: 978-1-61209-091-7 (eBook) Textbook on Evidence-Based Holistic Mind-Body Medicine: Research, Understanding Eating Disorders: Philosophy, Economy and Politics of Integrating Culture, Traditional Hippocratic Medicine Psychology and Biology Søren Ventegodt and Joav Merrick Yael Latzer, Joav Merrick and Daniel Stein 2012. ISBN: 978-1-62257-140-6 (Hardcover) (Editors) 2012. ISBN: 978-1-62257-171-0 (eBook) 2011. ISBN: 978-1-61728-298-0 (Hardcover) 2011. ISBN: 978-1-61470-976-3 (Softcover) Behavioral Pediatrics, 3rd Edition 2011. ISBN: 978-1-61942-054-0 (eBook) Donald E Greydanus, Dilip R Patel, Helen D Pratt and Joseph L Calles, Jr Advanced Cancer Pain (Editors) and Quality of Life 2011. ISBN: 978-1-60692-702-1 (Hardcover) Edward Chow and Joav Merrick (Editors) 2009. ISBN: 978-1-60876-630-7 (eBook) 2011. ISBN: 978-1-61668-207-1 (Hardcover) 2010. ISBN: 978-1-61668-400-6 (eBook) Rural Child Health: International Aspects Positive Youth Development: Erica Bell and Joav Merrick (Editors) Implementation of a Youth Program 2011. ISBN: 978-1-60876-357-3 (Hardcover) in a Chinese Context 2011. ISBN: 978-1-61324-005-2 (eBook) Daniel TL Shek, Hing Keung Ma and Joav Merrick (Editors) International Aspects 2011. ISBN: 978-1-61668-230-9 of Child Abuse and Neglect Howard Dubowitz and Joav Merrick Social and Cultural Psychiatry (Editors) Experience from the Caribbean Region 2011. ISBN: 978-1-60876-703-8 (Hardcover) Hari D Maharajh and Joav Merrick (Editors) 2010. ISBN: 978-1-61122-049-0 (Softcover) 2011. ISBN: 978-1-61668-506-5 (Hardcover) 2010. ISBN: 978-1-61122-403-0 (eBook) 2010. ISBN: 978-1-61728-088-7 (eBook)

Environment, Mood Disorders Narratives and Meanings of Migration and Suicide Julia Mirsky Teodor T Postolache and Joav Merrick 2011. ISBN: 978-1-61761-103-2 (Hardcover) (Editors) 2010. ISBN: 978-1-61761-519-1 (eBook) 2011. ISBN: 978-1-61668-505-8 (Hardcover) 2011. ISBN: 978-1-62618-340-7 (eBook)

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Alcohol-Related Cognitive Disorders: Research and Clinical Perspectives Leo Sher, Isack Kandel and Joav Merrick (Editors) 2009. ISBN: 978-1-60741-730-9 (Hardcover) 2009. ISBN: 978-1-60876-623-9 (eBook)

Complimentary Contributor Copy HEALTH AND HUMAN DEVELOPMENT

CANCER MANAGEMENT IN LATIN AMERICA I

NASOPHARYNGEAL TO RENAL CANCER

MAURÍCIO F SILVA GUSTAVO NADER MARTA LUIS CM ANTUNES FIONA LIM BO ANGELA WAN BEATRIZ AMENDOLA AND JOAV MERRICK EDITORS

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Names: Silva, Maurício F. (Maurício Fraga), editor. | Marta, Gustavo Nader, editor. | Antunes, Luís C. M. (Luís Carlos Moreira), editor. | Lim, Fiona, editor. | Wan, Bo Angela, editor. | Amendola, Beatriz E., editor. | Merrick, Joav, 1950- editor. Title: Cancer management in Latin America / [edited by Maurício F. Silva, Gustavo Nader Marta, Luis C.M. Antunes, Fiona Lim, Bo Angela Wan, Beatriz Amendola, Joav Merrick]. Description: New York : Nova Science Publishers, Inc., [2019-] | Series: Health and human development | Includes bibliographical references and index. | Contents: I. Nasopharyngeal to renal cancer -- | Identifiers: LCCN 2019051794 (print) | LCCN 2019051795 (ebook) | ISBN 9781536167337 (hardcover) | ISBN 9781536167344 (adobe pdf) Subjects: LCSH: Cancer--Treatment--Latin America. Classification: LCC RC279.L29 C36 2019 (print) | LCC RC279.L29 (ebook) | DDC 362.19699/40098--dc23 LC record available at https://lccn.loc.gov/2019051794 LC ebook record available at https://lccn.loc.gov/2019051795

Published by Nova Science Publishers, Inc. † New York

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CONTENTS

Introduction 1 Chapter 1 Cancer management in Latin America: Nasopharyngeal to renal cancer 3 Maurício F Silva, Gustavo Nader Marta, Luis CM Antunes, Fiona Lim, Bo Angela Wan, Beatriz Amendola and Joav Merrick

Section one Cancer management 5 Chapter 2 Management of nasopharyngeal cancer 7 Fabrício Scapini, Alexandre Arthur Jacinto, Fiona Lim, Bo Angela Wan and Maurício F Silva Chapter 3 Management of oropharyngeal cancer 21 Otávio Costa Diaz, Virgilio Zanella, Juliana Janoski de Menezes, Fiona Lim, Bo Angela Wan and Maurício F Silva Chapter 4 Management of oral cancer 31 Otávio Costa Diaz, Virgilio Zanella, Juliana Janoski de Menezes, Fiona Lim, Bo Angela Wan and Maurício F Silva Chapter 5 A review of laryngeal cancer management 43 Icaro Thiago de Carvalho, Daniel Marin Ramos, Fernando Mauro de Lima Prearo, Fiona Lim, Bo Angela Wan and Maurício F Silva Chapter 6 Management of non-small cell lung cancer in Latin America 53 Rafael Caparica, Flavia Carolina Gabrielli, Pedro H Nabuco de Araujo, Ricardo Mingarini Terra, Fiona Lim, Bo Angela Wan, Lavoisier Fragoso de Albuquerque and Mauricio F Silva Chapter 7 Management of esophageal cancer 69 Julio Pereira-Lima, Michele Bonotto, Julio Cesar Razera, Fiona Lim, Bo Angela Wan and Mauricio F Silva

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Chapter 8 Management of gastric cancer 81 Carlos A García, Fiona Lim, Bo Angela Wan, Rodrigo Torres-Quevedo and Mauricio F Silva Chapter 9 Management of pancreatic cancer 93 Sergio Pacheco, Andrés Troncoso, Nicolás Jarufe, Rodrigo Torres-Quevedo, Fiona Lim, Bo Angela Wan and Mauricio F Silva Chapter 10 Management of intrahepatic cholangiocarcinoma 103 Juan Carlos Díaz, Alexandre Sauré, Carlos Mandiola, Rodrigo Torres-Quevedo, Fiona Lim, Bo Angela Wan and Mauricio F Silva Chapter 11 Management of gallbladder cancer 119 Felipe Castillo, Xabier de Aretxabala, Rodrigo Torres-Quevedo, Fiona Lim, Bo Angela Wan and Mauricio F Silva Chapter 12 Management of liver metastases 133 Mario Uribe, Vincenzo Benedetti, Rodrigo Torres-Quevedo, Fiona Lim, Bo Angela Wan and Maurício F Silva Chapter 13 Management of hepatocellular carcinoma 153 Juan Francisco Guerra, María Inés Gaete, Andres Troncoso, Rodrigo Torres-Quevedo, Fiona Lim, Bo Angela Wan and Maurício F Silva Chapter 14 Management of colon cancer 163 Lauren Razzera Stefanon, Luís Carlos Moreira Antunes, Fiona Lim, Bo Angela Wan and Mauricio F Silva Chapter 15 Surgical treatment of locally advanced rectal adenocarcinoma 175 Francisco López-Köstner, José Miguel Reyes, Alejandro J. Zarate, Fiona Lim, Bo Angela Wan and Mauricio F. Silva Chapter 16 Management of anal cancer 185 Patrícia B Aguilar, Renata Peixoto, Fiona Lim, Bo Angela Wan and Maurício F Silva Chapter 17 Management of early breast cancer 199 Heloisa de Andrade Carvalho, Silvia Radwanski Stuart, Gustavo Nader Marta, Fiona Lim, Bo Angela Wan and Mauricio F Silva Chapter 18 Management of locally advanced breast cancer 217 Patricia Murina, Soledad del Castillo, Andrés del Castillo, Pablo Castro Peña, Fiona Lim, Bo Angela Wan and Mauricio F Silva

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Chapter 19 Management of uterine cancer 233 Neiro Waechter da Motta, Günther Alex Schneider, Carlos Eugenio Escovar, Rosilene Jara Reis, Fiona Lim, Bo Angela Wan and Maurício F Silva Chapter 20 Management of cervical cancer 251 Dolores de la Mata Moya, Luisa María Catalina Tenorio Téllez, Fiona Lim, Bo Angela Wan and Mauricio F Silva Chapter 21 Management of prostate cancer 285 Camila Casadiego Peña, Maribel Bruna Figueroa, Hugo Marsiglia, Fiona Lim, Bo Angela Wan and Maurício F Silva Chapter 22 Management of prostate cancer in the postoperative context and in metastatic disease 315 Camila Casadiego Peña, Maribel Bruna Figueroa, Hugo Marsiglia, Fiona Lim, Bo Angela Wan and Maurício F Silva Chapter 23 Bladder cancer: Epidemiological study in Latin America, trends and review of surgical aspects for the treatment of the disease 341 Paulo Rodrigues, Eduardo Barbieri, Angelo Bezerra de Souza Fede, Fiona Lim, Bo Angela Wan and Mauricio F Silva Chapter 24 Management of renal cancer in Latin America 363 Rafael Corrêa Coelho, Cleber Brenner, João Paulo Fogacci de Farias, Fiona Lim, Bo Angela Wan and Maurício F Silva

Section two Acknowledgments 387 Chapter 25 About the editors 389 Chapter 26 About the Radiation Oncology Unit, Santa Maria University Hospital (UFSM), Santa Maria, Brazil 393 Chapter 27 About the National Institute of Child Health and Human Development in Israel 395 Chapter 28 About the book series “Health and human development” 399

Section three Index 405 Index 407

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INTRODUCTION

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Chapter 1

CANCER MANAGEMENT IN LATIN AMERICA: NASOPHARYNGEAL TO RENAL CANCER

Maurício F Silva1-3, MD, PhD, Gustavo Nader Marta4, 5, MD, PhD, Luis CM Antunes6,7, MD, PhD, Fiona Lim8, MBBS, Bo Angela Wan9, MD, Phil Beatriz Amendola4, MD and Joav Merrick10-13, MD, MMedSci, DMSc 1Radiation Oncology Department, Santa Maria Federal University, Santa Maria, Brazil 2Radiation Oncology Unit, Hospital de Caridade Astrogildo de Azevedo, Santa Maria, Brazil 3Latin America Cooperative Oncology Group, Porto Alegre, Brazil 4Radiation Oncology Unit, Hospital Sírio Libanes, São Paulo, Brazil 5Instituto do Cancer do Estado de São Paulo, São Paulo, Brazil 6Clinica Viver, Santa Maria, Brazil 7Clinical Oncology Department, Santa Maria Federal University, Santa Maria,Brazil 8Department of Oncology, Princess Margaretti Hospital, Hong Kong, Chona 9Odette Cancer Centre, Sunnybrook Health Science Centre, Toronto, Canada 10National Institute of Child Health and Human Development, Jerusalen, Israel 11Department of Pediatrics, Mt Scopus Campus, Hadassah, Hebrew University Medical Center, Jerusalem, Israel 12Kentucky Children’s Hospital, University of Kentucky, Lexington, Kentucky, United States

ABSTRACT

This book is organized according to organ systems. Book one starts with cancers of the head and neck, followed by cancers of the respiratory and gastrointestinal systems. We

 Corresponding Author’s Email: [email protected]. Complimentary Contributor Copy 4 Maurício F Silva, Gustavo Nader Marta, Luis CM Antunes et al.

then move on to cancers of the reproductive system, and end on the management of renal cancer. We hope that this book will serve as a valuable resource of information to the health care professional and policy makers of Latin America.

INTRODUCTION

Historically, scientific development is mainly based on discoveries led by developed countries, with findings then extrapolated to the rest of the world. However, each geographic location has inherent local characteristics that influence the outcomes studied. Regardless of the source of research, all results should be validated trough scientific experiments, following evidence hierarchy based on the methodological quality of the means the data was obtained. This approach is fittingly termed “evidence-based medicine” and remains a pillar upon which western medicine is based. Latin America consists of 33 countries and represents about 10% of the global population. There is a huge amount of social and economic heterogeneity both within a country, and among different countries. Of particular note is Brazil, both the largest Latin American country and also unique in having Portuguese rather than Spanish as the official language. Furthermore, Brazil is different in terms of its economic development, as multiple ranking systems have considered it among the 10 largest economies worldwide based on the Gross Domestic Product. Despite its presence in terms of population and economic significance, Latin America lacks in producing research. Data published in Nature Journal in 2014 suggested that Latin America is responsible for only 4% of publications in indexed journals, and most importantly, the mean impact factor of the published manuscripts is only around 0.7. In view of the discrepancy between the presence of a large, unique population, and the lack of dedicated medical research focused on this population, the editors of the present book deemed it essential to develop a textbook focused on the management of cancer in Latin America. Among the topics discussed include the challenges of medicine in the real world, problems that need to be overcome, and the potential impact of proposed changes, from the perspective of treating expert oncologists and healthcare professionals working with the Latin American people. Our book is organized according to organ systems. Book one starts with cancers of the head and neck, followed by cancers of the respiratory and gastrointestinal systems. We then move on to cancers of the reproductive system, and end on the management of renal cancer. We hope that this book will serve as a valuable resource of information to the health care professional and policy makers of Latin America.

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SECTION ONE: CANCER MANAGEMENT

Chapter 2

MANAGEMENT OF NASOPHARYNGEAL CANCER

Fabrício Scapini1,, MD, PhD, Alexandre Arthur Jacinto2, MD, PhD, Fiona Lim3, MBBS, Bo Angela Wan4, MD(C) and Maurício F Silva5,6,7, MD, PhD 1Department of Surgery, Otolaryngology Unit at Santa Maria Federal University, Santa Maria, Brazil 2Department of Radiotherapy, Barretos Cancer Hospital, São Paulo, Brazil 3Department of Oncology, Princess Margaret Hospital, Hong Kong, PR China 4Odette Cancer Centre, Sunnybrook Health Sciences Centre, University of Toronto, Toronto, Ontario, Canada 5Radiation Oncology Unit, Santa Maria Federal University, Santa Maria, Brazil 6Radiation Oncology Unit, Hospital de Caridade Astrogildo de Azevedo, Santa Maria, Brazil 7Latin America Cooperative Oncology Group, Porto Alegre, Brazil

ABSTRACT

The overall annual incidence of nasopharyngeal cancer is 85,000 cases per year and an estimated 50,000 deaths annually worldwide. Although relatively uncommon in western countries, the disease is endemic in regions such as southern China and Southeast Asia, where they account for about half of the cases worldwide. This particular geographical distribution allowed the identification of environmental risk factors, especially those related to diet and Epstein-barr virus (EBV) infection. The main modality of treatment is radiation therapy and the great technological development in recent decades, such as intensity-modulated radiation therapy (IMRT), has allowed lower toxicity and higher survival rates. Concomitant chemotherapy, especially platinum-based, is associated with increased survival rates, especially for stage II or greater disease. The need for treatment with adjuvant or neoadjuvant chemotherapy has not yet been well established. Selected cases may benefit from neoadjuvant chemotherapy, especially bulky large tumors, when there may be technical difficulty in performing an adequate radiation therapy plan, the

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use of molecularly targeted therapy has still failed to demonstrate benefits over conventional therapy. Local recurrence or distant metastasis are still a challenge. Reirradiation, chemotherapy or even surgery are current options. Heavy-particle therapy is a future perspective, although the high cost is still a limiting factor.

INTRODUCTION

In adults, cancer of the nasopharynx is represented almost exclusively by squamous cell carcinoma. Other malignant tumors may also arise from the nasopharynx, such as adenoid cystic carcinoma, nasopharyngeal papillary adenocarcinoma, and lymphoma (1). In children, nasopharyngeal carcinoma (NPC) accounts for 35-50% of all malignant tumors of this region, with rhabdomyosarcomas and lymphomas making up most of the rest (2). The histopathological classification of NPC has undergone many changes over the decades. The World Health Organization (WHO) classification differed from those used in high-incidence countries such as China, which made it difficult to interpret the results of research involving NPC (3). Currently, the WHO classifies NPCs into types I (squamous cell carcinoma), II (differentiated non-keratinizing carcinoma), and III (undifferentiated nonkeratinizing carcinoma) (1). In the 2003 edition of its classification, WHO included basaloid carcinoma (4). The fourth edition, published in 2017, did not include significant additional changes (1, 5). Type I (keratinizing and well-differentiated) accounts for approximately 5- 10% of cases. In low-incidence regions (largely Western countries), however, type I is the most common (over 75% of cases). Conversely, in endemic areas, type III accounts for 97% of cases (3, 6). Symptoms vary depending on the stage of the tumor. They can be broadly grouped into auditory (aural fullness, hypoacusis, and tinnitus, due to eustachian tube dysfunction and consequent otitis media with effusion), nasal (obstruction, rhinorrhea, and epistaxis), and symptoms due to cranial extension of the tumor (headache, diplopia, facial pain, trismus). When present, a cervical mass denotes advanced disease. As the initial symptoms are nonspecific, most cases are diagnosed at advanced stages. Cervical masses resulting from locoregional metastasis may be present at initial evaluation in up to 80% of patients (7). Diagnosis is usually accomplished through an endonasal endoscopic biopsy. NPCs usually originate from the epithelium of the pharyngeal recess (also known as the fossa of Rosenmüller) (8). Imaging, especially computed tomography (CT) of the head, neck, and chest as well as magnetic resonance imaging (MRI), can be used to provide supplementary information for diagnosis and will guide the staging classification CT and MRI are complementary tests. CT is better for the evaluation of bone destruction and MRI is superior to CT to identify neural spread, intracranial extension or skull base invasion. In our practice routine we generally perform both CT and MRI to guarantee better loco-regional staging. During the diagnosis evaluation, positron emission tomography (PET-CT) should be reserved for suspected cases of occult primary tumor, before biopsy is considered (8). However, when diagnosis of NPC is already confirmed, the PET-CT should be ordered to exclude distant metastasis, especially in case of advanced loco-regional disease. Bone scan scintigraphy can be alternatively considered to evaluate bone metastasis for stage III and IVa NPC when PET- CT is not available.

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CLASSIFICATION AND STAGING

The progression of radiotherapy, chemotherapy, and surgical techniques has resulted in a significant improvement in survival. Thus, the classification and staging of NPC has undergone several changes over the last decade. The International Union Against Cancer (UICC)/American Joint Committee on Cancer (AJCC) TNM classification is based on clinical, endoscopic, and radiological (CT and MRI) evaluation. Invasion of soft tissues, cranial nerves, and skeletal structures are evaluated, as are locoregional lymph node involvement and the presence of distant metastases. The 8th edition of the UICC/AJCC TNM classification (9) included some modifications to the previous edition, which made it more accurate to distinguish prognoses between adjacent categories/stages (see Tables 1-2).

Table 1. TNM classification

Primary tumor (T) TX Primary tumor cannot be assessed T0 No tumor identified, but EBV-positive cervical node(s) involvement Tis Carcinoma in situ T1 Tumor confined to the nasopharynx, or extension to oropharynx and/or nasal cavity without parapharyngeal involvement T2 Tumor with extension to parapharyngeal space, and/or adjacent soft tissue involvement (medial pterygoid, lateral pterygoid, prevertebral muscles) T3 Tumor with infiltration of bony structures at skull base, cervical vertebra, pterygoid structures, and/or paranasal sinuses T4 Tumor with intracranial extension, involvement of cranial nerves, hypopharynx, orbit, parotid gland, and/or extensive soft tissue infiltration beyond the lateral surface of the lateral pterygoid muscle

Regional lymph nodes (N) NX Regional nodes cannot be assessed N0 No regional lymph node metastasis N1 Unilateral metastasis in cervical lymph node(s) and/or unilateral or bilateral metastasis in retropharyngeal lymph node(s), 6 cm or smaller in greatest dimension, above the caudal border of cricoid cartilage N2 Bilateral metastasis in cervical lymph node(s), 6 cm or smaller in greatest dimension, above the caudal border of cricoid cartilage N3 Unilateral or bilateral metastasis in cervical lymph node(s), larger than 6 cm in greatest dimension, and/or extension below the caudal border of cricoid cartilage

Distant metastasis (M)

cM0 No distant metastasis cM1 Distant metastasis pM1 Distant metastasis, microscopically confirmed

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Table 2. Prognostic stage groups

Stage T N M 0 Tis N0 M0 I T1 N0 M0 II T0-T1 N1 M0 T2 N0-N1 M0 III T0-T3 N2 M0 T3 N1-N2 M0 IVA T4 N0-N2 M0 T Any N3 M0 IVB T Any N Any M1

EPIDEMIOLOGY

In 2012, WHO estimated the global incidence of NPC at approximately 85,000 new cases, with about 50,000 deaths (10). Men are affected two to three times more commonly than women. In most countries, the incidence is less than 1 case per 100,000. Although it is a relatively uncommon cancer, accounting for only 0.7% of all malignancies, it is endemic in some areas, such as southern China (including Hong Kong) and Southeast Asia. In these regions, the incidence can be as high as 20-30 cases per 100,000 population per year, accounting for about half of all cancers. Chinese populations that migrate to low-incidence countries maintain a higher risk (20- to 30-fold), although there is a trend toward lower incidence as generations pass (11, 12).

GLOBOCAN 2012: Estimated Cancer Incidence, Mortality and Prevalence Worldwide, 2012. Accessed 2018 Sep 09. URL: http://www.globocan.iarc.fr.

Figure 1. Nasopharyngeal cancer: world estimated age-standardized rate of incidence, both sexes.

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In Latin America and the Caribbean, in 2012, there were 1,639 new cases and approximately 800 deaths (10). In high-incidence regions, the most common histological subtype is type III (95% of cases). In low-incidence countries, type I is most common. In low- incidence regions, risk increases gradually with age, while in high-incidence areas, it peaks around age 50 to 59 (13). Figure 1 illustrates the global geographic distribution.

RISK FACTORS

Epstein-Barr Virus

Although there is some geographical variation in EBV infection rates (it is uncommon in Denmark and the Netherlands, for instance) (14), it occurs in virtually all children in the regions where NPC is endemic and is generally asymptomatic. When infection occurs in adolescence and young adulthood, it presents as infectious mononucleosis in about half of cases (15). Transmission is usually through saliva. Its relationship with NPC was first posited in 1966, when antibodies against EBV viral capsid were found (16). Subtypes II and III are commonly associated with EBV, and have a better prognosis than subtype I, which is generally not EBV- related (6). The mechanisms involved in the relationship between EBV and the pathogenesis and progression of NPC have not yet been clearly defined. However, recent studies have demonstrated that EBV interferes with the regulation of several genes and intracellular processes related to tumor growth and invasion (17, 18).

Diet

The high incidence of NPC in certain specific regions, such as Guangdong province in southern China and Hong Kong, have led to extensive investigations into potential risk factors. One of the ethnic subgroups with the highest incidence NPC is the Tanka people or “boat dwellers” of southeast China. Their lifestyle includes intake of foods containing dimethylnitrosamine, especially salted fish (19). Daily salted-fish consumption increased the relative risk of NPC 2.45-fold, as did intake of preserved vegetables (3.17-fold) and salted/cured meat (2.09-fold) (20).

Tobacco and alcohol

Most studies report a 2- to 6-fold increase in the risk of NPC in smokers. However, this risk seems to be more evident for type I. For alcohol, most case-control studies have not shown an increased risk (13).

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Genetic susceptibility

Just as population groups may share the same environmental factors, these same groups may also carry genetic susceptibilities to NPC. In fact, the combination of these conditions may play a very important role in pathogenesis. Some loci have been implicated in the development of NPC in Chinese families. In addition, given the relationship between EBV and NPC, studies have reported increased relative risk with some human leukocyte antigen (HLA) alleles, such as HLA-A2, HLA-Bw46 and HLA-B17 (21).

TREATMENT

Radiotherapy (RT) is considered the main treatment strategy for these tumors. For stages I and II, RT can be employed as monotherapy, achieving overall survival (OS) rates around 90% (22). Most stage II cases with grade T2N0M0 are treated with concurrent chemotherapy and radiotherapy (CCRT). The evolve of precision RT and, also, the quality of image staging are associated to improved outcomes. Intensity-modulated radiation therapy (IMRT) has brought significant improvements in terms of local control (LC), survival and quality of life. IMRT for the treatment of NPC was first described in 2000 at the University of California. At the time, LC rates of up to 100% and 4-year OS rates of up to 94% were described. Subsequent studies corroborated these results (23-25). One of the most important benefit of IMRT for NPC is the reduced morbidity treatment related. The results of the Radiation Therapy Oncology Group Phase II (RTOG 0225) trial, published in 2009, showed LC >90% and a 2-year OS rate of 80.4%, with few cases of grade 3 xerostomia and no grade 4 adverse events (AEs) (23) . In 2012, a prospective randomized phase-III trial (26) comparing IMRT and 2DRT showed that the 5-year local recurrence-free survival (LRFS) rate was increased from 83.8% to 90.5% and OS was increased from 67.1% to 79.6% by IMRT. These important improvements in LC and OS with lower toxicity were demonstrated in no-endemic regions - RTOG trials - and endemic regions. Recently, a study carried out in an endemic region (China) with 455 NPC patients, most in stages III-IVb, obtained very similar results using the IMRT ± chemotherapy protocol of RTOG 0225/RTOG 0615, with 4-year OS rates of 83.8% and grade 3-4 toxicity (mainly mucositis) in 27.2% (24). The widespread use of IMRT for Head and Neck (H&N) cancer allowed exploration of daily dose escalation to gross tumor volume (Gross Target Volume-GTV) and the most common radiation fractionation scheme for H&N cancer is based on studies of NPC. The GTV is delineated so as to include the primary tumor and lymph nodes larger than 1 cm or with a necrotic center. Clinical target volume (CTV) of the high dose region (CTV-Hi) is defined as GTV + 5 mm. The planning target volume (PTV) of higher dose (P-hi) is the defined as CTV-hi + 5mm. The RTOG 0225 and RTOG 0615 protocols (23, 27) defined the dose of 70Gy, divided into 2.12 Gy/day over 33 days, as the dose of the PTV-hi, also defined as PTV70. NPC is a disease with high propensity to loco regional spread, so it is always necessary to define areas of risk of disease dissemination - intermediate risk and low risk areas - to include

Complimentary Contributor Copy Management of nasopharyngeal cancer 13 in the treatment volume, however with lower doses. Generally, the intermediated risk of subclinical disease, CTV-int, is defined as the volume encompassing the CTV70 + 5 mm + risk areas such as the entire nasopharynx, retropharyngeal nodal region, skull base, clivus, sphenoid sinus, parapharyngeal space, pterygoid fossa, posterior third of the nasal fossae, maxillary sinuses with pterygomaxillary fossae, and cervical levels I, II, III and V. The dose of PVT-int is 59,4Gy, in 33 fractions of 1,8Gy. When there is no macroscopic cervical lymphadenopathy the cervical level IV can be treated with 54Gy in 33 fractions of 1.64Gy and this regions is defined as PTL low. With the prolonged survival of NPC patients, one concern that is becoming increasingly relevant is late toxicity and quality of life. Organ at risk (OAR) irradiation has been significantly reduced by IMRT, but during treatment planning, delineation of CTV70 and PTV70 can increase the GTV by up to 10-15 mm. The ideal margin of these volumes is still controversial and has varied from trial to trial. In a retrospective study comparing reduced- volume IMRT (RV-IMRT) with large-target-volume IMRT (LV-IMRT), there was no reduction in 4-year LRFS, regional recurrence-free survival (RRFS), distant metastasis-free survival (DMFS), progression-free survival (PFS), or OS rates with RV-IMRT. Furthermore, there was a reduction in the late xerostomia toxicity score (p < 0.001) (28). On the other hand, inadequate dosimetry can also lead to worse outcomes. In a study by Ng et al., under-dosing (<95% of 70Gy) of a volume greater than 3.4 cc resulted in worse prognosis (29). A recent guideline published by Anne W. Lee and several other experts from several countries proposed several parameters for targeted delineation, including 5-mm margins for the primary CTV (primary GTV + 5 mm, or 1 mm in OAR), 10-mm for the secondary CTV (primary GTV + 10 mm), and margins for high-risk nodal areas (nodal GVT + 5 mm) and intermediate-risk nodal regions (nodal GVT + 10 mm) (30). Chemotherapy is current considered for some stage II tumors or more advanced cases. The most recommended regime is based on concurrent cisplatin at 100 mg/m² on days 1, 22, and 43 of the RT, followed by adjuvant cisplatin (80 mg/m²) on day 1 and fluorouracil (1,000 mg/m²/d) on days 1 through 4 every 4 weeks for three cycles. The greatest change in NPC treatment strategy regarding chemotherapy occurred after the publication of the randomized phase-III Intergroup study 0099 (31). In this study, both arms received the same RT, but the study group received cisplatin 80 mg/m² on days 1, 22, and 43, during RT, and 3 cycles of cisplatin 80 mg/m² on days 71, 99 and 127 and fluorouracil 1,000 mg/m²/day as a continuous infusion for 96 h on days 71-74, 99-102, and 127-130. Disease- free survival (DFS) improved from 24% to 69%, and OS, from 47% to 78% (3-year). For more advanced stages, the role of concurrent chemoradiation therapy (CCRT) is well documented in several trials and meta-analyses (32-34); it has been shown to increase 5-year OS rates from 56% to 62% (34). Interestingly, a randomized phase-III trial demonstrated that chemotherapy administered in conjunction with 2D-RT resulted in improved 5-year OS (85.8% to 94.5%) (35). However, the effect of combined chemotherapy with IMRT is not well established, since most trials of chemoradiotherapy were performed with 2D-RT. In a recent meta-analysis and systematic review, Liu et al., (36) found no benefit from the combination of chemotherapy with IMRT; in fact, there was increased acute toxicity. In a randomized, phase-III, multicenter study of 476 patients with locally advanced NPC, neoadjuvant chemotherapy with cisplatin (80 mg/m² d1) + fluorouracil (800 mg/m² d1-5) every three weeks for two cycles before chemoradiotherapy resulted in DFS improvement Complimentary Contributor Copy 14 Fabrício Scapini, Alexandre Arthur Jacinto, Fiona Lim et al. from 74.1% to 82% (p=0.028), although it did not change OS (37). However, in another study with stage-II patients, induction chemotherapy followed by chemoradiotherapy was associated with worse 5-year OS (87.9% versus 95.5%, p = 0.033) (38). A retrospective study of 602 patients with stage IVa-b disease who received induction chemotherapy followed by chemoradiotherapy with IMRT demonstrated an improvement in 5-year OS for induction chemotherapy over those who received only chemoradiotherapy (83.2% vs. 74.8%, p=0.022) as well as improved 5-year DMFS (83.2% vs. 74.4%, p = 0.018) (39). Currently, in our routine we consider induction chemotherapy in case of large tumors (T4, large N3) or when the tumor burden is surrounding critical structures (eg, optical apparatus, temporal lobe, spinal cord or brainstem) and RT is not feasible. The benefit of adjuvant chemotherapy after concurrent chemoradiotherapy is still debatable. A study with 797 patients with stages II to IVb (UICC 7th edition) showed that the combination of chemoradiotherapy with IMRT followed by adjuvant chemotherapy was associated with a small, though statistically nonsignificant, improvement in 1-, 2-, and 3-year OS at more advanced stages (40). Currently the NRG (former RTOG) is conducting a biomarker-driven study to define if adjuvant chemotherapy could be omitted to patient who have undetectable EBV-DNA on plasma after chemoradiotherapy (41).

RECURRENCE OR RESIDUAL DISEASE

Approximately 15 to 30% of patients with locally advanced NPC will experience local recurrence or distant metastases. Imaging modalities such as CT and MRI, nasal endoscopy with biopsy, and anti-EBV IgA measurement are the most widely used methods for follow-up and detection of recurrence. PET-CT can also be used to track local or locoregional recurrences or distant metastases. Studies have shown its superiority over MRI for detection of recurrence (42, 43). In addition, PET-CT can also be used as a parameter for prognostication, based on evaluation of several parameters. A recent meta-analysis showed that maximal standardized uptake value (SUVmax), metabolic tumor volume (MTV), and total lesion glycolysis (TLG) were associated a higher risk of adverse events and death (44). Management of recurrence is still a challenge. The treatment options for recurrence or distant metastasis are reirradiation (external, brachytherapy, or both), isolated chemotherapy, chemoradiotherapy, stereotactic surgery, or open surgery (45, 46). Many patients with advanced disease are not receptive to reirradiation or surgery. In these cases, chemotherapy has been the cornerstone of recurrence management in NPC (45). A recent systematic review showed that cisplatin-based chemotherapy regimens combined with other agents provide superior progression-free survival (PFS) and OS, and that regimens that include cisplatin are superior to cisplatin-free regimens. OS was 15.7-19.3 months for first-line therapies and 11.5- 12.5 months for second-line therapies (47). There is still no consensus as to the optimal therapy for small-volume recurrences (T1- T2). Brachytherapy is an option that has shown results equivalent to those of external reirradiation, but with less toxicity, thus improving quality of life (48).

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Considering that external RT is the most widely accepted treatment with curative intent, reirradiation has also been the most commonly used therapy in cases of recurrence (49). The increasing popularity of IMRT has brought significant benefits; however, reirradiation of patients previously treated with IMRT still has limited results. Han et al., (2012), in a retrospective study, achieved a 5-year OS rate of 44.9% with IMRT ± cisplatin in patients previously treated with IMRT. Younger age, smaller tumor size, higher dose fractionation, lower N(0), and lower recurrence stage were independent prognostic factors (50). One important aspect in reirradiation is toxicity. In the aforementioned study by Han et al., (50), 69% of patient deaths (120 out of 239 patients with recurrent NPC treated with IMRT) were attributed to radiation injury, the majority of which were severe cases of necrosis of the nasopharyngeal mucosa. In addition to necrosis of the mucosa and other soft tissues, osteoradionecrosis, temporal lobe necrosis, cranial nerve palsy, hearing loss, and rupture of the internal carotid artery are other complications observed in reirradiation. Surgical strategies may be endoscopic, open, or combined, especially through the maxillary swing approach. Options include transpalatal, infratemporal, and transmandibular approaches, as well as facial translocation; however, all are associated with substantial morbidity, including facial palsy, dysphagia, velopharyngeal insufficiency, osteomyelitis, osteonecrosis, and even carotid-artery rupture (51). However, it is import to consider the difficult to obtain R0 resection, particularly with endoscopic resection, which is generally associated with significant risk of local recurrence. Most patient submitted to salvage resection for primary recurrence most be considered for adjuvant reirradiation. Furthermore, the heterogeneity of tumor extension and techniques makes it difficult to establish evidence- based protocols. Although endonasal endoscopic surgery has progressed in the last two decades particularly in relation to resection of skull-base tumors, data on salvage treatment for patients with NPC are still limited. The largest case series was published by Chen et al., (52) in 2009. Of 37 cases, 17 were rT1N0M0, 18 were rT2a/bN0M0, and only 2 were T3N0M0. The 2-year OS rate was 84.2% overall, but for rT1 cases it was 100%. Ko et al., reported on the use of titanyl-phosphate laser in performing endoscopic nasopharyngectomy for early locally recurrent NPC in 28 patients. Twelve patients were classified as rT1N0 and had a 2-year OS of 90.9%. Another 16 cases were rT2aN0; in these, 2-year OS fell to 38.5% (53). The impact of surgery in cases of recurrence tends to be more positive in small tumors. For T3 and T4 tumors, further reirradiation with IMRT, with or without chemotherapy, should still be the primary consideration. Stereotactic radiosurgery (SR) and fractionated stereotactic radiotherapy (FSRT) has been an option for recurrence. Hara et al., (2008) showed 5-year OS of 69% in 82 patients with T1 to T4 tumors, in SR for recurrence after external bean radiotherapy (EBRT). Late toxicity was found in 5/17 and included radiation-related retinopathy, carotid aneurysm, and radiographic temporal lobe necrosis. Of 10 patients with temporal lobe necrosis, 9 had T4 tumors (54). Liu et al., (2013), using FSRT, showed a 5-year local failure-free survival (LFFS), freedom from distant metastasis (FFDM), OS, and DFS rates for all patients were 92.5%, 77.0%, 76.2%, and 73.6%, respectively, with no statistical significant differences found in LFFS, DFS and OS in patients with stage I/II versus stage III/ IV diseases. Around 14% of patients had late toxicity (55).

Complimentary Contributor Copy 16 Fabrício Scapini, Alexandre Arthur Jacinto, Fiona Lim et al.

FUTURE PERSPECTIVES

Molecular targeted therapy: Molecular targets have been studied in NPC. Epidermal growth factor receptor (EGFR), vascular endothelial growth factor (VEGF), c-KIT, and c-erbB-2 (HER2) are some of several molecular targets expressed and overexpressed in NPC. In 2004, a phase-III study of patients with pharyngeal and laryngeal squamous cell carcinoma demonstrated improvement in OS with addition of cetuximab to an RT regimen compared to RT alone (56) but cetuximab was inferior to concurrent chemoradiotherapy on the recent published NRG-RTOG 1016 (27). Additionally, a recent study of 715 NPC patients failed to demonstrate superiority of the addition of anti-EGFR agents (cetuximab and nimotuzumab) to chemoradiotherapy regimens when compared to chemoradiotherapy with induction therapy (57). Bevacizumab is an anti-vascular endothelial growth factor (VEGF) monoclonal antibody that has been extensively studied in several types of cancer. The RTOG 0615 study demonstrated a 2-year OS rate of 90.1% (27). For a similar protocol without bevacizumab, RTOG 0225 demonstrated an OS of 80.2% (23). However, Li et al., (2017), in a case-control study with 186 patients, found no differences in OS or DMFS in patients who received CCRT with bevacizumab when compared to CCRT alone (58). Heavy-particle therapy: The major difference between photon therapy and heavy-particle therapy is the Bragg peak, which is the characteristic radiation-releasing curve of particles such as protons, helium, and carbon ions. While photons release most of their ionizing energy in the first few centimeters of tissue, these particles have greater penetration and release most of their energy just before they come to rest, which allows them to reach greater depths without dissipating large amounts of radiation in their path (59). This feature is particularly interesting in anatomical regions surrounded by critical structures, as occurs in NPC. Proton therapy has been used for many years in tumors of the head and neck; just as IMRT, technological advances have enabled the development of highly conformal intensity- modulated proton therapy (IMPT). Initial results have shown that lower doses to OAR are possible, with good clinical outcomes (60, 61) Carbon-ion radiotherapy (CIRT) is a specific modality of heavy-particle therapy that is demonstrably able to release high doses of radiation within the tumor with low doses to OAR. In addition, it has a relative biological effectiveness ratio of 2 to 5:1 in relation to photons and protons. There are still few studies on the safety and effectiveness of CIRC, although preliminary results were promising (62, 63). The major limitation to wider use of these technologies is the high cost of center construction. The first CIRT center, built in Japan, took 10 years to complete and cost approximately US$300 million (64). A 2016 survey found only 10 CIRT centers and 55 centers with proton accelerators worldwide (65).

CONCLUSION

Progress in NPC management, especially in the last two decades, has significantly improved all measures of survival. The introduction of IMRT and concurrent chemotherapy has brought important advances in treatment. However, 10 to 15% of patients still experience locoregional Complimentary Contributor Copy Management of nasopharyngeal cancer 17 failure after receiving definitive treatment, and these cases are still challenging. New RT modalities and combined therapies may further improve prognosis in future, with lower toxicity rates and, consequently, better quality of life.

REFERENCES

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nasopharyngeal carcinoma: A phase III multicenter randomized controlled trial. Eur J Cancer 2017;75:14-23. [38] Li PJ, Mo HY, Luo DH, Hu WH, Jin T. The efficacy of induction chemotherapy in the treatment of stage II nasopharyngeal carcinoma in intensity modulated radiotherapy era. Oral Oncol 2018;85:95- 100. [39] Lan XW, Zou XB, Xiao Y, Tang J, OuYang PY, Su Z, et al. Retrospective Analysis of the Survival Benefit of Induction Chemotherapy in Stage IVa-b Nasopharyngeal Carcinoma. PLoS One 2016;11(8):e0160758. [40] Zhong Q, Zhu X, Li L, Qu S, Liang Z, Zeng F, et al. IMRT combined with concurrent chemotherapy plus adjuvant chemotherapy versus IMRT combined with concurrent chemotherapy alone in patients with nasopharyngeal carcinoma. Oncotarget 2017;8(24):39683-94. [41] Bethesda (MD): National Library of Medicine (US). Individualized Treatment in Treating Patients With Stage II-IVB Nasopharyngeal Cancer Based on EBV DNA (Identifier NCT02135042). URL: https://clinicaltrials.gov/ct2/show/NCT02135042?term=NCT02135042&rank=1 [42] Tsai MH, Shiau YC, Kao CH, Shen YY, Lin CC, Lee CC. Detection of recurrent nasopharyngeal carcinomas with positron emission tomography using 18-Xuoro-2-deoxyglucose in patients with indeterminate magnetic resonance imaging findings alter radiotherapy. J Cancer Res Clin Oncol 2002;128:279-82 [43] Yen RF, Hung RL, Pan MH, Wang YH, Huang KM, Lui LT, et al. 18-Xuoro-2-deoxyglucose positron emission tomography in detecting residual/recurrent nasopharyngeal carcinomas and comparison with magnetic resonance imaging. Cancer 2003;98(2):283-7 [44] Lin J, Xie G, Liao G, Wang B, Yan M, Li H, et al. Prognostic value of 18F-FDG-PET/CT in patients with nasopharyngeal carcinoma: A systematic review and meta-analysis. Oncotarget 2017;8(20):33884-96. [45] Lee AW, Ma BB, Ng WT, Chan AT. Management of nasopharyngeal carcinoma: current practice and future perspective. J Clin Oncol 2015;33(29):3356-64. [46] Suárez C, Rodrigo JP, Rinaldo A, Langendijk JA, Shaha AR, Ferlito A. Current treatment options for recurrent nasopharyngeal cancer. Euro Arch Otorhinolaryngol 2010;267(12):1811-24. [47] Prawira A, Oosting SF, Chen TW, Delos Santos KA, Saluja R, Wang L, et al. Systemic therapies for recurrent or metastatic nasopharyngeal carcinoma: a systematic review. Br J Cancer 2017;117(12):1743-52. [48] Yan H, Mo Z, Xiang Z, Rong D, Zhang Y, Chen G, et al. CT-guided 125I brachytherapy for locally recurrent nasopharyngeal carcinoma. J Cancer 2017;8(11):2104-13. [49] Kong L, Lu JJ. Reirradiation of locally recurrent nasopharyngeal cancer: history, advances, and promises for the future. Chin Clin Oncol 2016;5(2):26. [50] Han F, Zhao C, Huang SM, Lu LX, Huang Y, Deng XW, et al. Long-term outcomes and prognostic factors of re-irradiation for locally recurrent nasopharyngeal carcinoma using intensity-modulated radiotherapy. Clin Oncol (R Coll Radiol) 2012;24(8):569-76. [51] Ong YK, Solares CA, Lee S, Snyderman CH, Fernandez-Miranda J, Gardner PA. Endoscopic nasopharyngectomy and its role in managing locally recurrent nasopharyngeal carcinoma. Otolaryngol Clin North Am 2011;44(5):1141-54. [52] Chen MY, Wen WP, Guo X, Yang AK, Qian CN, Hua YJ, et al. Endoscopic nasopharyngectomy for locally recurrent nasopharyngeal carcinoma. Laryngoscope 2009;119:516-22. [53] Ko JY, Wang CP, Ting LL, Yang TL, Tan CT. Endoscopic nasopharyngectomy with potassium- titanyl-phosphate (KTP) laser for early locally recurrent nasopharyngeal carcinoma. Head Neck 2009;31(10):1309-15. [54] Hara W, Loo BW Jr, Goffinet DR, Chang SD, Adler JR, Pinto HA, et al. Excellent local control with stereotactic radiotherapy boost after external beam radiotherapy in patients with nasopharyngeal carcinoma. Int J Radiat Oncol Biol Phys 2008;71(2):393-400. [55] Liu F, Xiao JP, Xu GZ, Gao L, Xu YJ, Zhang Y, et al. Fractionated stereotactic radiotherapy for 136 patients with locally residual nasopharyngeal carcinoma. Radiat Oncol 2013;8:157.

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[56] Bonner JA, Harari PM, Giralt J, Azarnia N, Cohen RB, Raben D, et al. Cetuximab prolongs survival in patients with locoregionally advanced squamous cell carcinoma of head and neck: A phase III study of high dose radiation therapy with or without cetuximab. J Clin Oncol 2004;22(14 suppl):5507. [57] Lin M, You R, Liu YP, Zhang YN, Zhang HJ, Zou X, et al. Beneficial effects of anti-EGFR agents, Cetuximab or Nimotuzumab, in combination with concurrent chemoradiotherapy in advanced nasopharyngeal carcinoma. Oral Oncol 2018;80:1-8. [58] Li Y, Chen QY, Tang LQ, Liu LT, Guo SS, Guo L, et al. Concurrent chemoradiotherapy with or without cetuximab for stage II to IVb nasopharyngeal carcinoma: a case-control study. BMC Cancer 2017;17(1):567. [59] Mitin T, Zietman AL. Promise and pitfalls of heavy-particle therapy. J Clin Oncol 2014;32(26):2855- 63. [60] Lewis GD, Holliday EB, Kocak-Uzel E, Hernandez M, Garden AS, Rosenthal DI, et al. Intensity- modulated proton therapy for nasopharyngeal carcinoma: Decreased radiation dose to normal structures and encouraging clinical outcomes. Head Neck 2016;38(Suppl 1):E1886-95. [61] Holliday EB, Garden AS, Rosenthal DI, Fuller CD,Morrison WH, Gunn GB, et al. Proton therapy reduces treatment-related toxicities for patients with nasopharyngeal cancer: A case-match control study of intensity-modulated proton therapy and intensity-modulated photon therapy. Int J Particle Therapy 2015;2(1):19-28 [62] Amirul IM, Yanagi T, Mizoe JE, Mizuno H, Tsujii H. Comparative study of dose distribution between carbon ion radiotherapy and photon radiotherapy for head and neck tumor. Radiat Med 2008;26(7):415‐21. [63] Hu J, Bao C, Gao J, Guan X, Hu W, Yang J, et al. Salvage treatment using carbon ion radiation in patients with locoregionally recurrent nasopharyngeal carcinoma: Initial results. Cancer 2018;124(11):2427-37. [64] Mohamad O, Makishima H, Kamada T. Evolution of carbon ion radiotherapy at the national institute of radiological sciences in Japan. Cancers 2018;10(3):66. [65] Pompos A, Durante M, Choy H. Heavy ions in cancer therapy. JAMA Oncol 2016;2(12):1539-40.

Chapter 3

MANAGEMENT OF OROPHARYNGEAL CANCER

Otávio Costa Diaz1,, MD, Virgilio Zanella2, MD, Juliana Janoski de Menezes3, MD, Fiona Lim4, MBBS, Bo Angela Wan5, MD(C) and Maurício F Silva6,7,8, MD, PhD 1Radiation Oncology Unit, Santa Rita Hospital, Porto Alegre, Brazil 2Head and Neck Surgery Department, Santa Rita Hospital, Porto Alegre, Brazil 3Department of Oncology, Nossa Senhora da Conceição Hospital, Porto Alegre, Brazil 4Department of Oncology, Princess Margaret Hospital, Hong Kong, PR China 5Odette Cancer Centre, Sunnybrook Health Sciences Centre, University of Toronto, Toronto, Ontario, Canada 6Radiation Oncology Unit, Santa Maria Federal University, Santa Maria, Brazil 7Radiation Oncology Unit, Hospital de Caridade Astrogildo de Azevedo, Santa Maria, Brazil 8Latin America Cooperative Oncology Group, Porto Alegre, Brazil

ABSTRACT

Oropharyngeal cancer (OC) represents 0.5% of all cancers in the world. Tobacco and alcohol abuse are major risks factors, and in recent years, we have had an increase in OC related to human papilloma virus (HPV) infection. The prognosis of HPV related tumors is better than smoking related tumors. Early stage tumors can be effectively treated with primary surgery or radiation therapy. Radiation is done with hyperfractionated or accelereted schedules. For advanced stage tumors, the preferred treatment is radiation therapy with concomitant cisplatin and in this case, radiation is done with standard fractionation. Induction chemotherapy fails to show an improvement in overall survival, but is an option in patients with bulky cervical lesions. A multidisciplinary approach is essential in the treatment of this cancer.

 Corresponding Author’s Email: [email protected]. Complimentary Contributor Copy 22 Otávio Costa Diaz, Virgilio Zanella, Juliana Janoski de Menezes et al.

INTRODUCTION

According the last publication of Globocan (1), there will be nearly 92.000 cases of oropharyngeal cancer (OC) worldwide in 2018 with approximately 51,000 deaths. OC is the 26th most common type of cancer representing 0.5% of all cases. There are three cases in men for every case in women. The oropharynx is composed by the lateral and posterior oropharyngeal walls, tonsillar fossa (palatine tonsils, anterior and posterior palatine arches), base of tongue and valleculae (2). Squamous cell carcinomas account for nearly 95% of oropharyngeal cancers. Malignant Hodgkin and non-Hodgkin lymphomas also arise in the lymphoid tissue of the Waldeyer’s ring. Traditionally the risk factors for OC are smoking and alcohol abuse. Smoking raises the chance of having this tumor three fold and with concomitant alcohol abuse it can be up to 15 fold (3). The incidence of OC is rising because of the growing number of cancers caused by the human papilloma virus (HPV). HPV 16 is the virus subtype identified in more than 90% of all oropharyngeal HPV related tumors and this virus infection confers an approximate 14-fold increase in risk for oropharyngeal cancer (4). HPV infection raises the chances of cancer by inhibiting tumor suppressor genes p53 and retinoblastoma (Rb). There is a drastic difference in the prognosis of smoking-related and HPV-related tumors. a meta-analysis with 18 trials and 4424 patients showed a signiﬁcantly improved 5-year overall survival (OS) and 5-year disease-free survival for HPV positive tumors in comparison with HPV negative tumors (5). Table 1 shows the difference in survival of HPV related cancers in some prospective trials (2). In the 8th edition, the AJCC separated the staging of HPV positive and HPV negative oropharyngeal cancers. Major changes in the oropharyngeal cancer staging system from the 7th edition to the 8th edition are listed in Table 2. There are big differences in the prevalence of HPV related tumors worldwide. In North America and Europe, approximately 65% of tumors are HPV positive and in South America, approximately 35% (7). At our institution, which is a local referral centre for head and neck cancer treatment, 25% of oropharyngeal cancers were related to HPV in the last two years.

Table 1. HPV status and survival in prospective trials

Cooperative N RT Concurrent HPV+ Survival Survival p- group (reference) HPV+ HPV- Value TROG (24) 195 70 Gy Cisplatin +/- 28% 94% 77% 0.007 tirapazamine RTOG (13) 323 70 Gy Cisplatin 64% 79% 46% 0.002 DAHANCA (14) 156 62-68 Gy Nimorazole 22% 62% 26% 0.003 RT: radiotherapy; HPV+: human papilloma virus positive; HPV-: human papilloma virus negative; TROG: Trans-Tasman radiation oncology group; RTOG: radiation therapy oncology group; DAHANCA: Danish head and neck cancer group.

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Table 2. Summary comparing 7th and 8th edition AJCC staging of oropharyngeal Cancer (6)

LN: lymph node; ENE(+): extranodal extension present; ENE(-): extranodal extension absent; ipsi: ipsilateral; bi: bilateral; ctr: contralateral

OUR REVIEW

This chapter contains opinions and recommendations of the treatment of squamous cell carcinoma of the oropharynx based on a narrative literature review of the publications including books and peer-reviewed journal articles, adapted for the strengths and weakness of the health systems in Latin America.

STAGE I-II

Definition

Tumors ≤4 cm in greatest dimension without invasion into surrounding structures and with no clinical or radiographic evidence of lymph node involvement [AJCC 8th].

What’s the best treatment - surgery or radiotherapy? There are no randomized trials comparing the two approaches. Therefore, the morbidity associated with each treatment approach is an important factor in making treatment decisions. Complimentary Contributor Copy 24 Otávio Costa Diaz, Virgilio Zanella, Juliana Janoski de Menezes et al.

Primary surgery The surgical treatment for OC in the early stages (I-II) and its approaches depend on the subsite. The incidence of OSCC according each subsite is tonsil (63%), base of tongue (22%), soft palate (13%) and posterior wall (2%). We can manage tumors in the oropharynx with open surgery, transoral laser microsurgery or transoral robotic surgery (TORS). With regards to the primary lesion, we can easily treat tonsillar, posterior wall and soft palate T1 and T2 by transoral open surgery approach with an electrosurgical scalp or laser ablation. In the lower posterior wall or base of tongue, the use of transoral robotic surgery (TORS) is increasing in centers where it is available. This approach avoids cervical scarring for pharyngotomies or midline inferior lip incisions and also avoids the functional morbidity and complications associated to transmandibular and midline glossotomy procedures required for a wide field in open surgery (8, 9). Critics advocate that TORS is still not cost-effective (8). The use of transoral laser microsurgery is possible when the entire tumour margin is set in a single view through the laryngoscope field and a microscope and a CO2 laser are available. In neck management, the elective neck dissection is based on the risk of occult metastasis. The presence of a cervical node metastasis is one of the most significant prognostic factors in treating patients for oropharyngeal squamous cell carcinoma (SCC). Sixty percent of patients with OSCC have cervical metastases (10, 11). Therefore, at least a lateral (levels II-IV), and ipsilateral lymphadenectomy should be performed in T2 patients. As the base of the tongue and soft palate are sites that frequently have bilateral lymphatic drainage, is important to reinforce that patients with tumors close to midline should have a bilateral neck dissection performed. Patients with an already diagnosed metastatic lymph node must undergo radical or radical modified neck dissection.

Primary radiotherapy For early stage oropharyngeal cancers, the results of primary radiation therapy and primary surgery are similar and the choice of primary treatment will be based on the patients’ health conditions and possible treatment side effects (12). For base of tongue and soft palate tumors, we usually prefer treatment with radiation because base of tongue tumors treated initially with surgery usually need adjuvant radiation and soft palate tumors have the risk of swallowing difficulties. Altered fractionation radiation therapy showed improved local control and overall survival in randomized trials and meta-analyses when compared with standard fractionation (13-15). For logistic reasons our preferred treatment approach is the accelerated treatment used in the DAHANCA 6&7 Trial with 6 fractions of 2 Gy per week to a total dose of 66 Gy (14).

STAGE III-IV

Definition

T3 or T4 primary tumors without lymph node involvement and T1 or greater tumors with cervical node involvement but without distant metastases [AJCC 8th].

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Surgery vs. chemoradiotherapy There are no large randomized trials that compare a combination of chemotherapy plus radiotherapy versus an initial surgical approach followed by radiation or chemoradiotherapy in patients with locally advanced oropharyngeal cancer.

Primary surgery There are no trials that compare different surgical modalities of the primary tumor itself (17). Primary surgical treatment for locally advanced - T3 and T4 - is considered in patients who failed or are not candidates for chemoradiation therapy. The surgery is challenging in terms of both surgical skill and patient recovery. The tonsillar, posterior wall, and soft palate T3 and T4 are best treated by the transoral open surgery approach with an electrosurgical scalp or laser. Sometimes, the lateral mandibulotomy approach is required for better access. Lateral pharyngotomy is lesser used because of the limited exposure for large lesions. The use of TORS is limited by surgeon skill, cost, robot availability, and tumor extension. Park et al. (Seoul, South Korea) showed excellent oncological and functional outcomes with TORS in the treatment of stage III-IV OSCC. Clear margins were obtained using TORS- based therapy and patients with clear margins showed good local control (16). Advanced lesions at base of tongue/valleculas are rarely treated by surgery because of extreme swallowing dysfunction (8). The surgeon must be prepared for a large reconstruction using regional axial or free flaps. Different from the primary tumor, cervical lymph nodes have been the focus of a number of trials comparing different management approaches (17). The neck dissection is mandatory in advanced oropharyngeal cancer. In patients with advanced primary tumors and clinically negative neck nodes (N0), neck dissection is performed just in salvage cases after chemoradiation. When a node is diagnosed with central necrosis or as N3, a neck dissection may be performed before chemoradiation begins, avoiding the node percutaneous discharge. Again, as base of tongue and soft palate frequently have bilateral lymphatic drainage, it is important to reinforce patients who have tumors close to midline that they should have a bilateral neck dissection performed. The type of neck dissection - comprehensive or selective - is defined according preoperative staging. In N0, selective dissection (levels II-IV) is appropriate. In N3 patients, when feasible, neck dissection is the goal and the appropriate procedure is radical modified neck dissection (sparing internal jugular vein, spinal nerve and sternocleidomastoid muscle).

Adjuvant radiotherapy After surgery alone, the results of local control and survival for patients with locally advanced disease have not been satisfactory. Since 1957, with the first publications by Fletcher et al. (13) of combined modality therapy with surgery and adjuvant radiation therapy, we have been learning how to better stratify which patients need radiation after surgery. There are multiple publications showing the major risk factors for worse local control and survival, and the most important are: close/positive margins, extracapsular extension, perineural invasion, lymphovascular invasion, stage pT3/pT4, advanced nodal disease (N2 and N3), and high grade (18, 19).

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A very interesting randomized study from the MD Anderson group showed some important conclusions about adjuvant radiation therapy (20). This trial tested three hypothesis: 1- that patients with none of the adverse risk factors listed above did not need adjuvant treatment; 2- that the total duration of the treatment was important for local control; 3- that the dose of radiation was important. Patients were classified in three categories depending on the pathologic features: 1- low risk, with no adverse risk factors; 2- intermediate risk, with one adverse risk factor other than extracapsular extension; 3- high risk, with ≥2 adverse risk factors and/or extracapsular extension. The risk groups showed an inverse relationship with overall survival (OS); the higher the risk group the worse the OS (approximately 5-year survival 81% for low risk, 70% for intermediate risk, and 38% for high risk). Local control was very good for the low risk group, showing that radiation is not necessary for this group. The intermediate risk group receiving surgery and low dose radiation achieved similar local control with the low risk group. The high risk group, despite being treated more aggressively with surgery and high dose radiation, had more local failures than the other groups (5-year locoregional control in low and intermediate risk groups ≈90% and in high risk group ≈65%). Another interesting conclusion of this trial is that the total treatment time (time from the surgery date and the completion of radiotherapy) is important. Patients treated in <11 weeks had 5-year locoregional control rate of 76% and patients treated in > 13weeks had only 38% (p = 0.002).

Chemoradiotherapy or only radiotherapy? MACH-CH collaborative group updated a meta-analysis of chemotherapy in head and neck which used individual patient data of 16,485 patients included in 87 randomized trials performed between 1965 and 2000 and analyzed by tumor site. In the oropharynx site, 5878 patients with oropharyngeal cancer and 82 comparisons are included. The hazard ratio for concomitant chemoradiotherapy was 0.78 [95% CI 0.72-0.85] with absolute difference at 5 year of 5.3% [95% CI 2.8-7.8] when compared with Radiotherapy alone (21). Different chemotherapy regimens were evaluated, and found and platinum-based chemotherapy to be superior to non-platinum-based regimens. There was no significant difference between single- agent platinum and multi-agent concurrent chemotherapy. Therefore, we recommend chemoradiotherapy with single-agent platinum.

Induction chemotherapy The use of induction chemotherapy is controversial. We do not recommend induction chemotherapy. There are two trials that have shown addition of induction chemotherapy had no benefit in overall survival. The Spanish Head and Neck Cancer Cooperative Group, showed in a phase 3 clinical trial that the addition of induction chemotherapy was not superior when compared to chemoradiotherapy. Similarly, the GORTEC 2007-02 study showed that the addition of the taxotere scheme, cisplatin, and fluorouracil (TPF) did not improve outcomes compared with chemoradiotherapy in a population of patients with advanced cervical lymphadenopathy (22, 23).

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ABOUT HPV INFECTIONS - PROGNOSTIC AND PREDICTIVE

There are no data at present to indicate that human papilloma virus (HPV) associated cancers should be treated differently from other squamous cell carcinomas arising in the oropharynx, although several reports suggest that patients with HPV associated cancers have improved survival rates relative to patients with HPV negative cancers (Table 1). At this moment we have several trials investigating deintensification of treatment for HPV positive oropharyngeal cancers (NCT03215719, NCT01706939, NCT01855451, NCT01898494). Some strategies being tested are reducing radiation therapy dose, replacing cisplatin with cetuximab, and omitting chemotherapy during radiotherapy. The aim of these studies is to maintain the optimal local control and survival of HPV positive tumors while reducing the toxicities of treatment.

DISCUSSION

At our institution, HPV positive and HPV negative oropharyngeal tumors are currently treated the same. We use the information that a tumor is HPV positive or negative for prognostic reasons and to inform the patient the differences of HPV related and tobacco related tumors. The decision of treatment of T1-2, N0 tumors is based on the location and extension of the tumor and expected morbidities of each strategy. When the decision for treatment is with radiation therapy, we discuss with the patient the possibility of treatment with altered fractionation. Data from randomized studies (13, 14) and a meta-analyses (15) shows this strategy offers better local control and survival when compared to standard fractionation. Because of logistic reasons the preferred strategy is an accelerated treatment using 6 fractions a week, usually 2 fractions on Fridays during the whole treatment, as was done in the DAHANCA 6&7 Trial (14). In patients with locally advanced tumors, when surgery will not be done, the preferred strategy is conventionally fractionated radiotherapy with concomitant cisplatin. In advanced tumors we only use altered fractionation in cases where chemotherapy will not be used for any reason. In patients initially treated with surgery, when the surgical specimen does not have any risk factors, adjuvant treatment is usually not indicated. In cases where there is one risk factor, such as perineural or lymphovascular invasion, we discuss with the patient the pros and cons of the use of adjuvant radiation therapy. In cases with two or more risk factors, we treat with adjuvant radiation. Patients with extracapsular extension and/or positive margins will receive concomitant cisplatin during radiation therapy. We try to finish the whole treatment in less than 11 weeks such that in less than 4 weeks from the surgery the patient will have the first evaluation at the radiation therapy department, and if the surgical bed has healed, the treatment will begin. Cetuximab is not routinely used concomitant with radiation therapy as it is not supported by the National Health System.

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Induction chemotherapy is rarely used, because the major clinical trials failed to show a statistically significant benefit in survival while increasing side effects and financial costs (22, 23). In conclusion, the treatment of oropharyngeal squamous cell carcinoma is evolving and to achieve the best results, we need a multidisciplinary approach and great communication between all the professionals involved.

REFERENCES

[1] Bray F, Ferlay J, Soerjomataram I, Siegel RL, Torre LA, Jemal A, et al. Global cancer statistics 2018: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries. CA Cancer J Clin 2018;68(6):394-424, [2] Levendag PC, Teguh DN, Heijmen BJ. Chapter 42: Oropharynx. In: Halperin EC, Brady LW, Perez CA, eds. Perez and Brady’s principles and practice of radiation oncology, 5th edition. Philadelphia, PA: Lippincott Williams Wilkins, 2007:913-57. [3] Hashibe M, Brennan P, Chuang SC, Boccia S, Castellsague X, Chen C, et al. Interaction between tobacco and alcohol use and the risk of head and neck cancer: Pooled analysis in the International Head and Neck Cancer Epidemiology Consortium. Cancer Epidemiol Biomarkers Prev 2009;18(2):541-50. [4] Gunderson L, Tepper J. Clinical radiation oncology, third edition. Philadelphia, PA: Saunders, 2011. [5] Coordes A, Lenz K, Qian X, Lenarz M, Kaufmann AM, Albers AE. Meta-analysis of survival in patients with HNSCC discriminates risk depending on combined HPV and p16 status. Eur Arch Otorhinolaryngol. 2016;273(8):2157-6. [6] Masanari G, Day T. Oral cavity and oropharyngeal cancer: a new staging system for 2017. MUSC Otolaryngology - Head & Neck Surgery E-Update. URL: https://myemail.constantcontact.com/ MUSC-ENT-E-Update---Oral-Cavity-and-Oropharyngeal-Cancer--A-New-Staging-System-for- 2017.html?soid = 1103935396926&aid = mAakM-1krPU. [7] Martle C, Plummer M, Vignat J and Franceschi S. Worldwide burden of cancer attributable to HPV by site, country and HPV type. Int J Cancer 2017;141(4):664-70. [8] Turner MT, Byrd JK, Ferris RL. Current role of surgery in the management of oropharyngeal cancer. J Oncol Pract 2016;12(11):1176-83. [9] The American Cancer Society medical and editorial content team. Treatment Options for Oral Cavity and Oropharyngeal Cancer by Stage. Last Medical Review. URL: https://www.cancer.org/cancer/oral- cavity-and-oropharyngeal-cancer/treating/by-stage.html. [10] Snow GB, van den Brekel MW, Leemans CR, Patel P. Surgical management of cervical lymph nodes in patients with oral and oropharyngeal cancer. Recent Results Cancer Res 1994;134:43-55. [11] Woolgar JA. Histological distribution of cervical lymph node metastasis from intraoral/oropharyngeal squamous cell carcinomas. Br J Oral Maxillofac Surg 1999;37(3):175-80. [12] Pedro C, Mira B, Silva P, Netto E, Pocinho R, Mota A, Labareda M, et al. Surgery vs. primary radiotherapy in early-stage oropharyngeal cancer. Clin Transl Radiat Oncol 2017;9:18-22. [13] Fu K, Pajak T, Kian Ang K. A radiation therapy oncology group (RTOG) phase III Randomized study to compare hyperfractionation and two Variants of accelerated fractionation to standard Fractionation radiotherapy for head and neck squamous Cell carcinomas: first report of RTOG 9003. Int J Radiation Oncology Biol Phys 2000;48(1)7-16. [14] Overgaard J, Hansen HS, Evensen J, Danish Head and Neck Cancer Study Group. Five compared with six fractions per week of conventional radiotherapy of squamous-cell carcinoma of head and neck: DAHANCA 6&7 randomised controlled trial. Lancet 2003;362(9388):933-40. [15] Bourhis J, Overgaard J, Pignon JP, MARCH Collaborative Group. Hyperfractionated or accelerated radiotherapy in head and neck cancer: a meta-analysis. Lancet 2006;368(9538):843-54.

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[16] Park YM, Kim HR, Cho BC, Keum KC, Cho NH, Kim SH. Transoral robotic surgery-based therapy in patients with stage III-IV oropharyngeal squamous cell carcinoma. Oral Oncol 2017;75:16-21. [17] Oliver R, Clarkson JE, Conway D, Glenny AM, Macluskey M, Pavitt P, Sloan P. Interventions for the treatment of oral and oropharyngeal cancers: surgical treatment. Cochrane Database Syst Rev 2011;9:CD006205. [18] Adelstein D, Gillison ML, Pfister DG, Spencer S, Adkins D, Brizel DM, et al. NCCN Guidelines insights:head and neck cancers, version 2.2017. J Natl Compr Canc Netw 2017;15(6):761-70. [19] Maghami E, Koyfman S, Weiss J. Personalizing postoperative treatment of head and neck cancers. ASCO Educational book 2018;38:515-22. [20] Ang KK, Trotti A, Brown BW, Garden AS, Foote RL, Morrison WH, et al. Randomized trial addressing risk features and time factors of surgery plus radiotherapy in advanced head and neck cancer. Int J Radiat Oncol Biol Phys 2001;51(3):571-8. [21] Blanchard P, Baujat B, Holostenco V, Bourredjem A, Baey C, Bourhis J, et al. Meta-analysis of chemotherapy in head and neck cancer (MACH-NC): A comprehensive analysis by tumour site. Radiother Oncol 2011;100(1):33-40. [22] Hitt R, Grau JJ, López-Pousa A, Berrocal A, García-Girón C, Irigoyen A, et al. A randomized phase III trial comparing induction chemotherapy followed by chemoradiotherapy versus chemoradiotherapy alone as treatment of unresectable head and neck cancer. Ann Oncol 2014;25(1):216-25 [23] Geoffrois L, Martin L, De Raucourt D, Sun XS, Tao Y, Maingon P, et al. Induction chemotherapy followed by cetuximab radiotherapy is not superior to concurrent chemoradiotherapy for head and neck carcinomas: results of the GORTEC 2007-02 phase III randomized trial. J Clin Oncol 2018;36(31):3077-83. [24] Rischin D, Young RJ, Fisher R, Fox SB, Le QT, Peters LJ, et al. Prognostic significance of p16INK4A and human papillomavirus in patients with oropharyngeal cancer treated on TROG 02.02 phase III trial. J Clin oncol 2010;28(27):4142-8.

Chapter 4

MANAGEMENT OF ORAL CANCER

Otávio Costa Diaz1,, MD, Virgilio Zanella2, MD, Juliana Janoski de Menezes3, MD, Fiona Lim4, MBBS, Bo Angela Wan5, MD (C) and Maurício F Silva6,7,8, MD, PhD 1Radiation Oncology Unit, Santa Rita Hospital, Porto Alegre, Brazil 2Head and Neck Surgery Department, Santa Rita Hospital, Porto Alegre, Brazil 3Department of Oncology, Nossa Senhora da Conceição Hospital, Porto Alegre, Brazil 4Department of Oncology, Princess Margaret Hospital, Hong Kong, PR China 5Odette Cancer Centre, Sunnybrook Health Sciences Centre, University of Toronto, Toronto, Ontario, Canada 6Radiation Oncology Unit, Santa Maria Federal University, Santa Maria, Brazil 7Radiation Oncology Unit, Hospital de Caridade Astrogildo de Azevedo, Santa Maria, Brazil 8Latin America Cooperative Oncology Group, Porto Alegre, Brazil

ABSTRACT

In Brazil, oral cavity cancer is the seventh most frequent cancer. Smoke and alcohol abuse are the major risk factors and squamous cell carcinoma accounts for 90% of the cases. The last edition of AJCC staging system had incorporated depth of invasion as a major prognostic factor and some changes in the nodal classification as well. Surgery is the mainstay of the treatment, and chemotherapy and radiation therapy are important in locally advanced tumors. Early stage tumors have good outcomes after surgery, intermediate risk tumors need adjuvant radiation therapy and high-risk disease need adjuvant chemoradiation. Irresectable tumors are treated with concomitant radiation therapy and chemotherapy. Induction chemotherapy failed to show a statistically significant increment in overall survival and increases treatment costs over concomitant chemoradiation. The treatment of oral cavity squamous cell carcinoma is challenging, and multidisciplinary approach is crucial.

 Corresponding Author’s Email: [email protected]. Complimentary Contributor Copy 32 Otávio Costa Diaz, Virgilio Zanella, Juliana Janoski de Menezes et al.

INTRODUCTION

Oral cavity cancer accounted for 4.3% of all cancers in the world in 2012 with approximately 350,000 new cases, according to the International Agency for Research on Cancer (1). In Brazil, it is estimated by the National Cancer Institute (INCA) that we will have 15,000 new cases in 2018, with an incidence three times higher in males than in females, representing the 7th more frequent neoplasm; in 2013, we had 5,400 deaths from oral cancer (2). The rates of oral cavity cancer have declined in the past decades in many developed countries due to the decline in smoking prevalence (3). Rates of oral cavity cancer increased among men and women in some eastern and northern European countries where tobacco use remained common such as the Czech and Slovak Republics, Denmark, Estonia, and Finland. In addition, rates of oral cavity cancer increased among women only in a number of European nations, perhaps reflecting the delayed peak in smoking prevalence among women compared to men, as has been seen in other countries (4). Oral cavity tumors may arise from the epithelium, minor salivary glands or submucosal soft tissues. Squamous cell carcinoma is the histology of 90% of the neoplasms in the oral cavity and the other 10% is divided by adenoid cystic carcinoma, adenocarcinoma, melanoma, lymphoma and Kaposi’s Sarcoma (5). In this chapter we will discuss the treatment of oral cavity squamous cell carcinoma (OCSCC). Depending on stage, race, age, comorbidity and location in the oral cavity the 5- year survival varies from 85% to less than 20% (6). Other factors affecting survival of these patients are the 1-5% risk of a synchronous primary in the oral cavity or the aero-digestive tract and the 10% to 40% risk of methachronous tumors in the first decade (7, 8). The most important risk factors for oral cavity cancer are cigarette smoking and alcohol consumption. Smoking raises the chance of having this tumor 3-fold and with concomitant alcohol abuse it can be up to 15-fold (9). A directly proportional effect exists between the pack years of tobacco used and the risk of OCSCC (10). Human papillomavirus (HPV) infection, which is increasingly implicated as the cause of oropharyngeal squamous cell carcinoma, is rarely the etiologic factor in oral cavity cancer, with some studies showing the presence of the virus in only 4-5% of the biopsies (11, 12). Other etiologic factors reported are poor oral hygiene, wood dust exposure, dietary deficiencies, red meat and salted meat consumption (13-17). The most common premalignant lesions associated with OCSCC are leukoplakia and erythroplakia. Leukoplakia is a white patch or plaque in the mucosal surface usually associated with tobacco and alcohol use, with an annual rate of malignant transformation of about 1%. Erythroplakia is a red velvety patch with a higher malignant potential than leukoplakia. Excision constitutes the only modality for accurate diagnosis and treatment. The oral cavity is divided in six regions: lips, oral tongue, alveolar mucosa (maxillary and mandibular) and retromolar trigone, hard palate, buccal mucosa and floor of the mouth (see Figure 1). The most common locations of tumors in the oral cavity are the oral tongue, the floor of the mouth and retromolar trigone (see Figure 2) (18). This anatomic division is important because each subsite has different patterns of lymph node dissemination, with occult nodal metastasis ranging from 15% in hard palate tumors to up to 50% for large oral tongue tumors, and the most commonly affected lymph node chains are different as well, as illustrated in Table 1 (19).

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Figure 1. Oral cavity subsites (18).

Figure 2. Subsite distribution of oral cavity cancers (18).

Table 1. Prevalence of lymph node metastasis by primary site: elective radical neck dissection (46)

Level Tongue Floor of mouth Retromolar trigone Alveolar mucosa Buccal mucosa I 14% 16% 19% 27% 44% II 19% 12% 12% 21% 11% III 16% 7% 6% 6% 0 IV 3% 2% 6% 4% 0 V 0 0 0 2% 0 Adapted from: Shah JP, Candela FC, Poddar AK. The patterns of lymph node metastases from squamous carcinoma of the oral cavity. Cancer 1990;66(1):109-13.

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Table 2. Summary comparing 7th and 8th ed. AJCC staging of oral cavity cancer (10)

DOI: depth of invasion; LN: lymph node; ENE(+): extranodal extension present; ENE(-): extranodal extension absent; ipsi: ipsilateral; bi: bilateral; ctr: contralateral.

The most important prognostic factors are the size of the tumor and the presence of lymph node metastasis. In the 8th edition of AJCC staging system we had the introduction of depth of invasion (DOI) and extracapsular extension as major prognostic characteristics; Table 2 shows the changes from the 7th edition (20). Lymph node metastasis reduces the survival by 50% and the presence of extracapsular extension (ECE) portends worse regional and distant metastatic failure rates relative to nodal metastasis without ECE (regional recurrence, 28.9% v 19.2, and distant metastasis, 24.4% v 8.1%, respectively). ECE has negative impact on 5-year disease specific survival (DSS) and overall survival (OS) as well, comparing the presence of nodal metastasis with ECE relative to nodal metastasis without ECE (DSS, 48% v 66%, and OS, 29% v 51%, respectively) (21-23). An international study of more than 3.000 pathologic specimens documented the association of increasing DOI and more advanced disease and worse Disease Specific Survival (24).

LITERATURE REVIEW

This chapter contains opinions and recommendations of the treatment of oral cavity squamous cell carcinoma based on a narrative literature review of the publications including books and peer-reviewed journal articles, adapted for the strengths and weakness of the health systems in Latin America.

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TREATMENT

Biopsies of suspect lesions are obtained from the adjacent invasive front or from the depth of the lesion rather than the surface, thus avoiding necrotic tissue or excessive keratin deposits. Every patient must have a thorough head and neck exam to evaluate tumor location and depth of invasion, relationship with adjacent structures like mandible, hard palate or maxilla, trismus, enlarged lymph nodes and synchronous tumors. The tumor is visually inspected and palpated to assess its location and depth of invasion. Trismus (secondary to invasion of masticator space) and reduced tongue mobility (invasion of the extrinsic tongue musculature or hypoglossal nerve) are ominous clinical signs of advanced disease. Direct extension of a tumor to the mandible or maxilla is better assessed with CT scan. Coronal cuts can depict the depth of invasion into the maxillary sinus by an upper gingiva tumor or the relationship of a floor of mouth cancer with the mandible. MRI is superior in depicting soft tissue invasion (e.g., base of tongue or parapharyngeal extension of a tumor) but does not provide much bony details. As previously stated, tumours of different subsites have different behavior. Hard palate tumors have a lower chance of lymph node metastasis when compared to tongue and floor of the mouth tumors. Depth of invasion is the most important histological feature to be taken into consideration (25). Deeply infiltrating lesions have a significantly increased risk of lymph node metastasis and an adverse impact on prognosis, as stated in the AJCC Cancer Staging Manual 8 Ed. In general, patients with tumors of 4mm or more of depth of invasion have a progressively increased risk of lymph node metastasis and should therefore be candidates for elective neck dissection (26). Multidisciplinary management is imperative to obtain better survival and functional outcomes. Head and neck and reconstructive surgeons, dental professionals, speech and swallowing pathologists, radiation and clinical oncologist consultations are strongly advised. Cancer cure is the main goal. Preservation of function (swallowing, speech), minimization of sequelae (xerostomy, dental decay, trismus and osteonecrosis of the mandible) and aesthetics are important to rehabilitate patients. Surgery overall is the first line treatment. Small and superficial tumors of the oral cavity can be cured by single modality treatment, either surgery or radiotherapy alone. When considering cost, long term sequelae, convenience and patient compliance, surgery is usually the preferred treatment. More advanced tumors (T3 and T4) have poor prognosis and therefore should be treated with combined treatment, usually surgery followed by radio and/or chemotherapy. Clear surgical margins are the main goal when performing the surgical resection of an oral cavity squamous cell carcinoma. There should be at least 5mm clear margins in the formalin fixed resection specimen. In order to obtain that, the surgeon needs to perform the surgical resection with a 1-1.5 cm macroscopic margins from the tumor and frozen section analysis are taken from the specimen, minimizing the risk of false negative margins. Management of the mandible is crucial in OCSCC. Mandibular invasion by tumor can occur early in tumors of the floor of the mouth and inferior gum. Tumors invade the mandible through the dental sockets in the dentate mandible, and through the dental pores of the alveolar process in the edentulous mandible (27).

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Indications for segmental mandibulectomy: gross invasion by oral cancer, primary tumor or metastasis to the mandible, invasion of inferior alveolar nerve or canal by tumor, soft tissue disease adjacent to the full height of the occlusal surface of the mandible in edentulous patients precluding marginal resection and tumor fixed to the bone in previously irradiated patients. Surgical approaches depend on factors such as size and site of the tumor and involved structures. The most common surgical approaches are peroral, mandibulotomy, upper and lower cheek flap approaches, visor flap approach. The main purpose is to gain access to the tumor to perform an oncologically sound procedure and obtaining tumor clear margins of resection. The surgeon must be able to perform such approaches when clinically indicated. Restoration of form and function after resection of oral cavity tumors can be achieved by primary closure, skin grafts, local or locoregional flaps and microvascular reconstruction, depending on the defect extension. Primary closure is the method of choice for small defects secondary to ablation of early tumors. Reconstruction of larger and complex defects requires larger and more complex flaps, like submental island flap, pectoralis major and microvascular free flaps. The ability to reconstruct large surgical defects with microvascular free technics has contributed to improved oncologic outcomes in patients with locally advanced cancers by enabling more complete resections (28).

NECK MANAGEMENT

OCSCC can send metastasis early to the neck lymph nodes. The presence of lymph node metastasis is the single most important prognostic factor in OCSCC: survival is reduced by 50% when compared with similar primary tumors without cervical neck metastasis (29). Approximately 60% of patients with early stage oral cancer (T1-T2) will present with a clinically negative neck (cN0), and 20-30% harbor micrometastasis on histological examination after elective neck dissection (END). Risk factors for nodal metastasis are tumor site, histologic grade, depth of invasion, perineural invasion and lymphovascular invasion (30). Tongue and floor of the mouth tumors are more prone to cervical metastasis, and should be managed with END in the clinically N0 neck when the depth of invasion is 4mm or more. Hard palate and upper gingiva tumors have smaller but non-negligible risk of cervical metastasis and END was associated with lower rates of recurrence and improved survival (31). Oral cavity lymphatic drainage is mainly to cervical levels I through III. Therefore, in the cN0 neck elective neck dissection levels I-III (or supraomohyoid) is indicated. In patients with positive nodes on END neck recurrence is observed in 10-24%. The recurrence rates fall to less than 10% in the pathologically negative (pN0) neck. Sentinel node biopsy can be an alternative in staging the cN0 neck in early stage tumors. Technical challenges and expertise required to perform a sound procedure have hampered its adoption in low volume centers. Clinical or radiographic evidence of involved lymph nodes are indications for therapeutic comprehensive neck dissection addressing cervical levels I to V. Sacrifice of the spinal accessory nerve, sternocleidomastoid muscle, or internal jugular vein is dictated by metastasis size, location and infiltration. These non-lymphatic structures are preserved when there is no

Complimentary Contributor Copy Management of oral cancer 37 evidence of direct tumor invasion and radical neck dissection is performed only with clear evidence of extracapsular extension.

OUTCOMES

Clinical stage at presentation is an important predictor of survival but the most powerful predictor of outcome is the presence of metastatic lymph nodes. There is a 50% reduction in overall survival after the development of cervical metastasis. On the other hand, cure rates exciding 80% can be expected in early-staged tumors.

RADIATION THERAPY

After surgery alone, the results of local control and survival for patients with locally advanced disease are not satisfactory. Since 1957, with the first publications by Fletcher et al. (32) of combine modality therapy with surgery and adjuvant radiation therapy we are learning to better stratify witch patients need radiation after surgery. There are multiple publications showing the major risk factors for worse local control and survival, and the most important are: close/positive margins, extracapsular extension, perineural invasion, lymphovascular invasion, stage pT3/pT4, advanced nodal disease (N2 and N3) and high grade (33, 34). A randomized study from Mishra et al. reported better results with the addition of radiotherapy to surgery in 140 patients with pT3/pT4 N0-2 oral cavity cancers (35). Local control rates were 90% x 75% and 3-year disease free survival was 68% x 38% for patients receiving adjuvant radiation and surgery alone, respectively. A very interesting randomized study from the MD Anderson group showed some important conclusions about adjuvant radiation therapy (36). This trial tested three hypotheses: 1-that patients with none of the adverse risk factors listed above did not need adjuvant treatment; 2- that the total duration of the treatment was important for local control; 3- the dose of radiation. Patients were classified in three categories depending on the pathologic features: 1- low risk, with no adverse risk factors; 2- intermediate risk, with one adverse risk factor other than extracapsular extension; 3- high risk, with ≥2 adverse risk factors and/or extracapsular extension. The risk groups showed an inverse relation with overall survival, the higher the risk group the worse survival (approximately 5-year survival 81% for low risk, 70% for intermediate risk and 38% for high risk). The local control was very good for the low risk group, showing that radiation is not necessary for this group. The intermediate risk group receiving surgery and low dose radiation achieved similar local control with the low risk group. The high-risk group, despite being treated more aggressively with surgery and high dose radiation, had more local failures than the other groups (5-year locoregional control in low and intermediate risk groups ≈90% and in high risk group ≈65%). Another interesting conclusion of this trial is that the total treatment time (time from the surgery date and the completion of radiotherapy) is important. Patients treated in <11 weeks Complimentary Contributor Copy 38 Otávio Costa Diaz, Virgilio Zanella, Juliana Janoski de Menezes et al. had 5-year locoregional control rate of 76% and patients treated in >13weeks had only 38% (p = 0.002).

ADJUVANT CHEMOTHERAPY

Chemotherapy is not recommended to use alone after surgery for oral cancer. In patients with increased risk of recurrence, there are 2 randomized trials that demonstrated superiority of adjuvant chemotherapy with concurrent radiation to radiation alone. In EORTC 22931 (37), 334 patients were randomized (26% oral cavity) to radiation or radiation concurrent with chemotherapy (cisplatin 100mg/m2 D1, D22 and D43) and in the combination treatment group there was a significant improvement in 5-year disease free survival and overall survival. The same treatments were compared in RTOG 9501 (38), which enrolled 459 patients (27% oral cavity) and demonstrated a superior disease-free survival with the combined therapy, but no difference in overall survival. These two studies have some differences in eligible criteria, what can explain in part the opposite results in overall survival (see Table 3). A pooled analysis of these 2 trials (39) was published and showed a statistically significant overall survival with chemoradiation therapy over radiation alone in patients with positive surgical margins and/or extracapsular extension (ECE) (reduction of 28% in the risk of death, HR 0.776). In patients with intermediate risk factors, including vascular or perineural invasion, T3 and T4 pathologic stage or involvement of two or more lymph nodes there is no level 1 evidence that indicate chemoradiation therapy after surgery, this question is being investigated in a prospective trial RTOG-0920 (postoperative radiation therapy +/- cetuximab). At this moment, guidelines recommended either radiation or chemoradiation in this group of patients (33). Some retrospective studies showed that the number of metastatic lymph nodes is the most important risk factor, and is a critical predictor of oral cavity cancer mortality (40, 41). In one of these studies, just patients with ≥ 6 lymph nodes had improved survival with postoperative chemoradiation versus radiation, and patients with less than 6 metastatic lymph nodes had no benefit even when there was positive margin or ECE (41).

Table 3. Major differences between adjuvant chemoradiation trials

EORTC 22931 RTOG 9501 Randomized Patients 334 (26% oral cavity) 459 (27% oral cavity) Stage 57% N2-N3 94% N2-N3 Unfavorable risk factors ECE, positive margins, lymph nodes ECE, positive magins or at levels IV or V, vascular or involvement of 2 or more perineural invasion lymph nodes High Risk factors 70% of patients had one or both 59% of patients had one or (ECE, positive margins) both - % of patients Primary End Points Progression Free Survival Locoregional Disease Control Radiation Dose 66Gy 60-66 Gy End Points Improved locoregional failure, disease Improved locoregional failure, free survival and overall survival disease free survival

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Perhaps the author may see if want to discuss some evidence about use of Cetuximab with radiotherapy in those cases unfit for cisplatin.

DISCUSSION

At our Institution, patients tend to present in more advanced stages of disease. This reflects the difficulty in access to health services, lack of information, and misdiagnosis, common characteristics to almost all Latin American countries (42). In a historical cohort of our patients 47,2% presented with stage III and IV disease (43). Every effort is made to obtain free resection margins of at least 5mm in the resection specimen. In order to accomplish that the surgeon must be able to perform transoral or more complex accesses to the oral cavity. The neck is addressed with elective dissection levels I to III when the tumor depth of invasion is estimated as 4 mm or more in tumors of the tongue and floor off the mouth. Modified neck dissection levels I to V is indicated when there is evidence of lymph node metastasis. Post ablative reconstruction depends on the size and location of the surgical defect, patient health status and local expertise. The use of skin grafts, local and locoregional flaps, pectoralis major and other more complex procedures aims to restore speech and swallowing function and facial contour. Microsurgical free flaps are an excellent option to obtain these goals although not performed in many centers due to the required expertise. The radial forearm flap is commonly used to reconstruct tongue, floor of the mouth and buccal mucosa defects. The fibular flap is the method of choice for mandibular reconstructions. cT1-2 cN0 tumors are treated with surgery alone. Radiation therapy is used as the primary treatment modality when the patient has comorbidities that preclude anesthetic use or patient refuse to surgery. When the surgical specimen does not have any risk factors, adjuvant treatment is usually not indicated. In cases where there is one risk factor, such as perineural or lymphovascular invasion we discuss with the patient the pros and cons of the use of adjuvant radiation therapy and in cases with two or more risk factors we treat with adjuvant radiation. We try to finish the whole treatment in less than 11 weeks, so in less than four weeks from the surgery the patient will have the first evaluation at the radiation therapy department, and if the surgical bed has healed the treatment will begin. In advanced tumors, like cT3-4 cN2b/c-N3, when resection is possible, it is the first treatment modality and after resection we will do adjuvant radiation therapy or chemoradiation in cases of positive surgical margins and/or extracapsular extension. We discuss with the patient postoperative chemoradiation if ≥ 6 metastatic lymph nodes, when the margins and/or ECE are negative. When resection is not possible the treatment of choice is radiation therapy with concomitant Cisplatin (33). Cetuximab is not routinely used concomitant with radiation therapy as it is not supported by the National Health System, we consider using Cetuximab just in patients with health insurance and that are not candidates for Cisplatin. In patients not fit for treatment with Cisplatin 100mg/m2 D1, D22 and D43, we consider using cisplatin 30-40mg/m2 weekly. Induction chemotherapy is rarely used, because the major clinical trials failed to show a statistically significant benefit in survival and the side effects and financial costs of treatment increase (44, 45).

Complimentary Contributor Copy 40 Otávio Costa Diaz, Virgilio Zanella, Juliana Janoski de Menezes et al.

In conclusion, the treatment of oral cavity squamous cell carcinoma is challenging and there is a need for multidisciplinary approach to achieve the best tumor control with the minimal sequelae and side effects.

REFERENCES

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[21] Myers JN, Greenberg JS, Mo V, Roberts D. Extracapsular spread: A significant predictor of treatment failure in patients with squamous cell carcinoma of the tongue. Cancer 2001;92(12):3030-6. [22] Greenberg JS, Fowler R, Gomez J, Mo V, Roberts D, El Naggar AK, et al. Extent of extracapsular spread: A critical prognosticator in oral tongue cancer. Cancer 2003;97(6):1464-70. [23] Chinn SB, Myers JN. Oral cavity carcinoma: current management, controversies, and future directions. J Clin Oncol 2015;33(29):3269-76. [24] International Consortium for Outcome Research (ICOR) in Head and Neck Cancer: Primary tumor staging for oral cancer and a proposed modification incorporating depth of invasion: an international multicenter retrospective study. JAMA Otolaryngol Head Neck Surg 2014;140(12):1138-48. [25] Spiro R, Huvos A, Wong G, Spiro JD, Gnecco CA, Strong EW. Predictive value of tumor thickness in squamous carcinoma confined to the tongue and floor of the mouth. Am J Surg 1986;152:345-50. [26] Huang SH, Hwang D, Lockwood G, Goldstein DP, O’Sullivan B. Predictive value of tumor thickness for cervical lymph-node involvement in squamous cell carcinoma of the oral cavity: a meta-analysis of reported studies. Cancer 2009;115(7):1489-97. [27] Brown JS, Lowe D, Kalavrezos N, D’Souza J, Magennis P, Woolgar J. Patterns of invasion and routes of tumor entry into the mandible by oral squamous cell carcinoma. Head Neck 2002;24(4):370-83. [28] Hanasono MM, Friel MT, Klem C, hsu PW, Robb GL, Weber RS, et al. Impact of reconstructive microsurgery in patients with advanced oral cavity cancers. Head Neck 2009;31(10):1289-96. [29] Robbins KT, Ferlito A, Shah JP, Hamoir M, Takes RP, Strojan P, et al. The evolving role of selective neck dissection for head and neck squamous cell carcinoma. Eur Arch Otorhinolaryngol 2013;270(4):1195-202. [30] Woolgar JA, Scott J. Prediction of cervical lymph node metastasis in squamous cell carcinoma of the tongue/floor of mouth. Head Neck 1995;17(6):463-72. [31] Givi B, Eskander A, Awad MI, Kong Q, Montero PH, Palmer FL, et al. Impact of elective neck dissection on the outcome of oral squamous cell carcinomas arising in the maxillary alveolus and hard palate. Head Neck 2016;38(Suppl 1):E1688-94. [32] MacComb WS, Fletcher GH. Planned combination of surgery and radiation in treatment of advanced primary head and neck cancer. Am J Roentgenol Radium Ther Nucl Med 1957;77(3):397-414. [33] Adelstein D, Gillison ML, Pfister DG, Spencer S, Adkins D, Brizel DM, et al. NCCN Guidelines insights:head and neck cancers, version 2.2017. J Natl Compr Canc Netw 2017;15(6):761-70. [34] Maghami E, Koyfman S, Weiss J. Personalizing postoperative treatment of head and neck cancers. 2018 ASCO Educational book 2018;515-22. [35] Mishra RC, Singh DN, Mishra TK. Post-operative radiotherapy in carcinoma of buccal mucosa, a prospective randomized trial. Eur J Surg Oncol 1996;22(5):502-4. [36] Ang KK, Trotti A, Brown BW, Garden AS, Foote RL, Morrison WH, et al. Randomized trial addressing risk features and time factors of surgery plus radiotherapy in advanced head and neck cancer. Int J Radiat Oncol Biol Phys 2001;51(3):571-8. [37] Bernier J, Domenge C, Ozsahin M, Matuszewska K, Lefèbvre JL, Greiner RH, et al. Postoperative Irradiation with or without Concomitant Chemotherapy for Locally Advanced Head and Neck Cancer. N Engl J Med 2004;350(19):1945-52. [38] Cooper JS, Pajak TF, Forastiere AA, Jacobs J, Campbell BH, Saxman SB, et al. Postoperative Concurrent Radiotherapy and Chemotherapy for High-Risk Squamous-Cell Carcinoma of the Head and Neck. N Engl J Med 2004;350(19):1937-44. [39] Bernier J, Cooper JS, Pajak TF, van Glabbeke M, Bourhis J, Forastiere A, et al. Defining risk levels in locally advanced head and neck cancers: a comparative analysis of concurrent postoperative radiation plus chemotherapy trials of the EORTC (#22931) and RTOG (#9501). Head Neck 2005;27(10):843- 50. [40] Ho AS, Kim S, Tighiouart M, Gudino C, Mita A, Scher KS, et al. Metastatic lymph node burden and survival in oral cavity cancer. J Clin Oncol 2017;35(31):3601-9. [41] Zumsteg ZS, Luu M, Kim S, Tighiouart M, Mita A, Scher KS et al. Quantitative lymph node burden as a ‘very-high-risk’ factor identifying head and neck cancer patients benefiting for postoperative chemoradiation. Ann Oncol 2019;30(1):76-84.

Complimentary Contributor Copy 42 Otávio Costa Diaz, Virgilio Zanella, Juliana Janoski de Menezes et al.

[42] Wünsch-Filho V, de Camargo EA. The burden of mouth cancer in Latin America and the Caribbean: epidemiologic issues. Semin Oncol 2001;28(2):158-68. [43] Girardi FM, Zanella V, Kroef RG. Correlation between clinical and pathological data and surgical margins in patients with squamous cell carcinoma of the oral cavity. Braz J Othorhinolaryngol 2013;79(2):190-5. [44] Haddad R, O’Neill A, Rabinowits G, Tishler R, Khuri F, Adkins D, et al. Induction chemotherapy followed by concurrent chemoradiotherapy (sequential chemoradiotherapy) versus concurrent chemoradiotherapy alone in locally advanced head and neck cancer (PARADIGM): a randomised phase 3 trial. Lancet Oncology 2013;14(30:257-64. [45] Hitt R, Grau JJ, López-Pousa A, Berrocal A, García-Girón C, Irigoyen A et al. A randomized phase III trial comparing induction chemotherapy followed by chemoradiotherapy versus chemoradiotherapy alone as treatment of unresectable head and neck cancer. Ann Oncol 2014;25(1):216-25. [46] Shah JP, Candela FC, Poddar AK. The patterns of lymph node metastases from squamous carcinoma of the oral cavity. Cancer 1990;66(1):109-13.

Chapter 5

A REVIEW OF LARYNGEAL CANCER MANAGEMENT

Icaro Thiago de Carvalho1,, MD, Daniel Marin Ramos2, MD, Fernando Mauro de Lima Prearo3, MD; Fiona Lim4, MBBS, Bo Angela Wan5, MD(C) and Maurício F Silva6,7,8, MD, PhD 1Radiation Oncology Department at Hospital Israelita Albert Einstein, São Paulo, Brazil 2Head and Neck Surgery Department at Instituto do Câncer do Estado de São Paulo “Octávio Frias de Carvalho,” São Paulo, Brazil 3Medical Oncology Department at Instituto Brasileiro de Combate ao Câncer, São Paulo, Brazil 4Department of Oncology, Princess Margaret Hospital, Hong Kong, PR China 5 Odette Cancer Centre, Sunnybrook Health Sciences Centre, Toronto, Ontario, Canada 6Radiation Oncology Unit, Santa Maria Federal University, Santa Maria, Brazil 7Radiation Oncology Unit, Hospital de Caridade Astrogildo de Azevedo, Santa Maria, Brazil 8Latin America Cooperative Oncology Group, Porto Alegre, Brazil

ABSTRACT

Laryngeal cancer treatment in Latin America has unique characteristics related to the exposure to risk factors, socioeconomic level of the population and access to health systems. This chapter aims to perform a review of the literature produced in the last 20 years, including 39 studies, with prospective randomized studies, case series and case reports, on the treatment of early, advanced and metastatic laryngeal cancer, featuring literature produced in Latin America. In general, patterns of care adopted in Latin countries are very similar to that adopted in other countries.

 Corresponding Author’s Email: [email protected]. Complimentary Contributor Copy 44 Icaro Thiago de Carvalho, Daniel M. Ramos, Fernando Mauro de Lima Prearo et al.

INTRODUCTION

Malignant tumors of the head and neck (oral cavity, oropharynx, hypopharynx and larynx) have a worldwide prevalence of 7%, with an estimated 900,000 diagnosed cases per year. It is estimated that 25% of head and neck cancers have a laryngeal primary site (1). Larynx cancer treatment has evolved during time, from a tracheostomy performed by Trousseau in 1837 only to enable the patient to breath by passing through the larygofissure, to the first successful laryngectomy in 1873 performed by Billroth. Radiation treatment was first used in 1903 and is one of the options to radically treat patients in the early setting of disease, as an organ preserving therapy for some patients with advanced disease, and as adjuvant treatment, lowering the risk of relapse after surgery (2).

OUR SEARCH

We performed a PubMed search for manuscripts published in the last 20 years (September 1998 to September 2018), using the search terms “Laryngeal cancer,” “Larynx Carcinoma,” “Larynx Cancer,” and “Laringe,” limiting to studies published in English, Spanish or Portuguese, which resulted in 18,145 hits. All titles were initially appraised and search results that were duplicated were rejected, eliminating 8 publications. Abstracts were reviewed, selecting those published in Latin America or those with impact on treatment standards of care, resulting in 53 papers remaining. All selected articles identified were reviewed in full text.

OUR FINDINGS

The main objectives of the 53 studies can be partitioned into five main categories: epidemiological studies, studies regarding the treatment of early stage larynx cancer, studies about the treatment of advanced stage larynx cancer, salvage treatment, metastatic and phonatory rehabilitation.

Epidemiology

There is a striking geographical variation in the incidence of head and neck tumors, and Latin America is among the high-risk regions for all primary sites, particularly in the south and southeast of Brazil, Uruguay and Argentina (3). The main risk factors are smoking and alcohol consumption, with evidence that there is an interaction between these factors (4). Laryngeal cancer characteristically affects men, in a ratio of 7:1 (5). Unfortunately, the data available for reliable measurements of the true incidence and epidemiology of laryngeal cancer in Latin America are scarce. Most of the studies conducted do not assess the occurrence of laryngeal cancer in isolation (6, 7). This is compounded by the great heterogeneity between the countries that make up Latin America, both in the characteristics of the population and in the regional conditions of life and health. Complimentary Contributor Copy A review of laryngeal cancer management 45

The socioeconomic conditions of the population of these large regions, associated with the scarcity of health resources, often lead to late diagnosis which directly impacts the treatment outcomes and prognosis of the disease. Thus, it is estimated that 75% of cases are diagnosed as locally advanced disease.

Early stage laryngeal cancer

The main focus on treating patients with early stage laryngeal cancer is to preserve the larynx, and this can be accomplished by surgery alone or radiation alone. Both offer high local control rates, but there are some controversies in the literature about which modality offer the best voice quality after treatment, maintaining swallowing function and adequate airway patency. Oncological and functional results, as well low morbidity and lower cost make Transoral Laser Therapy (TLM) a treatment of choice in some oncologic centers, especially for Tis, T1, T2 and selected T3 tumors (8). Despite offering similar local control when compared to radiation therapy, some authors suggest there is some advantage to offer this modality of treatment especially for Tis-T1 tumors (9). For T1-2 tumors, it offers good locoregional control rates and good larynx preservation (85-90%), and it allows the use of other treatment modalities in case of tumor recurrence or second primary cancer (10). Patients treated with endoscopic surgery have a satisfactory voice quality. One study compared the Voice Handicap Index between patients treated with radiation or TLM for T1 tumors found no statistical difference between the two groups (11). Transoral Robotic Surgery (TORS) is only feasible for laryngeal tumors located in the supraglottis. The size of the robotic arms is impeditive to routine use for glottic tumors. This limitation will be addressed in the next generation of consoles (10). In Latin America, few teams are using robotic surgery as a routine treatment for supraglottic larynx tumors, and there are no large series results being published. Another option that offers excellent local control and voice quality is radiation therapy. It avoids the risks related with surgery, and thus is the initial treatment of choice prescribed for early stage lesions in many centers. In these cases, surgery is reserved for salvage after radiation therapy failure (11). In early stage glottic cancer, hypofractionated radiation schedules between 63 and 65.25 Gy in 28 and 29 fractions offers better local control and overall survival over conventional fractionated radiation of 60 Gy and 70 Gy in 30 and 35 fractions (12) and is more convenient for the patient. For T1 and T2 glottic tumors, the cervical lymph nodes are not electively treated, and limited small volume radiation are used to cover the primary lesion with margins (13, 14). Local control in 5 years is in the order of 74-95%, depending on tumor stage, and the risk of grade 3 late complications is in the order of 2-15%. For T1-T2N0 supraglottic tumors, radiation therapy is also a good option for radical treatment, with some studies favoring radiation over surgery, with better overall survival (15, 16). In these cases, the elective neck lymph nodes must be treated as well to avoid recurrences. The different modalities of open partial laryngectomy (frontal or vertical fronto-lateral, laryngopharyngeal cordectomy or supracricoid horizontal laryngectomy) can be employed to treat early laryngeal cancer patients too, with good oncological and functional results, in situations where no endoscopic or radiotherapeutic procedures can be used (17). Brumund Complimentary Contributor Copy 46 Icaro Thiago de Carvalho, Daniel M. Ramos, Fernando Mauro de Lima Prearo et al. et al. demonstrated a 5-year survival rate of 83.1% in T1 and 67.2% in T2 cases, in patients submitted to a frontal laryngectomy (18). For some early stage more extensive tumors, or for tumors affecting the anterior commissure, the open or combined approach may be more adequate. Open partial laryngectomies, despite being considered obsolete to treat early laryngeal tumors in some parts of the world (19) are still widely used in Latin America, mainly due to the scarcity of centers with infrastructure for endoscopic procedures.

Moderately advanced and advanced stage larynx cancer

Moderately advanced laryngeal cancer represents the most complex spectrum in the sense that it is the hardest to define the best treatment approach. It is the frontier between the initial tumors without impairment of function and with an excellent prognosis, and the advanced tumors that have loss of laryngeal functionality and expressive worsening of the prognosis. There is no greater challenge in laryngology than T3. Riga et al. performed a recent systematic review that illustrates the great difficulty of establishing protocols to treat laryngeal T3 tumors, mainly due to the divergence of sub-regions affected by the tumor and lack of controlled trials (20). The definition of T3 is imperfect in its objective of stratifying prognosis and standardizing therapeutic decisions. Based primarily on the concept of laryngeal mobility (which indirectly indicates depth of infiltration), it does not consider the antero-posterior location of the lesion. The potential involvement of the cricoid and arytenoid is extremely important in decision-making in these cases and is not contemplated by the TNM (21). The great question that seems to be relevant is: “Can the tumor be resected with laryngeal preservation either endoscopically or open?” If the only possible surgical treatment is total laryngectomy, in most cases it seems safe and opportune to perform non-invasive surgical procedures for organ preservation (22). Some authors advocate that the ideal patient for nonsurgical treatment protocols for laryngeal cancer are T2N+ and T3 (and some small T4) that could only be surgically treated with total laryngectomy (23). Shortly after the VA trial (24), which demonstrated that 66% of larynx could be preserved 2 years after treatment without survival disadvantage, the RTOG trial was published (25) and demonstrated 71% of locoregional control and 83% larynx preservation rate in 5 years with concomitant chemoradiation. Thereafter, protocols of organ preservation with radiotherapy and chemotherapy have become popular in the world and also in Latin America. Maddox et al. demonstrated a decrease in the number of total laryngectomies performed in the USA between 1997 and 2008 (26). In daily clinical practice, however, results obtained in controlled protocols cannot be used without individualized criteria (27). Another relevant issue is the late toxicity of non-surgical treatment in advanced laryngeal tumors. Dysphagia and aspiration seem to play an important role in decreasing the survival of these patients (28). Because of that, our approach is to offer laryngeal preservation for selected patients, particularly for those with a functioning larynx without cartilage destruction, and non-bulky tumors. Laryngeal preservation is often performed with chemoradiation with cisplatin-based chemotherapy using a dose of 100 mg/m2 every 21 days for 3 cycles or 30- 40 mg/m2 weekly (29). This translates into a 5-year overall survival benefit of about 4.5% over radiation alone. Complimentary Contributor Copy A review of laryngeal cancer management 47

Patients who are unable to receive cisplatin may receive concomitant cetuximab, a monoclonal antibody that inhibits EGFR (30), which also showed overall survival advantage. The standard radiation dose is 70 Gy in 35 fractions, delivered 5 times a week to the gross disease; and doses in the range of 45-54 Gy are delivered to sites with risk of microscopic spread of the disease. Altered fractionation schemes may lead to better local control and overall survival, especially in patients who can’t receive platinum-based regimes or cetuximab (31). Doses of 81.6 Gy in 68 twice daily fractions (RTOG 9003) (32) and 70 Gy in 35 fractions delivered 6 times a week (DAHANCA) (33) have been described and demonstrated superiority over standard fractionation. The question that still remains is if these schemes maintain their superiority when used with cisplatin or cetuximab. To date, induction chemotherapy failed to show any advantage over the concurrent chemotherapy approach. It is in the treatment of moderately advanced tumors of the larynx that the relevance of open partial laryngectomies (mainly supra-lateral laryngectomies) survives. The literature supports the use of these surgical treatment modalities that preserve laryngeal functionality with good oncological results (similar to radiotherapy combined with chemotherapy or not) (34). Sperry et al. showed a 5 years local control in 94% patients that underwent supracricoid laryngectomy (35). This modality of treatment is quite versatile, and can be used in cases of T2, T3 and even selected T4 disease. In this surgery, all the paraglottic space is removed, as well the two vocal folds and ventricular bands (8). Functional results of supracricoid laryngectomy are variable and difficult to compare between different places in the world, which is a barrier to their widespread use (36). Nowadays, most authors favor surgical treatment followed by adjuvant radiotherapy with or without systemic therapy in advanced tumors (T4) without distant metastasis. Gorin et al. obtained a sample of almost 500 patients with a survival rate of 25% in T4 tumors treated with chemotherapy and radiotherapy and 55% with surgery (37). Since the first description by Billroth in 1873, total laryngectomy has been playing an important role in the treatment of laryngeal cancer, and nowadays this role seems to rest on advanced tumors and on rescue cases without the possibility of partial surgical resection. A recent cohort study by Stokes et al. including patients of the largest cancer database in the USA (National Cancer Database-NCDB) demonstrated a greater overall survival of patients treated with surgery and adjuvant radiotherapy compared to organ preservation protocol modalities, however without statistical significance when compared with a smaller group of patients treated with induction chemotherapy followed by concomitant treatment of radiotherapy and systemic therapy (38). A recent meta-analysis demonstrated greater disease-free survival in laryngeal T3 and T4 patients treated with laryngectomy followed by radiotherapy when compared to the three nonsurgical treatment modalities (isolated radiotherapy, concomitant chemoradiation, and induction chemotherapy followed by chemoradiation) (39). Another meta-analysis showed benefit in survival and locoregional control in T4 tumors treated with total laryngectomy compared to different non-surgical treatment modalities, but without advantage of the surgical treatment in cases of T3 tumors 41. However, there are studies that validate preservation protocols with different schemes (induction and concomitance with two or three drugs - docetaxel, cisplatin and fluorouracil, in addition to cetuximab), in selected cases of T4 with preservation of laryngeal function and without gross cartilage involvement (40-42).

Complimentary Contributor Copy 48 Icaro Thiago de Carvalho, Daniel M. Ramos, Fernando Mauro de Lima Prearo et al.

Salvage

Approximately 40% of patients treated with organ preservation protocols for laryngeal cancer have tumor recurrence in the first years of follow-up, and, of these, about one-third will need salvage surgical procedures (laryngectomy and/or neck dissection) (43). The rates of complications in rescue surgeries are high. Putten et al. observed an incidence of complications of 68%, with cutaneous pharyngeal fistula in 23% of total laryngectomies (43). A systematic review of 50 studies with 3,292 patients showed a complication rate of 67.5% of cases of total laryngectomy, with emphasis on pharyngo-cutaneous fistula that occurs in 28.9% of the interventions (44). Studies suggest a decrease in the incidence of fistulas when tissue is used to reinforce the pharyngeal suture, with the pectoralis major muscle flap used most commonly (45). Partial surgery with preservation of laryngeal function can be performed for salvage treatment of selected cases but involves longer rehabilitation time. The individualized analysis of each case should be performed, considering patient aspects (comorbidities and lung status) and tumor aspects (preservation of laryngeal remnant capable of maintaining sphincter function with airway protection) (46). Both endoscopic procedures (TLM and TORS) and open procedures (vertical or horizontal partial laryngectomies) can be performed in rescue treatment of early tumors, and even in some cases of moderately advanced tumors (46). A systematic review performed by Zhong et al. shows satisfactory oncological results in recurrent T1 and T2 tumors with salvage endoscopic laser resection (47). For those patients who refuse or unable to receive surgical treatment, reirradiation can be an option, as 20-60% benefit from this approach (48, 49).

Metastatic laryngeal cancer

Metastatic laryngeal cancer is managed the same way as other head and neck squamous cell carcinomas. Nowadays the treatment of choice consists of platinum-based chemotherapy. The EXTREME trial demonstrated that the addition of cetuximab to platinum (cisplatin or carboplatin) plus 5-FU scheme improved median overall survival from 7.4 months to 10.1 months (50).

Phonatory rehabilitation

Since the 1980's when Singer and Bloom developed the first esophageal tracheal prosthesis with valve, this type of a laryngeal voice has been considered a gold standard for post- laryngectomy phonatory rehabilitation. However, among the three most common modalities of rehabilitation (esophageal voice, electronic laryngeal voice and tracheoesophageal prosthesis), esophageal tracheal prosthesis is the one that has the greatest cost, and for economic and social reasons, it is used less in Brazil and Latin America (51). In general, rates of phonatory rehabilitation are lower in these regions when compared to American and European services, not only due to the greater financial constraint, lack of

Complimentary Contributor Copy A review of laryngeal cancer management 49 materials and specialized centers, but also a lack of trained staff and a lower socio-economic status of patients.

CONCLUSION

This chapter aimed to demonstrate the current practices for laryngeal cancer treatment, giving emphasis to Latin America papers. Finding original and practice changing trials in Latin America was difficult, as reflecting a lack of investment in research. Treatment patterns in Latin America for laryngeal cancer patients are similar to that in developed countries, especially in places with greater resources. Since there are economic limitations and social inequalities, there is heterogeneity in the application of the most current guidelines in the different regions of Latin America.

REFERENCES

[1] Chin D, Boyle GM, Porceddu S, Theile DR, Parsons PG, Coman WB. Head and neck cancer: Past, present and future. Expert RV Anticancer Ther 2006;6(7):111-8. [2] Shim SY. Recent advances in management of laryngeal cancer. Cancer Res Treat 2004;36(1):13-8. [3] Ferlay J, Bray FI, Pisani P, Parkin DM. Globocan 2002. Accessed 2018 Jun 01. URL: http://globocan.iarc.fran. [4] Szymanska K, Hung RJ, Wünsch-Filho V, Eluf-Neto J, CUrado MP, Koifman S, et al. Alcohol and tobacco, and the risk of cancers of the upper aerodigestive tract in Latin America: a case-control study. Cancer Causes Control 2011; 22(7):1037-46. [5] Ferlay J, Bray FI, Pisani P, Parkin DM. International Agency for Research on Cancer (IARC). Globocan 2000: cancer incidence, mortality and prevalence worldwide. Lyon, France: IARC Press, 2004. [6] Schlecht NF, Franco EL, Pintos J Negassa A, Kowalski LP, Oliveira BV, Curado MP. Interaction between tobacco and alcohol consumption and the risk of cancers of the upper aero-digestive tract in Brazil. Am J Epidemiol 1999;150:1129-37. [7] Schlecht NF, Pintos J, Kowalski LP, Franco EL. Effect of type of alcoholic beverage on the risks of upper aerodigestive tract cancers in Brazil. Cancer Causes Control 2001;12:579-87. [8] Tamaki A, Miles BA, Lango M, Kowalski L, Zender CA. AHNS Series: Do you know your guidelines? Review of current knowlege on laryngeal cancer. Head Neck 2018;40(1):171-81. [9] Mo HL, Li J, Yang X, Zhang F, Xiong JW, Yang ZL, et al. Transoral laser microsurgery versus radiotherapy for T1 glottic carcinoma: A systematic review and meta-analysis. Laser Med Sci 2017;32(2):461-7. [10] Hartl DM, Brasnu DF. Contemporary surgical management of early glottic cancer. Otolaryngol Clin North Am 2015;48(4):611-25. [11] Greulich MT, Parker NP, Lee P, Merati AL, Misono S. Voice outcomes following radiation versus laser microsurgery for T1 glottic carcinoma: systematic review and meta-analysis. Otolaryngol Head Neck Surg 2015;152(5):811-9. [12] Stokes WA, Abbott D, Phan A, Raben D, Lanning RM, Karam SD. Patterns of care for patients with early-stage glottic cancer undergoing definitive radiation therapy: a national cancer database analysis. Int J Radiat Oncol Biol Phys 2017;98(5):1014-21. [13] Grégoire V, Evans M, Le QT Bourhis J, Budach V, Chen A, et al. Delineation of the primary tumour Clinical Target Volumes (CTV-P) in laryngeal, hypopharyngeal, oropharyngeal and oral cavity squamous cell carcinoma: AIRO, CACA, DAHANCA, EORTC, GEORCC, GORTEC, HKNPCSG,

Complimentary Contributor Copy 50 Icaro Thiago de Carvalho, Daniel M. Ramos, Fernando Mauro de Lima Prearo et al.

HNCIG, IAG-KHT, LPRHHT, NCIC CTG, NCRI, NRG Oncology, PHNS, SBRT, SOMERA, SRO, SSHNO, TROG consensus guidelines. Radiother Oncol 2018;126(1):3-24. [14] Bledsoe TJ, Park HS, Stahl JM Yarbrough WG, BUrtness BA, Decker RH, et al. Hypofractionated radiotherapy for patients with early-stage glottic cancer: patterns of care and survival. J Natl Cancer Inst. 2017;109(10). [15] Mendenhall WM, Dagan R, Bryant CM, Amdur RJ, Mancuso AA. Definitive radiotherapy for squamous cell carcinoma of the glottic larynx. Cancer Control 2016;23(3):208-12. [16] Patel KB, Nichols AC, Fung K, Yoo J, MacNeil SD. Treatment of early stage Supraglottic squamous cell carcinoma: meta-analysis comparing primary surgery versus primary radiotherapy. J Otolaryngol Head Neck Surg. 2018;47(1):19. [17] Graciano AJ, Sonagli M, de Silva AG, Fischer CA, Chone CT. Partial laryngectomy in glottic cancer: complications and oncological results. Braz J Otorhinolaryngol 2016;82(3):275-80. [18] Brumund KT, Gutierrez-Fonseca R, Garcia D, Babin E, Hans S, Laccourreye O. Frontolateral vertical partial laryngectomynwithout tracheotomy for invasive squamous cell carcinoma of the vocal cord: a 25-year experience. Ann Otol Rhinol Laryngol 2005;114(4):314-22. [19] Hartl DM, Brasnu DF. Contemporary surgical management of early glottic cancer. Otolaryngol Clin North Am 2015;48(4):611-25. [20] Riga M, Chelis L, Danielides V, Vogiatzaki T, Pantazis TL, Pantazis D. Systematic review on T3 laryngeal squamous cell carcinoma, still far from a consensus on the optimal organ preservation treatment. Eur J Surg Oncol 2017;43(1):20-31. [21] Virgilio A, Bussu F, Vincentiis M. Revisione basata sullévidenza delle opzioni terapeutiche nei pazienti con glottica carcinoma. Acta Otorhinolaryngol Ital 2012;32(4):256-7. [22] Chone CT. Changing paradigms in treatment of larynx cancer. Braz J Otorhinolaryngol 2014;80(2):96-7. [23] Forastiere AA, Weber RS, Trotti A. Organ preservation for advanced larynx cancer: issues and outcomes. J Clin Oncol 2015;33(29):3262-8. [24] The Department of Veterans Affairs Laryngeal Cancer Study Group, Wolf GT, Fisher SG, Hong WK, Hillman R, Spaulding M. Induction chemotherapy plus radiation versus surgery plus radiation in patients with advanced laryngeal cancer. N Engl J Med 1991;324(24):1685-90. [25] Forastiere A, Goepfert H, Maor M, Pajak TF, Weber R, Morrison W, et al. Concurrent chemotherapy and radiotherapy for organ preservation in advanced laryngeal cancer. N Engl J Med 2003;349(22):2091-8. [26] Maddox PT, Davies L. Trends in total laryngectomy in the age of organ preservation: a population- based study. Otolaryngol Head Neck Surg 2012;147(1):85-90. [27] Sanabria A, Chaves ALF, Kowalski LP, Wolf GT, Saba NF, FOrastiere AA, et al. Organ preservation with chemoradiation in advanced laryngeal cancer: The problem of generalizing results from randomized controlled trials. Auris Nasus Larynx 2017;44(1):18-25. [28] Britt CJ, Gourin CG. Contemporary management of advanced laryngeal cancer, Laringoscope Investig Otolaryngol 2017;2(5):307-9. [29] Blanchard P1 Baujat B, Holostenco V, Bourredjem A, Baey C, Bourhis J, et al. Meta-analysis of chemotherapy in head and neck cancer (MACH-NC): a comprehensive analysis by tumour site. Radiother Oncol 2011;100(1):33-40. [30] Bonner JA, Harari PM, Giralt J, Cohen RB, Jones CU, Sur RK, et al. Radiotherapy plus cetuximab for locoregionally advanced head and neck cancer: 5-year survival data from a phase 3 randomised trial, and relation between cetuximab-induced rash and survival. Lancet Oncol 2010;11(1):21-8. [31] Lacas B, Bourhis J, Overgaard J, Zhang Q, Grégoire V, Nankivell M, et al. Role of radiotherapy fractionation in head and neck cancers (MARCH): An updated meta-analysis. Lancet Oncol 2017;18(9):1221-37. [32] Beitler JJ, Zhang Q, Fu KK, Trotti A, Spencer SA, Jones CU, et al. Final results of local-regional control and late toxicity of RTOG 9003: a randomized trial of altered fractionation radiation for locally advanced head and neck cancer. Int J Radiat Oncol Biol Phys 2013;89(1):13-20.

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[33] Overgaard J1, Hansen HS, Specht L, Overgaard M, Grau C, Anderson E, et al. Five compared with six fractions per week of conventional radiotherapy of squamous-cell carcinoma of head and neck: DAHANCA 6 and 7 randomised controlled trial. Lancet 2003;362(9388):933-40. [34] Graciano AJ, Sonagli M, da Silva AG, Fischer CA, Chone CT. Partial laryngectomy in glottic cancer: complications and oncological results Braz J Otorhinolaryngol 2016;82(3):275-80. [35] Sperry SM, Rassekh CH, Laccourreye O, Weinstein GS. Supracricoid partial laryngectomy for primary and recurrent laryngeal cancer. JAMA Otolaryngol Head Neck Surg 2013;139(11):1226-35. [36] Schindler A, Pizzorni N, Mozzanica F, Fantini M, Ginocchio D, Bertolin A, et al. Functional outcomes after supracricoid laryngectomy: What do we do not know and what do we need to know? Eur Arch Otorhinolaryngol 2016;273(11):3459-75. [37] Gourin CG, Conger BT, Sheils WC, Bilodeau PA, Coleman TA, Porubsky ES. The effect of treatment on survival in patients with advanced laryngeal carcinoma. Laryngoscope 2009;119(7):1312-7. [38] Stokes WA, Jones BL, Bhatia S, Oweida AJ, Bowles DW, Raben D, et al. A comparison of overall survival for patients with T4 larynx cancer treated with surgical versus organ-preservation approaches: A National Cancer Data analysis. Cancer 2017;123(4):600-8. [39] Luo XN, Chen LS, Zhang SY, Lu ZM, Huang Y. Effectiveness of chemotherapy and radiotherapy for laryngeal preservation in advanced laryngeal cancer: a meta-analysis and systematic review. Radiol Med 2015;120(12):1153-69. [40] Fu X, Zhou Q, Zhang X. Efficacy Comparison Between Total Laryngectomy and Nonsurgical Organ- Preservation Modalities in Treatment of Advanced Stage Laryngeal Cancer: A Meta-Analysis. Medicine (Baltimore) 2016;95(14):e3142. [41] Mowery YM, Salama JK. A multidisciplinary approach to larynx cancer: one size does not fit all. J Oncol Pract 2016;12(8):725-6. [42] Lagha A, Chraiet N, Labidi S, Rifi H, Ayadi M, Krimi S, et al. Larynx preservation: what is the best non-surgical strategy? Crit Rev Oncol Hematol 2013;88(2):447-58. [43] Putten L, Bree R, Doornaert PA, Buter J, Erenstein SE, Rietveld DH, et al. Salvage surgery in post- chemoradiation laryngeal and hypopharyngeal carcinoma: outcome and review. Acta Otorhinolaryngol Ital 2015;35(3):162-72. [44] Hasan Z, Dwivedi RC, Gunaratne DA, Virk SA, Palme CE, Riffat F. Systematic review and meta- analysis of the complications of salvage total laryngectomy. Eur J Surg Oncol 2017;43(1):42-51. [45] Guimarães AV, Aires FT, Dedivitis RA, Kulcsar MA, Ramos DM, Cernea CR, et al. Efficacy of pectoralis major muscle flap for pharyngocutaneous fistula: A systematic review. Head Neck 2016;38(Suppl 1):E2317-21. [46] Chen MM, Holsinger FC, Laccourreye O. Salvage conservation laryngeal surgery after radiation therapy failure. Otolaryngol Clin North Am 2015;48(4):667-75. [47] Zhong A, Xu X, Fan H, Wang L, Niu Y. Transoral laser microsurgery for recurrent laryngeal carcinoma after primary treatment: A systematic review and meta-analysis. J Cancer Res Ther 2015;11(Suppl 2);173-8. [48] Bots WTC, van der Bosch S, Zwijnenburg EM, Dijkema T, van den Broek GB, Weijs WLJ, et al. Reirradiation of head and neck cancer: Long‐term disease control and toxicity. Head Neck 2017;39(6):1122-30. [49] Awan MJ, Zakem SJ, Ward MC, Machtay M, Riaz N, Caudell JJ, et al. Reirradiation outcomes after upfront larynx preservation or total laryngectomy: a multi-institutional analysis. Int J Radiat Oncol Biol Phys 2016;96(2):E376. [50] Vermorken JB, Mesia R, Rivera F, Remenar E, Kawecki A, Rottey S, et al. Platinum-based chemotherapy plus cetuximab in head and neck cancer. N Engl J Med 2008;359(11):1116-27. [51] Vartanian JG, Carrara-de-Angelis E, Kowalski LP. Practice of laryngectomy rehabilitation interventions: a perspective from South America Curr Opin Otolaryngol Head Neck Surg 2013;21(3):212-7.

Chapter 6

MANAGEMENT OF NON-SMALL CELL LUNG CANCER IN LATIN AMERICA

Rafael Caparica1,*, MD, Flavia Carolina Gabrielli2, MD, Pedro H Nabuco de Araujo2, MD, Ricardo Mingarini Terra2, MD, PhD, Fiona Lim3, MBBS, Bo Angela Wan4, MD(C), Lavoisier Fragoso de Albuquerque5, MD and Mauricio F Silva6,7, MD, PhD 1Institut Jules Bordet, Universite Libre de Bruxelles, Belgium 2Instituto de Câncer do Estado de São Paulo (ICESP), São Paulo, Brazil 3Department of Oncology, Princess Margaret Hospital, Hong Kong, PR China 4Odette Cancer Centre, Sunnybrook Health Sciences Centre, Toronto, Ontario, Canada 5Radiation Oncology Unit, Hospital Santa Catarina, São Paulo, Brazil 6Radiation Oncology Unit, Santa Maria Federal University, Santa Maria, Brazil 7Hospital de Caridade Astrogildo de Azevedo, Santa Maria, Brazil

ABSTRACT

Non-small cell lung cancer is the leading cause of cancer deaths globally and also in Latin America. Several treatment strategies are available, such as surgery and radiotherapy for early-stage disease, and chemotherapy, immunotherapy and targeted therapies for metastatic patients. The decision on which treatment is more appropriate for an individual patient depends on performance status, comorbidities, tumour staging, availability of resources, and risk of toxicities. A multidisciplinary approach involving medical oncologists, surgeons, radiation oncologists, respiratory medicine specialists and palliative care doctors is crucial for successful treatment of NSCLC. This chapter will discuss the main treatment strategies for NSCLC in Latin America, focusing on the limitations, singularities, and perspectives of NSCLC treatment in this region.

* Corresponding Author’s Email: [email protected]. Complimentary Contributor Copy 54 Rafael Caparica, Flavia Carolina Gabrielli, Pedro H Nabuco de Araujo et al.

INTRODUCTION

The incidence of Non-small cell lung cancer (NSCLC) is increasing all over the world, including in Latin America. In Brazil, 28,000 new cases are diagnosed every year, with 25,000 deaths attributable to NSCLC annually (1). The treatment of NSCLC is based on disease staging, with a multidisciplinary approach involving surgery, radiotherapy and systemic treatment being frequently necessary. The present chapter aims to review the standard-of-care treatment of NSCLC, and explore the singularities, limitations, challenges and patterns of care of NSCLC patients in Latin America, with a main focus in Brazil, where most of the authors practice.

SURGICAL TREATMENT

According to the Brazilian National Cancer Institute and the Sao Paulo State Cancer Registry estimates, around 2,400 new cases of Stage 1 and 1,700 cases of stage II NSCLC are diagnosed every year in Brazil (1, 2). Therefore, around 4,100 NSCLC patients are potential candidates for surgical treatment annually. We do not have precise data about the number of surgeries performed to treat lung cancer in Latin America; however, a federal Brazilian database (DATASUS) can provide us a rough estimation (3). According to DATASUS, the median number of pulmonary lobectomies and lumpectomies performed during the last seven years in Brazil was 964 procedures/year (3). This estimation needs to be interpreted with caution. First, lobectomies and lumpectomies could have been performed for diseases other than primary lung cancer, such as metastasis, inflammatory or infectious diseases. Second, they stand only for patients seen under the public national health system, which covers 75% of the Brazilian population, while the remaining patients have private health insurances and might not be accounted for in this database. Finally, there is concern about missing data and under reporting of procedures performed in remote and rural regions. If we do not account the 25% of patients with private health insurances, we would expect around 3,000 patients with potentially resectable lung cancer annually based on an estimation of cancer incidence in the whole population. Nevertheless, only at most about 1,000 would undergo surgery (as pointed out above). This significant discrepancy suggests that many patients with potentially resectable disease are not being treated with surgery, which is the gold standard according to international guidelines (NCCN, ACCP) (4, 5). Data from the Sao Paulo Registry confirms such finding: only 61% of patients diagnosed with stage 1 disease underwent surgical treatment (2). Access barriers to the appropriate treatment represent another issue. In analyzing Sao Paulo’s Registry data, we observe that patients with lower educational level are less likely to receive surgical treatment (2). Despite the fact that the website provides us with unadjusted data, and probably some bias, the difference between analphabet/basic education patients and those with high school and college is high. Moreover, such a finding is well established in international literature (6). Educational level can be used with some limitations as a surrogate for social status level. In a meta-analysis of twelve studies, the authors identified odds of 0.68 of receiving surgery in patients with low versus high socioeconomic status (7). Complimentary Contributor Copy Management of non-small cell lung cancer in Latin America 55

Apart from socioeconomic disparities, geographic distribution of medical facilities is also a factor that influences the number of procedures performed. Currently, there are around 900 thoracic surgeons in Brazil, who are mostly concentrated in the South and Southeast regions of the country, especially in capitals and large cities (8). In a recent survey conducted by the Brazilian Society of Thoracic Surgery, 51% of the participants declared to practice in cities with more than 1 million inhabitants (9). Therefore, even though the absolute number of thoracic surgeons in Brazil is adequate, their distribution is very heterogeneous. Another issue is the availability of video assisted thoracic surgery (VATS), a technique that is gaining importance in Brazil. In a recent survey by the Brazilian Society of Thoracic Surgery, 70% of the respondents declared they started their minimally invasive surgery program, including anatomic lung resections (10). However, the disposable devices needed for these surgeries are not routinely available in the public national health system. Thus, access to this modern technique is quite limited, mostly restricted to patients with private health insurances and some public university hospitals. In conclusion, the low percentage of early-stage NSCLC patients undergoing surgical treatment for lung cancer in Brazil is probably a consequence of unequal distribution of thoracic surgeons and resources. These issues need to be the focus of future health interventions in order to increase the number of patients that receive appropriate treatment.

RADIOTHERAPY

The radiation therapy (RT) scenario in Brazil is quite difficult to be evaluated since there are no high-quality data regarding cancer incidence for both public and private practices, and no official report regarding the status of RT facilities available, concerning techniques, waiting lines and number of patients treated. A recently conducted survey by the Brazilian Society for Radiation Oncology shows that most of the RT facilities are concentrated in the Southeastern part of the country whereas there are states in the Northern regions without a single facility (see table 1) (11). This information reflects the challenges faced by patients to have access to oncologic treatments. The World Health Organization (WHO) recommends one Linear Accelerator per 250,000-300,000 inhabitants. The impact of the lack of RT facilities in Brazil can be predicted by the evaluation of this ratio from region to region according to table 2, which shows that Brazil owns a little more than half of the necessary RT facilities (12).

Table 1. Distribution of RT facilities across Brazil

Region Size (km2) Population (millions) Linear accelerators Cobalt units Middle west 1,612,077 16 20 4 Northeast 1,556,001 50 62 4 North 3,869,638 16.3 16 2 Southeast 927,286 80 202 20 South 575,316 26 71 5 Total 8,516,000 207 371 35

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Table 2. Number of linear accelerator units per 300,000 inhabitants in Brazil regions in 2017

Region Linear Accelerator Units per 300,000 inhabitants Middle west 0.40 Northeast 0.33 North 0.40 Southeast 0.72 South 0.74 Brazil 0.55

Surgery plays a major role on early-stage patients treated with curative intention; however, less than a third of NSCLC patients are considered eligible for surgery, either because of locally advanced disease or due to the presence of comorbidities and low performance status. On the other hand, RT is an integral part of the multidisciplinary treatment for NSCLC, since patients with all disease stages can potentially benefit from it (13). If we take into account the fact that many of metastatic NSCLC patients will present bone and central nervous system disease that will require palliative RT, one can say that the lack of RT facilities could be associated with worse oncologic outcomes for those patients, including decreased quality of life. Not only are RT facilities lacking in Brazil, but the existing ones are concentrated in large centers. This is also an important issue for the 5th largest country in the world, since patients need to leave their homes for treatments that can last as long as 6 to 7 weeks and the travel distance or time required are barriers for receiving the appropriate RT treatment (14-16). Patients seeking for a RT treatment also usually face overbooked facilities with long waiting lists. In 2010, the mean time between the first appointment with a radiation oncologist and treatment start was around 114 days (11). Once again, the scenario can be even worse now, since just a few linear accelerators were added in the country despite a total of 420,000 new cases of cancer in Brazil annually (excluding non-melanoma skin cancer). Due to all those factors, around 90,000 patients that should receive RT end up without treatment. The incidence of cancer in Brazil is increasing around 5% per year, which may be explained by an increase in reporting and diagnosing. Either way, the number of patients without access to RT on the upcoming years is expected to increase (17). Stereotactic Body Radiation Therapy (SBRT) is a relative new technology but can be considered an option for patients with clinically inoperable early stage disease (18). SBRT is another issue pertaining to the RT situation in Brazil, since the technique is neither included on the public health list of RT procedures nor on the reimbursement list for private practice at present date. Therefore, only a few centers in the country can perform the procedure. Most of the medical and physicist residents in training do not have any experience with this technique, making it difficult to find trained staff to work in these scarce facilities. The exact small number of RT centers able to perform SBRT in Brazil is unknown, as is the number of patients who do not receive this treatment. In this situation, those patients remain treated by tridimensional conventional fractionation RT, with 5-year survival rates around 30% (19). In conclusion, the RT scenario in Brazil is quite challenging. Not only there is a lack of RT facilities throughout the country, but they are concentrated in a few centers. Technology availability is also another issue, since most patients are unable to perform SBRT, which is an

Complimentary Contributor Copy Management of non-small cell lung cancer in Latin America 57 important tool for early stage patients who are candidates for curative treatment. The lack of RT facilities in Brazil jeopardizes the treatment of NSCLC patients and should be considered a priority for health system investments over the next years in order to reduce disparities and improve patients’ outcomes.

ADJUVANT TREATMENT

We define adjuvant treatment as the one administered after surgical resection of NSCLC (20). Around 40-50% of stage Ib, 55-70% of stage II, and 80% of stage IIIa patients will present disease recurrence after surgery, despite a clear resection with adequate margins and no residual disease (R0) (21). The high recurrence rates may be explained by the fact that, in most cases, microscopic metastatic disease is already present at diagnosis. Adjuvant therapy aims to eliminate micro-metastatic disease, reducing the chances of disease recurrence and hence increasing patient survival.

Indications

In Latin America, in agreement with international guidelines on the management of early- stage NSCLC, adjuvant treatment is indicated in patients considered at high risk of recurrence, including stages II to IIIA (tumors > 5cm, and/or regional nodal metastases - N1 or higher) (4, 22, 23). In patients with tumors ranging from 4 to 5 cm, despite not being widely accepted, adjuvant treatment can be consideredasis(24).

Adjuvant treatment regimens

Adjuvant treatment consists of platinum-based chemotherapy for 3 to 4 cycles. The most frequently used regimens are Cisplatin + Vinorelbine and Cisplatin + Pemetrexed (for non- squamous histology) (24, 25). Adjuvant chemotherapy provides an absolute improvement of 5.4% in 5-year overall survival rates when compared to placebo (24). The benefit provided by adjuvant chemotherapy is significant, albeit modest, thus the decision on which patient should receive adjuvant chemotherapy must be individualized, and in accordance with patients’ expectations, performance status and comorbidities. Indeed, the risk of toxicities must be considered, especially for patients with advanced age, low nutritional status or poor performance status. The most frequent toxicities are nausea and vomiting, hematological toxicities, diarrhea, mucositis, peripheral neuropathy, and nephrotoxicity (24).

NEOADJUVANT TREATMENT

Neoadjuvant treatment is the one administered before surgical resection of NSCLC. The potential benefits of this strategy include:

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1) Evaluation of tumor´s response to treatment in vivo. 2) Reduce tumor burden and volume, facilitating a clear surgical resection. 3) Early initiation of systemic treatment aiming to eradicate micro metastases.

Indications

Neoadjuvant treatment provides an overall survival improvement of the same magnitude as the one provided by adjuvant therapy (26). However, neoadjuvant treatment is not routinely used for the following reasons:

 Response rates to chemotherapy (defined as a reduction of at least 30% in the sum of the diameters of measurable tumor lesions) are around 30%, which means most patients will not achieve tumor down-staging with treatment. Moreover, disease progression can occur during neoadjuvant treatment, jeopardizing the chances of a curative surgical intervention (26).  Indication for neoadjuvant treatment is based on clinical staging and imaging studies, which are less accurate than pathological staging (21).  Neoadjuvant chemotherapy can induce inflammatory responses and fibrosis at the tumor site, which may compromise surgical resection with adequate margins (26).

Due to the reasons mentioned above, surgery followed by adjuvant treatment represents the standard-of-care treatment of early NSCLC in most cases (5, 24).

SYSTEMIC TREATMENT

Metastatic disease is defined by the presence of tumor cells in sites non-contiguous to the primary tumor. NSCLC patients can present metastases at diagnosis or develop metastatic disease at recurrence. The most frequent sites of metastases are bone, liver, adrenals, lymph nodes, pleura and lungs (21). Treatment of metastatic disease is not curative, although it is effective in prolonging overall survival, reducing symptoms and improving quality of life (27).

Table 3. Eastern cooperative oncology group (ecog) performance status scale

ECOG performance status (28) Definition 0 Asymptomatic, performs all activities without assistance. 1 Presents symptoms related with the disease, but can walk and perform daily activities. 2 Presents symptoms related with the disease, with limitations, staying in bed less than 50% of the time. 3 Presents symptoms related with the disease, with limitations, staying in bed more than 50% of the time. Needs assistance for daily activities. 4 In bed all the time, incapable of any activity without assistance.

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Indications

Systemic treatment should be considered for every patient with a performance status on the Eastern Cooperative Oncology Group scale (ECOG) ≤2 (see table 3) (28). In situations where a high probability of response is expected, therapy can be considered even for patients with ECOG 3, such as in the case of patients with tumors harboring actionable target mutations/rearrangements including ALK (anaplastic lymphoma kinase) or EGFR (epidermal growth factor receptor) (29). In patients with low disease burden, for example those with pulmonary nodules or adrenal metastases, treatment initiation can be delayed until patient develops symptomatic disease. However, as NSCLC is a disease usually associated with rapid progression, watchful waiting is considered an exception and should only be considered after discussing the risks and benefits of this strategy thoroughly with patients.

Factors to be considered in the choice of the initial treatment

NSCLC is subdivided according to morphological and histological characteristics, the most frequent subtypes being adenocarcinoma (50%), squamous-cell carcinoma (35-40%) and large cell carcinoma (3-5%) (30). In Latin America, around 30% of adenocarcinomas harbor genomic alterations (ex. mutations, amplifications, translocations and rearrangements) that confer sensibility to specific drugs, defined as ‘driver mutations’ (31, 32). Also, around 30% of NSCLC patients present with a high (>50% of the tumor cells) expression of the protein PDL-1 (programmed death ligand 1), which binds to the receptor PD1 at the T lymphocytes, thus inducing T cell suppression and immune evasion (33). The histological subtype (squamous or non-squamous), the presence of a driver mutation, and the level of PDL1 expression (> 50% or < 50%) are the main factors analyzed to choose the most appropriate initial therapy for NSCLC patients. On the following topics, we will discuss in detail the treatment modalities available for the systemic treatment of NSCLC in Brazil, according to patient’s characteristics.

Chemotherapy

For the squamous subtype without elevated PDL1 expression (50%), and the non-squamous NSCLC without driver mutations and without elevated PDL1 expression, chemotherapy is still treatment’s cornerstone. Platinum doublets are more efficient than single-agent therapies (27). The most frequent chemotherapy regimens include the combinations of cisplatin or carboplatin with another agent (gemcitabine, paclitaxel, vinorelbine, or docetaxel), with response rates ranging from 30-40% (34). In observational studies and cohorts, median overall survival for metastatic NSCLC patients exclusively in best supportive care is around five months, whereas chemotherapy improves median overall survival to 10-11 months (27). In terms of efficacy, there is no proven difference between cisplatin and carboplatin; however, both drugs have different toxicity profiles, with cisplatin presenting more nephrotoxicity, nausea and neuropathy, and carboplatin presenting more hematological toxicities. These factors should be considered to choose the more appropriate treatment for an individual patient (35). All platinum doublets mentioned above are appropriate for first-line Complimentary Contributor Copy 60 Rafael Caparica, Flavia Carolina Gabrielli, Pedro H Nabuco de Araujo et al. treatment, with the choices guided by their different toxicity profiles, local expertise and guidelines, and costs. Pemetrexed is a drug that exerts its effect by blocking the cellular metabolism of folate in tumor cells (36). Randomized phase 3 trials have demonstrated pemetrexed to be more active in combination with platinum compounds for the non-squamous subtypes of NSCLC. Also, it had a favorable toxicity profile with low incidences of grade 3 and 4 adverse events, the most frequent ones being hematological, nausea, diarrhea and mucositis (36, 37). Therefore, pemetrexed is considered the preferred drug to combine with carboplatin or cisplatin for non- squamous histology.

Duration of chemotherapy

Chemotherapy shall be administered for 4 to 6 cycles. There is no demonstrated benefit in extending treatment beyond the fourth cycle; however in specific situations where clinical benefit exists and patients are not experiencing significant toxicities, we might consider extending treatment until six cycles (38). Baseline staging should be obtained before treatment, and then repeated every 2 or 3 cycles to assess treatment response. For the non- squamous subtypes, maintenance treatment with single agent pemetrexed given as a single- agent every 3 weeks after the fourth cycle of doublet treatments is indicated until disease progression or limiting toxicities, given the demonstrated survival benefit of this strategy (39). For squamous tumors, no maintenance treatment is recommended, and regular follow-up visits with imaging every 2 to 3 months are performed. In case disease progression or severe toxicities occur during treatment, an interruption in maintenance treatment followed by a switch to second-line treatment must be considered.

Antiangiogenic agents

Bevacizumab is a monoclonal antibody that targets the A subunit of vascular endothelial growth factor (VEGFa) (40). VEGF is involved in angiogenesis, a crucial process for tumoral growth and development (41). For non-squamous patients, the addition of bevacizumab to chemotherapy (carboplatin and paclitaxel) has yielded response rates of 35% versus 15% and an improvement in overall survival from 10.3 to 12.3 months in a randomized phase 3 trial when compared with chemotherapy alone (42). Due to the aforementioned results, bevacizumab plus carboplatin and paclitaxel is one of the accepted regimens for the first line treatment of non-squamous NSCLC. Bevacizumab is not recommended for squamous tumors, due to a high risk of bleeding and hemoptysis observed in preliminary studies (43).

MOLECULAR TARGETED THERAPIES

Although possessing similar morphological and histological features, lung adenocarcinomas comprise a heterogeneous group of tumors that harbor unique genetic features (mutations, base insertions or deletions, gene rearrangements, chromosomal translocations, and

Complimentary Contributor Copy Management of non-small cell lung cancer in Latin America 61 amplifications) (44). Frequently, tumor cells are dependent on the genomic alterations described above to acquire an evolutionary advantage that promotes tumor growth and cell division, with these mutations driving tumor progression, therefore being called “driver mutations”. Drugs that specifically target some of these altered pathways are available (for example EGFr and ALK) (45). To adequately diagnose these genomic alterations, it is crucial to obtain adequate tumor tissue samples not only for histological diagnosis, but also for DNA sequencing to seek for driver mutations (46). Blood sampling and detection of tumor genomic abnormalities on circulating tumor DNA (ctDNA) is a promising alternative to avoid tissue biopsies for obtaining tumor samples for genetic testing (47). Liquid biopsy presents high specificity and positive predictive values, and a positive test is considered enough to confirm the presence of an EGFr mutation without the need of performing a confirmatory tissue biopsy (47). The sensitivity of liquid biopsies is around 70% and the specificity is superior to 90% when compared to gold standard tumor tissue sampling. As so, a negative blood screen does not exclude the presence of an EGFr mutation, and tissue sampling is recommended to continue diagnostic investigation. However, an EGFr mutation detected by ctDNA is enough to establish the diagnosis and to start a targeted therapy for EGFr mutant NSCLC, given the high positive predictive value of this technique (47).

EGFr mutation

Epithelial growth factor (EGF) is a growth factor that stimulates cell division and angiogenesis in normal epithelial cells. When EGF binds to its receptor (EGFr), it activates signaling pathways that lead to cell proliferation, angiogenesis and invasiveness (48). In Brazil, around 25% of non-squamous NSCLC harbor a mutation in the EGFr gene that turns the receptor into a permanent active state, independently of EGF binding (31, 49). In Europe and USA, the prevalence of EGFr mutation is around 15%, and in Asia it is as high as 60% in some populations (32, 50). It is mandatory to test all non-squamous NSCLC patients for EGFr mutations as soon as possible, since it impacts directly on treatment decisions (46). In Brazil, sometimes it can be difficult to have access to the test since it is not widely available, especially at the poorest regions with lack of facilities and expertise to perform the test at the public health system. Moreover, EGFR tyrosine kinase inhibitors are not uniformly available in all regions of Latin America at the public health systems. EGFr pathway blockade by tyrosine kinase inhibitors (TKIs) significantly improved progression-free survival when compared to chemotherapy in the first line setting (10-12 months versus 5-6 months) and response rates (60-70% versus 30-40%) at several randomized phase 3 trials and meta-analysis (51, 52). For patients harboring EGFr mutations, it is highly recommended to start treatment with an EGFr inhibitor. In cases where mutation test results are only available after a patient has been started on chemotherapy, it is recommended to evaluate each case individually but generally maintain chemotherapy until the fourth cycle if clinical benefit is present and no serious adverse events are occurring. Tyrosine kinase inhibitors shall then be initiated as a maintenance therapy immediately after the last cycle of chemotherapy, until disease progression (53).

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At the present date, three EGFr tyrosine kinase inhibitors (TKI) are approved in Brazil: gefitinib, erlotinib and afatinib. There is no evidence that demonstrates the superiority of one drug over another. As so, all three drugs are considered appropriate options to treat NSCLC patients harboring EGFr mutations (4, 54). The main side effects associated with EGFr TKIs are acneiform rash, diarrhea and paronychia. The overall frequency of grade 3 or higher toxicities are lower than that observed in chemotherapy, with TKIs presenting a more favorable toxicity profile (51, 52).

ALK rearrangement

The anaplastic lymphoma kinase gene (ALK) encodes a protein that is important during human embryogenesis, but with no known function in normal adult cells (55, 56). In 3-4% of lung adenocarcinomas, a chromosomal rearrangement occurs, leading to DNA sequence translocations, with a promoter sequence (DNA region that signals for the transcription of the gene that is ahead of it) being inserted just before the ALK gene. This rearrangement leads to the transcription of the ALK gene, generating elevated levels of ALK, which stimulates cell cycle, proliferation, mitosis, and angiogenesis (57, 58). ALK rearrangement can be diagnosed by DNA sequencing, in-situ hybridization methods or immunohistochemistry (21, 47). The access to diagnostic methods of molecular biology is not widely available in Brazil, especially in rural areas and in the public health system. ALK blockade through specific TKIs leads to high response rates and improvement in progression free-survival in comparison to chemotherapy in ALK positive NSCLC in the first-line setting (59). The only TKI approved for this indication in Brazil at present date is crizotinib. Other molecules targeting ALK such as brigatinib, ceritinib and alectinib have already demonstrated superior results compared to crizotinib on recent clinical trials, but they have not been approved in Brazil yet (60-62).

Alternative driver mutations

In NSCLC, several other mutations or genomic abnormalities other than EGFr and ALK have been described, such as KRAS mutation (30%), ROS1 translocation (1%), MET amplification (1%), BRAF (2%), HER2 (3%), FGFR (4-5%), NTRK (1-2%) (44). In all of these examples, mutations lead to abnormal and constant activation of intracellular pathways leading to cell growth, tumor proliferation and angiogenesis. For all these driver mutations, there are molecular targeted therapies (TKIs or antibodies) under development and testing on clinical trials, with promising results on phase 1 and 2 trials (45, 63).

Immunotherapy

Immunotherapy exerts its effects by enhancing the host’s immune response, allowing the recognition of tumor cells as “non-self” to generate an immune response against the tumor (64).

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Nivolumab and pembrolizumab are synthetic antibodies that target the PD1 receptor expressed on the T lymphocytes. Activation of PD1 through the binding of its ligands (PDL1 and PDL2) generates negative stimuli over T cells, which inhibits the development of an effective immune response. NSCLC cells are capable of producing and expressing PDL1 that binds to PD1 on the lymphocytes and ultimately compromises the host’s immune response, in a phenomenon known as tumoral immune evasion (65). Immunotherapy, through the blockade of PD1 or PDL1, avoids the T lymphocyte to receive a negative stimulus from the tumor, thereby the T cell can effectively recognize tumor cells as a “non-self” structure and start the immune response (65). In randomized phase 3 trials involving NSCLC patients that have failed first-line treatment with platinum doublets, nivolumab and pembrolizumab have independently demonstrated superiority over second-line chemotherapy docetaxel, with significant improvements in overall survival and response rates ranging from 20-30% (66-68). Moreover, among patients who respond to immunotherapy, the median duration of response is superior to 12 months (69). Based on these results, pembrolizumab and nivolumab are the two immunotherapies approved in Brazil for NSCLC on the second-line setting as of the present date. Immunotherapy with pembrolizumab is also a first-line treatment option for patients presenting with high PDL1 expression at tumor samples, defined as >50% of tumor cells evaluated by immunohistochemistry. On a randomized phase 3 trial, pembrolizumab was compared to chemotherapy with platinum doublets at the first-line setting, with a significant improvement in overall survival and response rate in favor of pembrolizumab (33). It is noteworthy that the prevalence of patients with high PDL1 expression >50% is around 30% of NSCLC, so for the majority of patients, immunotherapy will still not be an option for the first-line treatment. It is fundamental to obtain adequate tumor sampling to perform PDL1 expression testing combined with DNA sequencing for driver mutations.

Third line treatment

The therapies approved at the third-line setting in Brazil are docetaxel, pemetrexed and erlotinib. Treatment duration will depend on the responses obtained and the toxicities presented with previous lines by each patient. Overall response rates range from 7 to 15%, with modest improvements in overall survival when compared to placebo (70, 71). For patients that do not harbor an EGFr mutation, erlotinib does not demonstrate any benefit when compared to docetaxel (72, 73).

Subsequent lines of treatment

After the third line, there are no therapies with a proven benefit in overall survival, and the standard of care should be best supportive care and symptom management. Some drugs have demonstrated activity in this scenario in small phase 2 trials or case series, and can be an option for selected cases, for example patients with ECOG 0 or 1 that have responded to previous lines of chemotherapy and are willing to tolerate the risks of an additional line of chemotherapy (74, 75).

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CONCLUSION

The main therapeutic modalities that are available for NSCLC treatment in Brazil have been reviewed in the present chapter. Systemic treatments have evolved largely over the last decade, being successful in alleviating symptoms, improving quality of life and increasing survival of NSCLC patients. Immunotherapy and molecular targeted therapies represent new cornerstones to lung cancer treatment, but unfortunately they are still not widely available in Latin America, especially in rural areas and poorer regions. New treatment strategies are necessary to improve the success rates and overcome resistance mechanisms. Investments on smoking cessation, lung cancer prevention, increasing the availability of diagnostic tests and ensuring adequate access to treatments including surgery, radiotherapy and systemic treatment are fundamental for Brazil and Latin America in the future years to improve patient’s well-being and quality of life in face this disease.

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Chapter 7

MANAGEMENT OF ESOPHAGEAL CANCER

Julio Pereira-Lima1,*, MD, PhD, Michele Bonotto1, MD, Julio Cesar Razera1, MD, Fiona Lim2, MBBS, Bo Angela Wan3, MD(C) and Mauricio F Silva4,5,6, MD, PhD 1Gastroenterology Department, Federal University of Health Sciences/Santa Casa de Porto Alegre, Porto Alegre, Brazil 2Department of Oncology, Princess Margaret Hospital, Hong Kong, PR China 3Odette Cancer Centre, Sunnybrook Health Sciences Centre, Toronto, Ontario, Canada 4Radiation Oncology Unit, Santa Maria Federal University, Santa Maria, Brazil 5Hospital de Caridade Astrogildo de Azevedo, Santa Maria, Brazil 6Latin America Cooperative Oncology Group

ABSTRACT

Esophageal cancer is among the eighth and ninth most common malignant neoplasms in the world, with a mortality rate of approximately 16/100,000(the sixth cause of cancer- related deaths). According to the American Cancer Society, at least 17,000 new cases are estimated in the United States for 2018, with 15,000 related deaths. In Latin America, the highest incidence is recorded in Argentina, Brazil, Paraguay and Uruguay (around 10- 12/100,000). We performed a Medline search of the manuscripts published in the last 10 years (January 2008 to June 2018). The results are described in this review.

INTRODUCTION

Esophageal cancer is among the eighth and ninth most common malignant neoplasms in the world, with a mortality rate of approximately 16/100,000(the sixth cause of cancer-related deaths) (1-3). According to the American Cancer Society, at least 17,000 new cases are estimated in the United States for 2018, with 15,000 related deaths. In Latin America, the highest incidence is recorded in Argentina, Brazil, Paraguay and Uruguay (around 10-

* Corresponding Author’s Email: [email protected]. Complimentary Contributor Copy 70 Julio Pereira-Lima, Michele Bonotto, Julio Cesar Razera et al.

12/100,000) (4). In Brazil, the National Cancer Institute (Instituto Nacional do Câncer - INCA) forecasts just over 10,000 new cases for the same period. In Rio Grande do Sul, the Brazilian state with the highest rates of esophageal neoplasia, the incidence is of 13/100,000 among men (5). Despite the advances in endoscopic, surgical and oncological treatment, the prognosis is still limited (mean survival time of 8.1 months) (2). Risk factors for squamous cells cancers include high temperature teas consumption (such as mate in South America and other teas in Iran), smoking and alcohol consumption, male gender, older age and some diseases such as achalasia, tylosis, Plummer-Vinson syndrome, personal history of lung and head and neck cancer, corrosive esophagitis and HPV infection. For esophageal adenocarcinoma, gastro-esophageal reflux disease and Barrett’s esophagus are the main risk factors alongside with obesity, smoking and alcohol playing a minor role (6-8).

OUR SEARCH

We performed a Medline search of the manuscripts published in the last 10 years (January 2008 to June 2018) using the following search terms in title and abstracts: 1-esophageal cancer, 2-esophageal neoplasia, 3-therapy 4-endoscopic treatment. We limited the search literature to published studies in English, Spanish and Portuguese which returned more than 1000 publications. Studies were selected according to the interest of this book chapter, resulting in a total of 32 studies.

OUR FINDINGS

The molecular biology associated with the development of esophageal cancer is similar to other neoplasms. The main processes involved are hyperexpression of growth factors, attenuation of antiproliferative mechanisms, apoptosis dysregulation, unrestrained cell replication, neoangiogenesis, among others (7). Until the 1960s, Squamous Cell Carcinoma represented about 90% of esophageal malignancies; however, there was a significant increase in the incidence of Adenocarcinoma in Europe and USA in the last two decades. While cases of adenocarcinoma increased dramatically in the United States, southern parts of South America and Western European countries, squamous cell cancers is still as prevalent as 30-40 years ago in countries such as Iran, China, Eastern Europe and Africa (1, 9, 10). For instance, in the southernmost state of Brazil, adenocarcinomas accounted for less than 3% of esophageal cancers in the 60’s and increased to 15% in the 90’s (5).

CLINICAL CONDITION

Early stages of the disease usually do not cause symptoms, which makes early diagnosis difficult. Symptoms appear in advanced disease, when the lesion affects most of the esophageal lumen (luminal diameter less than 13mm or roughly half of the circumference). As for topography, squamous cell carcinoma usually occurs in the middle third of the Complimentary Contributor Copy Management of esophageal cancer 71 esophagus; while adenocarcinoma usually occurs in the distal third (esophagogastric junction) (10). The most common symptoms are progressive dysphagia (gradually from solids to liquids) and disproportionate weight loss. Lack of appetite, anemia, gastrointestinal bleeding, odynophagia, recurrent vomiting, aspiration, and tracheobronchial fistulas may also occur. On physical examination, excessive salivation, malnutrition, cervical adenopathies, changes in pulmonary auscultation suggestive of bronchoaspiration and others may be present (6, 11). Differential diagnosis include esophagitis, achalasia, esophageal motor disorders, head and neck neoplasms, and benign esophageal strictures (6).

ENDOSCOPIC TREATMENT

Endoscopic therapy is used broadly in the extreme spectrum of esophageal cancer, i.e., in patients with intramucosal carcinoma as the gold standard or in patients with advanced cancer, mainly when other therapies have failed or are unfeasible. Endoscopic therapy with curative intent is the treatment of choice in tumors staged T1a (M1-intraepithelial, M2-with lamina propria invasion, and M3-with muscularis mucosa invasion). Early esophageal cancers are intramucosal, as opposed to early gastric cancers that could invade the submucosa and still be considered early carcinomas. Submucosal invasion is a contra-indication for endoscopic treatment with curative intent in esophageal neoplasias, since even SM1 neoplasias have a chance of lymph node metastases of at least 20% (12). Therefore, the need for accurate staging via en bloc tissue sampling. Early-staged carcinomas are detected through Barrett’s esophagus surveillance or found incidentally during endoscopies performed for other reasons or in lugol chromoendoscopy for patients with head and neck cancers or achalasia. There are two methods of endoscopic resection – endoscopic mucosal resection (EMR) and endoscopic submucosal dissection (ESD). There are a plenty of techniques for performing ESD or EMR, which are beyond the scope of this manuscript. EMR is preferred for targeted areas of up to 1-1.5 cm and ESD for larger areas, since areas > 2 cm will certainly require piece-meal resection when employing the EMR technique. ESD is not commonly performed in the Americas and in Europe and is widely used, even for small lesions, in Asia. In a metanalysis of 8 Asian studies, Guo et al. found that ESD is superior to EMR irrespective of lesion size (<2cm or >2cm) in terms of en bloc resection rate, curative resection rate (although with significant heterogeneity) and local recurrence rate, albeit with significant higher rate of complications (especially perforation) and procedure time (13). These Asian studies evaluated patients with squamous cell carcinoma. Endoscopic treatment of early esophageal cancer has been shown to present similar cancer-free survival as surgical therapy, with significant short and long-term lower morbidity and costs than classical surgical management. Despite advances in diagnosis and therapy, more than 50% of esophageal cancers are incurable at presentation, and the 5-year survival rate is below 10%. A large number of options are available for the palliation of unresectable esophageal cancer. Lumen obstruction and tracheoesophageal fistula formation are frequent complications alongside with malnutrition, weight loss and pulmonary infections. When considering palliation is very important to include patient, family and caregivers in the decision making. Stenting is the

Complimentary Contributor Copy 72 Julio Pereira-Lima, Michele Bonotto, Julio Cesar Razera et al. mainstay of endoscopic palliation. It allows the introduction of fully covered or partially covered stents through a malignant stricture or covering a fistula and re-establishing oral diet (14). Stent complications include migration, tumor ingrowth or overgrowth, bleeding, fistulisation, perforation and intolerable chest pain (14). Other indication of endoscopic stenting in esophageal cancer is to use it as a bridge to chemotherapy/radiotherapy in special situations. Other endoscopic options for palliation include dilation, enteral feeding and ablative or chemical debulking. Metal stenting is by far the best endoscopic choice. In a recent published Cochrane review including 3684 patients from 53 randomized studies evaluating different palliative interventions, the authors concluded that stent insertion was safer, more effective and quicker in palliating dysphagia than other methods (15). A suitable palliative alternative is high-dose intraluminal brachytherapy, which may provide an additional survival benefit. Furthermore, the combination of brachytherapy and stenting or radiotherapy reduced the requirement for reinterventions. And newly designed stents (Double-layered nitinol stents) led to longer survival and fewer complications (16). Another metanalysis comprising 250 patients and 6 studies showed that Double layer covered stents provides immediate relief of malignant dysphagia with a lower complication rate than covered or partially covered stents (16-18). Moreover, to reinforce the value of metal stenting for treating these cases, a multi-center randomized trial with 160 patients comparing conventional metal stents with 125I seeds -loaded stents demonstrated a median overall survival benefit in the irradiation group (177 vs. 147 days, p = 0.0046), and the same complication rate (19). Fortunately, most of these complications are within the control of the endoscopist and can be managed conservatively by inserting a second stent or by repositioning the migrated stent. Stent complications are related to the level of obstruction. Stents deployed in the proximal third of the esophagus are more hazardous than those placed more distally. In the experience of Verschuur et al., stents were effective for palliation of dysphagia in 104 patients with malignant stricture close to the upper esophageal sphincter, and although major complications (e.g., aspiration pneumonia, hemorrhage, fistula, perforation) occurred in 21% of the patients, no procedure related mortality was reported (19). In a comparative study, bleeding occurred in 14% of patients whose stents were placed in the proximal third of the esophagus, but in none with stents placed more distally (20). To date, the safety of placing metal stents for patients with inoperable esophageal cancer who are undergoing chemotherapy and/or radiotherapy before or after stent placement remains controversial. Sumiyoshi et al. evaluated morbidity and mortality in patients with esophageal cancer and stent placement after chemoradiotherapy (21). Most individuals with tumor invasion of the aorta died of massive hemorrhage. Conversely, in the experience of Raijman et al. among patients with no previous chemotherapy or radiotherapy, the occurrence of complications was only 9.5% (22). On the other hand, among patients who received radiotherapy, chemotherapy, or both, life-threatening complications occurred in 8% of cases. Another study compared complications in patients who had undergone chemotherapy and radiation versus those who had not. The study involved 116 individuals. Early and late complications were more frequent in patients who had undergone chemotherapy or radiation (23% vs. 3.3%, P < .002; and 21.6% vs. 5%, P < 0.02, respectively) (23). To clarify this finding, a prospective study following 200 patients found that stent placement after radiation was safe and prior treatment was not a contraindication. Retrosternal pain after stent placement occurred more often in patients undergoing treatment; this pain needs to be

Complimentary Contributor Copy Management of esophageal cancer 73 adequately treated because it compromises quality of life in these patients and may be a cause of stent retrieval (24).

SURGICAL MANAGEMENT OF RESECTABLE ESOPHAGEAL AND ESOPHAGOGASTRIC JUNCTION CANCERS

Esophageal cancer presents as localized disease, defined as adenocarcinoma or squamous cell carcinoma confined to the esophagus, in approximately 22 percent of all cases (25). The goal of surgical management is curative, and a surgical resection is the traditional mainstay of multidisciplinary therapy for patients with localized disease (2). Treatment strategies for esophageal malignancies can conceptually be divided along two axes: locoregional treatment and systemic therapy (26). Each patient should be individually assessed based on the type of cancer, local, or regional involvement, and his or her own functional status to determine an appropriate treatment regimen. Surgery continues to play an important role in achieving locoregional control in patients with esophageal carcinoma and offers the best chance for cure in localized and locally advanced disease (27).

STAGING OF ESOPHAGEAL CANCER

TNM categories are judged clinically (cTNM) based on imaging studies, with minimal histologic information. This distinguishes them from pathologic cancer facts (pTNM) obtained by and large through microscopic examination of resection specimens. These TNM cancer facts (Table 1) are central to treatment decision-making and rely on cTNM being an accurate reflection of pTNM (27). Cancer staging categories for cancer of the esophagus and esophagogastric junction:

T category  TX Tumor cannot be assessed  T0 No evidence of primary tumor  Tis High-grade dysplasia, defined as malignant cells confined by the basement  membrane  T1 Tumor invades the lamina propria, muscularis mucosae, or submucosa  T1a*Tumor invades the lamina propria or muscularis mucosae T1b* Tumor invades the submucosa  T2 Tumor invades the muscularis propria  T3 Tumor invades adventitia  T4 Tumor invades adjacent structures  T4a*Tumor invades the pleura, pericardium, azygos vein, diaphragm, or peritoneum  T4b* Tumor invades other adjacent structures, such as aorta, vertebral body, or trachea

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N category  NX Regional lymph nodes cannot be assessed  N0 No regional lymph node metastasis  N1 Metastasis in 1–2 regional lymph nodes  N2 Metastasis in 3–6 regional lymph nodes  N3 Metastasis in 7 or more regional lymph nodes

M category  M0 No distant metastasis  M1 Distant metastasis  Adenocarcinoma G Category

Squamous cell carcinoma G category  GX Differentiation cannot be assessed  G1 Well-differentiated. Prominent keratinization with pearl formation and a minor component of nonkeratinizing basal-like cells. Tumor cells are arranged in sheets, and mitotic counts are low  G2 Moderately differentiated. Variable histologic features, ranging from parakeratotic to poorly keratinizing lesions. Generally, pearl formation is absent  G3‡ Poorly differentiated. Consists predominantly of basal-like cells forming large and small nests with frequent central necrosis. The nests consist of sheets or pavement-like arrangements of tumor cells, and occasionally are punctuated by small numbers of parakeratotic or keratinizing cells

Squamous cell carcinoma L category*** LX Location unknown  Upper  Middle vein  Cervical esophagus to lower border of azygos vein  Lower border of azygos vein to lower border of inferior pulmonary  Lower esophagogastric junction  Lower border of inferior pulmonary vein to stomach, including

*, subcategories; †, if further testing of “undifferentiated” cancers reveals a glandular component, categorize as adenocarcinoma G3; ‡, if further testing of “undifferentiated” cancers reveals a squamous cell component, or if after further testing they remain undifferentiated, categorize as squamous cell carcinoma G3; ***, location is defined by epicenter of esophageal tumor.

The Japanese Society for esophageal cancer published the 11th Edition Japanese Classification of Esophageal Cancer in 2017 (29). According this Society the staging of esophageal cancer should be detailed and after that, surgery with multi-modality treatments should be planned after neoadjuvant chemotherapy, radiotherapy, or both. Besides that, salvage surgery should be considered for cases with residual tumor or cases with recurrent tumor after definitive chemoradiotherapy with more than 50 Gy radiation (29).

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ESOPHAGECTOMY FOLLOWING NEOADJUVANT CHEMOTHERAPY OR CHEMORADIOTHERAPY

The indications for initial chemoradiotherapy rather than upfront esophagectomy include:

 Patients with thoracic esophageal or esophagogastric junction tumors and full- thickness (T3) involvement of the esophagus with/without nodal disease.  Selected patients with T4a disease with invasion of local structures (pericardium, pleura, and/or diaphragm only) that can be resected en bloc, and who are without evidence of metastatic disease to other organs (eg, liver, colon).

The relative contraindications to esophagectomy include:

 Advanced age: advanced age is associated with greater morbidity following esophagectomy. However, age alone should not determine operability, as selected elderly patients have similar outcomes to younger patients.  Comorbid illness: comorbidities increase the risk of postoperative complications (eg, cardiorespiratory complications, anastomotic leakage, reoperation rates, wound infection) and death following esophagectomy. Obesity is not associated with any increase in overall morbidity following esophagectomy and should not be considered a contraindication for esophagectomy (30, 31). According to the Japanese algorithm, a brief overview, is that endoscopic therapy is recommended for mucosal cancer, whereas surgery is recommended for more invasive tumors if the tumor has resectability. For tumors that invade the muscularis propria or adventitia and/or with lymph node (LN) metastases, adjuvant and neoadjuvant therapies are combined. If the tumor has invaded an adjacent organ or if there are distant metastases, chemotherapy, radiotherapy, and chemoradiotherapy (CRT) are therapeutic options. For submucosal cancer without metastasis, CRT is selected as the definitive therapy in some cases.

MANAGEMENT OF LOCALLY ADVANCED, UNRESECTABLE AND INOPERABLE ESOPHAGEAL CANCER

Management of patients with unresectable or inoperable but nonmetastatic esophageal cancer requires a multimodality approach. This is a group of patients with potentially resectable (T4a) and unresectable (T4b) primary disease, poor surgical candidates, and those who decline surgery. Locally advanced, unresectable or inoperable esophageal cancer is incurable in the majority of patients. A major goal of treatment is improvement in quality of life by restoring and/or maintaining the ability to swallow, and thus, sustaining adequate nutrition. Combined modality therapy offers a small but real chance of sustained disease control and long-term survival. Furthermore, improvement in quality of life and prolonged relief of dysphagia are achieved in the majority of patients. Unfortunately, long-term outcomes remain poor as the vast majority of patients present with loco-regionally advanced or metastatic disease. Complimentary Contributor Copy 76 Julio Pereira-Lima, Michele Bonotto, Julio Cesar Razera et al.

Neoadjuvant chemotherapy or chemoradiation provides a modest survival advantage compared to surgical resection alone. Future gains in understanding the molecular biology of esophageal cancer will hopefully lead to improved therapeutics and resultant outcomes (30- 32). A simple analysis about the main criteria to resection are listed below (11). The indications for an esophagectomy as the initial therapeutic approach to the patient with an esophageal cancer include:

 Patients with clinical T1N0M0 lesions with submucosal invasion  Patients with clinical T2N0M0 lesions are candidates in many medical centers

The optimal management of esophageal cancer clinically staged as T2N0M0 is somewhat more controversial, depends on the stage and the reference center, but we should consider some variables, including the clinical aspects of the tumor, like the number of primary tumors, size and circumferential location. Maximum length (mm) and orthogonally oriented maximum width (mm), center of circumferential extent, and circumferential ratio of the tumor to the entire esophagus should be described. Another point to consider is the tumor location and the anatomical region. The esophagus is defined anatomically from the esophageal orifice to the esophagogastric junction. The esophageal orifice is at the lower margin of the cricoid cartilage. The esophagus lies between the hypopharynx and stomach and can be anatomically divided into the following portions; cervical esophagus (Ce), thoracic esophagus (Te) and abdominal esophagus (Ae). The zone of the esophagogastric junction is divided into the esophageal side (E) and gastric side (G) (11, 25, 26):

 Cervical esophagus (Ce): This extends from the esophageal oriﬁce to the sternal notch.  Thoracic esophagus (Te): From the sternal notch to the superior margin of the esophageal hiatus.  Upper thoracic esophagus (Ut): From the sternal notch to the tracheal bifurcation.  Middle thoracic esophagus (Mt): The proximal half of the two equal portions between the tracheal bifurcation and the esophagogastric junction.  Lower thoracic esophagus (Lt): The thoracic part of the distal half of the two equal portions between the tracheal bifurcation and the esophagogastric junction. Abdominal esophagus (Ae): The abdominal part of the distal half of the two equal portions between the tracheal bifurcation and the esophagogastric junction. (from the  Macroscopic ﬁndings Tumor location: Ce, Ut, Mt, Lt, Ae Macroscopic tumor type: Type 0-I, Type 0-IIa, Type 0-IIb, Type 0-IIc, Type 0-III, combined type, others Size of specimen: length (mm), width (mm) Size of tumor: length (mm), width (mm) Resection: en bloc resection, piecemeal resection Piecemeal resection: number of specimens Horizontal margin: HMX, HM0, HM1 Vertical margin: VMX, VM0, VM1 Multiple lesions: present, absent

Finally, the histological ﬁndings and the tumor invasion should be considered (11, 26):

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 Histologic type: squamous cell carcinoma, basaloid (-squamous) carcinoma, carcinosarcoma, adenocarcinoma, Barrett’s adenocarcinoma, adenosquamous carcinoma, mucoepidermoid carcinoma, adenoid cystic carcinoma, neuroendocrine cell tumor, undifferentiated carcinoma, other carcinomas, nonepithelial malignant tumors, GIST, malignant melanoma.  Depth of tumor invasion: pTX, pT0, pT1a (EP, LPM, MM), T1b (SM1, SM2, SM3) Pattern of inﬁltration: INFa, INFb, INFc Lymphatic invasion: ly (-), ly (?) Venous invasion: v (-), v (?) Size of tumor: length (mm) 9 width (mm) Horizontal margin: pHMX, pHM0, pHM1 Vertical margin: pVMX, pVM0, pVM1 Residual tumor: pRX, pR0, pR1, pR2 Curativity: pCur A, pCur B, pCur C12.

Management is based on location of tumor and stage - radiation therapy, chemoradiotherapy, neoadjuvant approaches and post-operative adjuvant therapy. For cervical esophageal cancer, management is mostly by chemoirradiation for organ preservation. For thoracic esophageal cancer, in theearly stage, one would usually consider radical surgery +/- adjuvant treatment. However, the optimal regimen is not established. For borderline resectable tumours, one may consider neoadjuvant chemoirradiation (improved survival among patients with potentially curable esophageal or esophagogastric-junction cancer) before definitive surgery. In locally advanced disease the indications for initial chemoradiotherapy rather than upfront esophagectomy include: patients with thoracic esophageal or esophagogastric junction tumors and full-thickness (T3) involvement of the esophagus with/without nodal disease (11, 26), and selected patients with T4a disease with invasion of local structures (pericardium, pleura, and/or diaphragm only) that can be resected en bloc, and who are without evidence of metastatic disease to other organs (eg, liver, colon). If there is a clear tracheoesophageal fistula, one usually may consider prophylactic stenting before radical chemoirradiation due to potential risk of aspiration. For esophageal-gastric junction adenocarcinoma, management will be more inclined to be similar to the stomach cancer approach. Advanced age is a factor to consider because it is directly associated with morbidity following esophagectomy. However, we should to consider the comorbidity together because some elderly patients have the same surgical outcome after esophagectomy as younger patients. The risk of postoperative complications (e.g., cardiorespiratory complications, anastomotic leakage, reoperation rates, wound infection) and death following esophagectomy is directly related to preoperative multifactorial selection criteria, including the surgeon’s dexterity (27, 28). Obesity is not associated with any increase in overall morbidity following esophagectomy and should not be considered a contraindication for esophagectomy. According to the Japanese algorithm, endoscopic therapy is recommended for mucosal cancer, whereas surgery is recommended for more invasive tumors if the tumor has resectability. For tumors that invade the muscularis propria or adventitia and/or with lymph node (LN) metastases, adjuvant and neoadjuvant therapies are combined. If the tumor has invaded an adjacent organ or if there are distant metastases, chemotherapy, radiotherapy, and chemoradiotherapy (CRT) are therapeutic options (28, 29).

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MANAGEMENT OF LOCALLY ADVANCED, UNRESECTABLE ESOPHAGEAL CANCER

Management of patients with unresectable requires a multimodality approach (30). Treatment is used mainly to help keep the cancer under control for as long as possible and to relieve any symptoms it is causing. Chemo may be given (possibly along with targeted drug therapy) to try to help patients feel better and live longer, but the benefit of giving chemo is not clear. Radiation therapy or other treatments may be used to help with pain or trouble swallowing (31, 32). Neoadjuvant chemotherapy or chemoradiation provides a modest survival advantage compared to surgical resection alone (32).

REFERENCES

[1] Ferlay J, Soerjomataram I, Dikshit R, Eser S, Mathers C, Rebelo M, et al. Cancer incidence and mortality worldwide: sources, methods and major patterns in GLOBOCAM 2012. Int J Cancer 2015;136(5):E359-86. [2] Tanaka Y, Yoshida K, Suetsugu T, Imai T, Matsuhashi N, Yamaguchi K, et al. Recent advancements in esophagel cancer treatment in Japan. Ann Gastroenterol 2018;2(4):253-65. [3] Ajani J, Barthel JS, Bentrem DJ, D'Amico TA, Das P, Denlinger CS, et al. Esophageal and Esophagogastric Junction Cancers. JNCCN 2011:9(8):830-87; [4] Barrios E, Sierra MS, Musetti C, Forman D. The burden of esophageal cancer in Central and South America. Cancer Epidemiology 2016;44(Suppl1):S53-61. [5] Barros SG, Vidal RM, Luz LP, Ghisolfi ES, Barlem GG, Komlós F, et al. Prevalence of adenocarcinoma of the esophagus and esophagogastric junction in a 10 year period at a cancer referral center in southern Brazil. Arq Gastroenterol 1999;36(1):32-6. [6] American Cancer Society. Cancer facts and figures. Atlanta, GA: ACS, 2018. [7] Feldman M, Friedman L, Brandt L. Sleisenger and Fordtran’s gastrointestinal and liver disease. Philadelphia, PA: Saunders, 2010. [8] de Barros SG, Ghisolfi ES, Luz LP, Barlem GG, Vidal RM, Wolff FH, et al. High temperature "matè" infusion drinking in a population at risk for squamous cell carcinoma of the esophagus. Arq Gastroenterol 2000;37(1):25-30. [9] Torre LA, Bray F, Siegel RL, Ferlay J, Lortet-Tieulent J, Jemal A. Global cancer statistics, 2012. CA Cancer J Clin 2015;65(2):87-108. [10] Blot WJ, McLaughlin JK. The changing epidemiology of esophageal cancer. Semin Oncol 1999;26(5 suppl 15):2-8. [11] Saltzman J, Gibson MK. Clinical manifestations, diagnosis and staging of esophageal cancer. UpToDate. URL: https://www.uptodate.com/contents/clinical-manifestations-diagnosis-and-staging-of- esophageal-cancer# [12] Averbach M, Ribeiro AVS, Ferrari AP Jr, Cappellanes C, Emija FH, Fang HL, et al. Carcinoma precoce do esofago. Endoscopia Digestiva. Diagnóstico e tratamento. São Paolo: Revinier, 2017. [13] Guo HM, Zhang XQ, Chen M, Huang SL, Zhou XP. Endoscopic submucosal dissection vs endoscopic mucosal resection for superficial esophageal cancer. World J Gastroenterol 2014;20(18):5540-7. [14] ASGE Standards of Practice Committee, Evans JA, Early DS, Chandraskhara V, Chathadi KV, Fanelli RD, et al. The role of endoscopy in the assessment and treatment of esophageal cancer. Gastrointest Endosc 2013;77(3):328-34. [15] Rana F, Dhar A. Oesophageal stenting for benign and malignant strictures: a systematic approach. Frontline Gastroenterol 2015;6(2):94-100.

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[16] Hussain Z, Diamantopoulos A, Krokidis M, Katsanos K. Double-layered covered stent for the treatment of malignant oesophageal obstructions: Systematic review and meta-analysis. World J Gastroenterol 2016;22(34):7841-50. [17] Dai Y, Li C, Xie Y, Liu X, Zhang J, Zhou J, et al. Interventions for dysphagia in oesophageal cancer. Cochrane Database Syst Rev 2014;(10):CD005048. [18] Zhu HD, Guo JH, Mao AW, Lv WF, Ji JS, Wang WH, et al. Conventional stents versus stents loaded with 125iodine seeds for the treatment of unresectable oesophageal cancer: a multicentre, randomised phase 3 trial. Lancet Oncol 15(6):612-9. [19] Freedman N, Abnet CC, Leitzmann MF, Mouw T, Subar AF, Hollenbeck AR, et al. A prospective study of tobacco, alcohol, and the risk of esophageal and gastric cancer subtypes. Am J Epidemiol 2007;165:1424-33. [20] Pottern LM, Morris LE, Blot WJ, Ziegler RG, Fraumeni JF Jr. Esophageal cancer among black men in Washington, D.C. (I. Alcohol, tobacco, and other risk factors. J Natl Cancer Inst 1981;67(4):777-83. [21] Appelqvist P, Salmo M. Lye corrosion carcinoma of the esophagus: a review of 63 cases. Cancer 1980;45(10):2655-8. [22] Leeuwenburgh I, Scholten P, Alderliesten J, Tilanus HW, Looman CW, Steijerberg EW, et al. Long- term esophageal cancer risk in patients with primary achalasia: a prospective study. Am J Gastroenterol 2010;105(10):2144-9. [23] Wang JM, Xu B, Rao JY, Shen HB, Xue HC, Jiang QW. Diet habits, alcohol drinking, tobacco smoking, green tea drinking, and the risk of esophageal squamous cell carcinoma in the Chinese population. Eur J Gastroenterol Hepatol 2007;19(2):171-6. [24] Islami F, Ren JS, Taylor PR, Kamangar F. Pickled vegetables and the risk of oesophageal cancer: a meta-analysis. Br J Cancer 2009;101(9):1641-7. [25] SEER Program. SEER Stat Fact Sheets: Esophagus; Survival and Stage. NCI.. URL: seer.cancer.gov/statfacts/html/esoph.html#survival [26] Rice TW, Patil DT, Blackstone EH. 8th edition AJCC/UICC staging of cancers of the esophagus and esophagogastric junction: application to clinical practice. Ann Cardiothorac Surg 2017;6(2):119-30. [27] Miyata H, Yamasaki M, Kurokawa Y, Takiguchi S, Nakajima K, Fujiwara Y, et al. Multimodal treatment for resectable esophageal cancer. Gen Thorac Cardiovasc Surg 2011;59(7):461-6. [28] Sohda M, Kuwano H. Current Status and Future Prospects for Esophageal Cancer Treatment. Ann Thorac Cardiovasc Surg 2017;23(1):1-11. [29] Japan Esophageal Society. Japanese classification of esophageal cancer, 11th edition. Esophagus 2017;14(1):37-65. [30] Lordick F, Hölscher AH, Haustermans K, Wittekind C. Multimodal treatment of esophageal cancer. Arch Surg 2013;398(2):177-87. [31] Paul S1, Altorki N. Outcomes in the management of esophageal cancer. J Surg Oncol 2014;110(5):599-610. [32] American Cancer Society. Palliative therapy for esophageal cancer. URL: https://www.cancer. org/cancer/esophagus-cancer/treating/palliative-therapy.html.

Chapter 8

MANAGEMENT OF GASTRIC CANCER

Carlos A García1,*, MD, Fiona Lim2, MBBS, Bo Angela Wan3, MD(C), Rodrigo Torres-Quevedo4, MD, PhD and Mauricio F Silva5,6,7, MD, PhD 1Clínica Las Condes, Surgery Department, Hospital Clínico San Borja Arriarán Santiago, Chile, University of Chile, Department of Radiology and Oncology, Faculty of Medicine, University of São Pau 2 Department of Oncology, Princess Margaret Hospital, Hong Kong, PR China 3Odette Cancer Centre, Sunnybrook Health Sciences Centre, Toronto, Ontario, Canada 4Unidad cirugía hígado, páncreas y vías biliares, Servicio de Cirugía, Hospital Guillermo Grant Benavente, Concepción, Chile 5Radiation Oncology Unit, Hospital de Caridade Astrogildo de Azevedo, Santa Maria, Brazil 6Radiation Oncology Unit, Santa Maria Federal University, Santa Maria, Brazil 7Latin America Cooperative Oncology Group, Porto Alegre, Brazil

ABSTRACT

Gastric cancer (GC) is the third most common cancer death at the global level, with an estimated 725,000 people who die for this annually; it is the fifth most common cancer worldwide. GC is one of the most common tumours in some Latin American (LA) countries, especially on the Pacific coast border. The aetiology of gastric cancer is multifactorial. Helicobacter pylori (HP), is responsible for over 80% of cases worldwide and in Latin America, especially the intestinal variety. There are currently no screening programs in asymptomatic patients in LA. The diagnosis is made through an upper digestive endoscopy and biopsy. The computed axial tomography (CT) of the abdomen, pelvis and thorax is considered as a minimum study for staging, which is primarily aimed at specifying the existence of lymphatic, hepatic and peritoneal metastases. Other diagnostic tools available are endosonography, laparoscopy, magnetic resonance and PET

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CT. The extent of the disease (cTNM) defines the treatment of the GC. For very early lesions (cT1a) endoscopic resection is indicated. For advanced loco-regional tumours, the combination of surgery, plus chemotherapy or radiotherapy is the most effective alternative. The sequence of each of them depends on factors associated with the patients, as well as the availability of the health centres. The management alternatives for metastatic tumours are surgery (bleeding or obstruction), chemotherapy and general medical support. The CG prognosis depends on the final or pathological TNM stage.

INTRODUCTION

In the early twentieth century and until the mid-70s, gastric cancer (GC) was the leading cause of death from oncological diseases in the world. In 1975, GC fell to second place after lung cancer (1). At present, it is the third most common cancer death at the global level, with an estimated of 725,000 people who die from stomach cancer annually. In incidence, GC is the fifth most common cancer type worldwide. Approximately one million new cases are diagnosed each year, the majority in eastern countries (China, Korea and Japan) (2). Despite this number, only 0,23% of the National Cancer Institute budget (2013) was dedicated to GC investigation. Globocan estimates that in 2012, about one million new cases of cancer and 500,000 deaths occurred annually in Latin America (LA), and this represents 5.6% of the total cases (incidence) and 8.1% of the total number of deaths due to cancer in the world (3,4). GC is one of the most frequent tumours in some LA countries, especially on the Pacific coast border. For example, in some areas of Chile, the incidence and mortality rates occupy some of the highest in the world. The same occurs in women in Guatemala, where the death rate from this cause is one of the highest in the world (5). It is unlikely that the incidence of GC will be significantly reduced in LA in the coming years, due to the high incidence of chronic Helicobactor pylori (HP) in young people. This situation could change with a massive HP eradication program (6-8). In this chapter, we will review the current situation of CG in LA, with a particular emphasis on aspects of epidemiology, pathogenesis and treatment.

EPIDEMIOLOGY OF GC IN LATIN AMERICA

Stomach cancer continues to be one of the five leading causes of cancer diagnosis and cancer death in most LA countries (9). There is a remarkable geographic variation in incidence and mortality. These rates vary between 5-7 times when comparing different countries of the continent. For example in Valdivia, Chile, the age-adjusted incidence rate for men is 29.1 per 100,000 inhabitants, which contrasts with the rate observed in Mexico or El Salvador, where it is between 3.7 to 4.6 100,000 inhabitants (5). Incidence and mortality in GC are higher in males than females. This concept is valid in all age groups. The peak incidence rate is in the group of 70-80 years old, and the average diagnosis is 60-62 years of age. In males, the highest incidence rates were observed in Chile (29.1) followed by Costa Rica, Colombia, Ecuador, Brazil, and Peru (ASRs ranging from 19.2 to 26.5) while the lowest Complimentary Contributor Copy Management of gastric cancer 83 rates were observed in Mexico, Bolivia and El Salvador (3.3- 4.6). In females, the highest ASRs were seen in Peru, Costa Rica, Ecuador, Colombia, Chile and Brazil (9.7-15.1) and the lowest rates were in Mexico, Bolivia and El Salvador (ASRs 3.0). The incidence and mortality of stomach cancer have been declining over the past decades in nearly all LA countries. In Chile, Brazil, Argentina and Costa Rica incidence and mortality rates in men declined significantly between 1990 and 2000, on average 3-4% annually. In women, both rates have declined significantly in Chile and Costa Rica (5). In part, this finding may be explained by declines in the prevalence of Helicobacter pylori infection and by improvements in sanitation, preservation and foods storage. From a geographic point of view, the CG is more frequent in the Pacific coast and high altitude areas along the Central American Mountain and the Andes. However, this relationship is not observed in Costa Rica and Chile, two of the countries with the highest CG incidence in the region. For the rest of the countries with high incidence, some hypotheses have been proposed that explain this correlation as the different HP strains or dietary factors. The altitude does not seem to explain these differences (10). Gastric cancer is frequently analyzed as a single clinical entity but two different anatomical and clinical subtypes are currently considered, cardiac gastric cancer (CGC) and non-cardiac gastric cancer (NCGC) and according to its histological pattern into intestinal (well-differentiated) or diffuse (undifferentiated) types (11). These two different classifications (location and histology) define different subtypes of gastric cancer with a distinctive characteristic in epidemiology, biology, clinical features, pathology, and precursor lesions. Recent global estimates reveal that 87% of all stomach cancer cases diagnosed in 2012 were NCGC, with most of the cases occurring in Eastern Asia (61%) followed by Central Asia (10%), Eastern Europe (7.5%), and South America (7.0%).

PATHOGENESIS

Aetiology of gastric cancer is multifactorial. However, one factor, Helicobacter Pylori (HP), is responsible for over 80% of cases worldwide. Other associated factors are dietary, lifestyles habits, occupations and geographical situations (12). Between the two subtypes of gastric cancer mentioned above, CGC is associated with obesity, gastroesophageal reflux and tobacco. Its incidence has remained stable and generally has a worse prognosis than the NCCG. Conversely, non-cardiac gastric cancer is associated with chronic infection with HP, high salt diets, tobacco, and low socioeconomic and educational levels (13). A percentage of around 10% are associated with infection by Epstein Barr virus. HP infection is the strongest risk factor for CG. HP colonizes gastric mucosa at early ages, establishing a long-lasting chronic inflammation and development of pre-neoplastic lesions (15). In Latin America, HP infection is very high affecting over 70% of adult populations. The reason for this situation can be explained by poor sanitation and low standard of socio-economic conditions (16). Prevalence of HP infection varies in different countries, for example in Argentina this rate is 49% and in Venezuela is 95% (17). In about 15% of CG cases, evidence of Epstein Barr virus infection has been found (18). The cases of CG associated with this infection are characterized by occurring in the upper or

Complimentary Contributor Copy 84 Carlos A García, Fiona Lim, Bo Angela Wan et al. middle third of the stomach (19). The role of Epstein Barr virus in the carcinogenesis of CG has not yet been fully established. This association has also been found in LA patients (14, 20). The pathogenesis of diffuse CG is different from that of the intestinal variety. In the first, the typical carcinogenic event is the loss of expression of E-cadherin, a protein related to intercellular junctions and therefore with adequate tissue organization (12). The gene that codes for E-cadherin is called CDH1 and is located in gene 16 q22.1. The mutation was first described in Maori families, whose members developed diffuse CG, at an early age and very aggressive (21). This mutation has also been described in LA patients (22). In the intestinal variety, the sequence of preneoplastic and epigenetic histological lesions observed in carcinogenesis has been clearly described (12), but in the diffuse variety there are no histological changes before the appearance of invasive cancer, and therefore the identification of precursor lesions is impossible. This explains the poor outcome of endoscopic follow-up in families affected by the mutation of the CDH1 gene, considering the alternative of prophylactic gastrectomy (23).

DIAGNOSIS

The diagnosis of GC in LA is generally in advanced stages with only 10% of an early cancer diagnosis. The reasons for this situation are multiple but mainly because of the limited accessibility to a specialized medical consultation (24). There are currently no screening programs in asymptomatic patients in LA. In the past, there were some programs supported by the government of Japan that carried out screening programs for the disease in an asymptomatic population using mainly double contrast radiology as a study method. These programs were carried out in the 1980s or 1990s in Chile and Venezuela (25, 26), with somewhat disappointing results in terms of obtaining early cancer screening figures similar to those reported in Japan or Korea. At present, screening programs are focused on symptomatic patients with clinical suspicion of cancer, those who have priority for endoscopy (16, 27). In advanced gastric cancer, the symptomatology is more extensive, being frequent abdominal pain and weight loss (60% of cases). They also usually present anorexia, nausea, vomiting, anaemia, dysphagia, digestive haemorrhage and early satiety. The spread of gastric cancer occurs preferentially to the liver and peritoneum, giving specific symptoms such as a palpable abdominal mass in the right hypochondrium or neoplastic hepatomegaly and ascites. Therefore, it is common to find patients who, at the time of diagnosis, are outside a stage in which surgery can be performed with curative intent. The diagnosis is made through an upper digestive endoscopy and biopsy. The endoscopy in addition to visualising the lesion shows its macroscopic shape, size, location and with experienced eyes, an estimate of the depth of a tumour. The Japanese classification of gastric cancer is used throughout the continent. Endoscopy reports often using this nomenclature to describe the different macroscopic forms of GC. The most frequent differential diagnosis is with peptic ulcers in incipient lesions and gastric lymphoma in advanced cancer. In recent years there have been improvements in endoscopy, such as endoscopic magnification, high- resolution and/or high-definition endoscopic devices, narrow-band imaging, virtual staining, or confocal microendoscopy which has led to better detection of early lesions (16, 28).

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Once the lesion is diagnosed, a dissemination study should be carried out. The computed axial tomography (CT) of the abdomen, pelvis and thorax is considered as a minimum study for this step, which is primarily aimed at specifying the existence of lymphatic, hepatic and peritoneal metastases, and in the latter, with a greater range of error (29). The accuracy of CT in the T staging of a gastric tumour is 69-89% but is very low, only 20-53%, in early gastric cancer (30). With an adequate preparation of the stomach, it is possible to specify the morphology, extension, and location of a primary tumour, achieving a reasonably accurate approach of the T factor, used in the TNM classification. In case of clinical suspicion of peritoneal carcinomatosis, we use staging laparoscopy, which in many cases avoids an unnecessary laparotomy (31, 32). Another diagnostic tool available is endosonography, which determines the depth of the lesion with greater precision than previous tests, with a higher value in the discrimination of mucosal lesions to the submucosal and therefore determine the best therapy (endoscopy or surgery) (33).

TREATMENT

The best known of the tumour biology of gastric cancer has allowed the current treatment to be defined as individualized, multidisciplinary and multimodal. Surgery is the primary option of curative treatment in GC (34-37). In the last few years, enough evidence has accumulated about the benefit of adjuvant and neoadjuvant (35). However, the current discussion focuses on determining what is the best treatment scheme; therefore accurate preoperative staging is essential (38). In recent years the irruption of laparoscopy and therapeutic endoscopy have changed the therapeutic approach of early gastric cancer. Early tumours with compromise only of the mucosal layer, small size, well or moderately differentiated and not ulcerated are feasible to resect endoscopically with curative intent (39). The probability that these tumours have lymph node involvement is practically zero, and the 5-year survival is near to 100%. This advanced technique must be performed in centres with high experience, in order to ensure that the results obtained are similar to those of traditional surgery. The irruption of laparoscopy is another advance in early gastric cancer surgery (40). Laparoscopic gastrectomy with lymphatic dissection D1+, has demonstrated in large oriental series, oncological results similar to traditional surgery, with the advantages of minimally invasive surgery. Currently, laparoscopic gastrectomy D1+ is considered a standard treatment for early gastric cancer not susceptible to endoscopic therapy (41). The mainstay of the treatment of advanced gastric cancer is surgery (42). The objective of this is to achieve an R0 resection. The controversial points of R0 surgery in advanced gastric cancer are:

a) Lymph node dissection: historical data and recent studies show that standardised extended (D2) lymphadenectomy leads to better results than limited (D1) lymphadenectomy. In the '90s three randomized studies evaluated the extension of lymphadenectomy in GC. All studies failed to show any beneficial effect of extended lymph node resection (D2) over limited dissection (D1) (43). However, one of these studies, showed over long time observation, that after a median follow-up of 15

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years, D2 lymphadenectomy is associated with lower local-regional recurrence and gastric-cancer-related death rates than D1 surgery (44). Because a safe, spleen- preserving D2 resection technique is currently available in high-volume centres. Hence D2 lymphadenectomy is the recommended surgical approach for patients with resectable GC (43, 45). b) Splenectomy: performing splenectomy routinely with resection of a primary tumour was controversial until some time ago. The objective of splenectomy is to perform an adequate lymph node dissection of the splenic pedicle as part of the D2 dissection. However, several authors have shown similar survival rates for the groups with and without splenectomy, but with greater morbidity for the resective group (46). The current indications for splenectomy in advanced gastric cancer are those of the upper third and greater gastric curvature or the cases with evident lymph node involvement at this level (47). c) Gastrectomy with curative must have sufficient margins of a primary tumour to ensure its complete eradication. A proximal margin of 3 cm is recommended for Borrmann I and II lesions and 5 cm for Borrmann III and IV lesions (48). An intraoperative biopsy is essential for the evaluation of the proximal margin in gastroesophageal cancer (49). d) Distal pancreatectomy: Distal pancreatectomy was a standard step in advanced gastric cancer surgery until some time ago. The objective was in block resection of the lymph nodes of the splenic artery. This resection implied an increase in mortality and postoperative morbidity without changes in survival results. The current indication for distal pancreatectomy is a direct invasion of the organ by a primary tumour or evident lymph node involvement of the splenic artery (48). e) Omentectomy: The resection of the greater omentum is part of the standard surgery for advanced gastric cancer. It does not imply a risk of morbi-mortality and ensures the resection of a biological tumour barrier. In early lesions, the preservation of most of the omentum is possible, with resection of the gastroepiploic vessels and their lymphatic chain (50). f) Laparoscopic gastrectomy for advanced gastric cancer: The irruption of laparoscopic or minimally invasive surgery occurred in recent years has made this also a surgical alternative for the treatment of advanced gastric cancer. Large series of patients operated on this route have been published, mainly from the East and for early gastric cancer (40, 51). The vast experience is for distal gastrectomies with lymphatic dissection D2. As in other digestive oncological pathologies, laparoscopic surgery is just one more way to approach this disease, concerning the specific oncological principles discussed in the points above. The value of laparoscopic surgery in advanced gastric cancer is still extremely controversial because there is no substantial evidence to support this approach (52, 53).

Table 1 shows some of the results of surgery with lymphatic dissection D2 in LA patients, regarding morbidity and operative mortality. These results show that this type of surgery has morbidity and mortality similar to Asian or European standards. The results of the exclusive D2 extended surgery in locally advanced gastric cancer achieve survival rates of less than 50% at 5 years, for which adjuvant therapy is a subject of debate in GC (54, 55) (see Table 2). Complimentary Contributor Copy Management of gastric cancer 87

Table 1. Results of surgery with lymphatic dissection D2 in LA patients, regarding morbidity and operative mortality

Reference Year N Morbidity Mortality Comments (%) (%) Csendes et al. (46) 2002 187 39 3,7 D2 vs D2 + splenectomy Stambuk et al. (55) 2006 108 17,5 0.9 D2 Total gastrectomy Portanova et al. (66) 2007 176 22,7 2,8 D2 in specialization center Souza et al. (67) 2008 285 - 3 D2 in GC team García et al. (4) 2008 423 37,9 3,3 D2 Total or subtotal gastrectomy Pilco et al. (68) 2009 71 26,7 6,7 D2 in general hospital Ruiz et al. (69) 2009 801 11.9 2.9 D2 in GC team Butte el al (42) 2010 74 16.9 3.4 D2 extended gastrectomy

Table 2. Results of the exclusive D2 extended surgery in locally advanced gastric cancer in selected Latin America series

Reference Year N Survival 5yrs (%) Comments Csendes et al. (46) 2002 187 36-42 D2 vs D2 + splenectomy Stambuk et al. (55) 2006 108 48,9 D2 Total gastrectomy Portanova et al. (66) 2007 176 41 D2 in specialization center Souza et al. (67) 2008 285 48 D2 in GC team García et al. (4) 2008 423 52 D2 Total or subtotal gastrectomy Pilco et al. (68) 2009 71 24 D2 in general hospital Ruiz et al. (69) 2009 801 47,5 D2 in GC team Butte el al. (42) 2010 74 31,4-50,9 D2 extended gastrectomy

There is particular interest in the promising results of neoadjuvant chemotherapy or chemoradiotherapy — the results of the MAGIC study (56), which compared two groups of patients with stages II and III undergoing perioperative chemotherapy versus exclusive surgery. In the group with chemotherapy, a decrease in tumour size and stage was observed, and more importantly, a significant improvement in disease-free time and 5-year survival rates. The conclusion is that this was the first prospective randomized study that showed the benefits of perioperative chemotherapy in advanced gastric cancer. These results have been confirmed in different series with similar, though not equal, chemotherapy schemes. Adjuvant chemotherapy (indicated after surgery) has been investigated for several years to try to reduce recurrences and improve survival in advanced gastric cancer. The initial results were disappointing (57). However, in 2007 the results of a cooperative Japanese randomized study that compared 5-year survival among patients who received postoperative chemotherapy based on S1 (oral fluoropyridine) versus exclusive surgery were published. The group that received S1 presented a 3-year survival superior in 10% with the exclusive surgery group (58). With these results, in the East, the standard adjuvant for gastric cancer is chemotherapy based on S1. The results published by McDonald using a postoperative chemo and radiotherapy regimen in advanced gastric cancer are also interesting and encouraging, although controversial (59). Adjuvant treatment consists of five post-operative cycles of 5- fluorouracil and Leucovorin plus 45 Gy of external radiotherapy. This series showed a significantly higher three-year survival for patients undergoing postoperative chemoradiation therapy. The most important criticisms to this treatment refer to the quality of surgery since in Complimentary Contributor Copy 88 Carlos A García, Fiona Lim, Bo Angela Wan et al.

90% of the cases it had a limited lymphatic dissection (D1-). Also, tolerance to treatment was limited since only 64% of the total group completed the planned treatment. Chemotherapy is the primary treatment for advanced or stage IV GC. New anticancer drugs, such as S-1, capecitabine, paclitaxel, docetaxel, irinotecan, and oxaliplatin have been developed in the last 20 years (60). Combination treatment using these potent new drugs have been actively introduced in chemotherapy for GC and are contributing to significant improvements in antitumor responses and patient survival. Which is the best alternative for these patients is controversial; Surgery alone (palliative resection) or chemotherapy or combination. Conversion therapy is a new alternative for some patients in stage IV GC. It is defined as a surgical treatment aiming at an R0 resection after chemotherapy or/and radiotherapy for tumours that were initially unresectable or marginally resectable for technical or oncological reasons (61). This definition is different from neoadjuvant chemotherapy (NaD). NaD is conducted for downstaging in tumours which are determined clinically resectable from the beginning of chemotherapy. In contrast, conversion therapy is a consequence of the development of active agents like chemotherapy or biological drugs. Recently, Yoshida et al. proposed the new biological categories for the classification of stage IV GC, determining that some patients with good response to initial chemotherapy (or another systemic treatment with o without radiotherapy) can be resected with R0 surgery. Some publications show surprising results in survival. Conversion surgery may improve the poor prognosis of GC, while further studies and careful assessment are necessary to determine the optimal regimen, as well as the number of courses that will be the ultimate treatment for each case (62).

PROGNOSIS

The most important prognostic factor is the tumour stage. TNM classification modified in the last edition is the most useful tool to evaluate the stage of the disease and make a very exact prognosis for the individual patient. Best prognosis is obtained with completed R0 resection according to with de Japanese Guidelines (48). Complete loco-regional tumour resection with adequate margins of clearance and complete lymph node dissection has been identified and widely accepted as a significant factor for reduction of locoregional tumour recurrences and improvement of survival (63). In the last year, several predictors systems have been developed with a good survival prediction (64, 65). In locally advanced or metastatic disease, there is also a role of supportive care for symptoms control such as bleeding, obstruction.

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[49] Songun I, Bonenkamp JJ, Hermans J, van Krieken JHJM, van de Velde CJH. Prognostic value of resection-line involvement in patients undergoing curative resections for gastric cancer. EJC 1996;32(3):433-7. [50] Kim MC, Kim KH, Jung GJ, Rattner DW. Comparative study of complete and partial omentectomy in radical subtotal gastrectomy for early gastric cancer. Yonsei Med J 2011;52(6):961-6. [51] Barchi LC, Jacob CE, Bresciani CJ, Yagi OK, Mucerino DR, Lopasso FP et al. Minimally invasive surgery for gastric cancer: time to change the paradigm. Arq Bras Cir Dig 2016;29(2):117-20. [52] Park DJ, Han SU, Hyung WJ, Kim MC, Kim W, Ryu SY, et al. Long-term outcomes after laparoscopy- assisted gastrectomy for advanced gastric cancer: a large-scale multicenter retrospective study. Surg Endosc 2012:26(6):1548-53. [53] Uyama I, Sugioka A, Fujita J, Komori Y, Matsui H, Hasumi A. Laparoscopic total gastrectomy with distal pancreatosplenectomy and D2 lymphadenectomy for advanced gastric cancer. Gastric Cancer 1999;2(4):230-4 [54] García C, Benavides C, Apablaza S, Rubilar P, Covacevich S. Peñaloza P et al. Surgical treatment of gastric cancer: results in 423 cases. Rev Med Chil 2007;135(6):687-95. [55] Stambuk J. Immediate results and late survival of radical gastrectomy in 108 patients with resectable gastric cancer. Rev Chilena Cirugía 2006;58:420-30. [56] Cunningham D, Allum WH, Stenning SP, Thompson JN, Van de Celde CJ, Nicolson M, et al. Perioperative chemotherapy versus surgery alone for resectable gastroesophageal cancer. N Engl J Med 2006;355(1):11-20. [57] Hermans J, Bonenkamp JJ, Boon MC, Bunt AM, Ohyama S, Sasako M, van de Velde CJ. Adjuvant therapy after curative resection for gastric cancer: meta-analysis of randomized trials. J Clin Oncol 1993;11(8):1441-7. [58] Sakuramoto S, Sasako M, Yamaguchi T, Kinoshita T, Fujii M, Nashimoto A, et al. Adjuvant chemotherapy for gastric cancer with S-1, an oral fluoropyrimidine. N Engl J Med 2007;357(18):1810- 20. [59] Macdonald JS, Smalley SR, Benedetti J, Hundahl SA, Estes NC, Stemmermann GN, et al. Chemoradiotherapy after surgery compared with surgery alone for adenocarcinoma of the stomach or gastroesophageal junction. N Engl J Med 2001;345:725-30. [60] Wagner AD, Grothe W, Haerting J, Kleber G, Grothey A, Fleig WE. Chemotherapy in advanced gastric cancer: a systematic review and meta-analysis based on aggregate data. J Clin Oncol 2006;24(18):2903-9. [61] Yoshida K, Yamaguchi K, Okumura N, Tanahashi T, Kodera Y. Is conversion therapy possible in stage IV gastric cancer: the proposal of new biological categories of classification. Gastric Cancer 2016;19(2):329-38. [62] Wu K, Nie Y, Guo C, Chen Y, Ding J, Fan D. Molecular basis of therapeutic approaches to gastric cancer. J Gastroenterol Hepatol 2009;24(1):37-41. [63] Siewert JR, Böttcher K, Stein HJ, Roder JD. Relevant prognostic factors in gastric cancer: ten-year results of the German Gastric Cancer Study. Ann Surg 1998;228(4):449-61. [64] Kattan MW, Karpeh MS, Mazumdar M, Brennan MF. Postoperative nomogram for disease-specific survival after an R0 resection for gastric carcinoma. J Clin Oncol 2003;21(19):3647-50. [65] Marrelli D, Caruso S, Roviello F. Prognostic factors and score systems in gastric cancer. In: de Manzoni G, Siquini W, eds. Surgery in the multimodal management of gastric cancer. Milan: Springer- Verlag Mailand, 2012:35-42. [66] Portanova M, Vargas F, Lombardi E, Mena V, Carbajal R, Palacios N, Orrego J. Results of specialization in the surgical treatment of gastric cancer in Peru. Gastric Cancer 2007;10(2):92-7. [67] Souza FO, Pereira DV, Santos LH, Antunes L, Chiesa J. Gastric cancer patients treated by a general or gastric surgical team: a comparative study. Arq Gastroenterol 2008;45(1):28-33. [68] Pilco P, Viale S, Ortiz N, Deza C, Juarez N, Portugal K, et al. Gastric cancer in a general hospital, Santa Rosa Hospital Exprience. Rev Gastroenetrol Peru 2009;29(1):66-74. [69] Ruiz E, Sanchez J, Celis J, Pavet E, Berrospi F, Chavez I, Young F. Cáncer gastric localizado: Resultados quirúrgicos de 801 pacinetes tratados con linfadenectomia D2. Rev Gastroenterol Peru 2009;29(2):124-31. Complimentary Contributor Copy Complimentary Contributor Copy In: Cancer Management in Latin America I ISBN: 978-1-53616-733-7 Editors: Maurício F Silva, Gustavo Nader Marta et al. © 2020 Nova Science Publishers, Inc.

Chapter 9

MANAGEMENT OF PANCREATIC CANCER

Sergio Pacheco1, MD, Andrés Troncoso1, MD, Nicolás Jarufe1,, MD, Rodrigo Torres-Quevedo2, MD, PhD, Fiona Lim3, MBBS, Bo Angela Wan4, MD(C) and Mauricio F Silva5,6,7, MD, PhD 1Department of Digestive Surgery, School of Medicine, Pontifical Catholic University of Chile, Santiago, Chile 2Hepatobiliary Surgery, University of Concepción, Guillermo Grant Benavente Hospital, Concepción, Chile 3Princess Margaret Hospital, Hong Kong, PR China 4Odette Cancer Centre, Sunnybrook Health Sciences Centre, Toronto, Ontario, Canada 5Radiation Oncology Unit, Santa Maria Federal University, Santa Maria, Brazil 6Radiation Oncology Unit, Hospital de Caridade Astrogildo de Azevedo, Santa Maria, Brazil 7Latin America Cooperative Oncology Group, Porto Alegre, Brazil

ABSTRACT

Pancreatic cancer is a gastrointestinal neoplastic disease with one of the worst prognoses. Despite aggressive surgical treatment with curative intent followed by adjuvant therapy, survival in these patients continues to be low. With the acquisition of new knowledge on imaging studies as well as diagnostic and therapeutic procedures in specialized centers, postoperative morbidity and mortality have decreased. In this chapter we will summarize pancreatic cancer with emphasis on studies of preoperative images, surgical treatment alternatives, and adjuvant therapy based on the evidence from several systematic reviews published in the literature.

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INTRODUCTION

The incidence of pancreatic cancer ranges from 8 to 12 per 100,000 people per year (1). The average age of presentation is 65 years. Worldwide, pancreatic cancer ranks 8th in deaths from cancer, with a survival rate of less than 20% at 1 year (2).

ANATOMIC-HISTOLOGICAL CLASSIFICATION

The pancreas is composed of endocrine and exocrine tissue, and each can give rise to a neoplasm (3). Of all pancreatic cancers, 95% is of exocrine origin. With respect to its anatomical location, 75% of cancers occur in the head and/or neck of the pancreas, 15-20% in the body and 5-10% in the tail (1).

PREOPERATIVE STUDY

Computed tomography (CT)

CT scan of the abdomen and pelvis is the most useful imaging study which provides the most information and staging of disease by evaluating the size of tumor, degree of tumor invasion, involvement of vascular structures, lymph node involvement and distant metastasis. It has a high sensitivity and specificity in lesions > 2 cm (close to 100%), however, this decreases to 77% in lesions smaller than 2 cm and to 67% in lesions

Magnetic resonance imaging (MRI)

MRI is not superior to CT and endosonography in staging, and even reports a lower sensitivity (84% vs. 91%). However, in the study of liver metastases, especially in patients with some type of liver damage (cirrhosis, steatosis, etc.), MRI is superior to CT in the investigation of small hepatic lesions (1).

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Positron emission tomography (PET) scan

This test in combination with CT (PET/CT) allows the detection of local and distant metastases. However, its use for staging is still controversial and is used only in selected cases. The uptake of 18-fluorodeoxyglucose is elevated in neoplastic cells. The sensitivity and specificity of the PET/CT is 94% and 90% respectively (1).

Endosonography (EUS)

This is the most sensitive examination for the detection of pancreatic lesions, even up to 2-3 mm, and is particularly useful in lesions smaller than 2 cm in which CT scans had lower sensitivity. For staging, it allows a better evaluation of the mesenteric axis, which is relevant in those patients with doubtful vascular compromise. The EUS can be complemented with a puncture of the fine needle lesion (FNA) of suspicious lesions (cystic tumors, lymph nodes) for cytological and tumor markers study (CEA, CA 19-9, mucin, etc.). It is also very useful to perform biopsies in borderline cases that are candidates for neoadjuvant treatment prior to surgery (1).

INVASIVE TECHNIQUES

Endoscopic retrograde cholangiopancreatography (ERCP)

ERCP provides a direct view of the papilla and duodenum, in addition to the instrumentation of the bile duct. It allows obtaining samples through brushing for cytology, performing contrast studies of the main bile duct, main pancreatic duct and detecting areas of stenosis or changes in caliber. However, it is not recommended as a diagnostic tool. In patients with jaundice that go to neoadjuvant or in those outside the therapeutic range, it allows the drainage of the bile duct with relief of jaundice and pruritus, as well as of infectious complications for the initiation of chemotherapy or as a palliative treatment (1).

Diagnostic laparoscopy

As mentioned above, sometimes imaging does not allow definition of the nature of small secondary lesions, both hepatic and peritoneal, which can be underdiagnosed up to 40% by CT. Laparoscopy is a useful tool in these cases. However, its ability to evaluate locally advanced tumors is limited. The use of laparoscopic ultrasonography improves the sensitivity in vascular invasion and detection of liver metastases. Diagnostic laparoscopy can modify therapeutic behavior between 4% and 40% (1).

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Table 1. Staging of pancreatic cancer AJCC seventh edition 2010

Stage Tumor (T) Regional lymph nodes (N) Metastasis (M) Description 0 Tis N0 M0 Carcinoma in situ. IA T1 N0 M0 Limited to the pancreas < 2 cm. IB T2 N0 M0 Limited to the pancreas > 2 cm. IIA T3 N0 M0 Extrapancreatic extension without arterial involvement. IIB T1,T2,T3 N1 M0 With metastases to regional lymph nodes. III T4 Any N M0 Commits the celiac trunk, its branches or the AMS. IV Any T Any N M1 Distant metastasis AMS: Superior mesenteric artery.

STAGING

Pancreatic cancer is staged according to the CT findings of the abdomen and pelvis, based on the TNM classifications of the AJCC (American Joint Committee on Cancer) in its 7th Edition 2010 (see table 1). Classically, TNM is defined as: tumor size, nodal involvement and distant metastasis, respectively. Depending on the above, they are classified in stages, which are directly related to the resectability of the tumor. Patients may have a localized disease (Stage I and II) and be amenable to resection, a locally advanced (Stage III) or metastatic disease (Stage IV). Regarding locally advanced tumors, there is a subgroup that may be susceptible to resection as long as patients meet certain conditions that will be mentioned later and subsequent to the use of chemo or neoadjuvant chemoradiation (borderline) (1).

TREATMENT AND PROGNOSIS

Surgery

The objective of the preoperative study is to classify patients into 3 groups: resectable, locally advanced/borderline and unresectable. Surgical resection is currently the only curative therapy for pancreatic cancer. However, only 20-30% of patients are resectable at the time of diagnosis. The approach will depend on the location of the tumor and its extension. Tumors that involve the head and are to the right of the mesenteric axis are resected by a pancreatoduodenectomy, with or without preservation of the pylorus. Tumors located to the left of the mesenteric axis are resected by a corporo-caudal pancreatectomy with or without splenic preservation. In cases of multifocal parenchymal involvement (for example, simultaneous cancers in the head and body of the pancreas) a total pancreatectomy is chosen (1). The resection indications have been extended in the past years. Currently mesenteric venous or portal venous compromise does not constitute a contraindication for resection. This can be carried out as long as an R0 resection is achieved (negative micro and macroscopic margins) and is technically possible (2).

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The subsequent reconstruction is achieved using vascular prosthesis or venous graft. With respect to those with arterial compromise, a category called borderline has been defined (4). These are tumors that have limited arterial compromise:

 Commitment less than 180 ° of the superior mesenteric artery, the celiac trunk and the common hepatic artery.  Commitment greater than 180 ° in a short segment of the common hepatic artery.

(A) CT coronal cut showing AMS commitment. (B) same tumor after three months of chemoradiotherapy, which shows regression of arterial involvement. (C) AMS: Superior Mesenteric Artery.

Figure 1. Cancer of the uncinate process of the pancreas.

It has been demonstrated after this type of tumor has been subjected to chemoradiotherapy, up to 30% have regression of arterial compromise, which allows its surgical resection (see figure 1). However, a variable percentage of them do not respond or even progress. Finally, there are no studies that show benefit in survival of arterial resection, even if this is R0.

Surgical techniques

Whipple operation Used in tumors to the right of the porto-mesenteric axis: pancreatic head and uncinate process. Corresponds to a pancreatoduodenectomy with or without antrectomy. The organs resected during the procedure are: the gastric antrum, gallbladder, distal bile duct, head of the pancreas and the entire duodenum. The reconstruction consists of: a pancreato-jejunum or pancreato-gastro anastomosis, hepatic-jejunal anastomosis and a gastro-jejunal anastomosis, all of these by a single loop of jejunum (Child's loop) or Roux-en-Y. Currently there are variations to the procedure such as the preservation of the pylorus (Longmire procedure) (1). Perioperative morbidity and mortality is variable, ranging between 20-40% and 2-5% respectively (see Figure 2) (5, 6).

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(A) Respective stage, and (B) reconstructive stage. AHC: Common Hepatic Artery, VMS: Superior Mesenteric Vein, AE: Splenic Artery, AGI: Left Gastric Artery.

Figure 2. Pancreatoduodenectomy without preservation of the pylorus, resective stage.

Distal pancreatectomy Choice procedure in tumors located to the left of the mesenteric axis. The preservation of the spleen is recommended in benign or malignant lesions of low grade. In adenocarcinoma, en bloc splenectomy is the procedure most used in order to extract all of the potentially compromised ganglia. The main complication of this procedure is the pancreatic fistula of the stump that can occur between 10 to 40% of cases (5, 7, 8).

Total pancreatectomy This is used in patients with multifocal lesions or intraductal papillary mucinous neoplasms (IPMN) of the main branch, malignant or not, which compromise the entire pancreatic duct. This procedure is associated with an important metabolic morbidity, highlighting the difficulty of managing diabetes associated with important episodes of hypoglycemia. The loss of exocrine function of the pancreas produces persistent diarrhea and steatorrhea. Due to the above it must be only indicated in very selected cases (1, 5).

Results of the surgery

The surgery alone gives a global survival close to 17% at 5 years and 9% at 10 years (9). That is why adjuvant treatment is a necessity to improve survival after surgery, which increases up to 25-30% at 5 years. In borderline tumors with pre-operative chemotherapy and which are then resected, survival is close to non-borderline tumors (10). The predictors of long-term survival are: tumors less than 3 cm in diameter, lymph nodes without neoplastic compromise and negative margins. The factors that are associated with postoperative recurrence and low survival are: lymphatic spread, tumor size greater than 2.5 cm and vascular invasion (1).

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Adjuvant therapy

Due to the risk of recurrence or persistence of disease even after R0 surgery, adjuvant treatment arises as an attempt to prolong survival. The use of chemotherapy or chemoradiotherapy in these patients has shown an improvement in overall survival and disease-free survival compared to surgery alone (11). Chemotherapy consists of the use of pyrimidine analogs such as 5-fluorouracil and analogs of nucleosides such as gemcitabine. The use of associated radiotherapy is controversial, since European studies have shown a lower survival than groups treated only with chemotherapy. The long-term results demonstrate a median survival of 20-23 months and 22-29% at 5 years (regardless of the drug and dose of radiation received) (12).

Neoadjuvant therapy and borderline tumors

There is a subgroup of locally advanced tumors that, given their characteristics (borderline), benefit from the use of preoperative chemo- or radiotherapy in order to evaluate their response and eventual resection (13). This has allowed between 30-60% of these patients who were previously considered unresectable to reach surgery and receive adjuvant treatments, with survival medians close to 30 months (14). Regarding the use of chemo or chemoradiotherapy in patients with resectable tumors prior to surgery (neoadjuvant), the results are promising and derive mainly from phase III studies. The use of this treatment strategy is based on: the low percentage of patients who manage to reach and complete adjuvant therapy (due to surgical, nutritional, poor tolerance, etc.), the micrometastasis treatment prior to surgery, which would increase the possibility of R0, the self-selection of patients with more aggressive and biologically distinct tumors that do not respond and progress during the neoadjuvant period, and the fact that the best delivery of the therapy is to a tumor that is intact and well irrigated (15). Several initial studies have shown a higher percentage of resectability, R0 and median survival (33 months) in patients undergoing neoadjuvant therapy (12, 16).

Unresectable disease: Palliative treatment

The objective in this type of patient is to provide adequate symptomatic management of jaundice, gastroduodenal obstruction and pain (17). Currently there are endoscopic and percutaneous alternatives to achieve this with the use of long-term prostheses (metal) both in the bile duct and in the duodenum. About 30% of patients with biliary obstruction will develop duodenal obstruction within the next 6 months so any palliative procedure should consider unclogging or bypass of the stomach and / or duodenum. However, sometimes this is not possible, so it is necessary to resort to surgical palliation consisting of a bilio-digestive anastomosis associated with a gastrojejunal-anastomosis (18). In addition, it is convenient to perform an alcoholization of the celiac plexus, which has been shown to significantly improve the quality of life by decreasing the consumption of narcotic analgesics. Additionally, palliation allows the patient to access palliative chemo- or radiotherapy. The ablation of the celiac plexus is also possible with percutaneous techniques and lately by endosonography with good results in terms of effectiveness of pain relief (12, 17). Complimentary Contributor Copy 100 Sergio Pacheco, Andrés Troncoso, Nicolás Jarufe et al.

Palliative chemotherapy has shown benefits in these patients, improving overall survival up to a median of 10-12 months. Schemes based on pyrimidine analogues such as 5- fluorouracil (5-FU), nucleoside analogues such as gemcitabine and platinum such as oxaliplatin are used. The latter in combination with 5-FU (FOLFIRINOX) has shown better results in survival than schemes using monotherapy (19, 20, 21).

REFERENCES

[1] Gong J, Tuli R, Shinde A, Hendifar AE. Meta-analyses of treatment standards for pancreatic cancer. Mol Clin Oncol 2016;4(3):315-25. [2] Lassen K, Coolsen MM, Slim K, Carli F, de Aguilar-Nascimento JE, Schäfer M, et al. Guidelines for perioperative care for pancreaticoduodenectomy: enhanced recovery after surgery (ERAS®) Society recommendations. World J Surg 2013;37(2):240-58. [3] Mao Y, Tao M, Jia X, Xu H, Chen K, Tang H, Li D. Effect of diabetes mellitus on survival in patients with pancreatic cancer: a systematic review and meta-analysis. Sci Rep 2015;5:e17102. [4] Denbo JW, Fleming JB. Definition and management of borderline resectable pancreatic cancer. Surg Clin North Am 2016;96(6):1337-50. [5] Michalski CW, Kleeff J, Wente MN, Diener MK, Büchler MW, Fries H. Systematic review and meta- analysis of standard and extended lymphadenectomy in pancreaticoduodenectomy for pancreatic cancer. Br J Surg 2007;94(3):265-73. [6] Ammori JB, Choong K, Hardacre JM. Surgical therapy for pancreatic and periampullary cancer. Surg Clin North Am 2016;96(6):1271-86. [7] Ricci C, Casadei R, Taffurelli G, Toscano F, Pacilio CA, Bogoni S, et al. Laparoscopic versus open distal pancreatectomy for ductal adenocarcinoma: a systematic review and meta-analysis. J Gastrointest Surg 2015:19(4):770-81. [8] Yang J, Huang Q, Wang C. Postoperative drain amylase predicts pancreatic fistula in pancreatic surgery: a systematic review and meta-analysis. Int J Surg 2015;22:38-45. [9] Gurusamy K, Toon C, Virendrakumar B, Morris S, Davidson B. Feasibility of comparing the results of pancreatic resections between surgeons: a systematic review and meta-analysis of pancreatic resections. HPB Surg 2015;2015:e896875. [10] Tol JA, Eshuis WJ, Besselink MG, van Guilk TM, Busch Or, Gouma DJ. Non-radical resection versus bypass procedure for pancreatic cancer - a consecutive series and systematic review. Eur J Surg Oncol 2015;41(2):220-7. [11] Martin RC. Management of locally advanced pancreatic cancer. Surg Clin North Am 2016;96(6):1371-89. [12] Paulson AS, Tran Cao HS, Tempero MA, Lowy AM. Therapeutic advances in pancreatic cancer. Gastroenterology 2013;144(6):196-203. [13] Lee JC, Ahn S, Paik KH, Kim HW, Kang J, Kim J, et al. Clinical impact of neoadjuvant treatment in resectable pancreatic cancer: a systematic review and meta-analysis protocol. BMJ Open 2016;6:e010491. [14] Evans DB, Erickson BA, Ritch P. Borderline resectable pancreatic cancer: definitions and the importance of multimodality therapy. Ann Surg Oncol 2010;17(11):2803-5. [15] D’Angelo F, Antolino L, Farcomeni A, Sirimarco D, Kazemi Nava A, De Siena M, et al. Neoadjuvant treatment in pancreatic cancer: evidence-based medicine? A systematic review and meta-analysis. Med Oncol 2017;34(5):85. [16] Zhan HX, Xu JW, Wu D, Wu ZY, Wang L, Hu SY, et al. Neoadjuvant therapy in pancreatic cancer: a systematic review and meta-analysis of prospective studies. Cancer Med 2017;6(6):1201-19. [17] Cannistrà M, Ruggiero M, Zullo A, Serafini S, Grande R, Nardo B. Metastases of pancreatic adenocarcinoma: a systematic review of literature and a new functional concept. Int J Surg 2015;21:S15-21.

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[18] Gillen S, Schuster T, Friess H, Kleeff J. Palliative resections versus palliative bypass procedures in pancreatic cancer - a systematic review. Am J Surg 2012;203(4):496-502. [19] Michalski CW, Erkan M, Hüser N, Müller MW, Hartel M, Friess H, et al. Resection of primary pancreatic cancer and liver metastasis: a systematic review. Dig Surg 2008;25(6):473-80. [20] Rombouts SJ, Walma MS, Vogel JA, van Rijssen LB, Wilmink JW, Mohammad NH, et al. Systematic review of resection rates and clinical outcomes after FOLFIRINOX-Based treatment in patients with locally advanced pancreatic cancer. Ann Surg Oncol 2016;23(13):4352-60. [21] Kim KS, Kwon J, Kim K, Chie EK. Impact of resection margin distance on survival of pancreatic cancer: a systematic review and meta-analysis. Cancer Res Treat 2017;49(3):824-33.

Chapter 10

MANAGEMENT OF INTRAHEPATIC CHOLANGIOCARCINOMA

Juan Carlos Díaz1,, MD, Alexandre Sauré1,2, MD, Carlos Mandiola1, MD, PhD, Rodrigo Torres-Quevedo3, MD, PhD, Fiona Lim4, MBBS, Bo Angela Wan5, MD(C) and Mauricio F Silva6,7,8, MD, PhD 1Hepato-Pancreato-Biliary and Liver Transplant Surgery, Department of Surgery, University Hospital, Santiago, Chile 2Department of Basic-Clinical Oncology School of Medicine, University of Chile, Santiago, Chile 3Hepatobiliary Surgery, University of Concepción, Guillermo Grant Benavente Hospital, Concepción, Chile 4Princess Margaret Hospital, Hong Kong, PR China 5Odette Cancer Centre, Sunnybrook Health Sciences Centre, Toronto, Ontario, Canada 6Radiation Oncology Unit, Santa Maria Federal University, Santa Maria, Brazil 7Radiation Oncology Unit, Hospital de Caridade Astrogildo de Azevedo, Santa Maria, Brazil 8Latin America Cooperative Oncology Group, Porto Alegre, Brazil

ABSTRACT

Intrahepatic cholangiocarcinoma (ICC) is the second most common primary liver tumor and the incidence is increasing worldwide. ICC originates from the epithelial cells of the intrahepatic bile ducts. Most of the risk factors for the development of ICC are related to pathologies affecting the biliary system that produce chronic biliary inflammation, bile stasis and cirrosis. Surgery is the only treatment option that offers a chance of long-term survival, but the resectability and curability remain low. The role of liver transplantation is controversial. Locoregional and systematic therapies may provide survival benefits,

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especially in patients with unresectable tumors. Multidisciplinary approaches are necessary to improve the outcomes of ICC.

INTRODUCTION

Cholangiocarcinoma is a pathological entity that includes various epithelial tumors with characteristics of cholangiocyte differentation. They are tumors that compromise the biliary epithelium, localized from its origin at intrahepatic level to the distal biliary tract. According to its anatomical location, cholangiocarcinoma can be classified as intrahepatic, if it arises in peripheral bile ducts within the hepatic parenchyma to the secondary biliary radicals, and extrahepatic if the tumor is located distal to these – excluding the ampulla of Vater. The cystic duct is the anatomical reference that distinguishes perihilar cholangiocarcinoma from distal cholangiocarcinoma (1) (see Figure 1). Each of these cholangiocarcinoma subtypes display a particular epidemiology, tumor biology and distinctive prognosis, which implies the need for a different clinical and therapeutic approachs. In this chapter, a review of such aspects will be made with emphasis on intrahepatic cholangiocarcinoma (ICC).

Figure 1. Types of cholangiocarcinoma. Adapted from Blechacz B, Komuta M, Roskams T, Gores GJ. Clinical diagnosis and staging of cholangiocarcinoma. Nat Rev Gastroenterol Hepatol 2011;8(9):512- 22.

Epidemiology

Cholangiocarcinoma is the most common hepatic malignancy after hepatocellular carcinoma, accounting for 3% of all gastrointestinal malignancies. Overall, perihilar and distal

Complimentary Contributor Copy Management of intrahepatic cholangiocarcinoma 105 cholangiocarcinoma represent 80% of all these tumors, being approx 50-60% perihilar and 20-30% distal (2, 3). The remaining 20% corresponds to intrahepatic cholangiocarcinomas. Globally, cholangiocarcinoma has had a progressive increase in its incidence during the last 4 decades, showing a clear geographical distribution (4). Its highest incidence is observed in East Asian countries, reaching more than 80 new cases per 100,000 inhabitants in Thailand, which exceeds the incidence of hepatocellular carcinoma in this region (4). In Western countries, the incidence of cholangiocarcinoma is 1-2 cases per 100,000 inhabitants, with the United States reporting ranges between 0.72 and 1.67 per 100,000 (5). It is interesting to note that the incidence of intrahepatic cholangiocarcinoma in the United States between 1992 and the year 2000 experienced an annual increase of 4%, while extrahepatic cholangiocarcinoma remained with an annual increase of 1% in the same period (6). The increase in incidence observed in this pathology has occurred independently of the tumor size or stage of disease, so it seems unlikely that it is due to its earlier detection, and instead suggests there being a real increase in the incidence of intrahepatic cholangiocarcinoma (7). Although the causes of these observations are unknown, this could be reflecting an increase in the risk factors identified for this entity, which in turn, could present a certain geographic aggregation. It should also be noted that the explanation for the differences in incidence rates referred to may correspond to certain ethnic variations observed within the same population. Thereby, it has been determined that the population of Hispanic-American origin has a higher incidence of intrahepatic cholangiocarcinoma (1.22 per 100,000) compared with African- Americans who have a lower incidence of approximately 0.3 per 100,000, which suggests that genetic characteristics could determine a differential susceptibility to the development of this disease (8).

Risk factors

Most of risk factors identified for the development of cholangiocarcinoma are associated with a process of irritation and chronic inflammation of the bile duct, and are shared by both intrahepatic and extrahepatic cholangiocarcinoma. Thus, it is known that the risk of primary diseases of the bile duct, such as primary sclerosing cholangitis and primary biliary cirrhosis, represent as risk factors for the development of ICC. Patients with primary sclerosing cholangitis present a risk of ICC of 5-10% during the lifetime, with half of the cases diagnosed within the first two years of diagnosis and at an earlier age, between the 3rd and 5th decade of life (9). Additionally, a higher risk of ICC has been demonstrated in patients with ulcerative colitis, but not in Crohn's disease (10). Cystic dilatations of bile duct, such as Caroli's disease or fibrocystic disease of the liver, have been associated with a 15% risk of ICC after the second decade of life. Biliary stasis, cholangitis and chronic inflammation of the biliary tract have been suggested as drivers of such risk (11).

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Parasitic infections by Clonorchis sinensis and Opisthorchis viverrini that compromise the bile duct and liver are well established risk factors for cholangiocarcinoma. 8-10% of people chronically infected with these parasites will develop ICC (9). The endemic infection by these agents in East Asian populations partially explains the higher incidence rates of cholangiocarcinoma observed in these geographical areas. Other variables associated with an increased risk of intra and extrahepatic cholangiocarcinoma are chronic pancreatitis, thyrotoxicosis, liver cirrhosis and alcoholic liver disease (12). Along with the above-mentioned factors, exposure to chemical agents such as thorium dioxide, asbestos and radon have been described as carcinogenic agents associated with the development of cholangiocarcinoma of historical significance, as well as occupational exposure to 1,2-dichloropropane and dichloromethane (9). Intrahepatic cholangiocarcinoma, in turn, has its own risk factors, some of which are shared with hepatocellular carcinoma. In this context, infection by hepatitis virus has been associated with an increased risk of ICC, with a 23% positive serology for HCV reported in patients with ICC vs 6.1% in control subjects, as well as genetic material of hepatitis C and B virus were integrated within 27% of samples of resected ICC tumors (13, 14). Although the association between infection with hepatitis B virus and ICC has been reported, the level of evidence is more controversial.

Table 1. Histologic classification of ICC and association with clinicopathologic, immunohistochemical, and molecular features. Adapted from Krasinskas AM. Cholangiocarcinoma. Surgical Pathol Clin 2018, 11(2):403-29

Histologic classification of ICC and association with clinicopathologic, immunohistochemical, and molecular features Large duct type (type 1) Small duct type (type 2) Location Perihiliar Peripheral Background condition Chronic biliary disease/hepatolithiasis Chronic liver disease, viral hepatitis, cirrosis Precursor lesión + (BilIN, IPNB, ITPN) (occasionally ITPN) Macroscopic growth pattern Variable (PI, IG, +/- MF) Mass forming Shape of tumor cells Columnar Cuboidal to low columnar Mucin production ++ +/- Gland morphology Large, widely spaced glands (similar Small tubules, fused or anastomosing glands to ECC); poorly differentiated Tumor fibrosis Diffuse, desmoplastic Central, sclerotic Perineural invasion ++ - LVI/LN metastases ++ +/- Tumor border Infiltrative Expansile or pushing, 1/Infiltrative Inmunophenotype S100P and TFF1 CD56 (NCAM), N-cadherin, CRP Molecular alterations KRAS mutations, FGFR2 IDH1/IDH2 mutations Translocations Abbreviations: BilIN, biliary intraepithelial neoplasia; CRP, C-reactive protein; ECC, extrahepatic cholangiocarcinoma; ICC, intrahepatic cholangiocarcinoma; IG, intraductal growth; IPNB, intraductal papillary neoplasm of bile duct; ITPN, intraductal tubulopapillary neoplasm; LN, lymph node; LVI, lymphovascular invasion; MF, mass forming; NCAM, neural cell adhesion molecule; PI, periductal infiltrating; -, rare; +/-, uncommon; +, common.

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Steatosis and non-alcoholic steatohepatitis, in the context of a metabolic syndrome, with obesity and type II diabetes mellitus, are risk factors associated with ICC. Non-specific liver cirrhosis has been identified as a strong predictor of ICC development (OR, 27.2; 95% CI, 19.9–37.1) (10). The clinical manifestation of the previously described variables and their pathogenic role in the development of chronic liver damage, leads to the process of hepatic fibrosis and cirrhosis, which could explain the association observed with ICC and hepatocellular carcinoma. In this sense, a common pathogenic mechanism has been proposed for both primary hepatic tumors, where the existence of carcinomas with hepatocellular and cholangiocellular component could correspond to an intermediate phase. The prevalence of these risk factors in addition to others, such as smoking and alcoholic liver disease, could partly explain the increase in the incidence of intrahepatic cholangiocarcinoma observed in Western countries during the last decades (10). Finally, biliary lithiasic disease is a known risk factor for bile duct cancer, with a strong association between the incidence of ICC and hepatolithiasis. Thus, in the Asian population the coexistence of hepatolithiasis has been demonstrated in up to 70% of resected cholangiocarcinomas (9). Despite the identification of multiple variables that could be involved in the development of intrahepatic cholangiocarcinoma, it should be noted that in 40% of cases of diagnosed ICC, no such risk factors are identified, suggesting the need for further research in this topic.

Pathology

Cholangiocarcinoma can also be classified based on its macroscopic pattern, its histological characteristics, and the cells from which it possibly originates. Taken together, these classification criteria are associated with a profile of clinical characteristics and risk factors present in the patients (15). From a macroscopic point of view, cholangiocarcinoma can acquire diverse growth patterns. The first one corresponds to tumors that show a mass forming pattern, consisting of solid tumors with firm consistency, well defined, grayish-white, not encapsulated, which in turn can form polylobular masses within the liver at a distance from hilum, without macroscopically discernible connections to a bile duct. The second is the periductal infiltrating type, characterized by a pattern of dissemination along the intrahepatic portal tracts associated with stenosis of the compromised ducts, with secondary proximal dilation and cholangitis. The intraductal growth type tumor is characterized by a papillary or polypoid lesion that grows inside of a dilated bile duct, and finally, a mixed growth pattern, determined by the combination of the previously indicated patterns (15, 16). Most ICC (65%) presents as a mass-forming type of tumor, while the periductal infiltrating and intraductal growth types tumors represent a significantly lower proportion rates with 6% and 4% respectively. 25% of all remaining cases of ICC are mixed type, combining mainly a mass-forming tumor with periductal infiltrating pattern. In turn, there is a relationship between the macroscopic growth patterns of ICC and the site of origin in the biliary tree, where tumors arising from ductules or small bile portal ducts, preferably develope tumors with a forming-mass growth pattern, whereas those arising from second- order bile ducts or intrahepatic segmental ducts more frequently show tumors with periductal infiltrating patterns, intraductal patterns, or mixed growth. Additionally, a ICC tumor could Complimentary Contributor Copy 108 Juan Carlos Díaz, Alexandre Sauré, Carlos Mandiola et al. arise from a non-invasive intraductal papillary neoplasm of a bile duct, which extends intraductally and superficially along the surrounding bile duct epithelium (16). In more advanced stages, multiple intrahepatic metastases of different sizes can arise with intrahepatic coalescent masses, which makes it difficult to characterize the initial growth pattern, usually observing a combination of these. Each of these types of growth patterns presents certain clinical characteristics with variable prognostic results, suggesting different biological behaviors. In this way, the forming-mass pattern without hilar invasion presents a lower survival after surgical resection compared with periductal infiltrating pattern, while mixed behavior tumors with forming- mass and periductal infiltrating type show a higher risk of portal vein invasion, lymph node involvement and positive surgical margins after resection, which determines a worse prognosis compared to other types of ICC (17). In turn, periductal infiltrating tumors and intraductal growth type may manifest with jaundice and cholangitis, associated with intrahepatic biliary fibrosis. Lymph node invasion rate of the IG-type is lower than those of the other types (16). Histologically, intrahepatic cholangiocarcinoma corresponds to a well, moderatel or poorly differentiated adenocarcinoma with variable degrees of desmoplasia and abundant irregularly distributed stroma. The tumor usually presents with a fibrotic center with foci of calcification or necrosis, associated with a peripheral zone where there are greater numbers of proliferating tumor cells, which invade the surrounding tissue by compression and/or infiltration along sinusoids with hepatocyte replacement, leaving the portal tracts included within the tumor mass. From early stages, invasion of portal veins, lymphatics and intrahepatic nerves is common. In addition to the classic adenocarcinoma previously described, there are rare histological variants that include squamous cell carcinoma and adenosquamous, mucinous, signet ring cell carcinoma, clear cell carcinoma, undifferentiated, lymphoepithelioma-like carcinoma, mucoepidermoid, neuroendocrine type and sarcomatous variant (15). Recently, in considering new research findings, a new histological classification of ICC was proposed, which has been associated with specific clinicopathological, immunohistochemical and molecular characteristics, differentiating it into two types: large duct (type 1) and small duct (type 2) (18). The large duct type develops from mucin-producing cholangiocytes present in large intrahepatic bile ducts (segmental and septal bile ducts). Tumor cells resemble those of the bile duct, with high columnar cells that usually contain mucin and form large glands within open luminal spaces, often associated with abundant desmoplastic stroma. The small duct ICC develops from cuboidal non-mucin-producing cholangiocytes present in small intrahepatic bile ducts, i.e., interlobular bile ducts and ductals. Tumor cells are similar to cholangiolar cells, cuboidal in appearance with little eosinophilic or amphophilic cytoplasm, which often form small or confluent glands without mucin production. In relation to clinicopathological aspects, the ICC of the large duct type is characterized by a predominantly perihilar location, conforming tumors of smaller size, unique, and with a greater degree of lymphatic and perineural invasion, compared to the ICC of the small duct type. In turn, large duct tumors occur more frequently in patients with chronic biliary disease and hepatolithiasis, associated with precursor lesions (intraductal biliary neoplasia, intraductal papillary neoplasm of the bile duct and intraductal tubulopapillary neoplasia), acquiring a variable growth pattern in its macroscopic presentation, mainly periductal infiltrating and Complimentary Contributor Copy Management of intrahepatic cholangiocarcinoma 109 intraductal growth patterns; while small ductal type ICC developes in patients with chronic liver disease/cirrhosis, especially of viral origin, forming tumors of predominantly peripheral location, sometimes multiple, that acquire a forming-mass type growth pattern (15, 16, 18) (Table 1). There are other classifications of recent use, which consider variables similar to those previously described, with certain cytological and histological architecture variants (19). As previously noted, ICC is considered a tumor that arises from topographically heterogeneous cholangiocytes within the different levels of the intrahepatic biliary tree. However, it is currently estimated that ICC could develop from any type of liver cell, due to cellular plasticity secondary to mechanisms of genetic reprogramming. Thereby, the ICC could develop from the intrahepatic epithelial surface of small and large bile ducts, as well as peribiliary glands, from the malignant transformation of biliary ducts, from liver pluripotent stem cells located of canals of Hering or peribiliary glands, and even from adult hepatocytes, through an oncogenic reprogramming process (20, 21). It is accepted that cholangiocarcinomas and hepatocellular carcinomas arise from different stem cell niches. However, recently it has been proposed that hepatic progenitor cells located in bile ductules that can differentiate into both in hepatocytes and cholangiocytes could be the origin of tumors with a mixed hepatocellular and cholangiolar differentiation component, which would explain the existence of hepato-cholangiocarcinomas that represent less than 1% of all primary liver tumors (16). Furthermore, one study has shown that up to 39% of cholangiocarcinomas show a histological diversity that includes focal hepatocytic differentiation and ductular areas (mixed tumors), these being similar to small duct type tumors (18). Currently, it has been proposed that tumors that are not classic hepatocarcinomas or cholangiocarcinomas can be classified as 1-combined hepato-cholangiocarcinoma (a tumor with mixed hepatocytic and cholangiocytic features or in separate areas within the same tumor), 2-intermediate cell carcinoma or 3-cholangiolocarcinoma (22).

STAGING

The most used ICC classification system recommended by expert consensus is that proposed by the AJCC with the TNM staging. In the 7th edition, the T category is based on the number of tumor nodules, vascular invasión, and direct extension to extrahepatic tissues. In the latest 8th edition, this also includes the tumor size, which introduces a cut-off point of 5 cm separating T1 category into subgroups T1a and T1b (23). In addition, the periductal invasion is no longer part of the T classification because it is a growth pattern that has an uncertain association with the outcomes. Thus, the T3 category are tumors that perforate the visceral peritoneum, while T4 are tumors that compromise local extrahepatic structures by direct invasion (see table 2). For the 8th edition, there are no changes in lymph node staging, which is based on the presence or absence of lymph node metastases (23). It should be noted that the recovery of at least 6 lymph nodes is recommended for a complete lymph node staging.

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Table 2. Staging of carcinomas of the intrahepatic bile ducts (Intrahepatic cholangiocarcinomas). Adapted from Amin MB, Edge SB, Greene FL, et al. AJCC cáncer staging manual. 8th edition. New York: Springer, 2017

AJCC staging classification (8th edition, 2017) pTX Primary tumor cannot be assessed pT0 No evidence of primary tumor pTis Carcinoma in situ (intraductal tumor) pT1 Solitary tumor without vascular invasion, ≤5 cm or >5 cm pT1a Solitary tumor ≤5 cm without vascular invasion pT1b Solitary tumor >5 cm without vascular invasion pT2 Solitary tumor with intrahepatic vascular invasion, or multiple tumors, with or without vascular invasión pT3 Tumor perforating the visceral peritoneum pT4 Tumor involving local extrahepatic structures by direct invasión N0 No regional lymph node metástasis N1 Regional lymph node metastasis present M0 No distant metastasis M1 Distant metástasis present Stage T N M Ia T1a N0 M0 Ib T1b N0 M0 II T2 N0 M0 IIIa T3 N0 M0 IIIb T4 N0 M0 T4 N1 M0 IV Any T Any N M1 Abbreviation: AJCC, American Joint Committee on Cancer.

DIAGNOSIS

The clinical presentation of intrahepatic cholangiocarcinoma is usually non-specific, and patients with early stages of the disease are usually asymptomatic. Patients may present symptoms such as abdominal pain, malaise, weight loss, and in more advanced cases, hepatomegaly and/or palpable mass (24). Biliary tract obstruction is relatively uncommon in patients with intrahepatic cholangiocarcinoma, but when the tumor grows toward the biliary confluence, some patients may present with painless jaundice. The diagnosis of ICC is challenging due to its low incidence and its non-specific presentation. Nevertheless, its diagnosis can be based on clinical presentation, laboratory tests and, especially, on a careful interpretation of imaging studies. Although biopsy of the lesion allows confirmation of the diagnosis, it is not routinely recommended or necessary if the patient is a candidate for surgical resection, while pathologic diagnosis would be mandatory if systemic chemotherapy and/or radiation therapy are planned. If it is performed, a negative pathological study does not rule out the diagnosis, due to sampling error, while in case of being positive, the most frequent finding is an adenocarcinoma with a certain degree of associated fibrous stroma. If the pathological study shows a non-specific adenocarcinoma, and the lesion is radiologically indeterminate, the diagnostic strategy should include the search for a primary tumor mainly of gastrointestinal origin (25). Plasma markers for intrahepatic cholangiocarcinoma tend to have high specificity but low sensitivity. The carbohydrate antigen 19-9 (CA 19-9) is the most used but it is not specific, being able to rise due to benign causes as well as by other tumors. Thus, CA 19-9 is elevated Complimentary Contributor Copy Management of intrahepatic cholangiocarcinoma 111 in 50% of patients with intrahepatic cholangiocarcinoma, while carcinoembryonic antigen (CEA) is elevated in 15-20% of cases (24). Thereby, both markers are not sensitive enough to definitively rule out the diagnosis of ICC when they are within normal ranges, whereas if CA 19-9 rises to values above 1000 U/mL, it has been associated with the presence of metastatic disease (26). Occasionally, transabdominal ultrasound is the first imaging modality that detects a suspicious lesion. In these cases, a suggestive image of ICC is a hypoechoic mass that could be associated with peripheral ductal dilatation, although these findings are not specific. The use of contrast in ultrasonography could show lesions with greater enhancement when there is a high density of cancer cells (27), however, this finding is also not specific for intrahepatic cholangiocarcinoma. On computed tomography (CT), the typical ICC image is characterized by a hypodense liver mass with irregular margins in the non-contrasted phase, with peripheral ring reinforcement in the arterial phase and progressive hyperatenuation in venous and delayed phases. Also, it may show retraction of the capsule, indicating hepatic atrophy (28). ICC is characterized by contrast uptake from the arterial to the venous phase, with increased uptake in delayed phases. This finding indicates a fibrous component that is slow to enhance but, in turn, retains contrast medium in delayed phases. In magnetic resonance imaging (MRI), the dynamics of contrast medium uptake for lesions suggesting ICC is similar to pattern observed in CT, with peripheral enhancement in arterial phase, followed by progressive and concentric filling in delayed stages. The ICC typically appears hypointense in T1-weighted images, and hyperintense in T2-weighted images, occasionally showing a central hypointensity suggestive of fibrotic areas in T2- weighted images (29). MRI with cholangiopancreatography has a diagnostic accuracy of up to 93%, and can help in visualizing the ductal system and vascular compromise, determining the anatomical extension of the tumor (30). The utility of positron-emission tomography (PET) for ICC diagnosis when CT and MRI have been performed is limited, and although 80-90% of tumors present high uptake of fluorodeoxyglucose, in the absence of suspected extrahepatic disease in the CT or MRI, the additional usefulness of PET has been questioned (25). Nevertheless, some studies have suggested that the use of FDG-PET could identify hidden metastatic disease in up to 20-30% of cases, and sometimes help rule out a hidden primary tumor (31). Therefore, the consensus recommendation of a group of experts is to selectively use this imaging test (25).

TREATMENT

Surgical resection with free margins (R0), remains up to now the only therapy with curative possibility for patients with ICC, achieving survival of 15-40% at 5 years and chances of cure close to 10% in selected cases (2, 24, 32, 33). This low cure rate is due to the difficulty in achieving free margins, the presence of metastasis and vascular compromise at the time of diagnosis produced by late detection in many cases (33-35). In fact, it is estimated that in order to fully resect the lesion (R0), 70% of the patients will require an extended hepatectomy, 20% of the bile duct will be resected and

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5% will require associated vascular resection, mainly venous. This radical resection is associated with morbidity greater than 50% and mortality up to 7% (34, 35-37). For many, arterial involvement (common hepatic artery or bilateral involvement of hepatic arteries), the presence of extrahepatic disease and the involvement of celiac trunk ganglia or para-aortic arteries are contraindication for surgery (38). Factors of poor prognosis are compromised margins, the size of the lesion, number of lesions, vascular invasion, the presence of associated cirrhosis, multifocality and the most important predictor, the presence of metastatic lymph nodes (35, 39, 40). Recurrence affects 50% of patients resected at one year, with intrahepatic recurrence being the most common (61%), followed by lymph node involvement 20-30% and in peritoneal metastasis in 20% (41-43).

Routine lymphadenectomy

Routine lymphadenectomy in ICC remains controversial, although between 25% to 50% of patients have positive lymph nodes at the time of surgery (38, 39, 42, 44, 45). This is probably due to the fact that until the 6th edition of the AJCC, ICC was classified together with hepatocellular carcinoma, and there it was considered that lymph node metastasis was unlikely. In addition, the lymphatic drainage of the liver is variable so that distant limph node metastases are likely to occur via multidirectional lymphatic outflow from the liver (46). What is clear is that routine lymphadenectomy does not improve prognosis or prevent recurrence, but it does have a role in improving patient staging (47, 48). In fact, patients with lymph node metastases have an average survival between 7 to 14 months (34, 42). Despite this, current consensus recommends routine lymphadenectomy of the hepatoduodenal ligament and the common hepatic artery (25). If the tumor is located in the right liver, it is recommended to associate the lymphadenectomy of the retropancreatic ganglia; however, if the tumor is located in the left liver, the nodes should be resected around the gastric cardia and the lesser curvature (25, 46). There is not yet an optimal number of resected nodes.

Staging laparoscopy

According to the literature, laparoscopy can avoid resective surgery in 25-36% of patients considered resectable initially, due to the finding of hidden metastases, especially if intraoperative ultrasonography is used (49-51). We believe that staging laparoscopy can be used in patients at high risk of having disseminated disease, like the presence of multicentric disease, suspicion of carcinomatosis in the images, suspected vascular invasion or elevated CA 19-9 (25).

Liver transplant

Liver transplantation is not yet a standard indication for ICC treatment due to the high recurrence of the disease and poor results observed in the retrospective series. However, Complimentary Contributor Copy Management of intrahepatic cholangiocarcinoma 113 promising results have been reported lately (83% survival at 5 years) (52). Regrettably the studies in most cases are retrospective, have few patients and the admission protocols are very different among them. We believe that in order to apply for this therapy, patients must have stable disease during neoadjuvant theraphy and they can not present with extrahepatic disease nor lymph node involvement, or vascular compromise (52, 53).

Systemic therapy in ICC

We know that the only curative therapy for ICC is complete resection; however more than 60% of the patients will have intrahepatic reccurence or metastatic desease and that is why some type of systemic therapy is desirable (41, 43). Unfortunately most studies about this therapy are Phase III, have few patients, include patients with incomplete resection and include other types of cancers such as gallbladder, extrahepatic cholangiocarcinoma and ampulla (54, 55). Adjuvant studies that only include ICC are mainly performed with chemotherapy used in pancreatic cancer based on gemcitabine, gemcitabine with capecitabine or gemcitabine with platinum analogue (cisplatin) (56). These studies found better survival in patients with adjuvant treatment; however this difference is diluted in the multivariate analysis. A recently published meta-analysis found that only patients with lymph node disease or positive margins benefitted from adjuvant treatment (57, 58). For patients with poor or non-response to these drugs, the options for second line chemotherapy include gemcitabine with capecitabine, FOLFOX or FOLFIRI (59).

Radiofrequency

Because ICC is a relatively uncommon disease with a poor prognosis, most studies evaluating radiofrequency are retrospective, with few patients. Furthermore, according to a study using the Surveillance, Epidemiology, and End Results (SEER) database, only 5.2% of patients receive radiofrequency as a single treatment, so it is difficult to establish the specific role of radiofrequency for ICC treatment (60). Apparently, the best results would be obtained in patients with unresectable disease or for intrahepatic recurrence, especially if the lession measures less than 3.5 cm in diameter. In this scenario, average survival of 20 months and 5-year survival up to 24% is described (61).

Intra-arterial embolotherapy

The most commonly used techniques are conventional transcatheter arterial chemoembolization (cTACE), drug-eluting beads (DEB)-TACE and Yttrium-90 radioembolization (Y90-RE) (62). Conventional TACE is the most commonly used in ICC. This modality consists of an emulsion of chemotherapeutics and an oil-based contrast agent (Ethiodol or Lipiodol) that is injected into the tumor-supplying branch of the hepatic artery, followed by the administration Complimentary Contributor Copy 114 Juan Carlos Díaz, Alexandre Sauré, Carlos Mandiola et al. of an embolizing agent. In the West, the most commonly used drug combination is doxorubicin, cisplatin, mitomycin-C, in form of emulsion with Lipiodol (63). The majority of the studies are retrospective and their main application would be in unresectable patients with median overall survival of 11-33 months (64). DEB-microspheres are administered in the same manner as cTACE, but they can also be loaded with specific chemotherapeutic agents (doxorubicin or irinotecan) and also have the potential of embolizing, increasing the exposure of the tumor to the drug. In most studies they are used together with systemic chemotherapy. Its main application would be in unresectable patients with median overall survival of 11-30 months (65, 66). Y90-RE is a form of selective internal radiation therapy (SIRT). This avoids the problem of external-beam radiation therapy, which has had limited use in the treatment of liver malignancies because liver tissue is very radiation-sensitive and maximal tolerable levels remain below tumoricidal levels. The idea is that intra-arterial delivery of small embolic particles (20-40 μm) containing the radionucleotide Y90 (β-radiation) can deliver a target dose of 120 Gy, which is a much higher local dose compared to external-beam radiation. These treatments have the objective of lengthening survival and producing dowstaging. The main indication is unresectable patients, and it can also be used concomitantly with systemic chemotherapy (67). Depending on whether there is a response or not, the overall survival is 18.2 versus 9.9 months (68).

Radiotherapy

The role of radiotherapy still needs to be defined as its use is mainly palliative, to treat residual disease or patients with unresectable disease. A problem of radiotherapy in the management of hepatic tumors is that the therapeutic dose far exceeds the radiotoxic dose for liver tissue. However, nowadays thanks to improvements in capturing images such as those through high-resolution multiphase helical CT and multiparametric MRI, and advances in the technique of external-beam radiation therapy (EBRT) as 3D conformal radiotherapy (3D-CRT) and intensity-modulated radiotherapy (IMRT), charged-particle (proton or carbon) beams over conventional X-ray beams, and accelerated and hypofractionated regimens like stereotactic body radiance therapy (SBRT). The security and efficacy of radiotherapy in the management of ICC has improved. Results in phase II and retrospective studies shows median overall survival of 22-30 months (69).

New therapies

There are emerging molecularly-directed therapies for the management of ICC. These include receptor-tyrosine-kinase inhibitors, therapeutics targeting epigenetic alterations and immunotherapy. At present, the clinical data on these therapies are limited and merits further investigation (69).

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CONCLUSION

ICC is rising worldwide, and because of its capricious biology, late diagnosis and the complexity of its management, it is a complex disease with a dismal prognosis. Surgery is still the only option capable of increasing long-term survival even though it is questionable for patients with lymph node or intrahepatic metastases. The benefits of neoadjuvant theraphy is uncetain and systemic treatment in the palliative setting is small. Liver transplantation and locoregional techniques like HAI, TACE, radio-embolization and targeted therapies (such as those targeting isocitrate dehydrogenase 1 or 2 mutations) are promising methods but they need more testing. Their real place in the treatment of ICC is one to be defined.

REFERENCES

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[37] de Jong MC, Nathan H, Sotiropoulos GC, Paul A, Alexandrescu S, Marquez H, et al. Intrahepatic cholangiocarcinoma: an international multi-institutional analysis of prognostic factors and lymph node assessment. J Clin Oncol 2011;29(23):3140-5. [38] Edge SB, Compton CC. AJCC Cancer Staging Manual, 7th edition. New York, NY: Springer, 2009. [39] Paik KY, Jung JC, Heo JS, Choi SH, Choi DW, Kim YI. What prognostic factors are important for resected intrahepatic cholangiocarcinoma? J Gastroenterol Hepatol 2008;23(5):766-70. [40] Murakami Y, Uemura K, Sudo T, Hashimoto Y, Nakashima A, Kondo N, et al. Prognostic factors after surgical resection for intrahepatic, hilar, and distal cholangiocarcinoma. Ann Surg Oncol 2011;18(3):651-8. [41] Hyder O, Hatzaras I, Sotiropoulos GC, Paul A, Alexandrescu S, Marques H, et al. Recurrence after operative management of intrahepatic cholangiocarcinoma. Surgery 2013;153(6):811-8. [42] Choi SB, Kim KS, Choi YJ, Park SW, Choi JS, Lee WJ, et al. The prognosis and survival outcome of intrahepatic cholangiocarcinoma following surgical resection: association of lymph node metastasis and lymph node dissection with survival. Ann Surg Oncol 2009;16(11):3048-56. [43] Yamamoto M, Takasaki K, Otsubo T, Katsuragawa H, Katagiri S. Recurrence after surgical resection of intrahepatic cholangiocarcinoma. J Hepatobiliary Pancreat Surg 2001;8(2):154-7. [44] Uenishi T, Kubo S, Yamazaki O, Yamada T, Sasaki Y, Nagano H, et al. Indications for surgical treatment of intrahepatic cholangiocarcinoma with lymph node metastases. J Hepatobiliary Pancreat Surg 2008;15(4):417-22. [45] Okabayashi T, Yamamoto J, Kosuge T, Shimada K, Yamasaki S, Takayama T, et al. A new staging system for mass-forming intrahepatic cholangiocarcinoma: analysis of preoperative and postoperative variables. Cancer 2001;92(9):2374-83. [46] Morine Y, Shimada M. The value of systematic lymph node dissection for intrahepatic cholangiocarcinoma from the viewpoint of liver lymphatics. J Gastroenterol 2015;50(9):913-27. [47] Clark CJ, Wood-Wentz CM, Reid-Lombardo KM, Kendrick ML, Huebner M, Que FG. Lymphadenectomy in the staging and treatment of intrahepatic cholangiocarcinoma: a population- based study using the National Cancer Institute SEER database. HPB (Oxford) 2011;13(9):612-20. [48] Morine Y, Shimada M, Utsunomiya T, Imura S, Ikemoto T, Mori H, et al. Clinical impact of lymph node dissection in surgery for peripheral-type intrahepatic cholangiocarcinoma. Surg Today 2012;42(2):147-51. [49] Goere D, Wagholikar GD, Pessaux P, Carrère N, Sibert A, Vilgrain V, et al. Utility of staging laparoscopy in subsets of biliary cancers : laparoscopy is a powerful diagnostic tool in patients with intrahepatic and gallbladder carcinoma. Surg Endosc 2006;20(5):721-5. [50] D'Angelica M, Fong Y, Weber S, Gonen M, DeMatteo RP, Conion K, et al. The role of staging laparoscopy in hepatobiliary malignancy: prospective analysis of 401 cases. Ann Surg Oncol 2003;10(2):183-9. [51] Joseph S, Connor S, Garden OJ. Staging laparoscopy for cholangiocarcinoma. HPB (Oxford) 2008;10(2):116-9. [52] Lunsford KE, Javle M, Heyne K, Shroff RT, Abdel-Eahab R, Gupta N, et al. Liver transplantation for locally advanced intrahepatic cholangiocarcinoma treated with neoadjuvant therapy: a prospective case-series. Lancet Gastroenterol Hepatol 2018;3(5):337-48. [53] Guro H, Kim JW, Choi Y, Cho JY, Yoon YS, Han HS. Multidisciplinary management of intrahepatic cholangiocarcinoma: Current approaches. Surg Oncol 2017;26(2):146-52. [54] Cereda S, Belli C, Reni M. Adjuvant treatment in biliary tract cancer: to treat or not to treat? World J Gastroenterol 2012;18(21):2591-6. [55] Primrose JN, Fox R, Palmer DH, Prasad R, Mirza D, Anthoney AD, et al. Adjuvant capecitabine for biliary tract cancer: the BILCAP randomized study. Journal of Clinical Oncology 2017;35(suppl):abstr 4006. [56] Neoptolemos JP, Moore MJ, Cox TF, Valle JW, Palmer DH, McDonald AC, et al. Effect of adjuvant chemotherapy with fluorouracil plus folinic acid or gemcitabine vs observation on survival in patients with resected periampullary adenocarcinoma: the ESPAC-3 periampullary cancer randomized trial. JAMA 2012;308(2):147-56.

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[57] Horgan AM, Amir E, Walter T, Knox JJ. Adjuvant therapy in the treatment of biliary tract cancer: a systematic review and meta-analysis. J Clin Oncol 2012;30(16):1934-40. [58] Valle J, Wasan H, Palmer DH, Cunningham D, Anthoney A, Maraveyas A, et al. Cisplatin plus gemcitabine versus gemcitabine for biliary tract cancer. N Engl J Med 2010;362(14):1273-81. [59] Lamarca A, Hubner RA, David Ryder W, Valle JW. Second-line chemotherapy in advanced biliary cancer: a systematic review. Ann Oncol 2014;25(12):2328-38. [60] Amini N, Ejaz A, Spolverato G, Kim Y, Herman JM, Pawlik TM. Temporal trends in liver-directed therapy of patients with intrahepatic cholangiocarcinoma in the United States: a population-based analysis. J Surg Oncol 2014;110(2):163-70. [61] Shindoh J. Ablative therapies for intrahepatic cholangiocarcinoma. Hepatobiliary Surg Nutr 2017;6(1):2-6. [62] Savic LJ, Chapiro J, Geschwind JH. Intra-arterial embolotherapy for intrahepatic cholangiocarcinoma: update and future prospects. Hepatobiliary Surg Nutr 2017;6(1):7-21. [63] Kiefer MV, Albert M, McNally M, Robertson M, Sun W, Fraker D, et al. Chemoembolization of intrahepatic cholangiocarcinoma with cisplatinum, doxorubicin, mitomycin C, ethiodol, and polyvinyl alcohol: a 2-center study. Cancer 2011;117(7):1498-505. [64] Seidensticker R, Seidensticker M, Doegen K, Mohnike K, Schütte K, Stübs P, et al. Extensive Use of Interventional Therapies Improves Survival in Unresectable or Recurrent Intrahepatic Cholangiocarcinoma. Gastroenterol Res Pract 2016;2016: 8732521. [65] Poggi G, Amatu A, Montagna B, Quaretti P, Minola C, Sottani C, et al. OEM-TACE: a new therapeutic approach in unresectable intrahepatic cholangiocarcinoma. Cardiovasc Intervent Radiol 2009;32(6):1187-92. [66] Schiffman SC, Metzger T, Dubel G, Andrasina T, Kralj I, Tatum C, et al. Precision hepatic arterial irinotecan therapy in the treatment of unresectable intrahepatic cholangiocellular carcinoma: optimal tolerance and prolonged overall survival. Ann Surg Oncol 2011;18(2):431-8. [67] Salem R, Thurston KG. Radioembolization with 90Yttrium microspheres: a state-of-the-art brachytherapy treatment for primary and secondary liver malignancies. Part 1: Technical and methodologic considerations. J Vasc Interv Radiol 2006;17(8):1251-78. [68] Filippi L, Pelle G, Cianni R, Scopinaro F, Bagni O. Change in total lesion glycolysis and clinical outcome after (90)Y radioembolization in intrahepatic cholangiocarcinoma. Nucl Med Biol 2015;42(1):59-64. [69] Rizvi S, Khan SA, Hallemeier CL, Kelley RK, Gores GJ. Cholangiocarcinoma - evolving concepts and therapeutic strategies. Nat Rev Clin Oncol 2018;15(2):95-111.

Chapter 11

MANAGEMENT OF GALLBLADDER CANCER

Felipe Castillo1,2, MD, Xabier de Aretxabala1,3,, MD, Rodrigo Torres-Quevedo4, MD, PhD, Fiona Lim5, MBBS, Bo Angela Wan6, MD(C) and Mauricio F Silva7,8,9, MD, PhD 1Clínica Alemana of Santiago, Department of Surgery, Santiago, Chile 2Barros Luco Hospital, University of Chile, Santiago, Chile 3Air Force Hospital Department of Surgery, Santiago, Chile 4Hepatobiliary Surgery University of Concepción, Concepción, Chile; Guillermo Grant Benavente Hospital, Concepción, Chile 5Princess Margaret Hospital, Hong Kong, PR China 6Odette Cancer Centre, Sunnybrook Health Sciences Centre, Toronto, Ontario, Canada 7Radiation Oncology Unit, Santa Maria Federal University, Santa Maria, Brazil 8Radiation Oncology Unit, Hospital de Caridade Astrogildo de Azevedo, Santa Maria, Brazil 9Latin America Cooperative Oncology Group, Porto Alegre, Brazil

ABSTRACT

Gallbladder cancer (GC) is considered a rare disease mainly affecting some countries in South America, Eastern Europe and places in India. Prognosis of the disease is commonly dismal, except in cases when diagnosis is performed after the exam of the cholecystectomy specimen of patients undergoing surgery for cholelithiasis. Gallstones disease is the most commonly associated factor, which in countries such as Chile, is observed in approximately 95% of GC patients. Among prognostic factors, the level of wall invasion and lymph nodes metastasis are the most important. Present GC classification is mainly based on these factors. Surgical resection is the only curative therapy, while chemotherapy and radiation have not shown significant benefit in either neoadjuvant or adjuvant setting. Cholecystectomy is a valid option of treatment in patients with invasion limited to the mucosa or muscular layers, while more extended operations including resection of the gallbladder bed and regional lymph nodes are

 Corresponding Author’s Email: [email protected]. Complimentary Contributor Copy 120 Felipe Castillo, Xabier de Aretxabala, Rodrigo Torres-Quevedo et al.

advised in patients with invasion of the subserosal layer and deeper. A R0 resection is the only option to affect the survival in patients undergoing surgery, palliative surgery would not have a role. Jaundice pain and outlet obstruction are the main symptoms to palliate, and endoscopy has shown to be the most cost-effective way for management.

INTRODUCTION

Although considered a rare disease, gallbladder cancer (GC) has increased in incidence during the past few years (1). At present, it corresponds to the 6th more frequent gastrointestinal tumor in the world, with higher variability according different geographical areas. Among biliary tumors, gallbladder cancer corresponds to the 80 to 95% of total tumors (1, 2). Diagnosis is frequently performed at advanced stages, mainly due to the presence of late symptoms and lack of specific screening methods (3). There are also a high number of cases that are detected after exams of cholecystectomy specimens. Management of this neoplasm is challenging, partly due to technical difficulties related to the anatomic area where the tumor is located and also due to the poor outcomes (5-12% overall 5 years survival). The introduction of laparoscopic cholecystectomy (LC) allowed the detection of a higher number of earlier tumors, improving the global GC survival (4). In this chapter, we will describe the present status of GC management with emphasis in the clinical characteristics, method of study, staging, and therapy

EPIDEMIOLOGY

One of the characteristics of GC is its geographical distribution (see Figure 1). In 2012, Stinson et al. reported the GC incidence around the world. They highlighted that South America and India showed the highest incidence with 19.8 and 22 per 100,000 inhabitants respectively (5). On the other hand, in US, this rate is lower than 2 per 100,000 inhabitants. Explanation for the Chilean higher incidence could be due to the higher incidence of GC in Chilean Mapuches, the local indigenous populations. Cholelithiasis is a factor associated with GC that is highly prevalent among this indigenous population. It must be also highlighted that the increase of GC incidence in Asia are mainly in Pakistan and Korea (5). Chile has the highest incidence in the world. This fact has led to changes in the public health programs with emphasis in the increase of cholecystectomies performed, to improve the detection of earlier GC. Roa et al. (6) published that among 29,840 cholecystectomies performed, they discovered 4.6%, 0.8% and 0.2% of GC, low grade dysplasia and adenoma respectively. There is also a relationship between higher incidence places of GC and higher prevalence of cholelithiasis and infection by Salmonella. This is also related with a lower access to elective cholecystectomy (7).

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Figure 1. Worldwide incidence of gallbladder cancer.

FACTORS ASSOCIATED WITH GALLBLADDER CANCER

The relationship between cholelithiasis and GC has been widely described. Approximately 80-90% of patients harboring GC have gallstones at the moment of diagnosis (1, 8). Patients with gallstones have a risk of developing GC ranging from 0.3-3%. In Chile, the prevalence of gallstones in women is approximately 50%, while the prevalence of GC among Mapuche women is 27.3 per 100,000 inhabitants. The development of GC is thought to begin with the presence of mucosal chronic inflammation. This event would be the first step in the transformation from dysplasia to proper malignancy. Persistent mucosal injury causes DNA damage, with repetitive attempts of tissue repair, cytokines and growth factors production predisposing to oncogenesis (cell death, cell proliferation, DNA metallization and angiogenesis) (9). Some gallstone characteristics such as size larger than 3 cm, cholesterol type and length of gallstones are associated with a greater risk of GC (10). Another conditions such porcelain or scleroatrophic gallbladder are also associated with a higher risk of developing GC. A long duration of inflammation would be factor related to carcinogenesis in the above conditions (10, 11). Among 340 patients who had calcifications in the gallbladder 21% had concomitant GC (11).

Polyps

Approximately 5% of the adult population have polyps in the gallbladder, with the majority corresponding to pseudopolyps without malignant potential (cholesterol, adenomyosis, inflammatory) (12). Among polyps, predictors of possible malignancy are size greater than 10 mm, solitary polyp, sessile shape, age more than 50 years and fast growth. The adenoma- adenocarcinoma sequence is observed in rare cases in GC, with the majority of patients who develop a GA, following the dysplasia carcinoma sequence. The adenoma-adenocarcinoma sequence is mainly observed in polyps in Asian areas (10, 12). Complimentary Contributor Copy 122 Felipe Castillo, Xabier de Aretxabala, Rodrigo Torres-Quevedo et al.

Obesity

A body mass index over 30 increases the risk of developing GC. Relative risk (RR) of this association is 1.8 and 2.1 for men and women respectively. Obesity is also related with increased gallstones prevalence (5).

Anomalous arrangement between biliary and pancreatic duct

This structural anomaly is associated with the development of GC and has been extensively described in Japan. Reflux of pancreatic juice inside the gallbladder could produce chronic inflammation in the same way as gallstones produce inflammation in the gallbladder mucosa (13)

Others

Infections including Salmonella and Helicobacter are associated with GC Among those patients harboring a typhoid infection, 6% are described to develop a gallbladder cancer (12 times risk increase) (1, 14). Primary sclerosing cholangitis would produce chronic inflammation and by this mechanism, the risk of developing a GC would be increased (15). Tabaco is a classical risk factor for many malignancies including GC. In Table 1 commonly described risk factors are highlighted.

Table 1. Risk factors for GC

Gallstones (5) > 3.0 cm Gender (2) Female Age (2) > 65 years Obesity (5) BMI > 30 Chronic Cholecystitis (16) > 20 years Parity (16).

MOLECULAR BIOLOGY AND HISTOLOGY

Some of the above described factors are associated with changes at genetic level, explaining the epidemiological and prognostic variability of GC. There are molecular and histologic differences associated with the anomalous pancreatobiliary arrangement and also with gallstones. GC observed in Japan is more commonly associated with anomalous arrangement, Kras mutations and a later appearance of P53 mutations. On the contrary, among Chilean patients with cholelithiasis, Kras mutations are not so common while the appearance of P53 mutations are earlier (17). Some of the oncogenes alterations are the following:

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 Mutations in the adenosine triphosphate-binding cassette transporter (ABCG8) would be related with the development of GC (18).  The tumor necrosis factor-alpha converting enzyme (ADAM-17), is associated with high grade tumors. Higher levels would be associated with a worse prognosis (18).  Changes in base excision originating from chronic inflammation are risk factors for the development of biliary duct cancer (19).  The loss of expression of E-cadherin is increased in GC while beta catenin is diminished.  Concerning natural killer cells, number of CD4+ and CD8 + T-cells is significantly higher in GC.  There are surface cells proteins which would be related with treatment and prognostic: CD24 is a marker associated with a worse prognosis, CD133+ is associated with chemotherapy resistance and CD147 is associated with distant metastasis.

Growth factors have been related with other types of tumors such as breast and colon. The epidermal growth factor (EGF) and transforming growth factor β1 (TGFβ1) play a role in GC. The EGF receptor is a survival predictor and also could have a role in the employment of specific therapies (20). Progression from dysplasia to carcinoma in situ is a well-known characteristic of gastrointestinal tumors. This transformation sequence is the most common pathway in GC. Time elapsed from dysplasia to advanced forms is approximately 15 years while average age of appearance of carcinoma in situ is 55 years old. From a histologic point of view, majority of tumors (90%) corresponds to adenocarcinoma. Other histologic types are squamous (4%), neuroendocrine (3%), sarcoma (1.6%), small cell, melanoma (<1%) and lymphoma (2%). Among adenocarcinoma, papillary is associated with a better prognosis (21). According the grade of differentiation, GC is classified into three different types from well differentiated to poorly differentiated tumors.

CLINICAL PRESENTATION

Diagnosis of GC can be performed before surgery, during the procedure or after the cholecystectomy during the exam of cholecystectomy specimen.

Pre-operative diagnosis

GC can be suspected due to the presence of classical symptoms such as jaundice, weight loss, or abdominal pain. Diagnosis of tumor at this stage is often performed when the disease is too advanced. Among these patients, only 25% are potential candidates for resection and 5-year survival is around 16%. Surgery is the only treatment with curative aim and it should be performed when a margin free resection is feasible (22). Symptomatology is generally

Complimentary Contributor Copy 124 Felipe Castillo, Xabier de Aretxabala, Rodrigo Torres-Quevedo et al. associated with a worse prognosis; for example, when jaundice appears, survival falls from 16 to 6 months. Abdominal ultrasound is performed as the first approach for diagnosis. Findings such as discontinuous mucosa, echogenic mucosa, and echolucent submucosal are more common in early malignancy compared with benign gallbladder disease. In some cases, intrahepatic biliary duct dilatation or the presence of an abdominal mass are the first signs to suspect GC. Computed tomography (CT) scan and magnetic resonance imaging (MRI) are both employed to stage the disease. To get a better survival and to reduce the number of unnecessary surgeries, complete pre-operative staging is essential (see Table 2).

Table 2. Gallbladder cancer staging

Staging T – Primary tumour N – Regional Lymph Nodes TX Cannot be assessed NX Cannot be assessed T0 No tumour N0 No regional lymph node metastasis Tis Carcinoma in situ N1 Regional lymph nodes metastasis (including cystic duct, common bile duct, common hepatic artery and portal vein nodes) T1 T1a invades lamina propia T1b invades muscular layer T2 T2a invades the perimuscular connective tissue M - Distant metastasis on the peritoneal side, without involvement of the serosa (visceral peritoneum). T2b invades de hepatic side, with no extension into the liver T3 Perforates the serosa (visceral peritoneum) M0 No distant metastasis and/or directly invades the liver and/or one other adjacent organ or structure (stomach, duodenum. Colon, pancreas, omentum or extrahepatic bile ducts T4 Invades main portal vein or hepatic artery or M1 Distant metastasis invades 2 or more extrahepatic organs o structures Stage Grouping Stage 0 Tis N0 M0 Stage I T1 N0 M0 Stage II T2 N0 M0 Stage IIIA T3 N0 M0 Stage IIIB T1, T2, T3 N1 M0 Stage IVA T4 Any N M0 Stage IVB Any T Any N M1 Adapting from AJCC Cancer Staging Manual, Eighth Edition.

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CT not only gives information about the type of mass but also gives information about lymph nodes, peritoneal implants and vascular invasion. MRI cholangiography has replaced the invasive diagnostic cholangiography in pre-operative studies (23). The main goal at this time is to be certain of disease resectability. The presence of liver metastasis, invasion into neighbor organs or para aortic lymph nodes and peritoneal dissemination are findings precluding resection. Although not clearly stated, positron emission tomography (PET) CT can be employed during staging. This method is mainly utilized when an incidental tumor is detected to identify recurrence in areas where it could be resected in a second operation (see Figure 2). On the other hand, PET CT can show false positive findings in a patient who has already undergone surgery (24).

Figure 2. Classical PET CT from gallbladder cancer.

Tumors markers related to GC are carcinoembryonic antigen (CEA) and CA 19-9. CEA elevation level is highly specific for GC; however, sensitivity is low as screening method (50%). On the contrary, CA 19-9 show 75% sensitivity when levels are higher than 200 U/ml (25).

Post-operative diagnosis or incidental tumors

An important proportion of patients with GC are those whose tumours are detected after the pathological examination of their cholecystectomy specimen. This fact emphasizes the importance of the cholecystectomy technique in order to avoid tumor dissemination in an unsuspected tumor. GC is recognized in 0.2-2% of cholecystectomy specimens (26). The more frequent symptoms in these patients are those typical of gallstone disease. Cholecystectomy specimen exam is the way of not only providing a diagnosis but also to identify the exact level of wall invasion. This information is extremely important in deciding the type of treatment. In general, prognosis is better among those with an incidental tumor, mainly due to the higher resectability (26). Complimentary Contributor Copy 126 Felipe Castillo, Xabier de Aretxabala, Rodrigo Torres-Quevedo et al.

On the other hand, finding residual tumor after cholecystectomy is associated with a worse prognosis (27, 28).

TREATMENT

To analyze the surgical treatment of GC, it is necessary to divide the patients according the level of wall invasion. T1a: Simple cholecystectomy is considered the standard management in these patients. Survival rate among the above patients ranged between 85-100% (29). T1b: The management of this type of tumor is controversial and the surgical community is divided. According some authors, radical surgery with a complete dissection of the hepatic pedicle and resection of the gallbladder bed would improve the 5-year survival rate. However, based in the lower frequency of residual disease, simple cholecystectomy could be also indicated as treatment (30, 31). Unfortunately, the low frequency of this disease makes difficult to perform a prospective trial to validate the effective therapy T2: Because the residual disease rate increases concomitantly with the T stage, lymph node residual disease can be observed in between 30-60% of these patients (32). On the other hand, overall survival improves in patients who underwent reoperation compared with those who did not undergo reoperation. A characteristic of this group of patients is the role of tumor location in prognosis. Tumor located in the hepatic side of the gallbladder is associated with worse prognosis compared with tumor in the peritoneal side. This is related to a higher rate of lymphatic, perineural and vascular involvement of tumors located in the gallbladder bed (33).

Surgical treatment in patients with locally advanced tumors

T3: The extension of the radical resection in this group of patients is under discussion. Although principles of management of this group of patients would be similar to the group of T2 patients, R0 resection is a basic rule to justify the execution of surgery. Resection of tumor extension to neighboring organs such as the biliary tree, duodenum or liver is justified only when an R0 resection is feasible. Routine biliary tree resection is not indicated, except when the cystic resection border is compromised (29,34). Lymphadenectomy of the hepatic pedicle must always be performed. This should contain at least 6 lymph nodes to obtain a good quality staging (35). In these patients, compromise of lymph nodes can be observed in around 45% of cases. Evaluation of paraaortic, and axis lymph nodes must be performed at the beginning of the resection. The existence of tumor compromise in the above structures determines the non- execution of the resection (29). T4: Extensive resections in this group of patients have not shown any benefit. On the other hand, the addition of vascular and liver resection has been associated with postoperative morbidity and mortality. Neo adjuvant chemotherapy to diminish the amount of tumor tissue and to allow the resection could have a role (34-36).

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Reoperative surgery in patients with incidental GC

Surgical principles of this procedure are the resection of the gallbladder bed along with a lymphadenectomy of the hepatic pedicle. Approximately 25% of patients have lymph node metastasis at the moment of reoperation. There is controversy about the relationship between the elapsed time between the cholecystectomy and the reoperation and its value in the prognosis (28). According some authors, to delay the reoperation will allow the appearance of metastatic disease not previously observed at the moment of cholecystectomy, thus avoiding unnecessary surgery.

Surgical tips for GC treatment

Lymphatic dissection must include lymph nodes located around the structures of the hepatic pedicle, hepatic artery and retro duodenum. The presence of compromise of N1 lymph nodes is not a contraindication to pursue the resection. On the contrary, N2 or M1 compromise is a contraindication for surgery. The magnitude of liver resection as part of the surgical treatment is in under debate. Although anatomical resections including segments IVb and V were formerly indicated, present evidence shows that there is no difference in survival according the size of the resection. The laparoscopic approach has shown to be an alternative to the open approach with similar oncologic results (33). In comparison with the classic open approach, laparoscopic technique follows the same principles with the proper advantages of a minimally invasive surgery (see Figure 3) (35). Although compromise of laparoscopic ports can be present in around 10-20% of patients with T2 or T3 tumors, routine resection is not indicated. It has been shown that compromise of laparoscopic ports is associated with abdominal recurrence and lower survival (34). Perforation of gallbladder wall during the cholecystectomy in patients harboring a GC is an important issue to be assessed. From our observations, the magnitude of peritoneal contamination by gallbladder content would be an important factor affecting prognosis (4).

Figure 3. Laparoscopic view of a hepatic pedicle lymphadenectomy. Complimentary Contributor Copy 128 Felipe Castillo, Xabier de Aretxabala, Rodrigo Torres-Quevedo et al.

Intraoperative diagnosis

GC can be suspected during a cholecystectomy for a presumed benign condition such as cholelithiasis. At this time, the goal of the surgeon is to verify the diagnosis of malignancy and to know the extent of the disease. Capability of the surgeon in performing the procedure will determine which procedure will be performed. However, a histologic precise diagnosis knowing the depth of wall invasion is necessary before pursuing a respectable procedure. On the other hand, we must take into account that this group of patients came into surgery for a presumed benign condition, and an informed consent for the new procedure is necessary. When the disease is localized to the gallbladder, cholecystectomy is indicated. Special care in the surgical technique to avoid wall rupture and violation of oncologic margins is important. Definitive surgery can be delayed for a second intervention. No differences in the outcome has been shown when definitive surgery is performed in a second procedure.

Adjuvant therapy

There is scarce evidence on the value of systemic therapy in GC. It is well known that after an R0 resection, distant recurrence is observed in almost 85% of patients (37). On the other hand, patients in whom a R0 could not be obtained have a higher local recurrence rate.

Adjuvant chemotherapy

Even after a R0 resection, local recurrence is commonly observed. Therefore, any kind of therapy to reduce local failure is essential (37). According to retrospective studies, adjuvant therapy has shown some beneficial effects in patients with advanced forms of the tumor. Phase III trials based on Gemcitabine have been carried out, showing survival improvements when compared with other types of schemes mainly based in 5-fluoruracil (5-FU) (38). Table 3 shows main ongoing clinical trials on GC.

Table 3. Trials on adjuvant chemotherapy in gallbladder cancer

Trials of adjuvant chemotherapy in GC Author Type of N Treatment arms Outcome Results Study Takada Phase 140 Surgery Five-year 26 v/s 14% et al. (45). III Surgery + 5-FU/ survival 16.4 v/s 14.1 mitomycin C Median months survival Primrose Phase 447 Surgery Median 51 v/s 36 months et al. (44). III Surgery + capecitabine survival (n/e) Edeline Phase 196 Surgery Median free 39 v/s 33%; HR et al. (45). III Surgery + survival 0.83, 95% CI gemcitabine/oxaliplatin 0.58-1.19

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Adjuvant radiotherapy

Adjuvant radiotherapy have shown only marginal benefit in patients with GC. There is only one study performed in patients with T2 or positive lymph nodes in whom median survival of those who underwent adjuvant radiotherapy showed benefit (15 vs. 8 months) (16). However, no differences at five years were observed.

PALLIATIVE MANAGEMENT

Objectives of palliative management must be specific with the focus on palliation of jaundice, obstruction, and pain. Jaundice is one of the most important problems to handle and is observed between 30-60% of patients at the moment of diagnosis. There are multiple ways to deal with this problem, including endoscopic retrograde cholangiopancreatography (ERCP), percutaneous transhepatic cholangiography (PTC) and bilioenteric drainages. At present, less invasive methods are preferred which allows a better quality of life in patients with life expectancy of less than 6 months. In some cases where resectability is unlikely, palliative methods can be employed as a “bridge therapy” before neoadjuvant therapy or resection (39, 40). Although success of PTC is higher compared with endoscopic methods, both are associated with high rates of morbidity and mortality (40, 41). On the other hand, surgical palliation through techniques such as segment II drainage are no longer employed because of better results obtained with the endoscopic and percutaneous approaches.

Chemotherapy as palliation

Chemotherapy can be employed for palliation, with response rates ranging from 10-60% (42). Majority of employed schemes were originally based in 5-FU, mitomicin C, doxorrubicin and methrotretaxe, which obtained response rates lower than 20%. At present, gemcitabine is the cornerstone of new palliative schemes. By employing gemcitabine, not only higher response rates were observed, but also less adverse effects and better quality of life.

Palliative surgery

Palliative surgery has a limited role in the management of GC. Majority of patients have advanced stages of the disease in whom the chance of palliation through an open or laparoscopic approach is unlikely. Jaundice represents the main problem to palliate, but GC compromise of biliary bifurcation and segmental branches make palliation a difficult task. MRI cholangiography allows identification of the exact biliary architecture, giving the required information to perform palliation through a stent inserted by ERCP (see Figure 4) (39).

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Figure 4. MRI showing extensive compromise of biliary duct as part of a gallbladder cancer.

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[36] Maker AV, Butte JM, Oxenberg J, Kuk D, Gonen M, Fong Y, et al. Is port site resection necessary in the surgical management of gallbladder cancer? Ann Surg Oncol 2012;19(2):409-17. [37] Jarnangin WR, Ruo L, Little SA, Klimstra D, D’Angelica M, DeMatteo RP, et al. Patterns of initial disease recurrence after resection of gallbladder carcinoma and hilar cholangiocarcinoma: implications for adjuvant therapeutic strategies. Cancer 2003;98(8):1689-700. [38] Sharma A, Mohanti B, Raina V, Shukla N, Pal S, Dwary A, et al. A phase II study of gemcitabine and oxaliplatin (Oxigem) in unresectable gallbladder cancer. Cancer Chemother Pharmacol 2010;65(3):497-502. [39] Saluja SS, Gulati M, Garg PK, Pal H, Pal S, Sahni P, et al. Endoscopic or percutaneous biliary drainage for gallbladder cancer: a randomized trial and quality of life assessment. Clin Gastroenterol Hepatol 2008;6(8):944-50. [40] Robson PC, Heffernan N, Gonen M, Thornton R, Brody LA, Holmes R, et al. Prospective study of outcomes after percutaneous biliary drainage for malignant biliary obstruction. Ann Surg Oncol 2010;17(9):2303-11. [41] Hejna M, Zielinski CC. Nonsurgical management of gallbladder cancer: cytotoxic treatment and radiotherapy. Expert Rev Anticancer Ther 2001;1(2):291-300. [42] Valle JW, Wasan H, Johnson P, Jones E, Dixon L, Swindell R, et al. Gemcitabine alone or in combination with cisplatin in patients with advanced or metastatic cholangiocarcinomas or other biliary tract tumours: a multicentre randomised phase II study - The UK ABC-01 Study. Br J Cancer 2009;101(4):621-7.

Chapter 12

MANAGEMENT OF LIVER METASTASES

Mario Uribe1,2,, MD, Vincenzo Benedetti1,2, MD, Rodrigo Torres-Quevedo3, MD, Fiona Lim4, MBBS, Bo Angela Wan5, MD(C) and Maurício F Silva6,7,8, MD, PhD 1Hepatobiliary Surgery and Liver Transplantation, Hospital del Salvador, and Clínica Las Condes, Santiago, Chile 2Department of Surgery Oriente, Faculty of Medicine, Universidad de Chile, Santiago, Chile 3Hepatobiliary Surgery, University of Concepción, Guillermo Grant Benavente Hospital, Concepción, Chile 4Department of Oncology, Princess Margaret Hospital, Hong Kong, PR China 5Odette Cancer Centre, Sunnybrook Health Sciences Centre, University of Toronto, Toronto, Ontario, Canada 6Radiation Oncology Unit, Santa Maria Federal University, Santa Maria, Brazil 7Radiation Oncology Unit, Hospital de Caridade Astrogildo de Azevedo, Santa Maria, Brazil 8Latin America Cooperative Oncology Group, Porto Alegre, Brazil

ABSTRACT

Liver is one of the organs most frequently affected by tumor metastases, particularly colorectal cancer, one of the most common neoplasms in the world. Liver metastases represent an important prognostic and therapeutic factor in these patients. Surgery has been considered the only potentially curative strategy, and also potentially impacts survival in some disease entities like neuroendocrine tumors and gastrointestinal stromal tumors. However, its application is limited by the advanced state of the disease at time of diagnosis. The objective of this review is to describe current evidence about the resection and ablative techniques available. Complete resection at both macroscopic and microscopic levels (R0 resection) is the main objective of metastasectomy. Resectability criteria have expanded lately. Perioperative chemotherapy impacts disease-free survival

 Corresponding Author’s Email: [email protected]. Complimentary Contributor Copy 134 Mario Uribe, Vincenzo Benedetti, Rodrigo Torres-Quevedo et al.

and overall-survival, although its evidence is limited. Ablative treatments are useful in patients who are not candidates for surgery. Techniques that aim at increasing hepatic reserve have shown promising preliminary results but have not yet been clinically validated. Liver transplantation has resurged as a possible therapeutic option in countries with a high rate of organ donation. The published Latin American series are concordant with the global experience, but it is limited to small and descriptive studies. Therefore, it is necessary to carry out new clinical trials to standardize the therapeutic options in patients with this relevant pathology.

INTRODUCTION

Among hepatic neoplasms, metastases are more frequent than primary hepatocellular tumors with an incidence of up to 20 times higher (1). Due to its anatomical and functional characteristics, the liver is one of the preferred sites of metastatic deposits for all tumor types. The existence of double portal and systemic circulations, together with the characteristic fenestrations of the sinusoidal epithelium seem to favor this phenomenon (2). The most frequent primary tumor origins are colorectal, and to lesser extents, other organs of the digestive system, breast, lung, and urogenital system (3, 4). Colorectal cancer (CRC) is the third most frequent malignancy in men and the second in women, with an incidence of 17.2 per 100,000 (both sexes), and a mortality of 8.3 per 100,000. The highest incidence is observed in Europe, Australia and North America; the lowest is observed in Africa and Asia. In Latin America, it ranks fourth in incidence among all cancers (14.0 per 100,000) and sixth in mortality (7.6 per 100, 00), accounting for 8% of cancer deaths (4). At the time of diagnosis, about 15–25% of patients with CRC present with synchronous metastasis in the liver, which increases up to 50% during the disease course (5, 6). This organ is the site of a single metastasis in 30–50% of cases (7), being in turn responsible for two thirds of the mortality among patients with CRC (8). In the Latin American population, a Brazilian study reported that the main place of metastatic spread in CRC was liver, similar to that reported in the literature, representing 20.5% of the patients evaluated. On the other hand, a study conducted in Chile reported that 78.3% of surgeries performed for liver metastases were secondary to CRC (9). The survival for patients with untreated liver metastasis (LM) from colorectal cancer (CRLM) is poor with a median survival not exceeding six months (10-12). Surgical resection of liver metastases has been shown to be the only strategy with curative potential, thus increasing the chances of long-term survival (10, 11). Nevertheless only 10% to 30% of patients are candidates for surgical treatment (13). On the other hand, ablative techniques such as radiofrequency ablation (RFA), microwave coagulation (MWC) and intra-arterial chemotherapy have not shown to be advantageous over surgery (6). In this sense, the current interest is aimed at expanding the respectability criteria of the CRLM, including new surgical techniques and the application of neoadjuvant protocols oriented to downstage those lesions initially considered unresectable to resectable (7). The purpose of this chapter is to synthesize the evidence regarding the various therapeutic alternatives available for the treatment of hepatic metastases from colorectal cancer and other primary tumors, considering also the published Latin American regional experience.

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OUR SEARCH

A systematic review of randomized controlled clinical trials (RCT) published over the last 20 years in the databases including EMBASE, MEDLINE and Cochrane Central Register of Controlled Trials (CENTRAL) was made, using the search terms “liver metastases”, “resection,” “Surgery,” “therapy” in titles, keywords and abstracts. Only studies published in journals, carried out in adults and available in English, Spanish or Portuguese were reviewed. The search identified 54 publications in EMBASE, 63 in MEDLINE and 259 in CENTRAL (which did not allow limiting by language or type of publication). All titles were reviewed, eliminating duplicate items. We reviewed the abstracts of primary studies, excluding those referring only to chemotherapy or those that did not have a resection or ablative therapy as the main intervention, and all those that did not qualify as an RCT (see Figure 1). In areas considered to be of essential interest for the present study bud did not meet the requirements stipulated above, a complementary free review was carried out, contemplating review articles and observational studies.

Figure 1. PRISMA diagram of systematic selection of controlled studies. Complimentary Contributor Copy 136 Mario Uribe, Vincenzo Benedetti, Rodrigo Torres-Quevedo et al.

To describe the Latin American experience, the SciELO regional database was reviewed, considering the limitations of the local environment of those articles published from retrospective observational studies and series of cases relevant to the main topic of this study.

OUR FINDINGS

Colorectal metastases

Resectable metastases Liver resection has been shown to be relatively safe, with acceptable results of morbidity, mortality and a short admission time. Published series reported morbidity between 17% to 26% and mortality between 1.5% to 4.3%, with improving results in the recent years (14, 15). It is necessary to achieve R0 resection to ensure better long-term survival. Traditional thought in potentially curative surgery is to achieve a ‘safe’ surgical margin of at least 1cm. However, recent clinical results showed comparable outcomes for those with free surgical margins greater than 1 mm and 1 cm. Local recurrence after resections with negative margins is estimated between 3% to 5% only. In these cases, it is reasonable to propose a new resection surgery, with comparable results in survival, morbidity and postoperative mortality (16). The optimal timing of the resection of synchronous liver metastases, which diagnosed together with the primary colorectal tumor, is the subject of debate (17). Given the morbidity of surgery used conventionally, sequential resection starting with surgery of the primary, followed by chemotherapy and subsequent metastasectomy carried out three to six months after the first resection is the preferred strategy (18, 19). Advocates of this approach also point out the possible benefits in optimizing patient selection for resection of hepatic metastases by identifying the poor prognostic group with early refraction to chemotherapy. On the other hand, a simultaneous confrontation allows solving both problems in a single surgical act, initiating early systemic therapy and avoiding the potential hepatotoxicity associated with chemotherapy, which would affect the resection of the CRLM (20). Ali et al. conducted a systematic review comparing morbidity, mortality and survival between sequential and simultaneous resection of CRLM including 25 observational studies and retrospective studies, and four published meta-analysis (21). The findings of these studies suggest that with current technical advances, there would be no significant differences between the two approaches, although with limited level of evidence.

Perioperative chemotherapy The combination of perioperative systemic chemotherapy and surgical resection is currently considered the first choice for patients with hepatic metastases from colorectal cancer (22, 23). The available evidence on systemic chemotherapy is highly suggestive of its benefit, although it is not confined to specific treatment schemes. Most patients undergoing liver resection will experience recurrence of intrahepatic or extrahepatic disease, with an estimated five-year survival between 24% to 58%, which still far exceeds the 0% to 5% survival of those left untreated (8). On the other hand, the five-year

Complimentary Contributor Copy Management of liver metastases 137 global survival of those patients with metastatic CRC treated with chemotherapy exclusively (considering current regimens) was estimated at 10.8% according to a US study (24). The current consensus points out the benefit of combination use of systemic agents including adding Oxaliplatin (FOLFOX scheme) or Irinotecan (FOLFIRI scheme) to 5- fluorouracil and Leucovorin and biological agents such as the EGFR inhibitor, Cetuximab, or the VEGF inhibitor, Bevacizumab (25). The multicenter study EORTC 40983 analyzed 364 patients with initially resectable CRLM comparing those randomized to perioperative chemotherapy with FOLFOX plus resection versus those who underwent exclusive surgery (26). A first breakthrough published in 2008 showed benefits in progression-free survival (PFS) at two years (HR = 0.73; 95% CI = 0.55-0.97; p = 0.025), however, the results of the long-term follow-up published in 2013 did not show an impact on the median overall survival (OS) (23). The perioperative chemotherapy group achieved a median OS of 61.3 months (95% CI = 51.0–83.4), while the exclusive surgery group 54.3 months (95% CI = 41.9–79.4). On the other hand, the use of local intra-arterial chemotherapy has not been able to demonstrate clear clinical benefits. The evidence from RCTs failed to show significant impacts on survival. Rudroff et al. (27) studied the effect of intra-arterial adjuvant chemotherapy after R0 resections of CRLM. Fourteen patients received four cycles of chemotherapy with Mitomycin C and 5-Fluorouracil at four-week intervals after surgery. Sixteen patients did not receive adjuvant chemotherapy. No significant differences were found in OS (p = 0.92) or PFS (0.79) between both groups. At the same time, the advantages of the use of systemic Oxaliplatin or Irinotecan have diminished the interest in this local strategy (25).

Resectability criteria Ekberg et al. (28) in 1986 and Steele et al. (29) in 1989 proposed criteria for the resection of LM based on the tumor and patient characteristics, partially corroborated by subsequent studies (30). These authors considered the following as unresectable: the presence of four or more LM, LM of a large size, the impossibility of achieving margins resection great or equal to 1 cm, and the existence of extrahepatic metastatic disease. Many studies that reaffirmed these criteria, considered paradigmatic for clinical practice for years, were later criticized for coming only from univariate analyzes that ignored the confounding effect of other risk factors (7). On the other hand, the development of important innovations in surgical technique, the availability of more effective cytotoxic agents and systemic agents directed to specific targets have resulted in a progressive and significant increase in the rate of tumor response in the LM which help overcome the limits of respectability. To study the impact of total number and size of CRLM on the effectiveness of resection, Allard et al. analyzed the records of LiverMetSurvey online database, a prospective multicenter cohort of patients operated by CRLM from 485 centers in 59 countries (31). Researchers compared the survival of patients operated on with curative intent between 2005 and 2013 with 10 or more exclusive liver metastases (n=529) versus those with fewer hepatic metastases (n=11,877). Multivariate analysis showed that the type of resection proved to be the main predictive factor of OS, strongly favoring R0 or R1 margins with subsequent RFA (HR = 0.35, 95% CI = 0.26-0.48, p < 0.0001), compared to those that resulted in R2. On the other hand, a maximum tumor size greater than or equal to 40 mm (HR = 1.49, 95% CI = Complimentary Contributor Copy 138 Mario Uribe, Vincenzo Benedetti, Rodrigo Torres-Quevedo et al.

1.09-2.03, p=0.02) and an age greater than or equal to 60 years (HR = 1.51; 95% CI = 1.13- 2.00; p = 0.005) were found to be independent predictors of poor prognosis. Patients with more than ten metastases who achieved R0 or R1 with RFA but without other poor prognostic factors obtained a median OS of 51 months, while those that with R2 were 27 months. 95% CI was not reported for these OS medians. Considering the current state of the art and future developments, current consensus abandoned the classical paradigm already presented and redefined respectability in CRLM to just like other tumors indication of the ability to achieve complete resection under adequate liver remnant reserve (16, 18).

Unresectable metastases One of the main limitations for carrying out a resection of CRLM with curative intention is the danger of removing an excessive volume of liver parenchyma in the perusal of R0 margins, resulting in an insufficient liver remnant to ensure adequate function of the organ (32). It is estimated that in a healthy liver, a remanence of 20% of total volume is the minimum required for sufficient function after hepatic resection. This percentage is expected to be higher in the presence of underlying liver disease, damage induced by chemotherapy, steatosis, hepatitis or cirrhosis (33, 34). Given the great anatomical variability in the lobar and segmental volume of each patient, a thorough preoperative evaluation with tomographic and magnetic resonance imaging techniques allows a more accurate measurement of the liver remnant expected post-surgery (FLR), with better clinical results for patients (35, 36). Patients with bilateral CRLM and insufficient estimated FLR represent a major therapeutic challenge, having multiple strategies developed to increase the FLR, increasing or decreasing the reserve parenchymal tissue proportion to dry.

Neoadjuvant chemotherapy The preoperative chemotherapy regimens that consider different combinations of 5- Fluorouraci l,eucovorin and Oxaliplatin or Irinotecan have shown significant improvements in tumor response, achieving in some cases in converting initially unresectable metastases into resectable ones (8, 37, 38). The inclusion of biological agents in the previous schemes would show, according to some studies and in selected patients, an even higher rate of conversion, thus achieving similar survival to those with initially resectable tumors (39, 40). Nevertheless, the evidence on their global benefit is not entirely conclusive (8). In this sense, the current consensus concludes that patients with metastatic disease that is clearly resectable from a technical perspective and that have favorable prognostic factors are candidates for upfront surgery (25). Evidence from several series suggested greater intraoperative morbidity in patients undergoing neoadjuvant chemotherapy, which contain Oxaliplatin or irinotecan due to the potential association with portal hypertension and steatohepatitis (41, 42). These effects could occur in a time-dependent manner. Welsh et al. presented a prospective series of 750 patients undergoing CRLM resection comparing those undergoing neoadjuvant chemotherapy versus surgery alone, finding significant differences in intraoperative times (p = 0.012) and postoperative infectious complications (p = 0.016) in favor those who have not underwent previous chemotherapy (43). When analyzed by subgroups, patients undergoing prolonged Complimentary Contributor Copy Management of liver metastases 139 preoperative chemotherapy for more than six months had higher morbidity rates (39% vs 27%) and mortality (11% vs 5%) postoperatively than controls and chemotherapy groups of shorter duration, although the differences were not statistically significant, probably because of the small size of this subgroup (n = 18). Zhao et al. (34) conducted a systematic review, consolidating eight studies with 788 patients, to evaluate the influence of liver damage associated with chemotherapy (CALI). The presence of severe preoperative sinusoidal dilation was significantly associated with greater postoperative morbidity (OR = 1.73, 95% CI = 1.02-2.95, p = 0.043). Those who developed steatohepatitis after chemotherapy had a higher rate of specific postoperative surgical complications (OR = 2.08, 95% CI = 1.18-3.66, p = 0.012). When considering the different chemotherapeutic agents, the use of regimens based on Oxaliplatin was associated with a higher probability of presenting severe sinusoidal dilatation (OR = 2.74, 95% CI = 1.67-4.49, p < 0.001), with the possible effects already described.

Missing metastases In some cases, the use of neoadjuvant chemotherapy is associated with a complete radiological response, that is, the disappearance of metastatic lesions on images. This phenomenon is also known as “missing,” “disappearing” or “vanishing” metastases, and its frequency has increased with the use of modern chemotherapy schemes, occurring in 4% to 38% of cases. Unfortunately, 83% of these cases persist with active microscopic disease (16, 44). Resection of the original metastatic site should be attempted in all cases where it is feasible (45). These patients would benefit from additional magnetic resonance imaging with special hepatobiliary techniques (specific contrasts, diffusion sequences) and tumor labeling with coils prior to chemotherapy, since completely blind liver resection would increase the operative risk by preventing estimation of an adequate liver remnant, without a clear impact on local recurrence (45).

Portal vein embolization Embolization of the portal vein (PVE) emerged as a therapeutic option after observing the development of contralateral compensatory hypertrophy in primary hepatic tumors invading the portal vein (46). This procedure consists of cannulating the portal branch ipsilateral to the metastatic lesion under fluoroscopic vision and embolizing the vessel with appropriate materials, obtaining an increase in FLR by 8 to 16%, which would allow a greater number of resections to be made. The different published series report morbidity rates between 5 and 8%. A potential FLR of less than 25% in patients with normal liver would be a general indication of PVE prior to hepatectomy (46). However, some observational and experimental studies in murine models suggested potential worse impacts on disease recurrence, and an acceleration of progression in both embolized and non-embolized hepatic areas (47-49). Understanding of the complex mechanisms of hepatic regeneration and tumor growth, with the identification of the underlying signaling pathways, could allow inhibition of the undesired effect of the technique. To minimize tumor progression after PVE, two proposals have been made: reducing the time elapsed between PVE and subsequent resection, and in addition. Using concomitant systemic chemotherapy (either neoadjuvant or adjuvant), which has not been shown to impair post-resection hepatic hypertrophy (50). Complimentary Contributor Copy 140 Mario Uribe, Vincenzo Benedetti, Rodrigo Torres-Quevedo et al.

Two-stage hepatectomy Two-stage hepatectomy (TSH) was originally proposed for unresectable bilateral liver metastases. This technique consists of an initial resection of the metastatic implants existing in the liver considered as a future remnant (usually the left hemi liver), after which hepatic hypertrophy during a period of three to four weeks is expected (51). This first resection has the advantage of leaving the maximum possible remnant parenchyma and avoiding the rapid progression observed in the metastases present in the tissue in hypertrophy (52). After the defined period, a second resection to remove the remaining metastases assured a better future liver function. Initial reports showed a high postoperative mortality in relation to this technique (9 to 15%), which was related to an insufficient residual liver volume (53). Therefore, it began to be used in combination with PVE to obtain larger liver remnants, which dramatically reduced morbidity and postoperative mortality. TSH is now an accepted technique in the treatment of multiple and bilateral colorectal liver metastases that otherwise are considered unresectable. It should always be performed for curative purposes, taking special care to ensure a sufficient remaining liver to avoid postoperative hepatic failure (7).

Associating liver partition and portal vein ligation for staged hepatectomy (ALPPS) Described by Baumgart et al. (54) in 2011, this technique seeks to increase FLR and decrease the waiting time between interventions, therefore decreasing tumor progression. ALPPS consists of an abdominal surgical exploration, ligature of the portal branch and liver transection in situ along the falciform ligament; in a second instance, hepatectomy is completed. The first series published by Schnitzbauer et al. (36) in 2012 present 25 cases of ALPPS, of which 16 corresponded to CRLM. Sandström et al. (55) published in 2017 the results of the LIGRO study (NCT02215577), the first multicenter RCT aimed at evaluating the effect on the resection rate of ALPPS versus standard TSH in Nordic patients with CRLM considered unresectable in a single surgical act due to an estimated FLR of less than 30% (55). In the ALPPS group, 92% of the patients achieved an FLR of more than 30% within 14 days, while in the TSH group, 57% of the patients achieved a FLR of 30% without evidence of tumor progression (p < 0.0001). The average interval between the two surgeries was 11±11 days for the first group, and 43 ± 15 days for the second (p < 0.0001), no significant differences in the total length of hospital stay (p = 0.15) between both branches. Moreover, there were no significant differences in morbidity from ≥ 3a complications of Clavien-Dindo (p = 0.99), mortality at 90 days (p = 0.68), nor in achievement of R0 resections (p = 0.11) in comparing both treatments. In the author's experience, patients undergoing ALPPS achieved an average FLR increase of 97% at 19 days, while 100% achieved an FLR of more than 30% within this period (56).

Liver transplantation Conceptually, liver transplant is an interesting alternative for patients with unresectable CRLM by allowing R0 resection with the greatest possible surgical margin and simultaneously renew the functional reserve of the organ. In patients with primary liver tumors, liver transplantation has been supported by evidence as the best therapeutic

Complimentary Contributor Copy Management of liver metastases 141 alternative, offering a five-year OS of 75%, the main problem being the insufficient availability of organs to meet the demand for transplants for all its potential indications (57). In reality, in patients with CRLM, the evidence has not been as favorable. A group of Austrian researchers performed 25 liver transplants between 1982-1994, and reports OS at one, three and five years of 76%, 32% and 12%, respectively, with recurrence of 64%. These findings are similar to other contemporary series (57, 58). Because of the poor results this practice was abandoned, leading to the diagnosis of CRLM considered as an absolute contraindication for liver transplantation (59). In response to the advances of the technique, a Norwegian group reconsidered this situation, initiating a controlled prospective pilot study in 2006 (SECA study) to evaluate the survival of unresectable CRLM patients undergoing liver transplantation, taking advantage of the unique aspect of their country in having a very favorable availability of organs for transplant (60). In 2013, the group presented a series of 21 patients studied, obtaining OS at one, three and five years of 95%, 68% and 60%, respectively. Another European group presented in 2017 the results of an uncontrolled retrospective series of 12 patients, describing OS of 83%, 62% and 50%, at one, three and five years, respectively (61). The findings of these studies are very promising, especially in countries with higher organ donation rates, reevaluating the current paradigm and suggesting better expectations for patients with currently unresectable CRLM. New studies with a higher level of evidence are needed better specify the indications of this potential therapeutic tool (57, 58).

Radiofrequency ablation Radiofrequency ablation (RFA) is one of the therapeutic alternatives that was developed and continues to evolve to offer better survival to patients who at the time of diagnosis do not meet the criteria to undergo curative surgical treatment (62). It is important to emphasize this concept, since RFA should be indicated for curative purposes in patients with limited liver disease, comorbidities that contraindicate surgery, insufficient liver functional reserve to tolerate a resection, and if negative margins cannot be achieved by surgical resection, in addition to patient choice after informed consent (63). Although it was traditionally accepted that this technique should be applied to tumors of up to 5 cm and in a number less than or equal to five, in the latest publications it has been suggested to apply this technique when the level of carcinoembryonic antigen (CEA) is less than 200 ng/mL, or if the dominant lesion is less than 3 cm in diameter and is 3 or less in total. It has been reported that under these conditions the best results are obtained in terms of survival, with an average of 28.9 months (compared to the 21 months that are achieved with the best chemotherapeutic treatments) (62,64). Lesions larger than 3 cm have a higher risk of local recurrence. RFA is a relatively low risk procedure, which can be applied percutaneously, laparoscopically or by open surgery, with a mortality and morbidity rate of 0.3% and 7.2% respectively. The following are described as early complications (within the first 30 days): pleural effusions (this would be the most frequent), perihepatic abscesses, symptomatic ascites, and hemorrhage in the needle tract, symptomatic bilomas, and acute hemorrhages at the site of ablation. Biliary fistulas, symptomatic bilomas, sinus ascites, and liver failure have been described as late complications. (65, 66). Survival of patients undergoing RFA at 3 years is 36% to 41%, being higher than the natural history of untreated metastases or that of those who have received only chemotherapy Complimentary Contributor Copy 142 Mario Uribe, Vincenzo Benedetti, Rodrigo Torres-Quevedo et al. treatment. These figures are very close to the survival of patients treated with surgery, which has led to the possibility of using RFA as a first-line treatment in selected cases. However, before that, randomized studies evaluating the effectiveness of RFA versus surgical resection as first line treatment should still be performed (64). A multicenter phase II study in 119 patients with unresectable liver metastases evaluated the effect of aggressive local treatment (surgical resection + RFA of remaining lesions) combined with systemic chemotherapy compared to single chemotherapy. After a median follow-up of 9.7 years, significant differences were found in overall survival (OS) (HR = 0.58; 95% CI = 0.38-0.88) and progression-free survival (PFS) (HR = 0.63; 95% CI = 0.42- 0.95) in favor of the combined treatment group, with a median PFS of 16.8 months (95% CI = 11.7-22.1 months) and OS median of 45.6 months (95% CI = 30.3-67.8 months) for the first group versus 9.9 months (95% CI = 9.3-13.7 months) of median FP and 40.5 months (95% CI = 27.5-47.7 months) in the exclusive chemotherapy group (67).

Microwave coagulation Microwave coagulation (MWC) was described by Tabuse (68) in 1979 as a useful technique in liver surgery, allowing simultaneous cutting and coagulation, significantly decreasing bleeding from the liver bed (69). Like the RFA, the MWC can be applied via open surgery, laparoscopy or percutaneously. Its potential advantages over other techniques include the generation of a higher intratumoral temperature, faster ablation times, improved convection profile, greater volume of tumor ablation, and the possibility of using multiple antennas and less pain associated with the procedure. (70). While there is suggestive evidence of MWC effectiveness in the treatment of primary liver tumors (71, 72), its usefulness in CRLM has not been clearly demonstrated. Shibata et al. performed a RCT comparing the survival of patients with multiple CRLM subjected to exclusive MWC (n = 14) versus exclusive hepatectomy (n = 16) but did not find significant differences in OS between both groups, with OS medians of 27 and 25 months, respectively (69). It should be noted that this study did not consider the use of neoadjuvant or adjuvant chemotherapy.

METASTASES OF OTHER PRIMARY TUMORS

Neuroendocrine tumors 75% to 80% of patients with neuroendocrine tumors (NET) have synchronous hepatic metastases (NELM) at the time of diagnosis, and up to 95% of them will develop them throughout their disease. NELM is a poor prognostic factor, with an estimated a five-year survival not greater than 25%-30% (73). Surgical resection of the primary tumor and hepatic metastasis is the therapeutic strategy with the best results at present, although only 20% of patients with NELM are eligible for resection with curative intention (74). No RCT was found that studied the different therapeutic alternatives for patients with NET and liver metastases. The available evidence comes from descriptive observational studies only. Based on this, hepatic resection is currently considered the treatment of choice for patients with NELM grade 1 or 2, without extrahepatic disease, obtaining a five-year

Complimentary Contributor Copy Management of liver metastases 143 survival of 74%, with a median OS of 10.25 years and postoperative morbidity of less than 5% (75). Patients with unresectable NELM without extrahepatic disease, and appropriate functional status can be considered potential candidates for liver transplantation, with 5-year OS from 33%-90% and 5-year disease-free survival (DFS) from 11%-77% (76). Local ablative therapies have a palliative indication in those not suitable for resection or transplantation, with acceptable symptomatic improvement results. A series of 89 patients undergoing laparoscopic RFA had a 6% morbidity after the intervention, with symptomatic improvement in 97% of the patients, achieving a median of DFS of 1.3 years (77).

Gastrointestinal stromal tumors Gastrointestinal stromal tumors (GIST) are the most frequent non-epithelial tumors of the digestive system. 15-25% of patients have metastases at diagnosis, mainly in the liver and peritoneum, and 20-25% will develop metachronous liver metastases (78). The introduction of tyrosine kinase inhibitors (TKI) for the treatment of these neoplasms led to a dramatic improvement in the prognosis of patients, from survival of less than 16 months to over five years at present. Despite their impact, TKIs are limited by the fact that they cannot prevent late progression of the disease and require lifelong use in those without progression (79). In the period prior to the use of the TKI Imatinib, resection of hepatic metastases of GIST (GLM) showed significant improvements in survival, although based on retrospective studies. Due to the above, multiple clinical guidelines retained liver resection surgery as an optional treatment for patients with GLM treated with TKI (79, 80). Kanda et al. presented the results of a prospective multicenter study comparing the results of exclusive R0 hepatic resection (n = 6) versus exclusive Imatinib (n = 5) (81). There was no mortality due to specific tumor causes in any of the groups during follow-up. All the operated patients presented with recurrence, with a median recurrence-free survival (RFS) of 145 days, after which they started treatment with Imatinib. 75% of patients in the TKI group did not have progression of the disease. The study had to be interrupted due to changes in the clinical guidelines after demonstrating the effectiveness of Imatinib. A non-randomized multicenter retrospective study conducted in northern China in patients with GLM compared the survival of those undergoing resection of hepatic metastases and adjuvant with Imatinib versus those with exclusive TKI, finding a median OS of 89 months versus 53 months, suggesting a benefit of the combined strategy (82). Bauer et al. described the results of an EORTC group retrospective study of 239 patients undergoing resection of GLM and adjuvant Imatinib, comparing those with surgeries with R0/R1 margins versus those with positive margins (83). The median OS in the first group was 8.7 years; the R2 group was 5.3 years (p = 0.0001). When excluding patients with progressive disease at the time of surgery, the median OS was not reached in the R0/R1 group; in the R2 group, it was 5.1 years. Likewise, the median PFS was not reached in the group R0/R1, while in the R2 group it was 1.9 years. These findings suggest the curative potential of complete metastatic resection in conjunction with adjuvant therapy with TKI, although studies of a higher level of evidence that require this affirmation are necessary.

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The Latin American experience

The published Latin American experience comes mainly from retrospective observational studies, with very low levels of evidence. No published randomized clinical trials analyzing this population were found.

Treatment of colorectal metastases In relation to CRLM resection, Latin American studies focus on describing the morbidity and mortality outcomes and postoperative survival, with similar results to the rest of the studies reviewed. A Costa Rican retrospective study analyzed 51 patients undergoing surgery CRLM resection comparing those undergoing systemic chemotherapy (76.5%) in any mode (neoadjuvant, perioperative and adjuvant), with those undergoing surgery alone. After a median follow-up of 1.6 months, the combined group showed a greater OS (HR = 0.37, 95% CI = 0.15-0.91) compared to the control group. The median of OS was 44.4 months (95% CI = 39.47-44.36) for the first group, and 36.3 months (95% CI = 21.12-51.48) for the exclusive surgery group (84). Agudelo et al. published the postoperative results of a series of 93 patients undergoing hepatectomy in a hospital in Medellin, Colombia between 2005 and 2015, with OS medians of 57.9 months for metachronous metastases and 45.5 months for synchronous ones; their results were similar to other global reports (85). Among these results, the reports referring to the ALPPS technique stand out. Torres et al. reported the results of a series of 39 patients undergoing ALPPS between 2011 and 2012 in nine Brazilian hospitals (86). 59.0% of patients had significant morbidity, reporting a 12.8% mortality. An average increase of 83% in the FLR is described, with a mean interval between surgeries of 14.1 days. The first patient undergoing ALPPS reported in Chile was in 2011 by Uribe et al. with favorable results (35). A subsequent series of 13 patients undergoing ALPPS between 2011 and 2015 presented by the same group showed a mean increase in FLR of 96.8% (p < 0.05) with a mean interval between surgeries of 19 days. There were 23.0% who had morbidities greater than IIIB based on the Clavien-Dindo classification and no mortality was reported at 90 days of follow-up (56), consistent with results as reported in literature (87).

Treatment of metastases from other primary origins In line with global literature, publications on Latin American experience in non-CRC liver metastases is very limited, with all reported series being composed of a small number of cases. Valadares et al. (88) reported the retrospective results of 22 Brazilian patients undergoing NELM resection between 1997 and 2007. After three years of follow-up, OS was 77.3% and at 5 years of follow-up, OS was 44.2%, with only 13.6% of DFS at 5 years. The median OS was not reported in this study. A descriptive study published by Silva et al. (89) that considered all patients with soft tissue sarcomas undergoing hepatic resection at the National Cancer Institute of Brazil between 1992 and 2002 (n = 11) showed a median OS of 38 months; however, it did not compare its results with those from other series.

Complimentary Contributor Copy

Table 1. Summary of studies included in the systematic review

Reference Population Intervention Comparison Results* Rudroff 30 patients with CRLM and mesenteric lymph-node R0 liver resection plus four courses R0 liver resection 5-year OS: 25% vs 31% (p = 0.92) et al. 1999 metastases underwent R0 liver resection from July of HAI of adjuvant chemotherapy alone (n = 16). Long-term† DFS: 15% vs 23% (27) 1984 to December 1985 with Mitomycin C and (p = 0.79) 5-Fluorouracil (n=14). Shibata 30 patients with multiple CRLM recruited between Microwave coagulation of CRLM Surgical resection of 3-years OS: 14% vs 23% (p = 0.65) et al. 2000 December 1990 and August 1997 in Toyonaka performed after laparotomy CRLM (n = 16). Mean DFS: 11.3 months vs 13.3 (69) Municipal Hospital (n = 14) months (p = 0.47) Allard 529 patients with ≥ 10 CRLM operated on with Macroscopically complete (R0/R1) R2 resection or no- HR = 0.35 (95% CI = 0.26-0.48, et al. 2017 intention to cure from January 2005 to June 2013, liver resection achieved (n = 346). resection at all p < 0.0001); (31) whose data were prospectively collected in because of 5-year OS: 39% vs 5% (p < 0.0001) LiverMetSurvey online registry from 485 centers intraoperative findings Median OS: 49 months vs 27 months across 59 countries. (n = 183). (95% CI no reported). Ruers 119 patients with unresectable CRLM, recruited from Systemic treatment‡ plus local Systemic treatment OS HR = 0.58 (95% CI = 0.38-0.88, et al. 2017 22 centers in Europe from April 2002 to June 2007 treatment by RFA ± resection alone (n = 59). p = 0.01) (67) (n = 60). Median OS: 45.6 months (95% CI = 30.3-67.8) vs 40.5 months (95% CI = 27.5-47.7) PFS HR = 0.63 (95% CI = 0.42-0.95, p = 0.025) Sandström 97 patients with CRLM and a standardized FLR ALPPS (n = 48) TSH (n = 49) Resection rate: 92% (95% CI = 84%- et al. 2017 <30% recruited from six centers of Denmark, Norway 100%) vs 57% (95% CI = 43%-72%) (55) and Sweden, between June 2014 and August 2016. OR = 8.25 (95% CI = 2.6-26.6, p < 0.0001) Complications grade ≥3a: OR = 1.01 (95% CI = 0.4-2.6, p = 0.99) 90-day Mortality: OR = 1.39 (95% CI = 0.3-6.6, p = 0.68) CRLM: Colorectal cancer liver metastases, OS: Overall-survival, HAI: Hepatic-artery infusion, DFS: Disease-free survival, HR: Hazards-ratio, RFA: Radiofrequency ablation, 95% CI: 95% Confidence interval, PFS: Progression-free survival, FLR: Future liver remnant, ALPPS: Associating liver partition and portal vein ligation for staged hepatectomy, TSH: Two-stage hepatectomy, OR: Odds-ratio. *Experimental group vs control group. †14 years of follow-up after liver resection. ‡ FOLFOX 4 plus bevacizumab.

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Yáñez et al. described their experience with Chilean patients undergoing hepatectomy for metastases of non-CRC and non-NET origin between 2000 and 2008 (n=17), reporting a median OS of 17 months, with a 50.9% survival to 3 years of follow-up, without finding significant differences between the different primary tumors and histological types, although it is necessary to keep in mind the reduced sample size for each group (90). A preliminary study published by Díaz et al. presents the results of three patients with synchronous liver metastases from gastric cancer, undergoing palliative gastrectomy and simultaneous metastasectomy, achieving an average OS of 22.7 months, in contrast to patients who underwent only primary tumor palliative surgery (n = 9), who had an OS average of 14.5 months (91). The authors did not report statistical analysis because of the limited sample.

DISCUSSION

The prevalence of colorectal cancer has increased worldwide recently, along with an increased interest in optimizing the treatment of patients who are frequently diagnosed late with poor prognosis, especially those with liver metastases. Thanks to advances in technology, more patients could now be considered candidates for potentially curative therapies. In this regard, it is important to point out that despite the innovations in chemotherapy; only surgical resection has demonstrated curative potential in these patients. However, pharmacological treatment do play an increasingly important role in optimizing the selection of better responders after neoadjuvant therapy, prolonging global survival, reducing recurrence rates, and even allowing the conversion of patients to surgery with curative intent. The different strategies to increase the FLR, the main limitation for resection in patients with CRLM, such as PVE, TSH and lately ALPPS, have shown encouraging but not achieved conclusive results in survival, morbidity, or mortality to be considered the standard therapy. The evidence from studies is of low methodological quality. This is also influenced by the difficulty to quantify the FLR prior to surgery, without consensus in relation to hepatic volumetric techniques. Controlled clinical studies are required to clarify the clinical impact of these surgical alternatives. Ablative therapies have not clearly demonstrated comparable results to surgery, and its usefulness for the time being is concentrated in those patients who are not candidates for surgery. Liver transplantation, a technique ruled out by classical practice in cases of liver metastases, has gained recent interest due to studies carried out in developed countries with high organ donation rates. Those preliminary results have not been studied in other countries that face important technical, logistical and cultural barriers for donation and transplantation. In NET and GIST with liver metastases, the evidence suggests a potential positive impact of metastasectomy in overall survival, although without clear benefits in PFS. The low prevalence of these tumors is a clear limitation for future studies that evaluate and elucidate the clinical importance of this possible association. Several groups in Latin America have presented their experience with some of the surgical and ablative techniques described, in some cases with results comparable with other

Complimentary Contributor Copy Management of liver metastases 147 international reports. However, the published articles available are scarce and exclusively descriptive. It is necessary to conduct analytical studies and multicenter collaborative clinical trials in this region, which adequately represent the characteristics of its population, to establish better therapeutic standards for this pathology.

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Chapter 13

MANAGEMENT OF HEPATOCELLULAR CARCINOMA

Juan Francisco Guerra1,, MD, María Inés Gaete1,2, MD, Andres Troncoso1,3, MD, Rodrigo Torres-Quevedo4, MD, PhD, Fiona Lim5, MBBS, Bo Angela Wan6, MD(C) and Maurício F Silva7,8,9, MD, PhD 1Medstar Georgetown Transplant Institute, Georgetown University, Washington, DC, United States 2School of Medicine, Faculty of Medicine, Pontificia Universidad Catolica de Chile, Chile 3Department of Surgery, Faculty of Medicine, Universidad de la Frontera, Chile 4Department of HPB surgery, Hospital Guillermo Grant Benavente, Concepción, Chile 5Department of Oncology, Princess Margaret Hospital, Hong Kong, PR China 6Odette Cancer Centre, Sunnybrook Health Sciences Centre, University of Toronto, Toronto, Ontario, Canada 7Radiation Oncology Unit, Santa Maria Federal University, Santa Maria, Brazil 8Radiation Oncology Unit, Hospital de Caridade Astrogildo de Azevedo, Santa Maria, Brazil 9Latin America Cooperative Oncology Group, Porto Alegre, Brazil

ABSTRACT

Hepatocellular carcinoma (HCC) is the most common primary liver malignancy with increasing incidence over the last years. Since most are diagnosed in the setting of cirrhosis, the vast majority of cases arise in geographic areas where Hepatitis B and Hepatitis C are prevalent. Other risk factors such as alcohol and non-alcoholic steatohepatitis (NASH) are involved in the pathogenesis of HCC. In terms of diagnosis of HCC, ultrasonography (US), CT-Scan and MRI all play a role and here we intend to discuss the rationale of the use of each imaging modality. In terms of HCC management, there are multiples staging systems that categorize different lesions according to liver

 Corresponding Author’s Email: [email protected]. Complimentary Contributor Copy 154 Juan Francisco Guerra, María Inés Gaete, Andres Troncoso et al.

function and tumor characteristics in order to select the most appropriate treatment modality for each case.

INTRODUCTION

Hepatocellular carcinoma (HCC) is the most common primary liver malignancy, representing more than 90% of all liver cancers (1). Up to 90% of cases arise within the context of cirrhosis (1, 2). Each year, the incidence of HCC is progressively growing, reaching a current rate of 500,000 cases per year worldwide (1, 2). The highest incidence rates are clearly found among the geographic areas where Hepatitis B (Hep B) and Hepatitis C (Hep C) are prevalent, such as Southeastern Asia and Sub-Saharan Africa. In the USA, HCC tends to be secondary to Hep C infection (2). Nowadays, HCC is the fifth most common cancer in men and the seventh most common in women, with a 2-4-fold increased incidence in males compared to females. The diagnosis of HCC is usually made at the seventh decade of life. One of its variants, fibrolamellar HCC, tends to behave more aggressively and often presents at younger age (20-30 yr). The overall 5-year survival rate in patients with no treatment is around 12% (2-4).

Risk factors

The most critical risk factor for the development of HCC is the presence of cirrhosis, secondary to the many associated factors that lead to chronic liver disease. Among these factors, the more important ones are described below.

Hepatitis B Virus (HBV) infection

HBV is horizontally transmitted via blood transfusion of contaminated individuals, intravenous injections, and sexual activity, as well as vertically transmitted from mother to fetus. This explains the relatively high incidence of pediatric cases in certain areas of the world (1-5). HBV is considered to be the only etiology in which HCC may arise without the development of cirrhosis; HBV+ patients are having a 10-25% risk of developing HCC over their lifetimes (1, 2). This risk may be considerably reduced with the use of different antiviral drugs available now. Here we describe some strategies for screening detection, as well as a rationale for using imaging modalities.

Hepatitis C Virus (HCV) infection

Around 80% of HCV infected patients will progress to chronic hepatitis. Of them, approximately 20% will develop cirrhosis (5). The occurrence of HCC almost exclusively occurs in patients with established cirrhosis. The risk of developing HCC is considerably

Complimentary Contributor Copy Management of hepatocellular carcinoma 155 reduced in patients who received antiviral therapy, especially those a with sustained viral response (1-6).

Alcohol consumption

The association between alcohol and liver disease is strictly related to the amount of alcohol ingested over a lifetime. Excessive alcohol abuse is clearly associated with HCC. Consumption of 3 or more drinks per day increases the likelihood of developing an HCC to 16%, while consumption of six or more drinks per day will raise this risk to 22% (4,7).

Non-alcoholic steatohepatitis (NASH)

Significantly linked to obesity, NASH dramatically increases the risk of developing HCC. Of note, the highest incidence occurs in men, in whom the liver damage is not as advanced as shown by clinical parameters (8, 9).

Other factors

Diabetes mellitus, (and maybe other states of glucose imbalance such as glucose intolerance) and tobacco consumption are well known associated factors for the development of HCC (10, 11).

Screening

The aim of surveillance and screening points towards the early detection of lesions with a high risk of progressing to HCC, and if so, optimize their management, with the idea of reducing HCC-associated morbidity and mortality. The cost-effectiveness of this strategy is well known and reported (9). Ultrasonography (US) is recommended for HCC screening, with a sensitivity ranging from 65-85% and specificity greater than 90% (2, 12). In patients with known cirrhotic nodules, both sensitivity and specificity are less optimal, but is still the method of choice especially when compared with serologic markers. The most essential limitation remains the fact that it depends on the operator’s experience and skill. The use of this screening method may be less reliable in the obese population, in which MRI may be a better choice (10). The most used recommendation is to perform US every 6 months for patients at high risk of developing HCC (4, 12).

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DIAGNOSIS AND MANAGEMENT

Diagnosis and management of a patient with HCC should be a multidisciplinary approach. In addition to clinical findings, a complete blood cell count, liver function tests (LFTs), serum alfa-fetoprotein (AFP) and some type of imaging modality are required as part of the initial work up. The type of further imaging including CT or MRI will be determined by the size and the characteristics of the liver mass. Care should be taken in analyzing the overall liver parenchyma, the degree of liver disease, vasculature patency/compromise, the presence of intralesional fat and the presence of tumoral thrombus. In the context of a lesion arising in a patient with risk factors and/or established cirrhosis, the chance of having a “true” HCC is very high.

Lesion less than or equal to 1cm in diameter

A lesion less than or equal to one cm as demonstrated by US, even in a cirrhotic patient, has a low likelihood of being a “real HCC”. The use of CT and/or MRI may help in characterizing this lesion, but the presence of vascularization may be equivocal in certifying an HCC (4, 12). However, this small lesion has potential to degenerate into a malignant nodule. This is why it must be followed. The lack of growth in a period over two years suggests that HCC can be ruled out. If the lesion grows, further workup is needed (see Figure 1).

Figure 1. Recommended algorithm regarding the management of lesion/nodule under investigation in HCC surveillance.

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Lesion 1-2 cm in diameter

A lesion in this size range has a high probability of being an HCC. Due to this size, further workup must be performed using two different imaging modalities, either CT or MRI, looking for the typical hypervascular pattern in the arterial phase and early washout in the venous phase. If both images are coincident in terms of hypervascularity, then the lesion should be diagnosed and managed as an HCC. If this characteristic hypervascular pattern is present in only one imaging study or demonstrated an atypical pattern in both studies, then a liver biopsy should be considered. Follow up is mandatory even if biopsy is negative (see Figure 1) (6, 12).

Lesion greater than or equal to 2 cm in diameter

A lesion of this size has a higher probability of being an HCC compared to the others mentioned above. Workup must include serum AFP and an imaging modality, either CT or MRI. If AFP is greater than or equal to 200 ng/ml and/or the image confirms the characteristic hypervascular pattern and/or multifocality, the probability of HCC is high, and the lesion should be managed as an HCC without the need of a liver biopsy. If AFP is less than 200 ng/ml, and/or the imaging pattern is not specific, then a liver biopsy should be performed (4, 12).

MANAGEMENT ACCORDING TO THE STAGING SYSTEM

After diagnosing HCC, the staging of the disease must be determined, and subsequently adequate treatment must be followed. Currently, there are three clinical and four pathological staging systems. The four pathologic staging systems include the Liver Cancer Study Group of Japan (13), the Japanese Integrated Staging Score (14), the Chinese University Prognostic Index for Hepatocellular Carcinoma (15) and the American Joint Committee on Cancer (16). The clinical staging systems include the Okuda Staging System (17), Cancer of the Liver Italian Program (CLIP) (18), and the Barcelona Clinic Liver Cancer Staging System (BCLC) (19). The BCLC Staging system (20-23) is a well-known and useful clinical tool for HCC management. This system groups patients into four different stages based on clinical aspects such as tumor stage, functional state, patient performance status, and cancer-associated symptoms: early, intermediate, advanced and terminal. It suggests treatment modalities and life expectancies according to the disease stage.

Early stage

Within this stage are patients with preserved liver function, such as Child A and some Child B patients in the Child-Pugh system, and with a single lesion or up to three lesions up to 3 cm each, with no extrahepatic disease. For this stage, the treatment options include surgical

Complimentary Contributor Copy 158 Juan Francisco Guerra, María Inés Gaete, Andres Troncoso et al. resection, liver transplantation or local ablation, all of them with overall 5-year survival rates ranging from 40-75% (20, 23). Due to pathological characteristics, with no microvascular invasion, there is a high chance of cure for patients in this stage (see Figure 2).

Intermediate stage

Here we can find patients with preserved liver function (Child A/B) with multifocal HCC, with no symptoms, no macrovascular invasion, nor extrahepatic disease. The treatment of choice in this particular stage is transarterial chemoembolization (20, 23) (see Figure 2).

Advanced stage

This stage includes patients presenting with cancer-related symptoms and/or vascular invasion or extrahepatic disease. In this complex clinical scenario, new therapeutic options arising from randomized control trials should be considered (20, 23) (see Figure 2).

Terminal stage

These are patients with massive infiltrative HCC, resulting in symptoms or physical limitations and/or liver function deterioration. These patients have minimal survival, and the treatment should be focused on palliative medicine and best supportive care (see Figure 2).

Figure 2. BCLC Staging System. BCLC staging scale, which indicates the most appropriate treatment to follow according to pathological stage. PST: Performance status test; N1, M1: Stage within TNM staging; PEI: Percutaneous ethanol injection; RF: Radiofrequency.

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Treatment modalities

As mentioned earlier, the choice of treatment is based on tumor size, localization, extrahepatic disease, underlying liver function, and performance status. Potential treatments are described below.

Surgical approaches

Resection Surgical resection is the treatment of choice in non-cirrhotic patients with a single tumor, no evidence of vascular invasion, and with preserved liver function. In this type of patient, surgery produces a 5-year overall survival of 50-75%. Surgical resection depends on tumor size, localization, baseline liver function, and post resection liver remnant in order not to increase postoperative morbidity and mortality (19-24). In fact, patient selection is one of the most critical determinants of surgical morbidity and mortality. Any presence of portal hypertension should be evaluated either from clinical parameters or from more invasive techniques such as gradient measure. Patients with portal hypertension have a high risk of developing postoperative hepatic decompensation, which directly affects postoperative survival. Most recurrences are evident within 1-2 years after resection, and it is thought to be secondary to micrometastases from the primary tumor. Recurrence rate may be as high as 70% after 5 years in some series. Patients with extrahepatic disease or with portal main trunk invasion should not be considered for surgical resection.

Liver transplantation (LT) LT is the best curative option for HCC in the setting of decompensated cirrhosis. There are well-known criteria for the utilization of liver grafts in patients with HCC in order to have a better selection in terms of oncologic outcomes. The most common criteria used are the Milan Criteria (25) and the University of San Francisco (UCSF) Criteria (26) (see Table 1). Some studies suggest that both criteria offer similar overall survival and recurrence rates, with 1- year and 5-year survivals of 90% and 75%, respectively (25-28). Nevertheless, the Milan Criteria has been used as the standard way to select patients for LT. Locoregional therapies, such as transarterial chemoembolization (TACE) and radiofrequency ablation (RFA), can be used as a bridge therapy or as a “downstaging” strategy, in order to enable patients to be within the selected criteria for transplantation.

Table 1. Criteria for liver transplantation in the HCC approach

Milan criteria The University of California San Francisco criteria (UCSF) 1. Unique nodule ≤5 cm in diameter. 5. Unique nodule ≤6,5 cm in diameter. 2. Up to 3 nodules, none of whichh have a 6. Up to 3 nodules, none which have a diameter diameter >3 cm. >4.5 cm, and sum of the diameters ≤8 cm. 3. No macroscopic vascular invasion. 7. No macroscopic vascular invasion. 4. Negative extension study. 8. Negative extension study.

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Non-surgical approaches

Transarterial chemoembolization (TACE) TACE is considered a first-line locoregional therapy, used to reduce tumors with sizes exceeding the criteria for transplantation. TACE is also used as the initial neoadjuvant therapy to reduce tumor burden and/or micrometastasis. The overall survival at 1- and 2-years in patients with unresectable HCC is 82% and 63% respectively. The mechanism of TACE involves the injection of a chemotherapeutic agent and the embolization of hepatic artery branches that supply the tumor. It is achieved by catheter infusion of agents such as alcohol, guided by imaging to produce selective tumor hypoxia and subsequently tumor necrosis. TACE morbidity is less than 5%, and its most frequent complications include abdominal pain, nausea, and fever, which are consistent with post-embolization syndrome. Contraindications of its execution are liver failure, the presence of a massive tumor, portal vein thrombosis, significantly reduced portal flow, and creatinine clearance < 30 ml/min (28, 29).

Transarterial chemoradiation Transarterial chemoradiation is a type of locoregional treatment based on catheter-directed internal radiation that administers small microspheres with radioisotopes directly to the existing tumor. This procedure, which has been found to be safe and effective, is indicated in cases where there is portal vein thrombosis and therefore contraindicated for TACE. Before injection, it is necessary to perform abdominal arterial imaging to evaluate the possible existence of an arterioportal bypass. The rate of complete tumor necrosis is 90% in subjects with HCC < 3 cm. The most common side effects include nausea and vomiting, fatigue, and abdominal pain, among others; however, these symptoms are generally well tolerated in patients (28, 30). This procedure should be avoided in subjects with a hepatopulmonary shunt due to the risk of high radiation exposure to lung and hence development of radiation pneumonitis.

Percutaneous local ablation Percutaneous ablation therapies involve both radiofrequency ablation (RFA) and ethanol injection (EI). RFA is the first-line treatment for the local lysis of hepatic tumors, since it produces coagulative necrosis while leaving a margin of safety around the lesion. The overall 5-year survival rate ranges from 33% to 55%, while the rate of complete tumor necrosis for tumors < 2 cm is higher than 90%; for tumors of 2-3 cm it is 70%. However, RFA has limitations in specific scenarios such as for tumors >3 cm, tumors adjacent to main blood vessels, and tumor located in a difficult position to access, such as those in segment 1 of the liver (19, 31).

Microwave ablation (MWA) MWA is a method very similar to RFA but uses electromagnetic waves with frequencies higher than 90 kHz to irradiate and remove tumor foci (1, 24, 28).

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Systemic therapy

Sorafenib is an oral drug which acts by inhibiting tumor angiogenesis and hence tumor proliferation. Its use is recommended for patients who have advanced HCC and preserved liver function, but who are not candidates for surgical approach and failed locoregional therapies. The main side effects include anorexia, weight loss, paresthesia, hypertension, thromboembolism, and bleeding risk, among others. Therefore, its administration can be difficult to tolerate (6, 19, 31).

REFERENCES

[1] El-Serag HB. Hepatocellular Carcinoma. N Engl J Med 2011;365(12):1118-27. [2] Balogh J, Victor D, Asham EH, Burroughs SG, Boktour M, Saharia A, et al. Hepatocellular carcinoma: a review. J Hepatocell Carcinoma 2016;3:41-53. [3] Lafaro KJ, Pawlik TM. Fibrolamellar hepatocellular carcinoma: current clinical perspectives. J Hepatocell carcinoma 2015;2:151-7. [4] Llovet JM, Burroughs A, Bruix J. Hepatocellular carcinoma. Nat Rev Dis Primers 2016;2:16019. [5] Petruzziello A. Epidemiology of Hepatitis B virus (HBV) and Hepatitis C virus (HCV) related Hepatocellular carcinoma. Open Virol J 2018;12:26-32. [6] Llovet JM, Ricci S, Mazzaferro V, Hilgard P, Gane E, Blanc JF, et al. Sorafenib in advanced hepatocellular carcinoma. N Engl J Med 2008;359(4):378-90. [7] Ramadori P, Cubero FJ, Liedtke C, Trautwein C, Nevzorova YA. Alcohol and hepatocellular carcinoma: adding fuel to the flame. Cancers (Basel) 2017;9(10):1-22. [8] Younossi ZM, Loomba R, Rinella ME, Bugianesi E, Marchesini G, Neuschwander-Tetri BA, et al. Current and future therapeutic regimens for nonalcoholic fatty liver disease and nonalcoholic steatohepatitis. Hepatology 2018;68(1):361-71. [9] Said A, Ghufran A. Epidemic of non-alcoholic fatty liver disease and hepatocellular carcinoma. World J Clin Oncol 2017;8(6):429-36. [10] Li X, Wang X, Gao P. Diabetes mellitus and risk of hepatocellular carcinoma. Biomed Res Int 2017;2017:5202684. [11] Fan JG, Farrell GC. Prevention of hepatocellular carcinoma in nonviral-related liver diseases. J Gastroenterol Hepatol 2009;24(5):712-9. [12] Bruix J, Sherman M. Management of hepatocellular carcinoma. Hepatology 2005;42(5):1208-36. [13] Kudo M, Matsui O, Izumi N, Iijima H, Kadoya M, Imai Y. Surveillance and diagnostic algorithm for hepatocellular carcinoma proposed by the liver cancer study group of Japan: 2014 update. Oncology 2014:87(suppl 1):7-21. [14] Nathan H, Mentha G, Marques HP, Capussotti L, Majno P, Aldrighetti L, et al. Comparative performances of staging systems for early hepatocellular carcinoma. HPB (Oxford) 2009;11(5):382- 90. [15] Chan SL, Johnson PJ, Mo F, Berhane S, Teng M, Chan AWH, et al. International validation of the Chinese university prognostic index for staging of hepatocellular carcinoma: A joint United Kingdom and Hong Kong study. Chin J Cancer 2014;33(10):481-91. [16] Chan ACY, Fan ST, Poon RT, Cheung TT, Chok KS, Chan SC, Lo CM. Evaluation of the seventh edition of the American Joint Committee on Cancer tumour-node-metastasis (TNM) staging system for patients undergoing curative resection of hepatocellular carcinoma: Implications for the development of a refined staging system. HPB (Oxford) 2013;15(6):439-48. [17] Duseja A. Staging of hepatocellular carcinoma. J Clin Exp Hepatol 2014;4(Suppl 3):S74-9. [18] Huo TI, Huang YH, Lin HC, Wu JC, Chiang JH, Lee PC, et al. Proposal of a modified Cancer of the Liver Italian Program staging system based on the model for end-stage liver disease for patients with hepatocellular carcinoma undergoing loco-regional therapy. Am J Gastroenterol 2006;101(5):975-82. Complimentary Contributor Copy 162 Juan Francisco Guerra, María Inés Gaete, Andres Troncoso et al.

[19] Au JS, Frenette CT. Management of hepatocellular carcinoma: Current status and future directions. Gut Liver 2015;9(6):437-48. [20] Lee JH, Kim HY, Kim YJ, Yoon JH, Chung JW, Lee HS. Barcelona Clinic Liver Cancer staging system and survival of untreated hepatocellular carcinoma in a hepatitis B virus endemic area. J Gastroenterol Hepatol 2015;30(4):696-705. [21] Kulik L. Is radioembolization ready for the barcelona clinic liver cancer staging system? Hepatology 2010;52(5):1528-30. [22] Hsu CY, Liu PH, Hsia CY, Lee YH, Al Juboori A, Lee RC, et al. Nomogram of the Barcelona Clinic Liver Cancer system for individual prognostic prediction in hepatocellular carcinoma. Liver Int 2016;36(10):1498-506. [23] Forner A, Ayuso C, Isabel Real M, Sastre J, Robles R, Sangro B, et al. Diagnóstico y tratamiento del carcinoma hepatocelular. Med Clin (Barc) 2009;132:272-87. [24] Balogh J, Victor D, Asham EH, Burroughs SG, Boktour M, Saharia A, et al. Hepatocellular carcinoma: a review. J Hepatocell Carcinoma 2016;3:41-53. [25] Mazzaferro V, Regalia E, Doci R, Andreola S, Pulvirenti A, Bozzetti F, et al. Liver transplantation for the treatment of small hepatocellular carcinomas in patients with cirrhosis. N Engl J Med 1996;334(11):693-9. [26] Yao FY, Ferrell L, Bass NM, Watson JJ, Bacchetti P, Venook A, et al. Liver transplantation for hepatocellular carcinoma: Expansion of the tumor size limits does not adversely impact survival. Hepatology 2001;33(6):1394-403. [27] Clavien PP-A, Lesurtel M, Bossuyt PMMP, Gores GJ, Langer B, Perrier A, et al. Recommendations for liver transplantation for hepatocellular carcinoma: an international consensus conference report. Lancet Oncol 2012;13(1):e11-22. [28] Bruix J, Sherman M. Management of hepatocellular carcinoma. Hepatology 2005;42(5):1208-36. [29] Meng XC, Chen BH, Huang JJ, Huang WS, Cai MY, Zhou JW, et al. Early prediction of survival in hepatocellular carcinoma patients treated with transarterial chemoembolization plus sorafenib. World J Gastroenterol 2018;24(4):484-93. [30] Park MS, Kim SU, Park JY, Kim DY, Ahn SH, Han KH, et al. Combination treatment of localized concurrent chemoradiation therapy and transarterial chemoembolization in locally advanced hepatocellular carcinoma with intrahepatic metastasis. Cancer Chemother Pharmacol 2013;71(1):165- 73. [31] Bruix J, Takayama T, Mazzaferro V, Chau GY, Yang J, Kudo M, et al. Adjuvant sorafenib for hepatocellular carcinoma after resection or ablation (STORM): A phase 3, randomised, double-blind, placebo-controlled trial. Lancet Oncol 2015;16(13):1344-54.

Chapter 14

MANAGEMENT OF COLON CANCER

Lauren Razzera Stefanon1,2,, MD, Luís Carlos Moreira Antunes1,2, MD, PhD, Fiona Lim3, MBBS, Bo Angela Wan4, MD(C) and Mauricio F Silva5,6,7, MD, PhD 1Hematology and Oncology Service, Santa Maria University Hospital, Federal University of Santa Maria, Santa Maria, Brazil 2Clinical Oncology Unit, Hospital de Caridade Dr. Astrogildo de Azevedo, Santa Maria, Brazil 3Department of Oncology, Princess Margaret Hospital, Hong Kong, PR China 4Odette Cancer Centre, Sunnybrook Health Sciences Centre, University of Toronto, Toronto, Canada 5Radiation Oncology Unit, Santa Maria Federal University, Santa Maria, Brazil 6Radiation Oncology Unit, Hospital de Caridade Astrogildo de Azevedo, Santa Maria, Brazil 7Latin America Cooperative Oncology Group, Porto Alegre, Brazil

ABSTRACT

This chapter is a review of colon cancer management in Latin America. We have focused on the current literature and especially the guidelines used in Brazil that show our experience in terms of colon cancer management. Latin America has great contrasts regarding cancer prevention, diagnosis and treatment. Some countries, such as Brazil, have unified health care systems, which are funded by the government and so are available to the entire population, as well as private health plans. Therefore, we are always looking for excellence in medicine based on a multidisciplinary approach.

 Corresponding Author’s Email: [email protected]. Complimentary Contributor Copy 164 Lauren Razzera Stefanon, Luís Carlos Moreira Antunes, Fiona Lim et al.

INTRODUCTION

Colon cancer is one of the most frequent cancers in the world. Its pathogenesis is multifactorial and includes both genetic and environmental risk factors. The GLOBOCAN 2012 estimates that there were 1.4 million cases and 693 thousand deaths from colon cancer in that year that being the second highest type of cancer in women and the third highest in men (1). Data from the Global Cancer Observatory 2018 shows that the incidence of colorectal cancer globally is 23.65 for every 100,000 men and 16.3 for every 100,000 women (2), while Latin America has a 20.6% incidence in men and 17.1% in women. In Brazil, a survey conducted by the National Cancer Institute (INCA) in 2018-2019 revealed an estimated 17.380 new cases among men and 18.980 new cases among women (3). Latin American countries present a different level of development. Therefore, in some of these countries, the precarious conditions of the public health system, besides the difficulties in performing the oncological diagnosis and in accessing new technologies, are factors that have contributed to an increase in cancer mortality, which is the second cause of death in such countries (1). According to a report provided by the Economist Intelligence Unit in 2017 (4), Latin America is making important efforts in cancer research, although there are still a number of challenges in managing and treating the disease. There have been improvements in the field of preventive healthcare, such as anti-smoking policies and stimulation of vaccination against HPV. It also should be noted that Latin America is currently undergoing a change in terms of dietary and social habits, which brings it closer to developed countries. This change leads to an increased risk of obesity and different types of cancer, which are associated with this new lifestyle. In Brazil, there are popular campaigns that encourage changes in lifestyle with the purpose of reducing risk factors for colorectal cancer (1). There has also been an expansion of screening tests in areas that previously were not taken into consideration, thus allowing an early diagnosis. Furthermore, it seems important to mention that PET/CT is already available in the public health system in Brazil. The purpose of this chapter is to present a summary of the recommended treatments for colon cancer as developed in the Latin America scenario.

MANAGEMENT OF COLON CANCER

Colonoscopy is considered the gold standard for diagnosis and screening of colon cancer. This procedure was introduced 50 to 75 years ago and it’s possible to be applied when suspected lesions are visible. On the other hand, a fecal occult blood test (FOBT) is recommended annually if colonoscopy is not available (5, 6). Patients who have a family history or have been diagnosed with colon cancer before the age of 50 can be investigated for genetic syndromes of the cancer, such as Lynch Syndrome. For an initial screening, we can use the Bethesda and Amsterdam criteria (see Tables 1 and 2). Patients who show positive criteria should undergo research in terms of the mismatch repair genes (6).

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Table 1. Amsterdam II criteria

At least three family members with a tumor of the Lynch syndrome spectrum (colorectal, endometrial, ovary, stomach, small intestine, renal ureter or pelvis, pancreas, biliary tract and tumors of the central nervous system, adenomas sebaceous and keratoacanthomas). One affected person must be a first-degree relative of the other two affected. At least two successive generations diagnosed with tumors of the spectrum. At least one diagnosis before 50 years of age. The diagnosis of familial adenomatous polyposis (FAP) should be excluded in cases of colorectal cancer.

Table 2. Revised Bethesda criteria

Cancer colorectal diagnosed before 50 years of age. Multiple primary tumors of the Lynch syndrome spectrum or multiple Cancer colorectals (synchronic or metachronous) diagnosed at any age. Cancer colorectal with histology compatible with tumors of high microsatellite instability (MSI-H): diagnosed before 60 years of age, presence of infiltration lymphocytic reaction, Crohn's lymphocytic reaction, mucinous or ring differentiation of skeletal or medullary growth pattern. Cancer colorectal diagnosed in one or more first-degree relatives of an individual with a tumor of the Lynch syndrome spectrum, one of the tumors being diagnosed before the age of 50 Cancer colorectal in two or more first or second degree relatives with Lynch syndrome, regardless of age at diagnosis.

Staging

Staging of colonic neoplasia is based on imaging tests to detect distant metastases. According to some guidelines found in protocols, such as the National Comprehensive Cancer Network (NCCN) and the Brazilian Gastrointestinal Tumour Group (GTG), it should be performed thoracic, abdominal and pelvic computed tomography, laboratory tests, including tests on liver and renal function, blood count and CEA. Patients who have not performed a colonoscopy with colon visualization due to the presence of obstructive tumors can undergo virtual colonoscopy, if it is available. Subsequently, these patients should be re-submitted to colonoscopy for evaluation of the entire colon (7, 8). PET/CT is not recommended for initial staging. However, it is recommended for a preoperative evaluation of resection for metastatic disease, reducing the number of futile laparotomies by 38% (9, 10). In the public healthcare system in Brazil, PET/CT is available only to patients with resectable metastatic colorectal liver cancer, as shown in Tables 3 and 4 (11).

Risk factors and pathology

The main environmental risk factors that cause colorectal cancer are: a fat-rich diet, with consumption of red meat and poor intake of vegetables, obesity, sedentary lifestyle, diabetes mellitus, smoking, inflammatory bowel disease (Crohn's disease and ulcerative colitis) (12). Complimentary Contributor Copy 166 Lauren Razzera Stefanon, Luís Carlos Moreira Antunes, Fiona Lim et al.

Familial Adenomatous Polyposis (PAF) and Lynch Syndrome (SL) are the main causes of hereditary colon cancer. Inherited genetic causes are responsible for 20 % of colon cancer cases. PAF is an autosomal dominant disease caused by a mutation in the APC gene, accounting for 1% of colorectal cancer cases. Individuals with the syndrome (PAF) develop the neoplasm in 100% of the cases. SL accounts for 3 to 5% of the cases (MLH1, MSH2, MSH6, and PMS2), and its carriers have an approximate 80% risk of developing colorectal cancer (13).

Table 3. AJCC -TNM staging system 8th edition

Primary Tumor (T) TX Primary tumor cannot be assessed T0 No evidence of primary tumor Tis Carcinoma in situ: intraepithelial or invasion of lamina propria T1Tumor invades submucosa T2 Tumor invades muscularis T3 Tumor invades through the muscularis propria into pericolorectal tissue T4a Tumor penetrates to the surface of the visceral peritoneum T4b Tumor directly invades or is adherent to other organs or structures Regional Lymph Nodes (N) NX Regional lymph nodes cannot be assessed N0No regional lymph node metastasis N1 Metastasis in 1-3 regional lymph nodes N1a Metastasis in one regional lymph node N1b Metastasis in 2-3 regional lymph nodes N1c Tumor deposit(s) in the subserosa, mesentery, or nonperitonealized pericolic or perirectal tissues without regional nodal metastasis N2 Metastasis in 4 or more regional lymph nodes N2a Metastasis in 4-6 regional lymph nodes N2b Metastasis in 7 or more regional lymph nodes Distant Metastasis (M) M0 No distant metastasis M1 Distant metastasis M1a Metastasis confined to one organ or site (for example, liver, lung, ovary, nonregional node) M1b Metastases in more than one organ/site or the peritoneum

Table 4. Anatomic stage TNM (AJCC, 8th edition)

0: I: IIA: IIIA: IVA: qqTqqNM1a TisN0M0 T1-2N0M0 T3N0M0 T1-2N1/N1cM0 OR T1N2aM0 IIB: IIIB: IVB: qqTqqNM1b T4aN0M0 T3-4aN1/N1cM0 or T2- 3N2aM0 or T1-2N2bM0 IIC: IIIC: IVC: qqTqqNM1c T4bN0M0 T4aN2aM0 or T3-4aN2bM0 or T4bN1-2M0 Complimentary Contributor Copy Management of colon cancer 167

Pathogenesis of colon cancer occurs due to the transformation of an adenoma into a carcinoma. This process may take up to 20 years and it is a consequence of the development of molecular mutations, especially in the APC and KRAS genes. Another process of colorectal cancer carcinogenesis is related to the presence of microsatellite instability (MSI) in about 20% of the cases. In this case, there is a loss in the DNA repair system (12). The prevention of colon cancer begins with changes in lifestyle habits, such as: following a healthy diet, reducing obesity, giving up smoking and excessive alcohol consumption. The use of colonoscopy for resection of polypoid lesions reduces the development of colon cancer. Patients who have had their colon polyps resected have to repeat the procedure (colonoscopy) annually (12).

Surgical treatment

A surgery with extensive colonic segmental resection and lymph node resection of at least 12 lymph nodes is the treatment of choice for stages of cancer without metastasis (14). A five- year overall survival (OS) is seen in 85% of the cases in stages I and IIA, 80% in stage IIB, 60% in stage IIC, ranging from 30% to 50% in stage III. The longitudinal margins of 5-10 cm and radial ≥ 1 mm are desirable (15). Randomized studies showed no difference between laparoscopic surgery and traditional laparotomy (16).

Adjuvant treatment

Patients with clinical stage 0 and I disease have a high chance of remission, so that exclusive surgery is the recommended treatment. Patients classified as ECII have a five-year overall survival rate, ranging from 85.5% for IIAs, 79.6% for IIBs and 58.4% for IICs (17). The use of adjuvant chemotherapy for patients with EC II is recommended based on a Risk Categorization Table. The QUASAR study showed an increase in overall survival in these patients with 5 fluorouracil (5FU) chemotherapy regimens. Thus, microsatellite instability research becomes important in this context, since its presence reveals tumors with a better prognosis and a lower rate of recurrence. Adjuvant chemotherapy is not recommended in this case (18-20). Other factors associated with a high risk of recurrence indicative on use of adjuvant fluoropyrimidine-based chemotherapy includes: intestinal tumors with perforation or obstruction, T4 tumors, aneuploidy, poorly differentiated tumors, lymphovascular and perineural invasion present and less than twelve resected lymph nodes, and the presence of microsatellite stability (17). In patients classified with EC III, oxaliplatin-based adjuvant chemotherapy is recommended. The first studies evaluating the effectiveness of adjuvant chemotherapy, based on 5FU and/or levamizole, in patients with colorectal neoplasia have shown an increase in overall survival rate. The MOSAIC study, which randomized 1,123 stage II and III patients, compared the use of 5FU as opposed to 5FU in combination with oxaliplatin (FOLFOX4) with a six-year overall survival rate of 67.4% against 73.3% respectively, thus recommending the use of oxaliplatin in patients with clinical stage III (21).

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Table 5. Systemic therapy-adjuvant

Roswell Park Leucovorin: 500 mg/m2 in 2 hour D1 4-6 cycles EC II 5-FU: 500 mg/m2 push D1, 1 hour after the beginning of leucovorin Weekly for 6 weeks, followed by 2 weeks without treatment. LV5FU2 Leucovorin: 200 mg/m2 (DL-Leucovorin) or 5-FU: 100 mg/m2 (L-Leucovorin), D1-2 5-FU: 400 mg/m2 bolus, D1-2 600 mg/m2 22hs, D1-2 Capecitabin Capecitabin: 1.250 mg/m2 twice a day, do D1-14 each 3 weeks for 24 8 cycles EC II weeks. mFOLFOX6 Oxaliplatin: 85 mg/m2 D1 12 cycles EC III Leucovorin: 400 mg/m2 D1 5-FU: 400 mg/m2 bolus D1 5-FU: 2400 mg/m2 in 46-48 hours each 14 days FLOX Leucovorin: Oxaliplatin 85mg/m²: D1,D15 and D29 3 cycles EC III 5-FU: Leuvorin 500 mg/m² and Fluoracil 500 mg/m² :D1, D8, Oxaliplatin: D15,D22, D29 and D36 Each 8 weeks

CAPOX Oxaliplatin: 130 mg/m2 D1 8 cycles EC III Capecitabine: 1,000 mg/m2 twice a day for 14 days in each 3 weeks Source: Oncologic Guideline, SBOC, 2017.

Due to toxicity associated with the oxaliplatin regimen, mainly neutropenia and peripheral neuropathy, other regimens have been studied and as a result became alternatives in the treatment of Colon Cancer ECIII, including the following: mFOLFOX6, FLOX and XELOX. One study randomized 2,407 patients to receive 5-fluorouracil and leucovorin weekly, or 5FU, leucovorin and oxaliplatin at weeks 1, 3 and 5. According to the FLOX scheme, progression-free survival at four years was 67% as opposed to 73.2%. Neuropathy was lower in the FLOX group, although this group presented more severe diarrhea (22). A follow-up to this study showed good disease-free survival outcomes, with no significant overall survival results. In addition, patients aged younger than 70 years showed better results (23). The XELOX regimen (capecitabine with oxaliplatin) was assessed in a study that randomized 1,886 patients and then compared with 5FU and leucovorin regimens, showing a reduction in the recurrence of cancer (24, 25). Therefore, the XELOX regimen is a good choice for adjuvant treatment in patients with stage III colon cancer. Due to the chemotherapy-related toxicity, many studies have been investigating the real benefits of adjuvant chemotherapy in patients over the age of 70. One particular study Complimentary Contributor Copy Management of colon cancer 169 analyzed data from seven other studies, thus comparing adjuvant chemotherapy with or without oxaliplatin in patients of different age groups. This study showed a lower benefit in the overall survival rate of patients over 70 years of age, however, there was no relevant difference in terms of disease-free survival (26). Other studies have suggested that the benefits are similar to both age groups, and each case should be examined considering the morbidities of each patient. (24, 26, 27). The possibility of reducing the duration of adjuvant treatment for patients with EC III was discussed in the International Duration Evaluation of Adjuvant Chemotherapy (IDEA) study, which presented noninferiority of three months of treatment in the low-risk subgroup (T1-3N1), but not in the high-risk group (T4 or N2), and three months of treatment in the low-risk group (28).

Table 6. Systemic therapy-metastatic

Capecitabin 1000 mg/m2 2x/d D1-D14 Oxaliplatin 130 mg/m2 D1 Bevacizumab 7,5 mg/kg D1 Each 21 days Capecitabin 1000 mg/m2 twice a day do D1-14 Bevacizumab 7,5 mg /kg each 3 weeks mFOLFOX6 Oxaliplatin 85 mg/m2 D1 Leucovorin 400 mg/m2 D1 5-FU 400 mg/m2 bolus D1 5-FU. 2400 mg/m2 in 46-48 hours Cetuximabe*OR 500 mg/m2 D1 Panitumumab* 6 mg/kg D1 each 14 days FOLFIRI Irinotecano 180 mg/m2 D1 Leucovorin 400 mg/m2 D1 5-FU 400 mg/m2 bolus D1 5-FU 2400 mg/m2 in D146-48 hours Bevacizumab*OR 5 mg/kg D1 Aflibercept *OR 4 mg/kg EV D1 Cetuximab*OR 500 mg/m2 D1 Panitumumab*OR 6 mg/kg D1 each 14 days FOLFOXIRI 5-FU 3200 mg/m2 in 48h D1+ 5-FU 400 mg/m2 D1 Leucovorin 400 mg/m2 D1 Irinotecan 165 mg/m2 D1 Oxaliplatin 85 mg/m2 D1 Bevacizumab* 5 mg/kg D1 Each 14 days Regorafenibe* 160 mg a day for 21 days each 28 days Source: Oncologic Guideline, SBOC, 2017. *Not available on the public network in Brazil. Complimentary Contributor Copy 170 Lauren Razzera Stefanon, Luís Carlos Moreira Antunes, Fiona Lim et al.

Management of metastatic disease

The choice of initial treatment is based on the RAS profile, patient's performance status, possibility of resectability of the metastatic lesions and laterality of the primary tumor (29, 30). Patients with respectable metastases have a greater benefit in receiving perioperative chemotherapy when compared to exclusive surgical treatment. According to data published in EORTC 40983, which compared the use of chemotherapy with FOLFOX4 protocol and six pre-surgery cycles and six post-surgery cycles, the group that received chemotherapy had a higher progression-free survival rate (31). Patients with partially resectable metastases should undergo a conversion chemotherapeutic treatment, aiming to reduce lesions and subsequent resection. The selection of the chemotherapeutic scheme includes the definition of RAS/BRAF status. For patients with RAS/wild-type BRAF and primary tumor on the left side of the colon, the use of FOLFIRI or mFOLFOX6, both combined with cetuximab or panitumumab, is suggested (30,31). For those with RAS mutations or with BRAF V600E mutation and / or primary tumor on the right side, the FOLFOXIRI, FOLFOX or FOLFIRI schemes are suggested. A four-drug treatment has increased the efficiency of first-line treatment, but the adverse effects were also higher when compared to three-drug regimens. In the case of patients who have metastatic disease, with no possibility of resectability, the initial treatment choice will depend on the patient's status, RAS mutation status and its laterality. NRAS and KRAS mutations are molecular markers of colon cancer that indicate no antibody responses to the epidermal growth receptor (EGFR), cetuximab and panitumumab. In addition, the presence of mutated BRAF confers a worse prognosis in patients with colorectal neoplasia, besides predicting the absence of response to anti-EGFR (32, 33). Laterality of the primary tumor, according to CALGB 80405 review, favors chemotherapy associated with bevaczumab in the right side tumors, due to a worse prognosis of this location. On the other hand, there are benefits with anti-EGFR therapy in tumors on the left side, i.e., tumors with better prognosis. OS was prolonged with cetuximab versus bevacizumab in the left-sided primary tumor group (39.3 months vs. 32.6 months), but shortened in the right-sided primary group (13.6 months vs. 29.2 months) (34). Therefore, patients with wildy type RAS tumors are treated with mFOLFOX6 or FOLFIRI regimens associated with bevaczumab, cetuximab or panitumumab, with preferential use of anti EGFR in left colon tumors. There are no differences in survival rates gain between the mFOLFOX6 or FOLFIRI regimens, only presenting different toxicities (35, 37). A study evaluated metastatic colon cancer patients with KRAS wild-type adding cetuximab or bevaczumab to FOLFOX or FOLFIRI, there was no difference in overall survival in either group, so both drugs could be considered as an initial treatment choice (36). The association of bevaczumab demonstrated increased progression-free time when associated with irinotecan and oxaliplatin regimens (36, 38, 39). The association between capecitabine, irinotecan plus bevaczumab is not inferior to FOLFIRI regime, but it has a major potential of toxicity (40). The efficiency of cetuximab was evaluated in the CRYSTAL study, which compared its association with FOLFIRI regimen with increased overall survival and increased progression- free survival. When oxaliplatin was associated with a better overall response (41, 42), similar Complimentary Contributor Copy Management of colon cancer 171 responses were observed with regard to panitumumab (42) with increased progression-free survival, with bevaczumab, cetuximab and panitumumab being used in first line therapy. The COIN study evaluated the addition of cetuximab to oxaliplatin regimens in association with fluouracil or capecitabine. In this study there was an increase response rate, without gains in overall survival with cetuximab addition in wild-type KRAS patients, and the association with capecitabine shows important side effects. Its use is not recommended in first line therapy (43). Patients with unresectable disease and RAS mutations can take FOLFOX or FOLFIRI associated or not with bevaczumabe as first-line therapy, following the same procedures presented by the studies previously mentioned. The capecitabine and bevaczumab regimen has been shown to be effective and well-tolerated in elderly or fragile patients (44). Therapeutic regimens should be maintained until progression or limiting the toxicity. The OPTMOX 1 and OPTMOX 2 studies evaluated temporary suspension of only the oxaliplatin or of all regimens until cancer progression, respectively. The first option did not represent a decrease in overall survival, as opposed to the total suspension (45, 46).

Subsequent lines of treatment Subsequent lines of treatment should be used in which patients have not yet been exposed. It is already known that the sequence of chemotherapy does not change survival outcomes. It is the patient who should be exposed to all drugs (35, 36). Aflibercept could be used in association with FOLFIRI in patients previously treated with oxaliplatina. There is an improvement in overall survival of13.5 versus 12 months (47). As a rescue regimen, we can mention regorafenib, but with a discrete gain in overall survival (49). Another option is to use immunotherapy with pembrolizumab, a humanized anti-PD1 monoclonal antibody used in patients with a deficiency of the DNA repair system who had failed with at least three treatment lines and had a 40% overall response rate and a 90% disease control rate (48).

FOLLOW-UP

As a follow-up procedure for patients with colon cancer, the Brazilian Gastrointestinal Tumour Group, in accordance with the global guidelines, suggests that all IC I patients should be evaluated with a clinical history, a physical examination and CEA every six months for two years and thereafter annually until completing five years of follow-up. A colonoscopy should be performed one year after surgery. If normal, it should be repeated every two to three years. Patients with stages II and III should be assessed with a clinical history, a physical examination and CEA every three months for two years and then semiannually until completing five years of follow-up. Imaging tests such as chest scans and total abdomen should be requested every six months for two years and then annually until five years of follow-up. Colonoscopy should be performed within one year after surgery. If normal, it should be repeated within two years (6).

Complimentary Contributor Copy 172 Lauren Razzera Stefanon, Luís Carlos Moreira Antunes, Fiona Lim et al.

CONCLUSION

In this review, we have shown our experience in treating colon cancer. There are regional differences in accessing new technologies and medicines in Latin America. However, we have some improvements in screening and in preventive health care, and an increase in the reach of these measures by the population. Nonetheless, where these improvements do not reach the population, it is necessary to resort to judicial measures. One positive is the incorporation of PET/CT, but this has already shown to be insufficient for all the population. We are in line with global guidelines like NCCN and continue to search for the best colon cancer treatments.

REFERENCES

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wildtype advanced or metastatic colorectal cancer: a randomized clinical trial. JAMA 2017;317(23):2392-401. [37] Saltz LB, Clarke S, Díaz-Rubio E, Scheithauer W, Figer A, Wong R, et al. Bevacizumab in combination with oxaliplatin-based chemotherapy as first-line therapy in metastatic colorectal cancer: a randomized phase III study. J Clin Oncol 20018;26(12):2013-9. [38] Hurwitz H, Fehrenbacher L, Novotny W, Cartwright T, Hainsworth J, Heim W, et al. Bevacizumab plus irinotecan, fluorouracil, and leucovorin for metastatic colorectal cancer. N Engl J Med 2004;350(23):2335-42. [39] Van Cutsem E, Lenz HJ, Köhne CH, Heinemann V, Tejpar S, Melezínek I, et al. Fluorouracil, leucovorin, and irinotecan plus cetuximab treatment and RAS mutations in colorectal cancer. J Clin Oncol 2015;33(7):692-700. [40] Souglakos J, Ziras N, Kakolyris S, Boukovinas I, Kentepozidis N, Makrantonakis P, et al. Randomised phase-II trial of capiri (capecitabine, irinotecan) plus bevacizumab vs folfiri (folinic acid, 5-fluorouracil, irinotecan) plus bevacizumab as first-line treatment of patients with unresectable/metastatic colorectal cancer (mCRC). Br J Cancer 2012;106(3):453-59. [41] Bokemeyer, Bondarenko I, Makhson A, Hartmann JT, Aparicio J, de Braud F, et al. Fluorouracil, leucovorin, and oxaliplatin with and without cetuximab in the first-line treatment of metastatic colorectal cancer. J Clin Oncol 2009;27(5):663-71. [42] Douillard JY, Siena S, Cassidy J, Tabernero J, Burkes R, Barugel M, et al. Final results from PRIME: randomized phase III study of panitumumab with FOLFOX4 for first-line treatment of metastatic colorectal cancer. Ann Oncol 2014;25(7):1346-55. [43] Maughan TS, Adams RA, Smith CG, Meade AM, Seymour MT, Wilson RH, et al. Addition of cetuximab to oxaliplatin-based fi rst-line combination chemotherapy for treatment of advanced colorectal cancer: results of the randomised phase 3 MRC COIN trial. Lancet 2011;377(9783):2103- 14. [44] Cunningham D, Lang I, Marcuello E, Lorusso V, Ocvirk J, Shin DB6, et al. Bevacizumad plus capecitabine versus capecitabine alone in eldery patients with previously untreated metastatic colorectal cancer (AVEX): an open-label, randomised phase 3 trial. Lancet Oncol 2013;14(11):1077- 85. [45] Chibaudel B, Maindrault-Goebel F, Lledo G, Mineur L, André T, Bennamoun M, et al. Can chemotherapy be discontinued in unresectable metastatic colorectal cancer? The GERCOR OPTIMOX2 study. J Clin Oncol 2009;27(34):5727-33. [46] Tournigand C, Cervantes A, Figer A, Lledo G, Flesch M, Buyse M, et al. OPTIMOX1: A randomized study of FOLFOX4 or FOLFOX7 with oxaliplatin in a stop-and-go fashion in advanced colorectal cancer - a GERCOR study. J Clin Oncol 2006;24(3):394-400. [47] Van Cutsem E, Tabernero J, Lakomy R, Prenen H, Prausová J, Macarulla T, et al. Addition of aflibercept to fluorouracil, leucovorin, and irinotecan improves survival in a phase III randomized trial in patients with metastatic colorectal cancer previously treated with an oxaliplatin-based regimen. J Clin Oncol 2012;24(28):394-400. [48] Le DT, Uram JN, Wang H, Bartlett BR, Kemberling H, Eyring AD, et al. PD-1 Blockade in tumors with mismatch-repair deficiency. N Engl J Med 2015;372(26):2509-20. [49] Grothey A, Van Cutsem E, Sobrero A, Siena S, Falcone A, Ychou M, et al. Regorafenib monotherapy for previously treated metastatic colorectal cancer (CORRECT): an International, multicentre, randomised, placebo-controlled, phase 3 trial. Lancet 2013;381(9863):303-12.

Chapter 15

SURGICAL TREATMENT OF LOCALLY ADVANCED RECTAL ADENOCARCINOMA

Francisco López-Köstner1,2,, MD, José Miguel Reyes2, MD, Alejandro J. Zarate1,3, MD, Fiona Lim4, MBBS, Bo Angela Wan5, MD(C) and Mauricio F. Silva6,7,8, MD, PhD 1Unit of Coloproctology, Las Condes Clinic Santiago, Chile 2Cancer Institute, Las Condes Clinic Santiago, Chile 3Department of Surgery. Finis Terrae University. Santiago, Chile 4Department of Oncology, Princess Margaret Hospital, Hong Kong, PR China 5Odette Cancer Centre, Sunnybrook Health Sciences Centre, Toronto, Ontario, Canada 6Radiation Oncology Unit, Santa Maria Federal University, Santa Maria, Brazil 7Radiation Oncology Unit, Hospital de Caridade Astrogildo de Azevedo, Santa Maria, Brazil 8Latin America Cooperative Oncology Group, Porto Alegre, Brazil

ABSTRACT

Colorectal adenocarcinoma is one of the leading causes of cancer death in developed countries, and in Latin America, the mortality is increasing. The cornerstone in the treatment of rectal cancer is surgical resection. Total mesorectal excision is the standard surgery for rectal carcinomas of the middle and lower rectum. Neoaduvant therapy, as radiotherapy and chemoradiotherapy is an option for selected patients. This chapter reviews the surgical treatment of locally advanced rectal adenocarcinoma and the adyuvant therapy for these cases.

 Corresponding Author’s Email: [email protected]. Complimentary Contributor Copy 176 Francisco López-Köstner, José Miguel Reyes, Alejandro J. Zarate et al.

INTRODUCTION

Colorectal adenocarcinoma is one of the leading causes of cancer death in developed countries (1). Incidences in Latin America are similar since its mortality has shown a persistent increase in the last two decades (2, 3). Interestingly, there is no consensus among specialists on the definition of rectal adenocarcinoma (RA), since for some it is all tumors located below the sacral promontory or those whose inferior border is within the last 15 cm measured from the anal verge (4). However, the therapeutic and prognostic differences are evident only in those tumors below the peritoneal reflection. In this way we will talk about rectal tumors for those located below the peritoneal reflection and/or located in the last 12 cm of the anal verge. The definition of locally advanced disease are those with invasion of neighboring organs and/or structures are considered together with those of a large volume that fixes them in the pelvic space, that is, cT3-T4 tumors. In Latin America, in order to late diagnosis, most rectal tumors are diagnosed in these conditions. The great challenge for the surgeon is to deal with a tumor located in an undeformable and deep space, which makes it susceptible to not being able to obtain radial and or tumor- free distal margins. This explains the high local recurrence rate observed after the removal of these tumors. An additional problem is functional disorders, that is, if safety is achieved in the oncological criteria (tumor-free margins), the urological and or sexual functional sequelae must be considered together with the evacuatory dysfunction. Thus, the treatment of RA should take into account multiple variables such as tumor reduction before surgery (neoadjuvant treatment) and we must select the most appropriate surgical technique. The gold standard over the last 100 years has been abdominoperineal resection with terminal colostomy (Miles operation). However, surgical alternatives in which the anal sphincter is preserved, such as low anterior, ultralow resection with or without intersphincteric dissection, have been strongly positioned in the last 30 years. All these resective options can be addressed through a laparotomy, videolaparoscopy or even robot- assisted videolaparoscopy. The purpose of this review is to analyze the treatment of locally advanced RA.

DEVELOPMENT OF SURGERY AND ADJUVANT THERAPY

The great crutch of surgery in RA is its high rate of local recurrence. The wide variation (5- 40%) led to standardization of surgical technique in the 80s with the pioneering work of Heald who proposed total mesorectal excision (TME) as the standard (5). This means resection of the tumor of the rectum respecting the mesorectal fascia, such that when analyzing the operative piece one should not only analyze the proximal and distal margin, but also the circumferential margin. After the TME surgery was widely accepted, other adjuvant treatments were developed that further reduced local recurrence and their effects analyzed. In 2001, a Dutch study was published that analyzed two randomized groups of patients with complete response (CR), one with radiotherapy followed by surgery with TME, and the second only with surgery with TME but without radiotherapy (6). After two years, it was reported that a decrease in local recurrence from 8.2% to 2.4% was achieved in the radiotherapy group. Ever since, evidence Complimentary Contributor Copy Surgical treatment of locally advanced rectal adenocarcinoma 177 was established that even for standardized surgery, radiotherapy has a significant influence on the reduction of local recurrence. Other points to consider in terms of adjuvant treatments to surgery are temporality and the addition of chemotherapy. In light of this, the study by Sauer et al. analyzed the temporality of adding chemoradiotherapy (CRT) to patients with RA. For this, patients with RA clinical stage T3 or T4, or with positive lymph nodes were randomized to receive pre or post-surgical CRT (7). Although the 5-year overall survival (OS) did not show significant differences, the local recurrence did show significant differences in favor of the group with preoperative CRT.

Neo-adjuvant therapy in advanced rectal adenocarcinoma

The use of long-term pre-operative radiotherapy (RT) has been the standard treatment for advanced RA, until Braendengen et al. demonstrated that the addition of fluorouracil (FU) to RT is accompanied by a statistically significant improvement both in the resectability of the tumor and in local control, time to treatment failure and distant metastasis (8). In addition, there was an improvement in OS that was not statistically significant. Although there was no difference in late toxicity, there was a difference in acute toxicity, especially with regards to gastrointestinal effects. This was more frequent in patients who received the combination of CRT with FU (9). Although the first CRT schemes contemplated the use of FU in bolus, later most of the authors adopted the use of prolonged continuous infusion based on the O'Connell study (10). Subsequently, Sauer et al. compared the use of preoperative versus postoperative CRT in 823 patients, and found that the preoperative use of CRT is associated with better local control and a decrease in toxicity, but without an improvement in the OS (7).

Table 1. Chemo-radiotherapy treatments and survival

Study Patients/ Study FSD% pCR OS (5 Local (Date) (primary aim) arms (5 years) years) recurrence (5 years) Brandengen T4/recurring CRT 63 16 66 et al., 2008 (5-year survival) (p = 0.003) (p = 0.04) (p = 0.09) (9) RT 44 7 53 FFCD 9203, Stage T3-4 Nx M0 RT 55.5 11.4 67.4 8.1 2006 (12) resectable (p = 0.96) (p < 0.0001) (p = 0.684) (p = 0.004) (OS) RT 59.4 3.6 67.9 16.5 EORTC Stage T3-4 Nx M0 CRT 56.1 14 65.8 8.7 22921, resectable (p = 0.52) (p = 0.005) (p = 0.84) (p = 0.002) 2006 (11) (OS) RT 54.4 5.3 64.8 17.1 Abbreviations: pCR, pathologic complete response; OS, overall survival; CRT, chemoradiation therapy; RT, radiotherapy

Interestingly, the authors caution that the preoperative assessment of nodal involvement has the risk of oversizing ganglion involvement by 18% (7). In turn, 22% of patients with straight RA classified as T3N0 before the combination therapy, either by ERUS or MRI, Complimentary Contributor Copy 178 Francisco López-Köstner, José Miguel Reyes, Alejandro J. Zarate et al. actually have pathologically positive lymph nodes. Thus, the indication of neoadjuvant therapy is established for patients with cT3-4 and/or N+ tumors.

Chemotherapy radiotherapy versus exclusive radiotherapy as neo-adjuvant treatments

In patients with advanced RA the combined use of chemotherapy and radiotherapy has shown a reduction in local recurrence, but no improvement in disease-free survival (DFS) or OS compared to the use of exclusive radiotherapy (11). Several studies have shown that the combination of chemo-radiotherapy improves local control, time to treatment failure and cancer-specific survival compared to exclusive RT, with similar tolerances for both treatments (see table 1) (9,12,13). Indeed, the preoperative use of CRT improves aspects such as local control (LC), DFS and pathological response (pCR), but does not improve OS. It should be noted that the studies differ in terms of methodology and patient selection, so the results should be viewed with caution. In some of these studies that had more therapy arms than those analyzed; groups directly comparing CRT versus RT alone preoperatively were analyzed.

Use of different agents in the chemotherapy scheme

The standard chemotherapy in the CRT scheme is the use of FU with leucovorin (LV) in continuous infusion during the RT period. This has replaced the use of chemotherapy in the first and last week of RT (10). Different groups have compared the use of capecitabine to replace FU-LV. The NSABBP R-04 study (14) compared the use of FU in continuous infusion five days per week versus capecitabine at a dose of 825 mg/m2 for five days per week, both with and without oxaliplatin. Although capecitabine showed a numerical increase in the complete pathological response, it was not statistically different from FU, nor was sphincter preserving surgery, nor surgical “downstaging.” Grade 3-4 diarrhea was not different between the groups. However, the percentage of dehydration was higher in the capecitabine group. Although capecitabine has not been shown to be superior to FU-LV, it has the advantage of oral administration, avoiding the use of continuous infusion pumps. We must bear in mind the availability to the compliance of the therapy shown by the patient. In those cases in which there is no certainty that the patient will comply with oral medication, the use of intravenous medication is preferable.

Intensification of the CRT scheme

Given that in metastatic patients the use of schemes combining FU-LV with oxaliplatin, it has been suggested that the incorporation of this drug in the CRT scheme could improve the results in terms of LC, DFS, and OS. Several studies have used this modified FOLFOX in the

Complimentary Contributor Copy Surgical treatment of locally advanced rectal adenocarcinoma 179

CRT scheme. In general, all have shown an increase in toxicity, but it is not clear that if they improve the efficacy parameters (14-18). As shown on Table 1, most of the studies have not reached the main objectives. Only the AIO-04 study has achieved, with the use of a modified FOLFOX scheme, an improvement in the PFS that was its main objective. Most studies only increase the toxicity without a clear benefit when adding oxaliplatin.

Conventional CRT vs shortened RT

The Stockholm I and II studies (19) demonstrated that the use of 5 Gy shortened radiotherapy in 5 fractions (5x5) reduces the risk of pelvic recurrence and that they can improve survival when combined with curative surgery which is similar to what was shown in the Polish study (20). This could be a very important aspect to highlight, especially for countries that have limited radiotherapy resources, because it allows shortened treatment times as well as huge economic savings. Recently published, the Stockholm III study randomized patients with rectal cancer to receive RT 5x5 Gy (5 Gy in 5 fractions) with immediate surgery, RT 5x5 Gy plus delayed surgery or prolonged RT (2 Gy in 25 fractions). This study sought the optimal fractionation for RT and showed that the three RT schemes produce similar results in terms of efficacy. However, the toxicity in terms of surgical morbidity is substantially lower in the short RT scheme that delayed surgery, such that today 5x5 Gy RT with delayed surgery can be considered the ideal fractionation for the management of patients who meet the criteria of selection of this study. A similar strategy has been followed by the Polish group (22). They randomized 541 locally very advanced patients (fixed T3-T4) to receive RT 5x5 followed by 3 cycles of FOLFOX (with delayed surgery) or to a conventional fractionation of 50.4 Gy in 28 fractions with the addition of FU the first and last week of treatment. Although there was no difference in loco-regional control of the disease, nor in the percentage of patients with R0 (main objective), at three years of follow-up there was a significant difference in OS at the limit of statistical significance (p = 0.046). This did not produce a significant difference in acute or late toxicity. These two recently published studies have helped to optimize the fractionation of the RT as well as a better monitoring with CRT in high risk patients or “ugly tumors”.

Adjuvant chemotherapy after preoperative therapies and surgery

The results of adding adjuvant chemotherapy after preoperative QTRT have been contradictory. The ADORE study showed improvement of the DFS in pathological stage 3 disease, and an improvement in the OS (23). The German study CAO/ARO/AIO-04 found an improvement in the DFS (17). Other published or recently presented studies include: EORTC 22921 (11); The Dutch Trial (24); The Chronicle Trial (25); the Italian study I-CNR-RT (26) and PETACC-6, which have shown no benefit in adding adjuvant chemotherapy (based on FU, capecitabine, or in combination with oxaliplatin, after adjuvant neo-adjuvant CRT based Complimentary Contributor Copy 180 Francisco López-Köstner, José Miguel Reyes, Alejandro J. Zarate et al. on FU). In the present, the clinical use of adjuvant therapy should be discussed case by case in a committee and be based mainly on the pathological findings after surgery.

SURGERY

Regarding surgical technique, one fundamental point is correct staging of patient, which includes pelvic magnetic resonance imaging, and abdominal and chest-computed tomography. The complete endoscopic evaluation of the rectum and colon, as well as the measurement of the distal edge of the tumor on the anal verge are needed to plan the possible preoperative therapy, as well as to define the surgical approach with regard to sphincter preservation.

Surgical margins

Considering local recurrence as a relevant factor, measuring the distance between the distal edge of the tumor to anal verge is relevant. It has been proposed that a free distal margin must be obtained. Decades ago, the margin was 5 cm; after the introduction of RTM and the CRT, this has decreased considerably such that a margin of 1 cm free of tumor is sufficient (27). However, a margin of less than 3 mm has been associated with greater local recurrence when considering the subgroup of patients with tumors and pT3-4 (28).

Surgical approach

Considering the above, the techniques that allow the preservation of sphincters have increased in recent decades. Currently the criteria for an abdominoperineal resection include tumors with direct invasion of the levator ani and/or the external anal sphincter. In addition, the distance from distal edge of tumor to the anal verge and potential patient functionality should be considered. That is, in tumors below five cm, it is very likely that the internal sphincter would be partially resected, which will compromise the patient's evacuation function. Patients selected for coloanal anastomosis should have an appropriate functional sphincter and should be instructed on the expected changes. For tumors over five cm and depending on the height of the anastomosis, surgeries such as low anterior resection with colorectal anastomosis and ultra-low anterior with mechanical coloanal anastomosis are currently proposed. Ultralow anterior resection with intersphinteric dissection (ISR) is indicated preferably in patients with tumors located between 5 and 2 cm in whom there is no safe margin for the distal section and/or a mechanical anastomosis. That is, when the distance between the lower border of the tumor and the upper edge of the anorectal ring is less than two cm. For any of the three surgeries mentioned, the marking of the ileostomy site by a stomatotherapist nurse is considered. In patients undergoing CRT with low anastomosis, we think that the use of transient defunctionalization through a loop ileostomy is mandatory.

Complimentary Contributor Copy Surgical treatment of locally advanced rectal adenocarcinoma 181

In low anterior resection we propose to start with dissection of the visceral pelvic fascia and the mesorectum in order to maintain the correct dissection plane. The pelvic and hypogastric nerve plexuses should be identified and preserved. Then the lateral ligaments should be dissected and sectioned. Subsequently, the anterior area of the reflection (rectouterine or rectovesical) is incised to advance distally; in men it is continued until the rectum separates from the seminal vesicles, dissecting the Denonvilliers fascia. In women who present with anterior tumors, the adjacent vagina should be resected. After the dissection described, access the pelvic floor and prepare the rectum for its section. The section is currently performed using the double mechanical suture technique. The described technique can be performed by laparotomy, as well as by videolaparoscopic surgery with or without robotic assistance. Although videolaparoscopic surgery is a standard in resection of colon tumors, this is not the case in rectal tumors, mainly because of the difficulties associated with tumors of the lower rectum. In fact, it has not yet been demonstrated that it is comparable to laparoscopic access, which has been published in two recent prospective and randomized multicenter studies (ALACART AND ACOSOG) (29, 30). The difficulties are due to the rigidity of the instruments, which become more evident in the narrow pelvises (male) of obese patients. This could be the where robotic surgery with instruments of greater maneuverability and better control of actions will be beneficial. However, it failed demonstrated any benefit in a multicenter, prospective randomized study (ROLARR) (31). In a recent systematic review involving 17 case-control studies, the robotic versus laparoscopic surgical approaches were compared for TME in patients with CR. At three years, there were no differences in terms of global survival or local recurrence. There were also no significant differences in terms of the positive circumferential margin or postoperative complications (32).

CONCLUSION

In conclusion, the treatment of patients with locally advanced tumors of the rectum starts with neoadjuvant treatment and then with resective surgery. We expect a positive rate of radial and distal margins of less than 10% along with a mesorectum preservation rate greater than 90%. These results are achieved more frequently in high volume centers, so the surgical team becomes a prognostic factor. The local recurrence rate should be less than 10% and most of these patients should preserve their anal sphincter (> 80%).

REFERENCES

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Complimentary Contributor Copy 182 Francisco López-Köstner, José Miguel Reyes, Alejandro J. Zarate et al.

[3] Souza DL, Jerez-Roig J, Cabral FJ, de Lima JR, Rutalira MK, Costa JA. (2014). Colorectal cancer mortality in Brazil: predictions until the year 2025 and cancer control implications. Dis Colon Rectum, 57(9): 1082-9. [4] Jorge JM, Wexner SD. (1997). Anatomy and physiology of the rectum and anus. Eur J Surg, 163(10): 723-31. [5] Heald RJ, Husband EM, Ryall RD. (1982). The mesorectum in rectal cancer surgery--the clue to pelvic recurrence? Br J Surg, 69(10): 613-6. [6] Kapiteijn E, Marijnen CA, Nagtegaal ID, Putter H, Steup WH, Wiggers T, et al. (2001). Preoperative radiotherapy combined with total mesorectal excision for resectable rectal cancer. N Engl J Med, 345(9): 638-46. [7] Sauer R, Becker H, Hohenberger W, Rödel C, Wittekind C, Fietkau R, et al. (2004). Preoperative versus postoperative chemoradiotherapy for rectal cancer. N Engl J Med, 351(17): 1731-40. [8] Swedish Rectal Cancer Trial, Cedermark B, Dahlberg M, Glimelius B, Påhlman L, Rutqvist LE, et al. (1997). Improved survival with preoperative radiotherapy in resectable rectal cancer. N Engl J Med, 336(14): 980-7. [9] Braendengen M, Tveit KM, Berglund A, Birkemeyer E, Frykholm G, Påhlman L, et al. (2008) Randomized phase III study comparing preoperative radiotherapy with chemoradiotherapy in nonresectable rectal cancer. J Clin Oncol, 26(22): 3687-94. [10] O'Connell MJ, Martenson JA, Wieand HS, Krook JE, Macdonald JS, Haller DG, et al. (1994). Improving adjuvant therapy for rectal cancer by combining protracted-infusion fluorouracil with radiation therapy after curative surgery. N Engl J Med, 331(8): 502-7. [11] Bosset JF, Calais G, Mineur L, Maingon P, Stojanovic-Rundic S, Bensadoun RJ, et al. (2014). Fluorouracil-based adjuvant chemotherapy after preoperative chemoradiotherapy in rectal cancer: long-term results of the EORTC 22921 randomised study. Lancet Oncol, 15(2): 184-90. [12] Gérard JP, Conroy T, Bonnetain F, Bouché O, Chapet O, Closon-Dejardin MT, et al. (2006). Preoperative radiotherapy with or without concurrent fluorouracil and leucovorinin T3-4 rectal cancer: results of FFCD 9203. J Clin Oncol, 24(28): 4620-5. [13] Bosset JF, Collette L, Calais G, Mineur L, Maingon P, Radosevic-Jelic L, et al. (2006). Chemotherapy with preoperative radiotherapy in rectal cancer. N Engl J Med, 355(7): 1114-23. [14] O'Connell MJ, Colangelo LH, Beart RW, Petrelli NJ, Allegra CJ, Sharif S, et al. (2014). Capecitabine and oxaliplatin in the preoperative multimodality treatment of rectal cancer: surgical end points from National Surgical Adjuvant Breast and Bowel Project trial R-04. J Clin Oncol, 32(18): 1927-34. [15] Gérard JP, Azria D, Gourgou-Bourgade S, Martel-Laffay I, Hennequin C, Etienne PL, et al. (2010). Comparison of two neoadjuvant chemoradiotherapy regimens for locally advanced rectal cancer: results of the phase III trial ACCORD 12/0405-Prodige 2. J Clin Oncol, 28(10): 1638-44. [16] Aschele C, Cionini L, Lonardi S, Pinto C, Cordio S, Rosati G, et al. (2011). Primary tumor response to preoperative chemoradiation with or without oxaliplatin in locally advanced rectal cancer: pathologic results of the STAR-01 randomized phase III trial. J Clin Oncol, 29(20): 2773-80. [17] Rödel C, Graeven U, Fietkau R, Hohenberger W, Hothorn T, Arnold D, et al. (2015). Oxaliplatin added to fluorouracil-based preoperative chemoradiotherapy and postoperative chemotherapy of locally advanced rectal cancer (the German CAO/ARO/AIO-04 study): final results of the multicentre, open-label, randomised, phase 3 trial. Lancet Oncol, 16(8): 979-89. [18] Jiao D, Zhang R, Gong Z, Liu F, Chen Y, Yu Q, et al. (2015). Fluorouracil-based preoperative chemoradiotherapy with or without oxaliplatin for stage II/III rectal cancer: a 3-year follow-up study. Chin J Cancer Res, 27(6): 588-96. [19] Martling A, Holm T, Johansson H, Rutqvist LE, Cedermark B, Stockholm Colorectal Cancer Study Group. (2001). The Stockholm II trial on preoperative radiotherapy in rectal carcinoma: long-term follow-up of a population-based study. Cancer, 92(4): 896-902. [20] Bujko K, Nowacki MP, Nasierowska-Guttmejer A, Michalski W, Bebenek M, Kryj M. (2006). Long- term results of a randomized trial comparing preoperative short-course radiotherapy with preoperative conventionally fractionated chemoradiation for rectal cancer. Br J Surg, 93(10): 1215-23.

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[21] Erlandsson J, Holm T, Pettersson D, Berglund Å, Cedermark B, Radu C, et al. (2017). Optimal fractionation of preoperative radiotherapy and timing to surgery for rectal cancer (Stockholm III): a multicentre, randomised, non-blinded, phase 3, non-inferiority trial. Lancet Oncol, 18(3): 336-46. [22] Bujko K, Wyrwicz L, Rutkowski A, Malinowska M, Pietrzak L, Kryński J, et al. (2016). Long-course oxaliplatin-based preoperative chemoradiation versus 5 × 5 Gy and consolidation chemotherapy for cT4 or fixed cT3 rectal cancer: results of a randomized phase III study. Ann Oncol, 27(5): 834-42. [23] Hong YS, Nam BH, Kim KP, Kim JE, Park SJ, Park YS, et al. (2014). Oxaliplatin, fluorouracil, and leucovorin versus fluorouracil and leucovorin as adjuvant chemotherapy for locally advanced rectal cancer after preoperative chemoradiotherapy (ADORE): an open-label, multicentre, phase 2, randomised controlled trial. Lancet Oncol, 15(11): 1245-53. [24] Breugom AJ, van Gijn W, Muller EW, Berglund Å, van den Broek CB, Fokstuen T, et al. (2015). Adjuvant chemotherapy for rectal cancer patients treated with preoperative (chemo)radiotherapy and total mesorectal excision: a Dutch Colorectal Cancer Group (DCCG) randomized phase III trial. Ann Oncol, 26(4): 696-701. [25] Glynne-Jones R, Counsell N, Quirke P, Mortensen N, Maraveyas A, Meadows HM, et al. (2014). Chronicle: results of a randomised phase III trial in locally advanced rectal cancer after neoadjuvant chemoradiation randomising postoperative adjuvant capecitabine plus oxaliplatin (XELOX) versus control. Ann Oncol, 25(7): 1356-62. [26] Sainato A, Cernusco Luna Nunzia V, Valentini V, De Paoli A, Maurizi ER, Lupattelli M, et al. (2014). No benefit of adjuvant Fluorouracil Leucovorin chemotherapy after neoadjuvant chemoradiotherapy in locally advanced cancer of the rectum (LARC): Long term results of a randomized trial (I-CNR- RT). Radiother Oncol, 113(2): 223-9. [27] Grosek J, Velenik V, Edhemovic I, Omejc M. (2016). The Influence of the distal resection margin length on local recurrence and long- term survival in patients with rectal cancer after chemoradiotherapy and sphincter- preserving rectal resection. Radiol Oncol, 51(2): 169-77. [28] Kim TG, Park W, Choi DH, Kim SH, Kim HC, Lee WY, et al. (2014). The adequacy of the distal resection margin after preoperative chemoradiotherapy for rectal cancer. Colorectal Dis, 16(8): O257- 63. [29] Stevenson AR, Solomon MJ, Lumley JW, Hewett P, Clouston AD, Gebski VJ, et al. (2015). Effect of Laparoscopic-Assisted Resection vs Open Resection on Pathological Outcomes in Rectal Cancer: The ALaCaRT Randomized Clinical Trial. JAMA, 314(13): 1356-63. [30] Fleshman J, Branda M, Sargent DJ, Boller AM, George V, Abbas M, et al. (2015). Effect of Laparoscopic-Assisted Resection vs Open Resection of Stage II or III Rectal Cancer on Pathologic Outcomes: The ACOSOG Z6051 Randomized Clinical Trial. JAMA, 314(13): 1346-55. [31] Jayne D, Pigazzi A, Marshall H, Croft J, Corrigan N, Copeland J, et al. (2017). Effect of Robotic- Assisted vs Conventional Laparoscopic Surgery on Risk of Conversion to Open Laparotomy Among Patients Undergoing Resection for Rectal Cancer: The ROLARR Randomized Clinical Trial. JAMA, 318(16): 1569-80. [32] Li X, Wang T, Yao L, Hu L, Jin P, Guo T, Yang K. (2017). The safety and effectiveness of robot- assisted versus laparoscopic TME in patients with rectal cancer: A meta-analysis and systematic review. Medicine (Baltimore), 96(29): e7585.

Chapter 16

MANAGEMENT OF ANAL CANCER

Patrícia B Aguilar1,, MD, PhD, Renata Peixoto2, MD, Fiona Lim3, MBBS, Bo Angela Wan4, MD(C) and Maurício F Silva5, MD, PhD 1Radiation Oncology Unit at Hospital Alemão Oswaldo Cruz, São Paulo, Brazil 2Oncology Center at Hospital Alemão Oswaldo Cruz, São Paulo, Brazil 3Department of Oncology, Princess Margaret Hospital, Hong Kong, PR China 4Sunnybrook Health Sciences Centre, Toronto, Ontario, Canada 5Radiation Oncology Unit, Santa Maria Federal University, Santa Maria, Brazil 6Radiation Oncology Unit, Hospital de Caridade Astrogildo de Azevedo, Santa Maria, Brazil 7Latin America Cooperative Oncology Group, Porto Alegre, Brazil

ABSTRACT

Squamous cell carcinoma (SCC) of the anus is a rare disease. Combined chemoradiotherapy has emerged as the preferred method of treatment because it can cure many patients while preserving the anal sphincter. Concurrent use of 5-fluorouracil (5- FU) plus mitomycin during radiotherapy (RT) rather or 5-FU plus cisplatin is the most commonly used scheme. Treatment response should be initially assessed clinically 8 to 12 weeks after completion of chemoradiotherapy. Based upon the results from the ACT- II trial, patients with persistent disease can be watched for up to six months following completion of chemoradiotherapy as long as there is no progression during this period of follow-up. For patients with evidence of progressive disease at any point or persisting disease at 26 weeks after completion of combined modality therapy and no evidence of metastatic disease, surgical treatment is recommended. Systemic chemotherapy is appropriate for the rare patient who develops metastatic disease. Although few data are available to guide the choice of regimen, first line therapy usually consists of cisplatin plus 5-FU. For patients with chemotherapy-refractory metastatic SCC of the anus, a trial of pembrolizumab or nivolumab, which are directed against the programmed cell death receptor 1 (PD-1), may be a newer option preferably used within the context of a clinical

 Corresponding Author’s Email: [email protected]. Complimentary Contributor Copy 186 Patrícia B Aguilar, Renata Peixoto, Fiona Lim et al.

trial. However, in our view, neither PD-1 nor programmed cell death ligand 1 overexpression should be used to select patients for these treatments.

INTRODUCTION

Anal cancer is a rare disease and represents about 4% of all lower gastrointestinal malignancies and comprises 2.5% of all digestive system malignancies in the United States (1, 2). The incidence of anal cancer in the general population has increased over the last 30 years. A higher incidence has been associated with female gender, infection with human papillomavirus (HPV), lifetime number of sexual partners, genital warts, cigarette smoking, receptive anal intercourse, and infection with HIV (3). From an etiologic standpoint, anal cancer is more similar to genital malignancies than it is to other gastrointestinal tract cancers. Substantial progress has been made in understanding the pathophysiology and the management of anal cancer. As a result of carefully conducted epidemiologic and clinical studies, it is now known that anal cancer is closely associated with HPV infection and that cure is possible in the majority of patients with preservation of the anal sphincter. In the past, patients with invasive anal carcinoma were routinely treated with an abdominoperineal resection (APR), with high local recurrences rates; 5-year survival was only 40% to 70%. In 1974, Nigro et al. observed complete tumor regression in patients treated with preoperative 5-fluorouracil (5-FU)-based concurrent chemotherapy and radiotherapy, suggesting that it might be possible to cure anal cancer without surgery and permanent colostomy (4). Subsequent nonrandomized studies using similar regimens and varied doses of chemoradiotherapy provided support for this conclusion (5,6). Results of randomized trials evaluating the efficacy and safety of chemotherapy with radiotherapy (RT) support the use of combined modality therapy in the treatment of anal cancer and will be discussed below.

Chemoradiotherapy

The necessity of including chemotherapy in the nonoperative treatment regimen for anal cancer has been addressed in at least two randomized trials. The United Kingdom Coordination Committee on Cancer Research (UKCCCR) Anal Cancer Trial (ACT I) randomly assigned 585 patients with stage 1 (T1) to stage 4 (T4) SCC of the anal canal or margin (51% clinical T3 disease, 20% positive nodes) to receive either RT alone (45 Gy external beam in 20 or 25 fractions plus a 15 Gy external beam or 25 Gy brachytherapy boost), or RT plus concurrent 5-FU (1000 mg/m2 for four days or 750 mg/m2 for five days during the first and the final weeks of RT) and mitomycin C (MMC) (12 mg/m2 on day 1 only) (7). Chemoradiotherapy was associated with significant reductions in local failure (61% versus 39%) and cause-related mortality (28% versus 39%). More acute morbidity, including six deaths, occurred with combined modality therapy; late morbidity was similar. Overall survival was similar between the two groups, and this was attributed to an early increase in non-anal cancer deaths in the first five years, which disappeared by year 10 (8). Only 11 patients in the chemoradiotherapy group suffered a locoregional relapse as a first event after five years. Complimentary Contributor Copy Management of anal cancer 187

In a second trial, The European Organization for the Research and Treatment of Cancer (EORTC) randomly assigned 110 patients with locally advanced (T3-4 or N1-3) anal cancer to receive RT (45 Gy with a 15 or 30 Gy boost) with or without concurrent 5-FU (750 mg/m2 per day on days 1-5 and 29-33) plus MMC (15 mg/m2 on day 1 only) (9). Chemoradiotherapy was associated with a significantly higher pathologic complete remission rate (80% versus 54%), an 18% higher 5-year locoregional control rate, a 32% higher colostomy-free rate, and higher event-free and progression-free survival. Overall survival was not significantly different, and in contrast to the UKCCCR trial, the incidence of acute and late side effects and treatment-related mortality did not differ between the groups.

Can chemotherapy be ruled out for early stage tumors?

Randomized trials demonstrate the superiority of chemoradiotherapy over RT alone in terms of disease-free survival, local relapse, and colostomy-free survival, but whether these benefits apply to early stage disease (T1-2N0) is unclear. Only one of the two randomized trials described above enrolled patients with T1 or T2 tumors, and results were not analyzed according to primary tumor stage (7). Several retrospective series report excellent outcomes for patients with T1-2N0M0 disease with RT alone. However, not all reports are favorable. National Comprehensive Cancer Network guidelines recommend definitive chemoradiotherapy for all patients with anal canal SCC, even those with T1-2N0M0 tumors. However, for the extremely elderly population with T1N0 tumors, or those with significant comorbidities, elimination of MMC and administration of 5-FU alone during RT could be considered. Local excision remains an option for patients with T1 tumors less than 1 cm in size. It has never been compared with RT or chemoradiation, which are considered the standards of care in this patient population.

Combined modality therapy

Although the original regimen described by Nigro used 5-FU 1000 mg/m2 on days 1-4 and 29-32 (plus MMC 10 to 15 mg/m2 on day 1 only) concurrent with RT (4), National Comprehensive Cancer Network (NCCN) guidelines suggest a modified regimen as was used in the Radiation Therapy Oncology Group (RTOG) 98-11 trial (10). The chemotherapy consists of 5-FU 1000 mg/m2 on days 1-4 and 29-32 plus MMC 10 mg/m2 on days 1-29 (as tolerated), maximum 20 mg per dose. European guidelines suggest a similar regimen of 5-FU plus MMC, although using MMC 12 mg/m2 on day 1 only (maximum 20 mg single dose) (11). HIV positive patients are generally treated similarly to those without HIV. Although outcomes appear to be comparable, treatment-related toxicity may be worse, particularly if the CD4 count is <200 cells/μL. Patients with a history of HIV related complications may require dosage adjustment or treatment without MMC.

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Role of mitomycin

The need for MMC in curative treatment of anal cancer was addressed in a joint trial from the Radiation Therapy Oncology Group (RTOG) 8704 and the Eastern Cooperative Oncology Group (ECOG) 1289 in which 310 patients with anal cancer of any tumour or nodal stage were randomly assigned to combined modality therapy with or without MMC (10). Patients who received MMC had significantly better four-year colostomy-free survival (71% versus 59%) and disease-free survival (73% versus 51%), but pathologic complete response rates and overall survival were similar. Grade 4 toxicity (23% versus 7%) and fatal neutropenic sepsis (4 versus 1 patient) were significantly more common in the MMC group. The authors concluded that despite greater toxicity, the use of MMC in a definitive complete response regimen for anal cancer was justified.

Replacement of mitomycin with cisplatin

Cisplatin is more active in the treatment of SCCs in general than is MMC. This issue has been addressed in three large controlled studies. The RTOG initiated a large phase III trial (RTOG 9811) to assess the benefit of induction chemotherapy and the replacement of MMC by cisplatin. In this study, patients were randomized to 1: standard 5-FU and MMC concurrent with radiation or 2: an experimental arm of induction 5-FU and cisplatin followed by chemoradiation with 5-FU and cisplatin (12). From 1998 to 2005, 682 patients were enrolled among the 2 arms. Inclusion criteria included T2 to T4 primaries and any nodal status, with 35% having T3 to T4 primary disease and 26% being node positive. The control arm was treated much as the 5-FU and MMC arm from RTOG 8704 with 5-FU 1000 mg/m2/d continuous infusion on days 1-4 and 29-32 and bolus MMC 10 mg/m2 on days 1 and 29. In the experimental arm, patients received the initial 2 cycles of chemotherapy alone and the final 2 cycles concurrent with radiation. Induction chemotherapy was continuous infusion 5-FU 1000 mg/m2/d on days 1-4, 29-32, 57-60, and 85-88 with bolus cisplatin 75 mg/m2 on days 1, 29, 57, and 85. For both arms, radiation was administered as 45 Gy in 25 fractions with AP-PA or multiple field techniques. The initial fields encompassed the pelvis, anus, perineum, and inguinal nodes with the superior border at L5 to S1 and inferiorly 2.5 cm below the anus and tumor. After 30.6 Gy, the superior border was reduced to the bottom of the sacroiliac joints and the pelvis was boosted to 45 Gy. For patients with T3 or T4 primaries, positive inguinal nodes, or T2 with residual disease, after 45 Gy, an additional radiation boost of 10 to 14 Gy at 2 Gy per fraction was delivered to the primary site and involved nodes. With a median follow-up of 2.5 years, there was no difference between groups in disease-free survival with a 3-year disease-free survival of 67% for the standard MMC arm versus 61% for cisplatin. The 3-year overall survival was also not significantly different (84% MMC vs 76% cisplatin). In contrast, 3-year colostomy rates were significantly worse with cisplatin (10% vs 16%). There was no difference in acute grade 3 to 4 nonhematologic side effects between the arms (74% for both arms), but acute grade 3 to 4 hematologic toxicity was significantly worse in the MMC arm (61% vs 42%). Severe late effects were similar between groups (11% vs 10%). In the long-term update, cisplatin was found to fare worse as a replacement for MMC, with 5-year disease-free survival (68% vs 58%; p = 0.006), overall survival (78% vs 71%), Complimentary Contributor Copy Management of anal cancer 189 and colostomy-free survival (72% vs 65%) all reduced in the cisplatin arm (13). Differences in locoregional failure (20% vs 26%) and colostomy rates (12% vs 17%) did not attain statistical significance. Additionally, the late grade 3 and 4 side effect rates were comparable over time (13% MMC vs 11% cisplatin). One potential explanation for the outcome differences between the 2 arms is the decreased efficacy of cisplatin in this setting relative to MMC. Another interpretation is based on the inclusion of induction chemotherapy in the experimental arm, which may have delayed definitive treatment with chemoradiation. Because of these results, chemoradiation with concurrent 5-FU and MMC remains the standard of care in the United States of America. The UKCCCR ACT II trial evaluated a more direct comparison of the role of cisplatin in place of MMC with pelvic radiation, as well as assessing whether maintenance chemotherapy would improve outcomes beyond chemoradiation alone (14). Between 2001 and 2008, 940 patients were accrued. T3 and T4 primaries made up 46% of patients and 32% had involved nodes. Patients were randomized in a 2 x 2 design to 1 of 4 arms: (a) 5-FU and cisplatin with radiation and no maintenance, (b) 5-FU and cisplatin with radiation followed by maintenance 5-FU and cisplatin, (c) 5-FU and MMC with radiation and no maintenance, or (d) 5-FU and MMC with radiation followed by maintenance 5-FU and cisplatin. Concurrent chemotherapy was administered as 5-FU 1000 mg/m2/d continuous infusion on days 1 to 4 and 29 to 32 with either bolus cisplatin 60 mg/m2 on days 1 and 29 or MMC 12 mg/m2 on day 1. Maintenance chemotherapy was given as an additional 2 cycles of 5-FU on days 71-74 and 92 -95 and cisplatin on days 71 and 92. Radiotherapy was prescribed to 50.4 Gy total in 28 fractions using AP-PA fields, with a field reduction at 30.6 Gy. Treatment response was assessed at weeks 11, 18 and 26 from the start of treatment. The final assessment at 26 weeks included digital anorectal examination and computed tomography imaging; routine biopsy was not recommended. Of the patients assigned to receive maintenance chemotherapy, 80% began treatment, although only 44% completed maintenance without dose reduction or delay. When comparing MMC versus cisplatin, there was no difference in clinical complete response rates by primary site (89.6% vs 90.5%) at 26 weeks. With a median follow-up of 5 years, there was no difference between groups in progression-free survival by maintenance (74%) versus no maintenance (73%). There was also no difference in overall survival or colostomy-free survival, regardless of maintenance regimen or concurrent chemotherapy used. Additionally, there was no difference in acute grade 3 or 4 overall side effects between MMC and cisplatin (71% vs 72%), although there were more hematologic events in the MMC arms (26% vs 16%). A post hoc analysis examining the timing of clinical assessment after treatment was recently reported (15). Although the initial publication defined complete clinical response as response at the primary site only, the updated analysis revised this assessment now using both primary and nodal response. Based on this, at the initial 11-week assessment, 64% of patients were found to have a clinical complete response. By the 26-week (final) assessment, 85% demonstrated clinical complete response. Of the patients who did not experience complete responses at the time of initial assessment, 72% went on to achieve a complete response. The authors examined overall survival based on the presence or absence of complete response by assessment time. At the first assessment, patients with complete response had a 5-year overall survival of 85% versus 75% in those without complete response. By the final assessment at week 26, patients with complete response had a 5-year overall survival of 87% versus 48% in Complimentary Contributor Copy 190 Patrícia B Aguilar, Renata Peixoto, Fiona Lim et al. those patients without response. This study confirms that delayed assessment of tumor response after treatment allows for further tumor regression and provides better prognostic value over the response observed at earlier time points. Although the ACT II trial did not observe the same detriments in disease control and colostomy-free survival that were noted with the replacement of MMC by cisplatin in RTOG 9811, there was also not a significant benefit to this regimen. Furthermore, maintenance chemotherapy does not seem to provide a benefit in improving clinical responses or reducing recurrence rates. Based on the results of the ACT II trial, 5-FU and MMC remain the standard treatment regimen for definitive chemoradiation in localized anal cancer. However, cisplatin- based chemotherapy can be considered as an alternative regimen in patients who may not tolerate the hematologic toxicity associated with MMC. The French Action Clinique Coordonnées en Cancérologie Digestive (ACCORD-03) trial was designed to test the benefits of both induction chemotherapy and a radiotherapy boost (16). Unlike prior randomized trials, MMC was not included in the chemotherapy regimen. Between 1999 and 2005, 307 patients were randomized in a 2 x 2 design. Inclusion criteria encompassed patients with primary tumors greater than 4 cm or with involved nodes. The 4 arms were (a) induction 5-FU and cisplatin followed by concurrent 5-FU and cisplatin with radiation to 45 Gy plus a standard 15 Gy primary tumor boost, (b) same as arm 1 with the addition of a 20- to 25-Gy high-dose radiation boost, (c) chemoradiation without induction delivered with a standard radiation boost, and (d) chemoradiation with a high-dose radiation boost. Induction chemotherapy consisted of 5-FU 800 mg/m2/d continuous infusion on days 1 - 4 and 29 - 32 with bolus cisplatin 80 mg/m2 on days 1 and 29. The same chemotherapy and dosages were administered concurrently with radiation. Radiation was delivered with an AP/PA or 4-field conformal technique treating superiorly to L5 to S1 and inferiorly the perianal region with a 3 cm normal tissue margin below the tumor. The initial radiation treatment was prescribed as 45 Gy in 25 fractions. The radiation boost began 3 weeks after completion of whole pelvis radiation and was delivered with either external beam or iridium- 192 brachytherapy. Standard radiation boost arms received 15 Gy, whereas in the high-dose boost arms, patients received radiation dose based on response (25 Gy for a <80% response; 20 Gy for a >80% response). In the arms receiving induction chemotherapy, 79% to 82% of patients received the planned course of concurrent chemotherapy with radiation, and in the non-induction arms, 94% to 98% of patients received the planned concurrent chemotherapy. After a median follow-up of 50 months, induction chemotherapy did not significantly improve 5-year colostomy-free survival (76.5% induction vs 75% no induction). Likewise, a high-dose radiotherapy boost was not found to significantly improve 5-year colostomy-free survival, although this value did approach significance (74% standard boost vs 78% high dose boost). It should also be noted that a 3-week treatment break was given before the start of the radiotherapy boost, which may have impaired the efficacy of the high dose radiation treatment. There were no differences in 5-year overall survival between groups regardless of induction or high-dose boost. Collectively, these results indicate that neither induction chemotherapy nor radiotherapy dose escalation (at least in the setting of a planned radiation treatment gap) improves outcomes over standard chemoradiation alone.

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It’s important to remember that MMC is not commercially available in some countries of South America and cisplatin is the standard treatment. There appears to be no role for induction chemotherapy or a continuation of chemotherapy beyond concurrent chemoradiotherapy.

Capecitabine as an alternative to fluorouracil

At least some data suggest that substituting daily oral capecitabine for 5-FU in conjunction with IV MMC during RT is well tolerated with minimal toxicity (17, 18). In a phase II trial of 31 patients, 77% had a complete clinical response (cCR) four weeks after completion of therapy (19). At a median follow-up of 14 months, there were three locoregional recurrences. The combination of capecitabine and MMC is an acceptable substitute for infusional 5-FU plus MMC for chemoradiotherapy.

Intensity-modulated radiotherapy in reducing the acute toxicity of chemoradiation

The difficulty that remains in administering standard chemoradiation with 5-FU and MMC is the significantly high rates of grade 3 and higher acute morbidity. Intensity-modulated radiotherapy (IMRT) is a form of advanced radiation delivery that uses fluctuating radiation beam intensities to target the radiation dose to the tumor while minimizing dose to the surrounding normal organs. One practical advantage is that the use of IMRT in anal cancer may reduce the chemoradiation acute side effect profile and prevent or reduce treatment breaks that may negatively affect outcomes. IMRT may also allow for further radiation dose escalation in high-risk localized disease. Although not randomized, RTOG 0529 was a phase II trial investigating the use of IMRT in reducing the acute side effects of standard 5-FU and MMC chemoradiation treatment (20). In comparison with patients treated on the MMC arm of RTOG 9811, IMRT resulted in significantly lower grade 2 and higher hematologic (73% vs 85%), grade 3 and higher gastrointestinal (21% vs 36%), and grade 3 and higher dermatologic (23% vs 49%) acute events. The median duration of radiotherapy was 42.5 days using IMRT (range, 32–59), as compared with 49 days (range, 0–102) on the MMC arm of RTOG 9811. Therefore, with modern radiation treatment planning and delivery, the necessity of treatment breaks should become less of an issue, allowing for timely administration of combined modality therapy and the potential of radiation dose escalation. As experience with IMRT increases, its benefits in reducing acute morbidity (small and large bowel, genitalia, pelvic skin, and soft tissues) have been increasingly apparent when it is administered by experienced radiation oncologists. Although long-term effects are not yet fully characterized, IMRT has been increasingly adopted by the radiation oncology community and should no longer be considered investigational for the treatment of anal cancer.

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Radiation therapy dose and schedule

Patients are typically treated with external beam RT using fields that initially encompass the pelvis from the S1-S2 level, inguinal lymph nodes (even if palpably negative), and anus. After a dose of 30 to 36 Gy is reached, the treatment fields are reduced to the low pelvis encompassing the anal tumor, and the total dose to the primary tumor is 45 to 50 Gy in daily 1.8 to 2 Gy fractions. If there is palpable or radiographic evidence of inguinal node metastases, an RT boost is typically added to the affected groin (10). Chemotherapy (typically infusional 5-FU plus MMC, see above) is administered concurrently with the first and fifth weeks of RT. The ACT-II trial proponents emphasize the "success" and acceptable toxicity of their radiation schedule – 50 Gy in 25 fractions with only one infusion of MMC on day 1 (14). This chemoradiotherapy regimen is effective but can be toxic. During the five- to six- week course of irradiation and chemotherapy, there is frequently marked regression of the tumor as well as a brisk perineal skin reaction. In the two trials comparing RT with and without chemotherapy, significant acute gastrointestinal toxicity occurred in 33 to 45 of patients treated with chemoradiotherapy while 49% to 76% of patients had significant acute dermatologic toxicity (8, 9). RT using lower chemotherapy doses has been used for older adult patients with anal canal SCC. One report evaluated 58 patients who were older than 70 years who received RT (39.6 Gy followed by a delayed boost of 20 Gy) with or without 5-FU (median dose 600 mg/m2 per day, days 1 through 4, and 29 through 32) plus MMC (median dose 9.5 mg/m2 on day 1 only) (21). The toxicity of this regimen was comparable to that seen in younger patients treated with higher chemotherapy doses, and efficacy was preserved (five-year survival and local control rates were 54% and 79%, respectively). The optimal dose of external beam RT for the treatment of anal canal cancer is the subject of considerable debate. At least two retrospective studies suggest that 30 Gy of RT with concurrent chemotherapy after an excisional biopsy might be adequate for selected patients with early stage disease (22,23). In the larger report, the entire group of 25 patients had a five-year colostomy-free survival of 91% (23). Two trials have evaluated the potential benefit of higher doses of external beam RT above 54 Gy (24, 25). In an RTOG study, 47 patients with anal cancers received 59.4 Gy RT in a "split dose" schedule (two-week delay after 36 Gy) plus concurrent 5-FU and MMC, and the results compared with those of a previous RTOG trial in which patients were treated with 45 Gy in a continuous schedule plus the same chemotherapy regimen (10). Although cross-trial comparisons such as these can be misleading, the patients receiving 59.4 Gy had comparable toxicity, but the two-year colostomy rate was much higher than expected (30% versus 9% in the previous trial). A similar split-course schedule of RT was studied in an ECOG trial in which 19 patients received 59.4 Gy concurrent with two courses of 5-FU and cisplatin (25). Although the response rate was 95%, toxicity, particularly hematologic, was prohibitive. Data demonstrating that continued regression occurs up to six months after completion of chemoradiation make it difficult to interpret these data.

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Assessing the response to primary chemoradiotherapy

A clinical assessment of response by physical examination is typically performed from six to eight weeks following the completion of therapy. Early assessment of response by MRI is unhelpful and not recommended (26). There is considerable controversy regarding the optimal time to assess post-treatment response. SCCs regress slowly and continue to decrease in size for up to 26 weeks following therapy. This was shown in an analysis of data from the ACT II trial, in which 940 patients were randomly assigned to 5-FU plus either MMC or cisplatin during concurrent RT, and then were further randomized to receive or not receive maintenance chemotherapy (15). The protocol required three response assessments, at 11 and 18 weeks (with digital rectal examination (DRE) with or without examination under anesthesia (EUA)), and at 26 weeks (DRE, EUA, abdomen and pelvis CT, and chest radiograph). Biopsies were not routinely performed. The complete clinical response (cCR) rate increased over time in both chemoradiotherapy groups (52%, 71%, and 78% at 11, 18, and 26 weeks, respectively). Importantly, 72% of those not in a cCR at 11 weeks achieved it at 26 weeks. These data support the view that anal SCCs continue to regress for up to 26 weeks after the completion of chemoradiotherapy and that the decision to pursue APR for persisting disease is best deferred until at least 26 weeks. Progression of disease at any time or a clinical suspicion for persisting disease after completion of combined modality therapy should prompt a biopsy, with APR for those with biopsy-proven disease persistence/recurrence.

ROLE OF SURGERY

Post-chemoradiotherapy local recurrences can be successfully salvaged with surgery, but locally recurrent anal SCC can be a difficult clinical problem that is associated with profound morbidity and long-term disease control in only approximately 25% to 40% of cases (27-29). In a series of 185 consecutive patients with anal cancer treated with either RT alone or chemoradiotherapy, 42 developed local failure requiring salvage therapy (30). Twenty-six patients (62%) underwent potentially curative surgery, including 23 APRs and 3 local excisions. The five-year rates of overall survival, secondary local control, and locoregional control were 45%, 53%, and 43%, respectively. APR is also the treatment of choice for patients who have persisting disease after completion of combined modality therapy. Patients who have a clinical suspicion of persistent disease at 26 weeks should undergo biopsy, and those with histologic confirmation of persisting disease should be offered APR. The results of surgical salvage are similar to those for patients with locally recurrent disease. This was shown in a series of 111 patients with anal cancer who were treated with chemoradiotherapy or RT alone, followed by APR for persistent (n = 61) or recurrent (n = 50) disease (29). The estimated five-year survival rate disease free was 30%. In univariate analysis, outcomes were similar for patients with persistent versus recurrent disease. In multivariate analysis, only three factors significantly influenced prognosis: the status of the

Complimentary Contributor Copy 194 Patrícia B Aguilar, Renata Peixoto, Fiona Lim et al. surgical margin, perineural and/or lymphatic invasion, and whether or not the nodes in the resected specimen were involved with tumor. Major wound complications are common, reported in 36% to 80% (31). Muscle flap reconstruction has been associated with significantly lower rates of such complications without major donor-site morbidity (32, 33). Pedicled muscle flaps have shown a significantly lower rate of recipient site complications than V–Y advancement flaps, with the vertical rectus abdominis myocutaneous flap showing superior results compared with the gracilis flap in terms of the overall reduction of complications (34). Because of potential surgical morbidity after initial chemoradiation, inguinal lymphadenectomy is reserved for those patients who have either persistent or recurrent disease in the inguinal lymph nodes. Patients should be considered for additional radiation to the involved inguinal region. The management of these patients must be individualized taking into account prior exposure to radiation and the extent and depth of inguinal nodal disease.

TREATMENT OF METASTATIC DISEASE

Distant metastases are rarely found in anal canal cancer. Most patients present with locoregional disease and only 10-20% of them develop metastatic lesions following chemoradiation (7, 9, 14). In addition, distant metastases are reported in 5-8% of initial diagnoses. When present, liver is the most frequent site of metastases (35), with other common locations including lungs, retroperitoneal lymph nodes and skin, which usually appear late and in the context of local persistent or recurrent disease (11). Unfortunately, there are no randomized trials evaluating the optimal treatment for metastatic squamous cell carcinoma of the anus. Patients typically receive a first line combination of cisplatin with a fluoropyrimidine (either 5-FU or capecitabine), which is endorsed by international guidelines and currently considered standard of care (36, 37). Most retrospective studies report a response rate of 35-60% for this regimen, with a median progression free survival of 5-6 months and a median overall survival of approximately 20-22 months (38-40). Some groups also use taxane-based regimens in the first-line setting of metastatic anal cancer, with overall response rates of 53% (38, 39). A more aggressive regimen with docetaxel, cisplatin and 5-FU (DCF) has been tested in 8 patients who had previously failed chemoradiotherapy (41). Half of them achieved a complete remission. Three of these patients underwent surgery for metastatic sites and had pathological complete response was confirmed. Interestingly, all patients who responded had immunohistochemical studies revealing a p16(+)/p53(-) phenotype (41). In terms of further therapies, data are even more sparse in the literature. Most came from case reports using regimens that are effective in other similar malignancies, such as head and neck squamous cell carcinoma and cervical cancer, which are strongly associated with oncogenic strains of HPV. For instance, the TIP regimen (paclitaxel, ifosfamide and cisplatin) has been tested in patients with metastatic anal cancer who had progressed on cisplatin and 5- fluorouracil with alleged high response rates. However, this triplet regimen should only be used in young and fit patients (42, 43). Single-agent chemotherapies have had their activities described in metastatic anal cancer with some success. Weekly paclitaxel confirmed activity in patients with 5-FU and cisplatin-

Complimentary Contributor Copy Management of anal cancer 195 resistant metastatic disease. In a report from seven patients receiving paclitaxel, there were 4 objective responses and 1 stable disease (44). Solitary case reports also described objective response for carboplatin, doxorubicin, and irinotecan (45-47). So far, no targeted therapies have prospectively proved their efficacy in metastatic squamous cell carcinoma of the anal canal and no particular genomic abnormality can guide therapeutic strategies. Anal cancers universally express the epidermal growth factor receptor (EGFR). Tumor shrinkage was retrospectively reported in patients using cetuximab (anti- EGFR) monotherapy or cetuximab with irinotecan combination as first or subsequent treatment line (48). Activity was noted only in RAS wild-type tumors. Another case series of patients receiving either cetuximab or panitumumab in combination with other chemotherapy agents, mostly in the second line setting, described a response rate of 35% (49). Although promising, prospective validation of these findings is needed before anti-EGFR can be adopted in routine clinical practice. In parallel with many other malignancies, promising results have been reported with immune checkpoint inhibition targeting the PD-1 pathway in metastatic anal cancer. In the phase II trial including 37 patients with chemo-refractory metastatic anal cancer, activity of nivolumab was evaluated, independently of PD-L1 expression (50). The overall response rate was 24%, with 2 complete responses. Median overall survival was also promising at 11.5 months with a good toxicity profile (50). Pembrolizumab was also tested in the multicohort phase Ib trial KEYNOTE-028 for PD-L1 positive advanced anal cancer (51). Among 24 patients, overall response rate was 17% with a stable disease rate of 42%. As expected, adverse events were tolerable. There might also be a role for surgery in the metastatic setting. However, when compared to other primary sites, there is far less experience with resection or nonsurgical local ablative procedures for patients with anal carcinoma. Two case reports have described successful hepatectomies for patients with liver-limited metastases achieving long-term disease-free survival (52, 53).

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Chapter 17

MANAGEMENT OF EARLY BREAST CANCER

Heloisa de Andrade Carvalho1,2,, MD, PhD, Silvia Radwanski Stuart1,3, MD, Gustavo Nader Marta1,2, MD, PhD, Fiona Lim4, MBBS, Bo Angela Wan5, MD(C) and Mauricio F Silva6,7,8, MD, PhD 1Department of Radiology and Oncology, Faculty of Medicine, University of São Paulo, Brazil 2Hospital Sírio-Libanês, São Paulo, Brazil 3Instituto Brasileiro de Controle do Câncer, São Paulo, Brazil 4Department of Oncology, Princess Margaret Hospital, Hong Kong, PR China 5Odette Cancer Centre, Sunnybrook Health Sciences Centre, Toronto, Ontario, Canada 6Radiation Oncology Unit, Santa Maria Federal University, Santa Maria, Brazil 7Hospital de Caridade Astrogildo de Azevedo, Santa Maria, Brazil 8Latin America Cooperative Oncology Group, Porto Alegre, Brazil

ABSTRACT

This chapter is an overview of the current policies in the management of early breast cancer in Latin America, based on relevant papers published over the last ten years in the literature. We examine the recommendations for breast cancer diagnosis and staging, and treatment for Stage 0 through Stage IIB (T1-2, N0-1) disease. Early stage breast cancer management by the radiation oncologist may be as simple as considering breast conservative surgery followed by irradiation of the whole breast as the standard of care. However, in daily practice, different scenarios of the same disease may represent a challenge, mostly regarding regional lymph node irradiation in the presence of risk factors versus avoiding adjuvant irradiation. Each department should develop guidelines based on a multidisciplinary approach and tailor radiotherapy not only in the indication, but also in the definition of the radiation targets and respective doses.

 Corresponding Author’s Email: [email protected]. Complimentary Contributor Copy 200 H. de Andrade Carvalho, S. Radwanski Stuart, G. Nader Marta et al.

INTRODUCTION

Over the past decade, there have been fundamental changes in our understanding of the biology of breast cancer. We now think of breast cancer as a group of diseases that originate from breast epithelial tissue but with different molecular characteristics (identified by gene expression profiling, immunohistochemistry, proteomics, next-generation sequencing, and other molecular techniques) and hence have different sensitivities to therapies, prognoses, patterns of recurrence and dissemination after primary multidisciplinary treatments. Worldwide, breast cancer accounts for approximately 25% of all cancers diagnosed in women and almost 15% of all cancer deaths (1). Latin America accounts for 8.3% of this incidence, with an estimated 115,000 women diagnosed every year (2). Approximately 60% of deaths due to breast cancer occur in developing countries, and in Latin America, 37,000 women die each year representing about 14% of all cancer deaths (3). Epidemiological data are scattered and are of varying quality in Latin America. However, the burden of breast cancer in the region is considerable and growing due to demographic changes, particularly the aging population, and socioeconomic development. Early diagnosis and population-wide access to evidence-based treatment remains unresolved problems, despite progress achieved by some countries. Early stage (I and II) comprises about 65 to 70% of breast cancer presentation considering six Latin American countries with available data, with the highest rates in Uruguay (81%) (4). However, survival rates rarely exceed 70% as compared with the expected 85% or more observed in countries with better outcomes, due to the higher numbers of advanced disease at presentation (4). This chapter examines the recommendations for breast cancer diagnosis, staging, and treatment for Stage 0 through Stage IIB (T1-2, N0-1) disease. Early breast cancer can be defined as tumors not more than 5 cm in diameter, with lymph nodes (palpable or not) that are not fixed, and with no evidence of distant metastases. Treatment of early breast cancer involves surgery to remove the tumor (lumpectomy or mastectomy) and management of the axilla. The axilla is examined to assess the stage of the disease (whether it has spread from the breast to surrounding lymph nodes) so as to determine further treatment options and prognosis. Generally, radiotherapy is part of local and regional treatment of the disease and chemotherapy will treat the risk of systemic disease. The current management of early breast cancer requires a multidisciplinary team of specialists to achieve better clinical outcomes. The objective of this chapter is to provide an up-to-date summary of the highest grade of evidence available that are related to the management of early breast cancer worldwide, with special focus in Latin American reports. The results may be used as a guidance for treatment decisions that are tailored to individual patients.

OUR SEARCH

An overview of the most relevant papers published over the last ten years in the literature was performed. Specific manuscripts related to Latin America were searched as well, either in English, Spanish or Portuguese. The search was performed in Pubmed and SCielo databases,

Complimentary Contributor Copy Management of early breast cancer 201 using the following keywords: “breast cancer,” “Latin America,” “early stage,” “radiotherapy.” Since a systematic review was not the purpose of this manuscript, the results will be presented in respective related items, according to the most current information retrieved.

FINDINGS

Initial evaluation requires a complete medical history and physical evaluation, with special attention to the breast exam and draining lymph nodes. Most patients who present with early- stage disease are asymptomatic, and diagnosis is made by screening mammography. In other instances, they may present as a palpable lump or nipple discharge of blood. Mammography is the mainstay of screening for detecting clinically occult disease. Mammography, however, has well-recognized limitations. Recently, other imaging modalities including ultrasound and magnetic resonance imaging (MRI) have been used as adjunctive screening tools, mainly for women who are at increased risk for developing breast cancer (5). The lifetime probability of developing invasive breast cancer in women is around 12%, and increases with age by an additional risk of 1.9% in patients up to 49 years, 2.3% from 50 to 59 years, 3.4% from 60 to 69 years and 6.8% from 70 years and older (6). The American Society of Breast Imaging (ASBI) and American College of Radiology (ACR) recommends breast cancer imaging screening starting at the age of 40 and is individualized according to the following risk groups (5):

1. Women at average risk for breast cancer  Annual screening from age 40 2. Women at increased risk for breast cancer 3. Women with certain BRCA1 or BRCA2 mutations or who are untested but have first- degree relatives (mothers, sisters, or daughters) who are proved to have BRCA mutations.  Yearly starting by age 30 (but not before age 25). 4. Women with ≥ 20% lifetime risk for breast cancer on the basis of family history (both maternal and paternal)  Yearly starting by age 30 (but not before age 25), or 10 years earlier than the age of diagnosis of the youngest affected relative, whichever is later. 5. Women with mothers or sisters with pre-menopausal breast cancer:  Yearly starting by age 30 (but not before age 25), or 10 years earlier than the age of diagnosis of the youngest affected relative, whichever is later. 6. Women with histories of mantle radiation (usually for Hodgkin's disease) received between the ages of 10 and 30:  Yearly starting 8 years after the radiation therapy, but not before age 25. 7. Women with biopsy-proven lobular neoplasia (lobular carcinoma in situ – LCIS, and atypical lobular hyperplasia), atypical ductal hyperplasia (ADH), ductal carcinoma in situ (DCIS), invasive breast cancer or ovarian cancer.  Yearly from time of diagnosis, regardless of age.

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Screening mammography (± adjunct MRI) should begin earlier in high-risk populations, such as prior thoracic radiotherapy (e.g., mantle-field radiotherapy), genetic predisposition, strong family history or prior history of LCIS/atypical hyperplasia. In Brazil, the health care system policy recommends screening starting after 50 years old (7).

Pathology

Prior to initiating a treatment, a pathologic diagnosis of cancer must be confirmed. Biomarkers including estrogen receptors (ER), progesterone receptors (PR), and Her-2 status should be requested at the time of pathology review (2). DCIS comprises 15–20% of all breast cancers. Prognostic variables for DCIS include tumor size, margins, nuclear grade, necrosis, multifocality, and age. High-grade DCIS tend to be continuous, with 25% expressing ER; low-grade DCIS present with increased multifocality and multicentricity, with 90% expressing ER. Lobular neoplasm (former LCIS, which is no longer the accepted nomenclature, and has been removed from the AJCC-TNM staging system) is a marker for bilateral breast cancer with approximately 20-25% lifetime risk for developing ipsilateral or contralateral cancer, with the risk dependent on age of diagnosis. They are often mammographically silent, ER/PR positive, Her2 negative, and 22 to 26% are associated with DCIS or invasive disease. Invasive (infiltrating) ductal carcinoma (IDCA) is the most common type of breast cancer (85% of invasive cases), and is referred to as invasive carcinoma of no special type (NST). Invasive lobular carcinomas (ILCA) has prognosis similar to that of ductal carcinoma, and are associated with increased risk of bilateral, multifocal breast cancer. Tubular, medullary, and mucinous carcinomas generally have better prognosis.

Staging

The AJCC 8th Edition was made in order to categorize patients within uniform cohorts for better assessment of prognosis and treatment options. To preserve the relevance of the TNM classification and recognizing the need for anatomic staging for the entire world, major changes were made to integrate biomarkers as a second tier of prognostic modifiers (8) (see Tables 1 and 2).

Prognostic factors

Stage at diagnosis and axillary lymph node status remain independent predictors of patient outcome. Patient age and menopausal status, histology and grade of primary tumor, hormone receptors and HER-2 status, lymphovascular invasion, extensive intraductal component and resection margins are also important and influence treatment decisions.

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Table 1. AJCC -TNM staging system - 7th Edition

Stage T N M 0 Tis N0 M0 IA T1 N0 M0 IB T0 N1mi M0 T1 IIA T0 N1 M0 T1 T2 N0 IIB T2 N1 M0 T3 N0 IIIA T0 N2 M0 T1 T2 T3 N1 N2 IIIB T4 N0 M0 N1 N2 IIIC Any T N3 M0 IV Any T Any N M1

Table 2. Examples of major changes in the AJCC -TNM 8th edition including biomarkers (8). Full line indicates translation to worse prognostic group when biomarkers are considered as compared to the 7th edition. Dashed lines, better prognostic group

T N M G HER ER PR 7th ed 8th ed 2 stage stage Biomarkers 1 0 0 1 - - - IA IIA 1 0 0 3 - + - IA IIA

3 1-2 0 1 + + + IIIA IB

Oncotype DX recurrence score < 11 for ER-positive tumors 2 0 0 Any - + Any IIA IB 1-2 1 0 Any - + Any IIA/IIB IB 0-2 2 0 1-2 + + + IIIA IB Legend: G = grade; ER = estrogen receptor; PR = progesterone receptor. Legend: G = grade; ER = estrogen receptor; PR = progesterone receptor.

Family history

Approximately 10% of breast cancer cases are associated with a germline mutation, including p53 (Li Fraumeni), BRCA1, and BRCA2. BRCA mutation carriers have 40–85% lifetime risk of breast and 25–65% lifetime risk of ovarian cancer. BRCA2 mutation carriers have a similar risk of breast cancer as BRCA1, and 10–15% lifetime risk of ovarian cancer. Complimentary Contributor Copy 204 H. de Andrade Carvalho, S. Radwanski Stuart, G. Nader Marta et al.

Table 3. Randomized trials for ductal carcinoma in situ with or without radiotherapy after breast conserving surgery. Adapted from EBCTCG 2010 (10)

Trial Period N Follow-up Local recurrence (%) Overall survival (%) (years) RT No RT Yes RT No RT Yes NSABP B-17* 1985-90 818 17.25 35 19.8 86 87 EORTC* 10853 1986-96 1010 15.8 30 17 90 88 UK/ANZ DCIS 1990-98 1030 12.7 19.4 7 97.9 96.2 SweDCIS* 1987-99 1067 20 20 32 77.7 73 RTOG 9804 1998-06 636 7.17 6.7 0.9 95.1 91.7 * 20% with positive margins. Legend: N = number of patients; RT = whole breast radiotherapy.

Management of stage 0 disease

Ductal carcinoma in situ Local treatment options include breast conservation surgery with adjuvant radiotherapy, breast conservative surgery alone, total mastectomy with or without sentinel lymph node biopsy, with or without reconstruction. The role of radiotherapy after conservative surgery for DCIS was evaluated in several trials, with its benefit already well demonstrated. The long-term toxicities identified from the use of adjuvant radiotherapy was very acceptable (9, 10) (see Table 3). These randomized trials provide strong and consistent evidence that radiotherapy after breast-conserving surgery for DCIS approximately halved the rate of ipsilateral breast events during the subsequent decade with little effect on contralateral or distant events. A meta- analysis conducted by the European Breast Cancer Trialists Collaborative Group (EBCTCG) found that the absolute magnitude of the 10-year risk reduction was 15%, and in the irradiated group, both the number of women with recurrent DCIS or invasive breast cancer in the conserved breast were substantially reduced. The proportional reduction in the rate of ipsilateral breast events with radiotherapy was greater in older than in younger women, but there were no other significantly different factors (10). The use of a boost dose in DCIS after whole breast radiotherapy has been analyzed. For patients with ductal carcinoma in situ and a life expectancy of more than 10 to 15 years, the addition of a radiation boost dose may be considered to provide an incremental benefit in improving local control after whole-breast radiotherapy (11). Radiotherapy after breast conservative surgery for DCIS is conventionally delivered in opposed tangential fields to the ipsilateral breast. The standard dose prescribed to the whole breast is 45-50 Gy in 1.8-2.0 Gy per fraction, with an additional boost dose of 10-16 Gy to the tumor bed with a 1.5-2.0 cm margin when necessary. Although accelerated hypofractionated regimens in 16 fractions have been shown to be equivalent to conventional RT for invasive breast cancer, few studies have reported results of using hypofractionated RT in DCIS with the same results (12-14). The American Society for Radiation Oncology (ASTRO) recently published guidelines for the use of hypofractionated radiotherapy for whole breast irradiation that includes DCIS (15). There is a debate about de-escalation of treatment for DCIS to avoid overtreatment after surgery especially for small lesions, low grade histology and after clear resection with wide margin. Complimentary Contributor Copy Management of early breast cancer 205

The long-term follow-up updates of the four first-generation randomized trials comparing lumpectomy with and without radiation therapy have confirmed that radiation halves the local failure rates. The risk of dying of breast cancer increases about 18 times after experiencing an invasive local recurrence. This suggest that at least some DCIS have the potential to progress to a life-threatening disease. At the same time, none of the more recent prospective trials that tested the outcome after excision alone in low-risk DCIS achieved a 10-year local failure rate below 10%. DCIS is not a uniform disease. Its clinical behavior is heterogeneous, but no up to date are available that allow a precise identification of patients with low or very low progression risk who do not need irradiation (16).

Management of Stage I to IIB disease

Treatment recommendations The efficacy of postoperative radiotherapy after breast conservative surgery has been repeatedly demonstrated through various prospective randomized trials. Since 1990, it is considered the preferred treatment option for the majority of patients with early stage invasive disease after breast conservative surgery because it allows organ preservation while maintaining equivalent survival rates to those achieved with mastectomy and axillary dissection (17). However, a significant number of patients still undergo a modified radical mastectomy, some because they want to omit further treatment, and others due to contraindications for breast conservative surgery such as multicentricity, unfavorable ratio of tumor size to breast size, pregnancy and collagen vascular disease. Protracted time commitment from the patient and distance from the treatment centers sometimes are burdensome and may affect adherence to treatment. The logistical problem of conventional fractionation of radiotherapy has led investigators to study alternative accelerated schedules of treatment. Several randomized studies have found similar local control and survival outcomes between patients treated with conventionally fractionated (CF) whole breast irradiation (WBI) and those receiving hypofractionated (HF)-WBI. Cosmetic outcomes were also similar between the groups (18) (see Table 4).

Table 4. Results of the main randomized trials of hypofractionated whole breast irradiation. Adapted from Whelan T et al. 2008 (18)

Trial Years N Fractionation (Gy∕fractions) 10-year local recurrence RMH∕GOC 1986 - 1998 1410 50∕25 12% 42.9∕13 10% 39∕13 15% OCOG 1993 – 1996 1234 50∕25 7% 42.5∕16 6% START A 1998 -2002 2236 50∕25 7% 41.6∕13 6% 39∕13 8% START B 1999 - 2001 2215 50∕25 5% 40∕15 4% Legend: N = number of patients. Complimentary Contributor Copy 206 H. de Andrade Carvalho, S. Radwanski Stuart, G. Nader Marta et al.

Table 5. Guidelines of ASTRO and DEGRO regarding hypofractionated (15 or 16 fractions) whole breast irradiation for breast cancer patients

AGO and DEGRO*(19) ASTRO 2011 (15) ASTRO 2018 (15) Age > 40 years ≥ 50 years Any age (sequential boost allowed) Stage whenever regional lymph T1-T2 N0 Any stage if no additional field is nodes included, conventional required for regional lymph nodes fractionation irradiation. (25 – 28 fractions) DCIS is allowed Chemotherapy Any chemotherapy. None Any chemotherapy Neoadjuvant to be confirmed Dose Large breasts are not an  7% in the central Volume of breast tissue receiving homogeneity exclusion criterion axis ≥ 105% should be minimized regardless of dose-fractionation *DEGRO guidelines emphasize age as a major criterion regarding hypofractionated radiotherapy with individualized criteria for patients above 65 years such as: to consider no boost and omission of radiotherapy after individual risk assessment.

Currently, hypofractionated radiotherapy for breast cancer had been proposed as an available option by at least two international guidelines including ASTRO (15), the German Society for Radiation Oncology (DEGRO-Deutsche Gesellschaft für Radioonkologie) and members of the Working Party of Gynecologic Oncology (AGO) Breast Committee (19). Briefly, age, stage, chemotherapy delivery and dose homogeneity are considered and no hypofractionation should be performed when regional lymph nodes irradiation is indicated (see Table 5).

Boost after whole breast irradiation The EORTC conducted a randomized trial to evaluate the impact of additional radiotherapy dose to the lumpectomy site. The study enrolled 5569 patients with stage I and II disease. All patients underwent a lumpectomy with negative margins and whole breast irradiation with 50 Gy. Randomization was between an additional 16 Gy boost in the tumor bed versus none. The boost treatment was associated with a lower recurrence rate of 4.3% vs. 7.3% compared with patients receiving no boost. The maximum benefit of boost dose was observed in younger women aged < 40 years (20).

Patient selection for safely omitting radiotherapy Adjuvant radiotherapy is currently recommended in all patients after lumpectomy, regardless of age, size of the primary disease, and hormonal receptor status. The objective of the CALGB C9343/INT trial was to evaluate the role of post- lumpectomy radiotherapy in the elderly. The study enrolled 636 patients over the age of 70 years with ER-positive stage T1N0 disease. Following lumpectomy, patients were randomized to tamoxifen alone vs. tamoxifen and radiotherapy. At 5-year follow-up they observed statistically significant differences with a lower recurrence rate when both tamoxifen and RT were used, 1% vs. 4% (p < 0.001), respectively. However, no difference in survival was observed between the two groups. When treating the very elderly, one could consider individualizing the risk-benefit ratio of adjuvant treatment concerning the patients’ overall health and comorbidities (21).

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Breast cancer tends to be less aggressive and more indolent in women who are 70 years of age or older than in younger women. The rate of ipsilateral recurrence decreases with age, an effect likely to be enhanced by tamoxifen.

Accelerated partial breast irradiation (APBI) The concept of APBI was developed based on the findings that about 80% of breast cancer recurrences are located around the incision site (22). Vicini et al. found that only 9% of patients with breast cancer underwent resection of extramural residual tumor at 1.5 cm or greater from the margins of the original resection (23). Therefore, partial breast irradiation (PBI) may be sufficient. Because the irradiation area is narrowed, accelerated large-division irradiation does not result in acute or late radiotherapy responses. PBI further reduces the radiation doses to the heart, lung, chest wall, contralateral breast, as well as to the ipsilateral mammary gland. Although APBI technology has many advantages, controversy remains regarding its indications. At present, there are four major published standards: ASTRO (24), Groupe Européen de Curietherapie - European Society for Radiotherapy and Oncology (GEC- ESTRO) (see Table 6), American Brachytherapy Society (ABS), and American Society of Breast Surgeons (ASBrS). In addition to the consistent criteria regarding tumor size and negative margins, other criteria vary, including age, molecular typing, lymph node invasion, and other characteristics. As more results from evidence-based medicine are published, the standards are iteratively updated. In 2017, ASTRO reduced the minimum recommended age for APBI from 60 years to 50 years (25-28).

Table 6. ASTRO (24) and GEC-ESTRO (25) criteria for APBI indication

Criteria ASTRO ESTRO ASTRO ESTRO ASTRO ESTRO Acceptable Low risk Cautionary Intermediate On Trial High risk (all factors) (acceptable) (any factor) (possible) only (any (contra- factor) indicated) Size < 2cm T1-T2 2-3cm T1-T2 > 3cm T3-T4 Age ≥ 50 years* ≥ 50 years 50-59 years 40-50 years < 50 years < 40 years BRCA Negative - - - Positive - Histologic type ICA ICA ILC ILC DCIS - Margin Negative Negative < 2mm < 2mm Positive Positive Grade Any - - - - LVI Negative Negative Focal Negative Extensive Positive Estrogen Positive Any Negative Any - - Receptor DCIS / Not allowed Not allowed  3 mm Not allowed > 3 cm Present intraductal extension Presentation Unicentric Unicentric - Unicentric - Multicentric Lymph nodes Negative Negative Negative Negative Positive Positive Neoadjuvant ChT Not allowed Not allowed Not allowed Not allowed Yes Yes *updated in 2017 (28). Legend: ICA = Invasive carcinoma; ILC = invasive lobular carcinoma; DCIS: ductal carcinoma in situ; LVI = lymphovascular invasion; ChT = chemotherapy.

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Several meta-analyses comparing whole breast with partial breast irradiation have been published regarding local recurrence, breast cancer-related mortality, nodal recurrence, systemic recurrence, and overall survival (29-31). Among patients who had received breast- conserving treatment for early breast cancer, the rate of local recurrence was significantly higher for APBI than for WBI. However, both rates were very low (< 5-8%) and non-breast cancer deaths were less common for APBI than for WBI. There were no statistically significant differences in nodal recurrence, systemic recurrence, overall survival, or mortality rates between APBI and WBI groups. The incidence of acute skin toxicity was lower in the APBI groups, but no significant differences were observed for later skin toxicity or cosmetic effect (32).

Management of patients with 1 to 3 positive lymph nodes (pN1a)

One of the most challenging situations regarding the management of breast cancer patients is the presence of one to three positive axillary lymph nodes in early stage disease. This is not only an issue for the radiation oncologist, but also for the surgeon and the clinical oncologist. Many studies looked at risk factors involving this situation and some factors were identified as allied to a higher risk of recurrence, including young age (<50 years old), histological grade 3 tumor, presence of lymph-vascular invasion, proportion of positive lymph nodes above 20%, primary tumor with four cm or more, extracapsular tumor extension in the lymph node, no expression of hormonal receptors or triple negative or HER-2 positive, more than one positive lymph node, and high risk genomic profile. More recently, a few remarkable studies were published and highlighted some specific situations related to the presence of positive sentinel node(s) (SN) with or without axillary dissection. The results of these studies will be presented here.

Positive sentinel node biopsy with no axillary node dissection (ALND) At least four contemporary randomized studies looked at the effect of not performing axillary lymph node dissection in patients with positive SN biopsy: the ACOSOG Z0011, IBCSG 23- 01, EORTC 10981-22023 AMAROS and the OTOASOR (33-36). The first two (ACOSOG and IBCSG) looked at the effect of avoiding axillary treatment after a positive SN biopsy (33, 34). Patients with positive SN were randomized into further ALND or no axillary treatment. Overall and disease-free survivals were similar in both arms. Important to note is that in the ACOSOG Z0011 there was a violation in the radiotherapy protocol observed in 15 to 20% of the patients that received additional irradiation of the axillary and supraclavicular nodes, and a similar amount received whole breast irradiation using “high” tangents fields that may include at least part of level 1 axillary nodes (37). AMAROS and OTOASOR trials investigated whether one axillary treatment is superior to the other through randomising patients with positive SN biopsy between ALND and radiotherapy including the axilla (35, 36). In the same way, overall and disease-free survival were similar in both arms of studies. However, the surgery arm was associated with a 2-3 times higher rate of lymphedema in the AMAROS study.

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Table 7. Randomized studies that compared patients with positive sentinel node submitted or not to axillary lymph node dissection. ACOSOG and IBCSG compared no subsequent local treatment with axillary dissection and AMAROS and OTOASOR compared subsequent treatment with axillary dissection or irradiation. Survival outcomes were not statistically different between the groups in each trial, respectively

ACOSOG IBCSG EORTC OTOASOR Z0011 (33) 23-01 (34) AMAROS (35) (36) Period 1999 - 2004 2001 - 2010 2001 - 2010 2002 – 2009 N patients 445 x 446 464 x 467 744 x 681 261 vs 265 Randomization ALND ALND ALND x RT ALND x RT Yes x No Yes x No Age (years) 55 54 55 55 T1 70% 69% 80% 65% Estrogen receptor positive 82% 90% 78% 84% Lymph vascular invasion present 37% NR NR NR Grade 3 30% 28% 28% 30% Additional positive lymph nodes 27% 13% 33% 38% Radiotherapy 90% 97% 90% 87% Systemic treatment 97% 96% 90% (per protocol) Median follow-up 6.3 years 5.1 years 6 years 8 years Legend: N = number; ALND = axillary lymph node dissection; RT = radiotherapy; NR = Not reported.

In summary, we have two studies demonstrating that in specific scenarios of positive SN biopsy, no further axillary treatment would be necessary; we have two other studies suggesting that treatment of the axilla brings similar results irrespective of the methods used. Table 7 summarizes the main aspects of these studies. Overall in these studies, there was about a 30% risk of having additional positive lymph nodes when ALND was performed in similar groups of patients. This is considerably high and should be taken in account when we decide on regional nodal irradiation. This risk may even be higher as reported in a meta-analysis of studies including 7765 patients submitted to SN biopsy followed by ALND in which there was a 42% rate of positive SN biopsy with 53% of additional positive lymph nodes after axillary dissection (38). A number of nomograms were developed to predict the individual risk of each patient that may help in the decision- making process.

Axillary lymph node dissection and lymph node irradiation A large meta-analysis conducted by the Early Breast Cancer Trialists Collaborative Group (EBCTCG) studied the effect of radiotherapy after mastectomy in 8135 patients who were randomized between comprehensive irradiation of the surgical bed and total nodal irradiation (TNI) versus no adjuvant radiotherapy (39). In general, all patients with positive nodes who received radiotherapy had superior disease- free and overall survival. Stratification according to the number of positive nodes also demonstrated benefit even for the 1,314 patients with 1 to 3 positive nodes, regardless of systemic treatment. However, there was no tailoring of the radiation fields according to the lymph nodes stations. This means that if one is willing to achieve the same results, irradiation of the surgical bed with TNI should be indicated.

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Table 8. Randomized studies that compared whole breast or surgical bed irradiation with or without total nodal irradiation

Study MA.20 (39) EORTC (40) Period 2000-2007 1996-2004 N patients 916 vs 916 2002 vs 2002 Age (years) 54 54 Stage I – IIB I - III T1-T2 99% 99% Breast conserving surgery 100% 76% > 10 dissected lymph nodes 67% 86% N0 10% 44% 1 to 3 positive lymph nodes 85% 43% Estrogen receptor positive 75% 75% Systemic treatment 90% 85% Survival TNI TNI No x Yes No x Yes 10-year overall survival 82 x 83% 81 x 82%** 10-year disease-free survival 77 x 82%* 69 x 72%* 10-year metastasis- free survival 82 x 86%* 75 x 78%* * Statiscally significant difference. ** p = 0.06. Legend: TNI = Total nodal irradiation.

But how do these findings apply to early stage disease? It was already stated earlier in this chapter that in selected patients with 1 to 3 positive axillary lymph nodes, different approaches lead to similar outcomes considering the risk factors, including the omission of irradiation in patients with ALND. Two important studies deserve attention regarding patient selection for lymph node irradiation in early stage disease: The MA.20 and the EORTC trials (40, 41). Both had similar designs, and included patients with positive axillary lymph nodes or high risk negative axillary lymph nodes who underwent whole breast or surgical bed irradiation who were randomized between yes or no regional nodal irradiation. Overall survival was the main outcome. Unfortunately, the 10-year overall survival outcome of both studies were negative, with no benefit of adding TNI. However, disease-free survival was better with TNI and a lower number of deaths due to breast cancer was also observed in this group of patients (see Table 8). The rate of regional recurrence was very low (< 6.5%) in the arms that did not receive TNI, even lower in the internal mammary chain. Important to notice is that in the MA.20 study, most patients presented 1 to 3 positive lymph nodes (40). A summary of both studies is presented in Table 8.

Radiotherapy technique

Three-dimensional conformal radiation therapy (3D CRT) is the gold standard for the most common types of cancer in the Caribbean, Central and South America (42). The role of more advanced technology such as IMRT or VMAT in the outcomes of breast cancer patients is not yet clarified, except for lowering toxicity. However, simple strategies to homogenize the Complimentary Contributor Copy Management of early breast cancer 211 dose, based on 3D planning, include wedges, compensators, field-in-field techniques, and the so-called “forward planning IMRT.” These strategies allow better dose distribution especially in patients with large breasts or large distance between the field entrances. In addition, other factors that may influence cosmesis and late toxicity and are not related to RT technique include body mass index, pre-RT cosmesis, post-operative infections, and smoking habit, among others. Thus, 3D CRT is desirable for the irradiation of these patients.

CONCLUSION

Early stage breast cancer management by the radiation oncologist may be as simple as considering breast conservative surgery followed by irradiation of the whole breast as the standard of care. However, in daily practice, different scenarios of the same disease may represent a challenge mostly regarding regional lymph node irradiation in the presence of risk factors or in which adjuvant irradiation may be avoided. Most information regarding breast cancer in Latin America is related to epidemiology, screening policies, diagnosis and risk factors. There is non-uniform and little information from the different countries in Latin America regarding breast cancer treatment overall. Each department should develop guidelines based on a multidisciplinary approach and tailor radiotherapy not only to the indication, but also to the definition of the radiation targets and respective doses. In our current practice at Hospital das Clínicas da Faculdade de Medicina da Universidade de São Paulo radiotherapy in early stage breast cancer is described as in Appendix 1.

APPENDIX 1

Current practice at Hospital das Clínicas da Faculdade de Medicina da Universidade de São Paulo for radiotherapy in early stage breast cancer

Breast conserving surgery

Stage Tis-T2 N0 M0 General approach: whole breast irradiation

 Tailored approach  Hypofractionation (15 or 16 fractions) for patients with 40 years or more  Boost dose: Patients with less than 50 years or margins less than 5 mm or neoadjuvant chemotherapy

Stage T1-T2 N1a General approach: whole breast irradiation the same as for N0 patients and regional nodal irradiation according to risk factors.

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 Tailored approach  Patients with age < 50 years (considered the strongest risk factor) all receive adjuvant nodal irradiation.  All the others should have at least two of the following risk factors associated in order to receive nodal irradiation: high grade tumor, presence of lymphovascular invasion, 20% or more positive lymph nodes, tumor of 4 cm or more, extracapsular extension, triple negative or Her2 positive, positive higher axillary level (2 or 3).  In general, when nodal irradiation is indicated, supraclavicular and axillary levels 2 and 3 are included. Axillary level 1 is included only if less than 10 lymph nodes were resected.  Hypofractionation is allowed for regional irradiation in patients with 70 years or more and in patients with 60 to 69 years with comorbidities.

Mastectomy

Stage Tis-T2 N0 M0  General approach: no adjuvant irradiation  Tailored approach: consider radiotherapy of surgical bed in invasive tumors with 4 cm or more.

Stage T1-T2 N1a  General approach: tailoring according to the risk factors already described.

Special situations

Tissue expanders or implants If radiotherapy indicated, use conventional fractionation scheme.

Nipple sparing or skin sparing mastectomy Should follow the same indications as for mastectomy except if the amount of residual breast tissue is more than 5 mm thickness, or if extensive DCIS is present with nipple sparing, or invasive tumor less than 2 cm from the nipple in nipple sparing mastectomy.

RT technique The most common technique is 3D CRT using strategies for dose homogeneity when necessary, to keep 50% of the PTV with less than 108% (up to 112%) of the prescribed dose. If hypofractionated regimens are used, the maximum accepted dose in 50% of the PTV should be 110% or less. In patients where the thoracic anatomy impairs appropriate target coverage or the organs at risk constraints are not achieved, IMRT/VMAT or deep inspiration breath hold techniques may be used.

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REFERENCES

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[22] Fowble B, Solin LJ, Schultz DJ, Rubenstein J, Goodman RL. Breast recurrence following conservative surgery and radiation: patterns of failure, prognosis, and pathologic findings from mastectomy specimens with implications for treatment. Int J Radiat Oncol Biol Phys 1990;19(4):833– 42. [23] Vicini FA, Kestin LL, Goldstein NS. Defining the clinical target volume for patients with early-stage breast cancer treated with lumpectomy and accelerated partial breast irradiation: a pathologic analysis. Int J Radiat Oncol Biol Phys 2004;60(3):722-30. [24] Smith BD, Arthur DW, Buchholz TA, Haffty BG, Hahn CA, Hardenbergh PH, et al. Accelerated partial breast irradiation consensus statement from the American Society for Radiation Oncology (ASTRO). Int J Radiat Oncol Biol Phys 2009;74(4):987-1001. [25] Polgár C, Van Limbergen E, Pötter R, Kovács G, Polo A, Lyczek J, et al. Patient selection for accelerated partial-breast irradiation (APBI) after breast-conserving surgery: recommendations of the Groupe Européen de Curiethérapie-European Society for Therapeutic Radiology and Oncology (GEC- ESTRO) breast cancer working group based on clinical evidence (2009). Radiother Oncol 2010;94(3):264-73. [26] Shah C, Vicini F, Shaitelman SF, Hepel J, Keisch M, Arthur D, et al. The American Brachytherapy Society consensus statement for accelerated partial-breast irradiation. Brachytherapy. 2018;17(1):154- 70. [27] American Society of Breast Surgeons. Consensus statement for accelerated partial breast irradiation. URL: http//www.breastsurgeons.org/new_layout/about/statements/PDF_Statements/APBI.pdf. [28] Correa C, Harris EE, Leonardi MC, Smith BD, Taghian AG, Thompson AM, et al. Accelerated partial breast irradiation: executive summary for the update of an ASTRO evidence-based consensus statement. Pract Radiat Oncol 2016;7(2):73-9. [29] Marta GN, Macedo CR, Carvalho H de A, Hanna SA, da Silva JL, Riera R. Accelerated partial irradiation for breast cancer: systematic review and meta-analysis of 8653 women in eight randomized trials. Radiother Oncol 2015; 114(1):42-9. [30] Ribeiro GG, Magee B, Swindell R, Harris M, Banerjee SS. The Christie Hospital breast conservation trial: an update at 8 years from inception clinical oncology. Clin Oncol 1993;5(5):278-83. [31] Vaidya JS, Bulsara M, Wenz F, Coombs N, Singer J, Ebbs S, et al. Reduced mortality with partial- breast irradiation for early breast cancer: a meta-analysis of randomized trials. Int J Radiat Oncol Biol Phys 2016;96(2):259-65. [32] Liu G, Dong Z, Huang B, Liu Y, Tang Y, Li Q, et al. Efficacy and safety of accelerated partial breast irradiation: a meta-analysis of published randomized studies. Oncotarget 2017;8(3):59581-91. [33] Giuliano AE, Hunt KK, Ballman KV, Beitsch PD, Whitworth PW, Blumencranz PW, et al. Axillary dissection vs no axillary dissection in women with invasive breast cancer and sentinel node metastasis: a randomized clinical trial. JAMA 2011;305(6):569-75. [34] Galimberti V, Cole BF, Zurrida S, Viale G, Luini A, Veronesi P, et al. Axillary dissection versus no axillary dissection in patients with sentinel-node micrometastases (IBCSG 23-01): a phase 3 randomised controlled trial. Lancet Oncol 2013;14(4):297-305. [35] Donker M, van Tienhoven G, Straver ME, Meijnen P, van de Velde CJ, Mansel RE, et al. Radiotherapy or surgery of the axilla after a positive sentinel node in breast cancer (EORTC 10981- 22023 AMAROS): a randomised, multicentre, open-label, phase 3 non-inferiority trial. Lancet Oncol 2014;15(12):1303-10. [36] Sávolt Á, Péley G, Polgár C, Udvarhelyi N, Rubovszky G, Kovács E, et al. Eight-year follow up result of the OTOASOR trial: the optimal treatment of the axilla - surgery or radiotherapy after positive sentinel lymph node biopsy in early-stage breast cancer: a randomized, single centre, phase III, non- inferiority trial. Eur J Surg Oncol 2017;43(4):672-9. [37] Jagsi R, Chadha M, Moni J, Ballman K, Laurie F, Buchholz TA, et al. Radiation field design in the ACOSOG Z0011 (Alliance) trial. J Clin Oncol 2014;32(32):3600-6. [38] Kim T, Giuliano AE, Lyman GH. Lymphatic mapping and sentinel lymph node biopsy in early-stage breast carcinoma: a metaanalysis. Cancer 2006;106(1):4-16. [39] EBCTCG (Early Breast Cancer Trialists' Collaborative Group), McGale P, Taylor C, Correa C, Cutter D, Duane F, et al. Effect of radiotherapy after mastectomy and axillary surgery on 10-year recurrence Complimentary Contributor Copy Management of early breast cancer 215

and 20-year breast cancer mortality: meta-analysis of individual patient data for 8135 women in 22 randomised trials. Lancet 2014;383(9935):2127-35. [40] Whelan TJ, Olivotto IA, Parulekar WR, Ackerman I, Chua BH, Nabid A, et al. Regional nodal irradiation in early-stage breast cancer. N Engl J Med 2015;373(4):307-16. [41] Poortmans PM, Collette S, Kirkove C, Van Limbergen E, Budach V, Struikmans H, et al. Internal mammary and medial supraclavicular irradiation in breast cancer. N Engl J Med 2015;373(4):317-27. [42] Isa N. Evidence based radiation oncology with existing technology. Rep Pract Oncol Radiother 2013;19(4):259-66.

Chapter 18

MANAGEMENT OF LOCALLY ADVANCED BREAST CANCER

Patricia Murina1,, MD, Soledad del Castillo2, MD, Andrés del Castillo2, MD, Pablo Castro Peña1, MD, Fiona Lim3, MBBS, Bo Angela Wan4, MD(C) and Mauricio F Silva5,6,7, MD, PhD 1Radiation Oncology Unit, Instituto Zunino, Cordoba, Argentina 2Instituto Modelo de Obstetricia y Ginecologia (IMGO), Córdoba, Argentina 3Department of Oncology, Princess Margaret Hospital, Hong Kong, PR China 3Odette Cancer Centre, Sunnybrook Health Sciences Centre, Toronto, Ontario, Canada 5Radiation Oncology Unit, Santa Maria Federal University, Santa Maria, Brazil 6Hospital de Caridade Astrogildo de Azevedo, Santa Maria, Brazil 7Latin America Cooperative Oncology Group, Porto Alegre, Brazil

ABSTRACT

Breast cancer is the most common cancer in women and its management often presents with difficult decisions about the most appropriate treatment. Locally advanced breast cancer (LABC) is a heterogeneous entity that includes advanced stage primary tumors, cancers with extensive lymph node involvement and inflammatory breast carcinomas. The prognosis of such tumors is often unfavorable; despite aggressive treatment, many patients eventually develop distant metastases and die from the disease. Advances in systemic therapy, including radiation treatment, surgical techniques and the development of new targeted agents, have significantly improved clinical outcomes for patients with this disease. The optimal management of LABC requires a multidisciplinary approach, a well-coordinated treatment program and close cooperation between medical, surgical and radiation oncologists. The purpose of this review is to discuss this type of cancer in the context of practice with a modern approach to its definition and treatment strategies.

 Corresponding Author’s Email: [email protected]. Complimentary Contributor Copy 218 Patricia Murina, Soledad del Castillo, Andrés del Castillo et al.

INTRODUCTION

Locally advanced breast cancer constitutes a major clinical challenge since majority of patients will experience disease recurrence in spite of aggressive multimodal treatments and eventually die. It is estimated that between 7% and 30% of the patients present with locally advanced disease at the moment of diagnosis (figures vary depending or not on the methods of early detection used in each country). The disease generally involves stage III, defined as tumor T0-T3 with axillary, ipsilateral subclavicular, supraclavicular or internal mammary lymph nodes (disease N2 or N3), or with tumor extension to the chest wall or skin, irrespective of node staging. In some instances, this definition also includes patients with clinical stage IIB disease, primary tumor ≥ 5 cm and no node involvement (T3 N0). Inflammatory breast carcinoma is a specific, highly aggressive entity with clinical diagnosis made by presence of skin erythema and edema (generally known as peau d’orange or orange-peel skin). Clinical diagnosis is generally accompanied by pathologic findings such as tumor embolism in skin lymph nodes, although this is not necessary (if clinical symptoms are not present) to confirm diagnosis. At this stage of presentation, the possibilities of surgical management with curative intent are low because of the high likelihood of local persistence (which is related to higher incidences of loco-regional recurrence, higher probability of systemic micrometastatic spread of the disease with the resulting higher risk of bone, lung, liver, brain and other distant recurrences), lower possibility of conservative surgical procedures and higher need of aggressive treatments, such as radiation therapy and chemotherapy. Combined treatment using systemic and locoregional modalities requires well- coordinated treatment planning and close multidisciplinary relationships among medical, surgical and radiation oncologists. It is clear that the wide diversity of presentations of the disease within this category has made it difficult to draw firm conclusions regarding the potential benefits and limitations of the various treatments and their combinations. What remains clear is that there are women without evidence of long-term recurrence (30%) at ten years. Therefore, it is essential that proper therapeutic management be implemented to achieve maximum benefit.

DEFINITION

Breast cancer is the most frequently diagnosed malignant neoplasia and the second cause of death most commonly related to female cancer worldwide. According to data provided by Surveillance, Epidemiology and End Results (SEER), survival rates at five years in patients with breast cancer stages IIIA and IIIB are 52% and 48% respectively, and mean survival for Stage III is 4.9 years (1, 2). Inflammatory cancer (IC) is a relatively rare disorder which represents approximately 1- 5% of invasive breast cancer (3, 4) and 8.5% of locally advanced disease (5). As reported by the M.D. Anderson Cancer Center, in their series of 752 patients with stage III breast cancer, 24% had IC (6). Long-term prognosis of IC remains deficient. According to data provided by SEER, breast cancer survival at two years (BCSS) was significantly worse for IC than for non- Complimentary Contributor Copy Management of locally advanced breast cancer 219 inflammatory locally advanced cancer (84% versus 91%, HR 1.43 [IC 95%, 1.097-1.854]), irrespective of race, age or hormonal receptor status (7). This result suggests that new strategies developed within the IBC context may have a positive impact on IBC patients (8). The definition of locally advanced disease has been changing with availability of various treatments. When surgery was the only effective therapeutic tool in past, locally advanced breast cancer consisted of a group of patients who did not have any benefit from surgical procedures, such as those with diffuse breast involvement affecting almost the whole breast volume, focal or diffuse skin infiltration (whether or not associated with inflammation), skin ulceration, fixation to deep planes due to involvement of the chest wall, and large involvement of the regional lymph nodes. These women were considered surgically unresectable, and supportive care was the only approach before the advent of radiotherapy, hormone therapy and chemotherapy. Later, radiation therapy became the loco-regional treatment of choice. From that moment on, the definition of the disease has undergone various revisions. Currently, patients presenting the following characteristics are included in this IC category:

1) Tumor larger than 5 cm, involvement of chest skin or wall, axillary nodes connected to each other or to the vascular axillary bundle; clinical evidence of cancer in supraclavicular, subclavicular or mammary internal nodes and inflammatory breast cancer. 2) Within this definition, some research groups include patients with surgically resectable disease but who cannot be treated with initial conservative treatment.

The population included is very heterogeneous: some patients present with extremely large tumors but without systemic or node involvement, while others have rapidly growing smaller tumors with little local effect but rapidly spreading to the nodes. This variety makes studies rather complex, since the large number of publications focus on the global analysis of all tumors (9). Inflammatory breast carcinoma is an infrequent condition of rapid development; it has different prognostic perspectives and is included within the group of patients with locally advanced breast cancer. It is characterized by redness, skin edema and local warmth, which does not necessarily cause pathologic involvement of the skin lymph nodes. This last histologic observation was considered pathognomonic for this tumor to be included in the group, although at present, it is known that there may exist an inflammatory clinical involvement with no evidence of skin involvement, and in some occasions with no clear evidence of inflammation but of diffuse skin lymph node involvement. Peritumor lymph infiltrations should be differentiated from ulcerating tumors of the skin.

CLASSIFICATION

The different stages included in the group of locally advanced disease can be grouped following the AICC (American Joint Cancer Committee for staging of breast cancer):

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Stage IIB: T3N0M0 Stage IIIA: T0N2M0, T1N2M0, T2N2M0, T3N1M0, T3N2M0 Stage IIIB: T4N0M0, T4N1M0, T4N2M0 Stage IIIC: any TN3M0 (includes inflammatory carcinoma T4d

According to the presence or absence of inflammatory characteristics:

Non-inflammatory disease Inflammatory disease

DIAGNOSIS AND PRETREATMENT EVALUATION

This includes the following aspects:

1) Complete medical history, proper physical examination including measurement of all the evaluable lesions, even photographic documentation with marking, and description and measurements of the affected areas (10). 2) A biopsy must be done to confirm the diagnosis. It can be performed with a thick needle or biopsy for pathological studies, determination of hormone receptors (HR), HER2, ki67, and simultaneously, in the case of regional node involvement, with a puncture of the most conspicuous node structure (PAAF or with a thick needle). Laboratory evaluations: platelet count, hemogram, renal and liver functions (10). 3) Imaging studies: digital mammography, breast ultrasound (which helps to determine the extension of the primary disease, assessment of the presence of multifocal or multicentric disease, study of the contralateral breast to rule out the presence of synchronic disease and to offer the possibility for the patient to be a potential candidate for conservative surgery, poster-anterior and lateral chest X-ray, abdominal and gynecological ultrasound.

These characteristics are indicators of functional changes in the proliferative behavior of the tumor (10). A correct pre-treatment staging helps to assess predictive and prognosis factors in order to inform patients about the treatment plan chosen. Since a percentage of the patients may undergo surgery first, a rapid pre-operative staging and then a deep pathologic staging contributes to selecting the most appropriate pre-operative treatments. In those patients for whom the first therapeutic measure is systemic treatment (chemotherapy, hormone-therapy, monoclonal antibodies or a combination) the extension of the disease must be evaluated at the beginning and end of the treatment to define locoregional treatments (surgery and radiotherapy). Response to therapy varies, depending on the molecular profile of the tumor. In a high percentage of patients, tumor size will decrease and regional node involvement will become negative so that post-operative treatments must adapt not only to the initial stage but also to the magnitude of response.

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PROGNOSTIC FACTORS

Prognostic factors in locally advanced disease are similar to those of early disease, with locoregional node involvement and tumor size having the greatest prognostic impact. Most of the patients with locally advanced disease have axillary node involvement and a lower percentage of involvement of other lymphatic regions (such as the supraclavicular, the subclavicular or the internal mammary regions). The internal mammary chain nodes are located just next to the internal mammary artery and vein subjacent to the intercostal cartilages and muscles. Their number is highly variable, being more frequent in the first intercostal spaces. They drain mostly from the breast internal quadrants, even though lymphoscintigraphy studies indicate that any quadrant may send lymph flow both qualitatively and quantitatively. Prognosis for patients without node involvement is better than for those with; the number of nodes involved has prognostic impact as well. With regards to the presence or absence of hormone receptors, positive receptor status indicates a good prognostic factor for survival and a predictive factor of response to neo adjuvant hormone, while negative receptors status indicates the need of chemotherapy.

TREATMENT

Within the focus of combined modalities, in most of the cases surgery follows systemic therapy and precedes radiation treatment. Historically, mastectomy was the routine surgical approach for these patients. However, the success of neoadjuvant systemic therapies has significantly increased the interest in conservative treatment of the breast, which demands a thorough loco-regional assessment before treatment by means of mammography, echography and IMR of breast and axilla (11). It is important to point out that marking the primary tumor at the time of biopsy prior to treatment is essential to ensure that the correct area of breast tissue can be identified and removed after systemic treatment (12, 13). The choice of surgical procedure depends on the stage of the disease before treatment and response after neoadjuvant treatment. The treatment for locally advanced breast cancer requires the combination of systemic treatment (chemotherapy, hormone therapy for HR+, or trastuzumab for HER2+), surgery and radiotherapy to improve the probabilities of controlling the disease with curative intent. Radical surgery was the procedure initially performed, but local control with surgery alone was achieved in only 50% of the cases. Supraclavicular node involvement, arm edema, multiple satellite skin nodes, and inflammation and diffuse edema of the breast were regarded as criteria for non-resectable disease because of high possibilities of recurrence after surgery. Radiotherapy was then considered the strategy of choice, with adjustment of doses and fields according to the technological possibilities at that time. Limitations to this strategy were high probabilities of loco-regional and systemic recurrence in addition to the toxic effects of the treatment (chest wall fibrosis, brachial plexopathy, arm lymphedema, skin ulceration, soft tissue necrosis).

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The use of neoadjuvant chemotherapy as initial treatment was investigated as early as 1958, with 70% to 90% of local disease objective response including partial and complete response. This treatment modality allowed the removal of tumors initially thought to be unresectable and increased the probability of preserving the breast in patients who would otherwise be considered for radical surgery. The benefits of induction chemotherapy include potentially eradicating micrometastatic disease by attacking the local disease even with intact vascularity, by studying tumor response to the prescribed chemotherapy, and by offering the opportunity to study the biological effects of treatments on the tumor. Nevertheless, starting the strategy with induction systemic treatment results in losing the possibility of assessing two main prognostic factors, namely tumor size and number of involved nodes in the pathological study. Present-day evidence shows that in those patients who can undergo surgery and adjuvant chemotherapy or else begin with induction therapy and then operated later on, the possibilities of achieving cure have improved; therefore, both modalities are considered valid. Those patients who cannot be treated with conservative surgery perhaps can receive either modality therapy without modifying cure possibilities (14). With regards to the selection of chemotherapy agents, several schemes are considered standard and those containing anthracycline are commonly recommended for initial treatment. The addition of taxanes to anthracyclines increases the probability of global response, enhances probability of complete pathological response, and hence, provides higher chances of cure. However, the optimal time and sequencing of these two drugs in the treatment scheme is not clear. Simultaneous use increases the likelihood of toxic effects and impacts quality of life; therefore, sequential use is recommended. For women with HER2 overexpression by immunohistochemistry (IHQ) or genetic amplification by fluorescence in situ hybridization (FISH), adding trastuzumab combined with pertuzumab (dual blocking) to the neoadjuvant chemotherapy scheme increases the response rate and possibly results in higher clinical and pathologic complete responses. Its use is recommended but should not be combined with anthracyclines due to their potential cardiotoxicity; however, they can be simultaneously administered with taxanes (15). With regards to the number of chemotherapy courses, were recommend completing the total number of planned courses of six to eight cycles, and later define the local and regional strategy. In the case of HER2-positive disease, patients should continue trastuzumab following surgery and radiotherapy until completion of the first year of treatment, together with hormone-therapy in the case of hormone-receptor positive tumors. Chemotherapy schemes with a higher chemotherapy dose density and intensity are not currently recommended because of lack of evidence of benefits when compared with conventional schemes. The group of patients with hormone-dependent cancers and cancers with characteristics of the luminal A molecular subtype (Estrogen and progesterone hormone receptors positive, HER2 negative, and low proliferation index (Ki67)), are potentially candidates for neoadjuvant treatment with hormone therapy alone. It should be bear in mind that this modality demands more time to work (in general two to four months) and hence requires a longer time to achieve a proper response prior to locoregional strategy.

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The possibilities of response with tamoxifen have been described mainly in the group of patients older than 65 years, ranging from 33% to 68%. The possibilities of response increase with the use of aromatase inhibitors, mainly with letrozole or exemestane.

LOCOREGIONAL TREATMENT FOLLOWING NEOADJUVANT TREATMENT

In patients considered unresectable from the onset who had completed neoadjuvant chemotherapy, the general recommendation is the use of radiotherapy as the sole modality for local control. In those patients assigned to surgery after initial chemotherapy, local control can be obtained but do not fare better in terms of overall survival when compared with radiotherapy; however, the association of both local treatments provides the best results with regards to local control. Even though the use of neoadjuvant chemotherapy offers possibilities of clinical response in most patients with disappearance of palpable disease in some cases, it succeeds in eradicating the disease completely in a lower percentage according to the pathological studies of surgical specimens. The following points must be considered for decision-making with regards to locoregional management of the disease:

1) Pretreatment clinical assessment including physical examination, mammography, mammary ultrasound and nuclear magnetic resonance (NMR). 2) In patients with node-negative axilla prior to treatment, the study of sentinel nodes may be used to assess their pathologic status and define the behavior with nodes at the time of deciding on surgery, radiotherapy or both. If the nodes are positive, axillary node removal should be considered. 3) The decision for conservative surgery will depend strictly on the surgeon’s skill to remove the tumor with negative margins. Patients having multicentric disease from onset or diffuse microcalcifications are excluded from this possibility.

For patients treated with mastectomy, the use of radiation therapy to the thoracic wall and node areas will depend on the pathological status of the axilla after surgery. Radiotherapy should be given to Stage III pre-adjuvant therapy patients if there were residual positive nodes, or if the sentinel node before neoadjuvant therapy was positive. Response assessment following neoadjuvant treatment is important as correlation with pathologic evaluation shows the limitations of imaging with a false positives and false negatives ranging from 20-65% before treatment and 10-57% after treatment. Nevertheless, NMR with contrast is at present the best method to evaluate response to treatment. According to the evidence from the studies of National Surgical Adjuvant Breast and Bowel Cancer Project NSABP B-18 and B-27 and other studies in the United States, node complete response is observed in 20% and 40% of the patients receiving neoadjuvant chemotherapy. If this response occurs only in the sentinel node, then the false negative rate would be significantly high. This concept has not been demonstrated in the studies published until now: a meta-analysis has reported a sentinel lymph node identification rate of 90% and a percentage of false-negative of 12% (16). Complimentary Contributor Copy 224 Patricia Murina, Soledad del Castillo, Andrés del Castillo et al.

CONSERVATIVE SURGERY AFTER ADJUVANT THERAPY

A major benefit of adjuvant chemotherapy in selected patients with large primary tumors at diagnosis is that they may be treated with conservative surgery after response to pre-operative treatment has been obtained. The response may become clinically evident as a concentric reduction of the tumor, which makes removal more feasible. The likelihood of local recurrence in the pre-operative group compared with the post-operative group was 7% vs 7.6% (not statistically significant) according to the NSABP B-18 experience (16). However, when comparing patients initially eligible for mastectomy who underwent conservative surgery to patients initially deemed eligible for conservative surgery, the risk of recurrence was 15.7% vs 9.9% (p < 0.04). The benefit of surgery remains even in the patients who have a complete clinical and imaging response following pre-operative treatment. Conservative surgery must be selected after a thorough interdisciplinary and multidisciplinary review. It is advisable to use clips to mark the location and extension of the primary tumor prior to neoadjuvant treatment for the surgeon to identify the area to be removed. Patients in whom free margins can be assured must be a priority for conservative surgery followed by radiotherapy (16). Women who have undergone conservative surgery after primary chemotherapy clearly benefit from radiotherapy to the breast volume. Regional irradiation gave benefits in local control and survival. Postmastectomy radiotherapy in the context of neoadjuvant therapy is important since, in general, the patients included in neoadjuvant treatment have large tumor volumes, and even when reduction of the tumor size in at least 80%, recurrence risk is high. A retrospective study conducted at the MD Anderson Hospital in Houston, Texas, demonstrated that the likelihood of local recurrence after neoadjuvant therapy and mastectomy was higher compared with that of patients who underwent mastectomy at the onset, taking into account the anatomic extension of the post-neoadjuvant disease (17). Additional retrospective evidence reports that the extension of the disease before neoadjuvant therapy as well as after is of value for predicting risk of locoregional recurrence of the disease. In initial Stage III patients, the risk of locoregional recurrence was 20% despite an excellent response after neoadjuvant therapy (tumor < 5 cm or 0 involved nodes). The benefit of post-mastectomy irradiation is recommended for stage II patients with negative axillary nodes once adjuvant treatment is completed. This recommendation is supported by randomized prospective studies designed to respond to this question, and until this occurs, the patients should be acquainted with the limitations of the benefit of postmastectomy irradiation in this group. The efficacy of radiotherapy to eradicate microscopic disease from the regional lymph nodes is widely accepted. Even though there is enough evidence regarding the effect of irradiation to all the regional nodes on local control and survival (18,19), at present the trend is to differentiate risk groups taking into account prognostic factors for metastasis: tumor characteristics, number of nodes involved, immunohistochemistry, molecular biology and age. It is suggested that radiotherapy should start approximately between 4 and 6 weeks after surgery. Standard dose schemes of 50 to 50.4 Gy in fractions of 1.8 to 2 Gy have been widely replaced lately by a hypofractionation regimen of 40-42.5 Gy given in 15-17 fractions. (20- 22). Breast conserving- surgery must be followed by a boost of 10-18 Gy to the tumor bed.

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As the EORTC boost trial showed, there was a significant reduction of local failure risk in those patients who received a boost (23). In a recent meta-analysis including three randomized trials (MA.20, EORTC 22922-10925 and the French trial) addressing the value of radiotherapy to the regional lymph nodes, node irradiation was associated with significantly increased disease-free survival (HR = 0.85) and overall survival (HR = 0.83) (24). Locally advanced breast cancer patients who cannot become suitable for surgery with systemic therapy are generally treated with definitive radiotherapy. Irradiation with external beam radiotherapy is associated with a loco-regional failure rate (LRF) of approximately 30%; however, lower LRF rates of 10% to 20% can be achieved using high dose rate brachytherapy with interstitial implantation (20 to 30 Gy) as a boost after external radiotherapy (25).

IRRADIATION TO LYMPH NODE AREAS

Axilla

Tumor size, nuclear grade and tumor site in the breast are prognostic factors for metastasis in the axillary nodes with a variable risk between 5% for T1N1 and 50% for T3 with any nuclear grade (26). Irradiation to the axilla is indicated when the patient has one or more positive nodes and has not undergone node dissection. Irradiation is also given when the sentinel node is positive and the patient refuses to have axillary surgery. At least three randomized trials show that the results yielded by both radiotherapy and dissection are similar. In addition, radiotherapy is also indicated to consolidate the response to neoadjuvant chemotherapy in locally advanced cancer.

Supraclavicular nodes

The probability for these nodes to be invaded increases with the number of metastatic axillary nodes. When more than three positive axillary nodes are observed, the probability of supraclavicular metastasis is more than 15%. Conversely, if only one positive node is found, the probability is lower. It is important to consider this aspect since supraclavicular irradiation must be indicated in case there is a risk of metastasis. Otherwise, it should not be given due to the possible toxicity in the carotid artery and brachial plexus (27, 28).

Internal mammary chain

When the primary tumor is smaller than 2 cm and localized in the outer quadrants, the probability for the internal mammary nodes to be invaded is less than 3%. On the contrary, when the tumor is larger than 2 cm and localized in the internal quadrants, the probability of metastasis is as high as 65%. The internal mammary nodes constitute the initial step of metastasis of medially located tumors. Some studies have shown that patients with a tumor

Complimentary Contributor Copy 226 Patricia Murina, Soledad del Castillo, Andrés del Castillo et al. localized in the inner quadrants without treatment of the internal mammary chain had worse survival when compared to women with tumors in the outer quadrants (29-31). Indications for radiotherapy to the internal mammary chain have been discussed for over forty years and there is controversy in the literature regarding its use. At present, an EORTC randomized trial has contributed to solving this dilemma (32, 33). The criterion is to irradiate internal mammary nodes in patients with axillary nodes involved or with high risk factors. The results of works by Overgaard and Ragaz have demonstrated benefits in local control and survival at 20-year follow-up in low- and high-risk patients who received chemotherapy alone (34, 35). The concept of risk factors and probability of node metastasis is similar in patients with mastectomy and conservative treatment.

NEW FRACTIONATION FOR BREAST CANCER RADIOTHERAPY

Hypofractionated whole-breast radiotherapy

For some women, the six or seven weeks of daily radiotherapy is associated with problems caused by travelling to the radiation center, finding accommodation a long distance from their homes or simply a lack of family support. This is the reason why approximately 30% of women do not receive radiotherapy in the USA, Japan and other countries. In order to find a solution to this problem, a wide range of hypofractionated schemes have been delivered and proven safe and effective at short or median follow-up (36).

Radiobiological equivalence

Radiobiological models suggest that a higher daily dose (hypofractionation) delivered over a shorter period (accelerated) might be as effective as 25 fractions of 2 Gy daily for the treatment of breast cancer. It is known that there are differences regarding the mechanism of origin of normal tissue injury, the efficiency and the kinetics of the repair. Several types of cancer and normal tissue show intrinsic differences in sensitivity to changes in individual fraction size in radiation therapy. The implementation of a new radiotherapy schedule would be different not only in daily dose but also in the total treatment time when compared with the standard schedule. This new schedule demands investigation of the biological equivalence based mainly on the knowledge of early and late reaction of the normal tissues and the likelihood of tumor control; hence, the bio-mathematical linear quadratic model is used to compare different fractionations. Sensitivity to fractionation is measured by the relationship between alpha and beta. For instance, the relationship alpha/beta for reversible acute effect on rapidly proliferating normal tissues, such as the skin and the mucosa, is 10 Gy or higher, whereas for irreversible late effect on the nervous or glandular tissue, the relationship is in the range of 2-4 Gy (37-39). For a long time, the alpha/beta relationship of the tumors was thought to be similar to that of the acutely responding normal tissues, about 10 Gy. However, it may have a wide range, between 1.5 and 10 Gy or higher. There is evidence that the alpha/beta value for breast adenocarcinoma may be much lower than once considered before and close to the value

Complimentary Contributor Copy Management of locally advanced breast cancer 227 estimated for late responding normal tissues. START A and B trials have offered a reliable estimation of alpha/beta values of approximately 3 Gy for mammary gland tissue and 4 Gy for breast adenocarcinoma (20-22). If the hypothesis that sensitivity of breast adenocarcinoma fractionation is similar to that of normal tissues is accepted, the use of few large fractions could maintain the therapeutic effect without significantly increasing the toxicity. Between 1993 and 1996, Whelan conducted a multicenter randomized trial on 1234 patients (612 in the control group and 622 in the hypofractionated group). His findings were published with a median twelve-year follow-up. All the patients had undergone tumorectomy with free margins and negative axillary dissection. The 50 Gy standard scheme to breast volume in 25 fractions over thirty- five days (intermediate holidays are included in the total length of treatment) was compared with a hypofractionated accelerated scheme of 42.5 Gy in 16 fractions, 2.65 Gy daily, over a period of twenty-two days. The local recurrence rate at ten years was almost identical: 6.7% for 50 Gy and 6.2% for 42.5 Gy (22). Cosmetic results classified as fair and bad at 10 years of follow-up were similar in both groups: 28.7% for 50Gy and 30.2 for 42.5 Gy (38). Two other large trials conducted in England: UK Standardization of Breast Radiotherapy START A with 2236 patients and START B with 2215 patients showed results similar to those in Whelan’s study (20-22).

Radiotherapy toxicity

Cardiac death has always been the most worrying long-term toxic effect of radiotherapy. The EBCTCG (Early Breast Cancer Trialists’ Collaborative Group) meta-analysis published in 2000 reported a high cardiovascular mortality rate associated with postmastectomy radiotherapy. The authors suggested that routine use of new techniques would prevent cardiac death as observed in new studies (40). A long-term analysis of 300,000 patients with early breast cancer included in the USA cancer registry (SEER) assessed heart-related mortality and homolateral lung cancer secondary to radiotherapy. Results obtained from three periods were compared: between 1973 and 1982, 1983 and 1992, and 1993 and 2001. A progressive decrease of mortality due to heart toxicity and homolateral lung cancer was observed in the last period as compared with the other two. Cardiac death decreased at fifteen years and was directly associated with the use of three-dimensional technology (41). It is also important to prevent or minimize the probability of brachial plexopathy and carotid artery injury in patients receiving supraclavicular irradiation. These complications seldom occur if the radiation dose is equal to or lower than 50Gy. Moderate or severe arm edema caused by both complete axillary dissection and radiotherapy adversely affects women’s quality of life. If both treatments are combined, the rate can reach up to 35%. Two treatments to the axilla are not usually necessary; therefore, if full dissection has been performed, there is no need for axillary radiotherapy, unless capsule rupture or fat invasion into the pathological sample are detected. According to the time of occurrence, complications are divided into early and late. During radiotherapy treatment, a mild erythema is frequently observed with breast irradiation, whereas it may be moderate or severe in case of internal mammary chain irradiation with electrons. These effects are generally temporary, but in some patients mild or moderate edema of the breast and areola, localized hyperpigmentation of the Complimentary Contributor Copy 228 Patricia Murina, Soledad del Castillo, Andrés del Castillo et al. skin and tenderness to palpation may persist for several months or even one year. However, the occurrence of these effects is low, as reported in a publication by Kirova et al. In this study, the cumulative incidence of radiation-induced sarcoma in 16,000 irradiated patients was 0.07% at five years, 0.27% at 10 years and 0.48% at 15 years (42). Follow-up after radiotherapy and the review of randomized trials with long-term follow- up confirm that regular physical examination and yearly mammography are effective enough to detect recurrences. It would be convenient to combine ultrasound with mammography. Other tests to detect metastasis should not be used routinely but adapted to each patient according to risk factors or symptoms. During follow-up, the presence of local recurrence, contralateral cancer, metastasis, toxicity or secondary cancer induced by oncological treatments must be investigated. In line with the multidisciplinary management criterion, it is convenient for the radiation oncologists to assess the patient once a year. The follow-up interval and extension during the patient’s life are debatable issues. It should be taken into account that relapses, second cancers, cardiac toxicities, lung toxicities and others, may appear ten or fifteen years after the completion of therapy (43).

RECONSTRUCTIVE SURGERY

The possibility of reconstructive surgery (following mastectomy and as part of conservative surgery if resection of a large amount of tissue is needed) improves patient quality of life. There is no evidence that performing conservative surgery may alter the efficacy of treatments, local control or survival. However, treatments such as radiotherapy and chemotherapy may affect the possibilities of a satisfactory reconstruction. By contrast, post-reconstruction radiotherapy may increase the risks of periprosthesis fibrosis and encapsulation of the prosthesis. Autologous tissue reconstruction tolerates radiotherapy better. The placement of an immediate prosthesis may affect the irradiation technique. For these reasons, some centers propose immediate reconstruction using expanders that allow for residual volume setting and better adaptation to the technical needs of irradiation.

INFLAMMATORY BREAST CANCER

Inflammatory breast cancer is a rare disease (1.5% to 4%). However, it shows ominous prognostic characteristics if treated with surgery as the sole modality. It is considered the most aggressive type of breast cancer and perhaps, because of its biological features, may be thought to be a different disease altogether. The mean survival is 19 months, and only 6% of the patients remain alive at 5 years of follow-up. According to publications by various authors, the results yielded by surgical management of inflammatory breast cancer have been discouraging, which led to its consideration as a contraindication for surgery. Radiotherapy delivered in appropriate doses and techniques allows improvement of local control by replacing surgery as the initial therapeutic weapon and leaving it for a chance of rescue later. The introduction of chemotherapy as part of a Complimentary Contributor Copy Management of locally advanced breast cancer 229 therapeutic strategy to eradicate loco-regional disease after loco-regional treatment yielded better results (adjuvant criterion) that decreased the chances of local and systemic recurrence, thus increasing overall survival (44). The results were more encouraging when chemotherapy began to be used as neoadjuvant modality followed by appropriate treatment.

REFERENCES

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[18] Ragaz J, Jackson SM, Le N, Plenderleith IH, Spinelli JJ, Basco VE, et al. Adjuvant radiotherapy and chemotherapy in node-positive premenopausal women with breast cancer. N Engl J Med 1997;337(14):956-62. [19] Overgaard M, Hansen PS, Overgaard J, Rose C, Andersson M, Bach F, et al. Postoperative radiotherapy in high-risk premenopausal women with breast cancer who receive adjuvant chemotherapy. N Engl J Med 1997;337(14):949-55. [20] START Trialists’ Group, Bentzen SM, Agrawal RK, Aird EG, Barrett JM, Barrett-Lee PJ, et al. The UK Standardisation of Breast Radiotherapy (START) Trial A of radiotherapy hypofractionation for treatment of early breast cancer: A randomised trial. Lancet Oncol 2008;9(4):331-41. [21] START Trialists’ Group, Bentzen SM, Agrawal RK, Aird EG, Barrertt JM, Barrett-Lee PJ, et al. The UK Standardisation of Breast Radiotherapy (START) Trial B of radiotherapy hypofractionation for treatment of early breast cancer: A randomised trial. Lancet 2008;371(9618):1098-107. [22] Whelan TJ, Pignol JP, Levine MN, Julian JA, MacKenzie R, Parpia S, et al. Long-term results of hypofractionated radiation therapy for breast cancer. N Engl J Med 2010;362(6):513-20. [23] Bartelink H, Horiot JC, Poortmans P, Struikmans H, Van den Bogaert W, Barillot I, et al. Recurrence rates after treatment of breast cancer with standard radiotherapy with or without additional radiation. N Engl J Med 2001;345(19):1378-87. [24] Budach, W, Kammers K, Boelke E, Matuschek C. Adjuvant radiotherapy of regional lymph nodes in breast cancer a meta-analysis of randomized trials. Radiat Oncol 2013;8:267. [25] Calitchi E, Kirova YM, Otmezguine Y, Feuilhade F, Piedbois Y, Le Bourgeois JP. Long-term results of neoadjuvant radiation therapy for breast cancer. Int J Cancer 2001;96(4):253-9. [26] Poortmans P. Evidence based radiation oncology: breast cancer. Radiother Oncol 2007;84(1):84-101. [27] Du X, Freeman JL, Nattibger AB, Goodwin JS. Survival of women after breast conserving surgery for early stage breast cancer. Breast Cancer Res Treat 2002;72(1):23-31. [28] Strom EA, Woodward WA, Katz A, Buchholz TA, Perkins GH, Jhingran A, et al. Clinical investigation: regional nodal failure patterns in breast cancer patients treated with mastectomy without radiotherapy. Int J Radiat Oncol Biol Phys 2005;63(5):1508-13. [29] Farrus B, Vidal-Sicart S, Velasco M, Zanon G, Fernandez PL, Munoz M, et al. Incidence of internal mammary node metastases after a sentinel lymph node technique in breast cancer and its implication in the radiotherapy plan. Int J Radiat Oncol Biol Phys 2004;60(3):715-21. [30] Stemmer SM, Rizel S, Hardan I, Adamo A, Neumann A, Goffman J, et al. The role of irradiation of the internal mammary lymph nodes in high-risk stage II to IIIA breast cancer patients after high-dose chemotherapy: a prospective sequential nonrandomized study. J Clin Oncol 2003;21(14):2713-8. [31] Lohrisch C, Jackson J, Jones A, Mates D, Olivotto IA. Relationship between tumor location and relapse in 6,781 women with early invasive breast cancer. J Clin Oncol 2000;18(15):2828-35. [32] Freedman GM, Fowble BL, Nicolau N, Sigurdson ER, Torosian MH, Boraas MC, et al. Should internal mammary lymph nodes in breast cancer be a target for the radiation oncologist? Int J Radiat Oncol Biol Phys 2000;46(6):805-14. [33] Romestaing P, Ecochard R, Hennequin C, Bosset JF, Maingon P. The role of internal mammary chain irradiation on survival after mastectomy for breast cancer. Results of a phase III SFRO trial. Radiother Oncol 2000;56:306. [34] Poortmans P. A bright future for radiotherapy in breast cancer. Radiother Oncol 2007;82(3):243-6. [35] Ragaz J, Olivotto IA, Spinelli JJ, Phillips N, Jackson SM, Wilson KS, et al. locoregional radiation therapy in patients with high-risk breast cancer receiving adjuvant chemotherapy: 20-year results of the British Columbia randomized trial. J Natl Cancer Inst 2005,97(2):116-26. [36] Bartelink H, Horiot JC, Poortmans PM, Struikmans H, Van den Bogaert W, Fourquet A, et al. Impact of a higher radiation dose on local control and survival in breast-conserving therapy of early breast cancer: 10-year results of the randomized boost versus no boost EORTC 22881-10882 trial. J Clin Oncol 2007;25(22):3259-65. [37] Halperin EC, Wazer DE, Perez A, Brady LW. Principles and practice of radiation oncology. Sixth Edition. Philadelphia:Wolters Kluwer-Lippincott Williams & Wilkins, 2013. [38] Sarin R. Evidence-based clinicoradiobiological model for fractionation. Lancet Oncol 2006;7(6):445- 7. Complimentary Contributor Copy Management of locally advanced breast cancer 231

[39] Whelan TJ, Pignol JP, Levine MN, Julian JA, MacKenzie R, Parpia S, et al. Long-term results of hypofractionated radiation therapy for breast cancer. N Engl J Med 2010;362(6):513-20. [40] Early Breast Cancer Trialists’ Collaborative Group. Favourable and unfavourable effects on long-term survival of radiotherapy for early breast cancer: an overview of the randomised trials. The Lancet 2000;355(9217):1757-70. [41] Giordano SH, Kuo YF, Freeman JL, Buchholz TA, Hortobagyi GH, Goodwin JS. Risk of cardiac death after adjuvant radiotherapy for breast cancer. J Natl Cancer Inst 2005;97(6): 419-24. [42] Kirova YM, Vilcoq JR, Asselain B, Sastre-Garau X, Fourquet A. Radiation-induced sarcomas after radiotherapy for breast carcinoma: A large-scale single-institution review. Cancer 2005;104(4):856- 63. [43] Kirova YM, De Rycke Y, Gambotti L, Pierga JY, Asselain B, Fourquet A, et al. Second malignancies after breast cancer: the impact of different treatment modalities. Br J Cancer 2008;98(5):870-4. [44] Gonzalez-Angulo A, Hennessy BT, Broglio K, Meric-Bernstam F, Cristofanili M, et al. Trends for inflammatory breast cancer: is survival improving? Oncologist 2007;12(8):904-12.

Chapter 19

MANAGEMENT OF UTERINE CANCER

Neiro Waechter da Motta1,, MD, PhD, Günther Alex Schneider1, MD, Carlos Eugenio Escovar2, MD, Rosilene Jara Reis3, MD, Fiona Lim4, MBBS, Bo Angela Wan5, MD(C) and Maurício F Silva6,7,8, MD, PhD 1Radiation Oncology Department, Hospital Santa Rita, Santa Casa de Misericórdia de Porto Alegre, Universidade Federal de Ciências da Saúde de Porto Alegre, Brazil 2Clinical Oncology Department, Hospital Santa Rita, Santa Casa de Misericórdia de Porto Alegre, Brazil 3Gynecology Department, Hospital Santa Rita, Santa Casa de Misericórdia de Porto Alegre, Universidade Federal de Ciências da Saúde de Porto Alegre, Brazil 4Department of Oncology, Princess Margaret Hospital, Hong Kong, PR China 5Odette Cancer Centre, Sunnybrook Health Sciences Centre, University of Toronto, Toronto, Ontario, Canada 6Radiation Oncology Unit, Santa Maria Federal University, Santa Maria, Brazil 7Radiation Oncology Unit, Hospital de Caridade Astrogildo de Azevedo, Santa Maria, Brazil 8Latin America Cooperative Oncology Group, Porto Alegre, Brazil

ABSTRACT

In developing countries, uterine cancer is the most common gynecological cancer and its incidence has continued to increase over the past decade. Among women, it is the second most prevalent cancer after breast cancer. Surgery, when possible, constitutes the definitive primary treatment. Some patients may benefit from adjuvant treatment with radiotherapy and/or systemic treatment after radical surgery, depending on stage, age, depth of myometrial invasion, lymphovascular space invasion, and tumor grade. For patients with advanced and recurrent inoperable disease, radiation therapy,

 Corresponding Author’s Email: [email protected]. Complimentary Contributor Copy 234 Neiro Waechter da Motta, Günther Alex Schneider, Carlos Eugenio Escovar et al.

chemotherapy, and hormonal therapy are utilized to relieve symptoms such as pain and bleeding. This chapter is a review of management of uterine cancer in Latina America. The prognosis of women who experience disease progression following first-or second- line therapy is poor. Given that currently available treatments are palliative, we encourage the participation in clinical trials.

INTRODUCTION

In 2012, 527,600 women were diagnosed with uterine cancer in the world. The mortality rate was 1.7 to 2.4 per 100,000 women (1). In the developing countries, it is the most common gynecological cancer and its incidence has continued to increase over the past decade. There is an estimate of 757,190 women living in the United States with a previous diagnosis of uterine corpus cancer and an additional of 60,050 new cases diagnosed in 2016. Cancer of the uterine corpus is the second most prevalent cancer among women after breast cancer. The median age at diagnosis is 62 (2). In Brazil, as is in the other developing countries, it is the second most common gynecological neoplasia and the estimation of the Instituto Nacional do Câncer (INCa) is that, in 2018, 6,600 new cases of uterine cancer will be diagnosed, which represent 3.3% of female neoplasia (3). In the uterus, the endometrium is the most frequent site of cancer. The main drive for the development of endometrial carcinoma is the excess of endogenous or exogenous estrogen without proper opposition by progesterone. Known risk factors are obesity, nulliparity and therapeutic use with tamoxifen. Genetic predisposition like Lynch syndrome (also known as HCCNP -hereditary nonpolyposis colorectal cancer) also increases the risk of endometrial cancer significantly. The most common histological type is adenocarcinoma. There are two histological categories that differ in the incidence, responsiveness to estrogens and prognosis (5, 6):

 Type I:endometrioid histology, Grade 1 or 2, which represent 80% of endometrial carcinomas. They have favorable prognosis. Their development was estrogen dependent and often preceded by an intraepithelial neoplasia.  Type II:Represents 10-20% of endometrial carcinomas. They have a different molecular profile that are associated with more virulent disease and diminished survival. This type include grade 3 endometrioid tumors, uterine serous papillary carcinomas (UPSC) and clear cell carcinomas. They are not associated with stimulation by estrogen.

The Cancer Genome Atlas (TCGA) has recently defined four molecular subtypes of endometrial cancer based on somatic mutations, copy number alterations, and microsatellite instability status. In most patients, vaginal bleeding is the most common symptom and is the reason patients are diagnosed early. At the time of diagnosis, 67% patients present with a disease confined to the uterus, 21% with lymph node involvement and only 8% with distant metastases. In literature, the 5 years survival rate is 90% (4).

Complimentary Contributor Copy Management of uterine cancer 235

Surgical staging, according to TNM Classification 2017 (FIGO), includes a total hysterectomy, bilateral salpingo‐oophorectomy, and pelvic and para-aortic lymph node sampling, which can be performed via a laparotomy, laparoscopy, or robotic surgery approach. Surgery, when possible, constitutes the definitive primary treatment for endometrial carcinoma. Some patients may benefit from adjuvant treatment with radiotherapy and/or systemic treatment after radical surgery, depending on stage, age, depth of myometrial invasion, lymphovascular space invasion, and tumor grade. For patients with advanced and recurrent disease which are inoperable, radiation therapy, chemotherapy, and hormonal therapy are utilized to relief symptoms as pain and bleeding.

MANAGEMENT OF UTERINE CANCER

A generally recommended protocol is that the abdomen should be opened with a vertical midline abdominal incision and peritoneal washings taken immediately from the pelvis and abdomen, followed by careful exploration of the intra-abdominal contents. The momentum, liver, peritoneal cul-de-sac, and adnexal surfaces should be examined and palpated for any possible metastases, followed by careful palpation for suspicious or enlarged nodes in the aortic and pelvic areas. The standard surgical procedure should be an extra fascial total hysterectomy with bilateral salpingo-oophorectomy. Adnexal removal is recommended even if the tubes and ovaries appear normal as they may contain synchronous tumors or micrometastases. Vaginal cuff removal is not necessary, nor is there any benefit from excising parametrial tissue in the usual case. When obvious cervical stromal involvement is demonstrated preoperatively, a modified radical hysterectomy has been historically performed. However, there is consensus (ESMO-ESGO-ESTRO) that simple hysterectomy with free margins together with pelvic lymphadenectomy can be enough (9).

Primary treatment and surgical staging

For the staging of operable patients with endometrioid histology clinically confined to the fundal portion of the uterus, the recommended surgical procedure includes: total hysterectomy/bilateral salpingo-oophorectomy with selective surgical staging (10). When indicated, surgical staging is recommended to gather full pathologic and prognostic data for decisions regarding adjuvant treatment in selected patients who do not have medical or technical contraindications to lymph node dissection. During surgery, the intraperitoneal structures should be carefully evaluated, and suspicious areas should be biopsied. Although it does not specifically affect staging, FIGO recommends that peritoneal cytology should be collected, and results should be recorded. Enlarged or suspicious lymph nodes should be excised to confirm or rule out metastatic disease. For patients with incomplete surgical staging and high-risk intrauterine features, imaging is often recommended, especially in patients with higher-grade and more deeply invasive tumors (11, 12). Surgical restaging, including lymph node dissection, can also be

Complimentary Contributor Copy 236 Neiro Waechter da Motta, Günther Alex Schneider, Carlos Eugenio Escovar et al. performed (13). Recommended adjuvant treatment options will be based on the imaging and/or surgical restaging results. Tables 1 and 2 show risk stratifications.

Table 1. Stage I risk stratification

Risk Stage Grade Pathology Low IA I, II Endometrioid Intermediate IA III Endometrioid IB I, II High IB III Endometrioid Any:serous papillary clear cell

Table 2. Sub-classification of intermediate risk

GOG 99 PORTEC 1 Age>=70 Age>=60 Grade II-III Grade II-III LVI+ Deep invasion Deep invasion High intermediate risk High intermediate risk Age 70 plus one factor Two risk factors Age 50 plus 2 factors Any age plus 3 factors

Limited to uterus (endometrioid carcinoma)

Total hysterectomy with bilateral salpingo-oophorectomy and surgical staging is indicated. If patient desires fertility, fertility sparing therapy may be considered. For highly selected patients with stage IA disease, with biopsy-proven grade I endometrioid adenocarcinoma and no metastatic disease who wish to preserve their fertility, continuous progestin-based therapy may be considered (14, 15). Likewise, it may also be selectively used for young patients with endometrial hyperplasia who desire fertility preservation. Patients also need to receive counseling that fertility-sparing therapy is not the standard of care for the treatment of endometrial carcinoma and total hysterectomy and bilateral salpingo-oophorectomy with surgical staging is recommended after childbearing is complete or if progression occurs. Fertility-sparing therapy is not recommended for high-risk patients (e.g., those with high-grade endometrioid adenocarcinomas, uterine serous adenocarcinoma, clear cell adenocarcinoma or carcinosarcoma).

Gross cervical involvement (endometrioid carcinoma)

Total hysterectomy with bilateral salpingo-oophorectomy and surgical staging is indicated followed by the possibility of radiotherapy (11) (see the radiation therapy section for more).

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Extrauterine disease (endometrioid carcinoma)

Total hysterectomy with bilateral salpingo-oophorectomy and surgical staging is indicated. The possibility of debulking and adjuvant treatment must be discussed based on the risk factors (11) (see the radiation therapy section for more).

Uterine serous adenocarcinomas, clear cell adenocarcinomas, and carcinosarcomas

Multimodality therapy is typically recommended for these histologically aggressive tumors. Primary treatment includes total hysterectomy and bilateral salpingo-oophorectomy with surgical staging, peritoneal lavage for cytology, omental and peritoneal biopsies, and consideration of maximal tumor debulking for gross disease (16). Adjuvant therapy is highly individualized (17, 18). For patients with stage IA without myometrial invasion, options include observation, chemotherapy, or tumor-directed radiation therapy (19). For all other patients with more advanced disease, chemotherapy with (or without) tumor-directed radiation therapy is the preferred option (20-23).

Minimally invasive procedures

Recent studies have demonstrated that laparoscopic removal of the uterus and adnexal appears to be safe. Whereas there is no difference in terms of major complications between open abdominal or laparoscopic surgery, the laparoscopic approach is associated with a significantly decreased risk of major surgical adverse event, a shorter hospital stays, less pain, and quicker resumption of daily activities (24, 25). Since the oncological safety of the laparoscopic approach has now been demonstrated in several randomized studies (26, 27), hysterectomy and bilateral salpingo-oophorectomy should be performed with laparoscopy in those patients with no contraindications (e.g., large-volume uterus). This approach can be accompanied by a laparoscopic lymphadenectomy, if surgical staging is to be undertaken (9). Robotic surgery for the surgical management of the morbidly obese patient is an option only in experienced hands. In such cases, the surgical management using robotics has been reported to be safe and have less perioperative complications compared with open surgery (28). Retrospective studies have suggested equivalent oncologic outcomes compared with traditional laparoscopic surgery (29, 30). Although mandated through the staging system, lymphadenectomy of the pelvic and para-aortic areas remains controversial. Selective node sampling is of dubious value as a routine and complete lymphadenectomy should be reserved for cases with high-risk features. Many individuals with endometrial cancer are obese or elderly, with other medical problems, and clinical judgment is required to determine if additional surgery is warranted. Any deeply invasive tumor or radiological suggestion of positive nodes is an indication for retroperitoneal lymph node evaluation, with removal of any enlarged or suspicious nodes. Documentation of positive nodes identifies a high-risk population and helps to tailor adjuvant treatment, since patients with Stage III disease appear to benefit from chemotherapy (31). Possible Indications for aortic node sampling would

Complimentary Contributor Copy 238 Neiro Waechter da Motta, Günther Alex Schneider, Carlos Eugenio Escovar et al. include suspicious aortic or common iliac nodes, grossly positive adnexal grossly positive pelvic nodes, and high-grade tumors showing full thickness myometrial invasion. Patients with clear cell, papillary serous, or carcinosarcoma histologic subtypes are also candidates for aortic node sampling. In summary, robotic surgery has advantages of providing three-dimensional vision, greater mobility of the tweezers and movements, lower learning curve and make minimally invasive complete surgery feasible with lymphadenectomy in very obese patients;with disadvantages of cost in acquiring and maintaining this technology. Therefore, surgery minimally invasive (laparoscopy or robotics) can be considered as a new standard for treatment / staging of the endometrial cancer.

Lymphadenectomy

Since 1988, when FIGO introduced the need for lymphadenectomy for the staging of endometrial cancer, many questions have been raised, mainly regarding the extent of lymphadenectomy, indications, risks, and benefits related to overall survival and recurrence (9). Previously, a full standard lymphadenectomy (ie, dissection and assessment of both pelvic and para aortic nodes) was recommended for all patients; however, a more selective and tailored lymphadenectomy approach is now recommended to avoid systematic overtreatment (32). No randomized trial data support routine full lymphadenectomy (33), although some retrospective studies suggested that it is beneficial (34, 35). Two randomized clinical trials from Europe reported that routine lymph node dissection did not improve the outcome of patients with endometrial cancer, but lymphadenectomy did identify those with nodal disease (36, 37). However, these findings remain a point of contention (10, 38, 39). To avoid over interpretation of these results, it is important to address the limitations of these randomized studies, including selection of patients, extent of lymph node dissection, and standardization of postoperative therapy (40, 41). The other concerns include the lack of central pathology review, subspecialty of surgeons, and adequacy of statistical power. Decisions about whether to perform lymphadenectomy, and if so to what extent (eg, pelvic nodes only, or both pelvic and paraaortic nodes), can be made based on preoperative and intraoperative findings. The following criteria have been suggested as indicative of low risk for nodal metastases:

1) Less than 50% myometrial invasion, 2) Tumor less than 2 cm, 3) Well or moderately differentiated histology (42, 43); however, these may be difficult to accurately determine before final pathology results are available.

Another associated benefit of lymphadenectomy is for diagnosing nodal metastases to help guide the selection of appropriate adjuvant treatment to improve survival or decrease toxicity. However, one of the 2 European randomized trials was not designed to address this question (28). Therefore, there was no standardization of adjuvant treatment after staging surgery with lymphadenectomy. In fact, the use of lymphadenectomy did not translate into an increased use of adjuvant therapy. This may have contributed to the lack of difference in Complimentary Contributor Copy Management of uterine cancer 239 recurrence and survival between the two groups. Studies show that in 15% to 20% of cases, the preoperative grade (as assessed by endometrial biopsy or curettage) is upgraded on final fixed pathologic evaluation of the hysterectomy specimen (44). As the grade of the tumor increases, the accuracy of intraoperative evaluation of myometrial invasion decreases (i.e., assessment based on gross examination of fresh tissue). The question of whether to add para-aortic lymphadenectomy to pelvic node dissection has been debated. Prior studies have shown conflicting information regarding the risk of paraaortic nodal metastases in patients without disease in the pelvic nodes (42, 45-47). A high rate of lymphatic metastasis was seen above the inferior mesenteric artery, suggesting a need for systematic pelvic and paraaortic lymphadenectomy. Hence, periaortic lymphadenectomy up to the renal vessels may be considered for selected high-risk situations, including patients with pelvic lymphadenectomy or high-risk histologic features. Selected patients with apparent uterine confined endometrial carcinoma may be candidates for sentinel node mapping, which assesses the pelvic nodes and is a less morbid procedure than standard lymphadenectomy. In summary, lymph node dissection identifies patients requiring adjuvant treatment with radiation therapy and/or chemotherapy (48). A subset of patients may not benefit from lymphadenectomy; however, these patients are difficult to identify preoperatively because of the uncontrollable variables of change in grade and depth of invasion on final pathology. At this point, the literature recommends that lymphadenectomy be performed for selected patients with endometrial cancer, with para aortic lymphadenectomy performed as indicated for high-risk patients while pending further trials to define the clinical benefit of lymphadenectomy (49). Lymphadenectomy is contraindicated for patients with uterine sarcoma. Sentinel node mapping may be considered for selected patients with apparent uterine-confined endometrial disease.

Radiation therapy Radiation therapy is often used as an adjuvant treatment after surgery, or as definitive treatment for patients who are medically inoperable or in recurrences.

Stage I Treatment options for patients after surgery follow the pathological findings and risk stratification include observation, vaginal brachytherapy or pelvic radiation therapy. For patients classified as Low Risk and Low Intermediate Risk, surveillance without adjuvant radiation therapy is a reasonable option (50). For patients classified as high intermediate risk, vaginal brachytherapy is as effective as pelvic radiation therapy at preventing vaginal recurrences and is preferred. RT can reduce the risk of a local recurrence, although it does not appear to improve OS. (51, 52, 55, 57, 64-71). Patients classified as High Risk may benefit from pelvic radiation to prevent pelvic recurrences. Pelvic RT is the preferred adjuvant treatment option over chemoradiation as supported by preliminary results from the PORTEC-3 trial, which demonstrated similar outcomes but fewer toxicities with pelvic RT (51, 53, 54, 59, 77).

Stage II After surgery, patients with pathologic finding of cervical stroma invasion may benefit from pelvic radiation to prevent pelvic recurrences (56). Patients with bulky cervical extension can

Complimentary Contributor Copy 240 Neiro Waechter da Motta, Günther Alex Schneider, Carlos Eugenio Escovar et al. be treated with preoperative pelvic radiation therapy with or without brachytherapy followed by surgery, if possible.

Stage III and respectable Stage IV IIIA: Adjuvant chemotherapy followed by pelvic radiation therapy is the preferred treatment for most stage III endometrial cancer patients and the additional use of radiation therapy should be based on risk factors (57, 58, 60-67). IIIB: Treatment of patients should be individualized with respect to sites and volume of disease. Patients with vaginal extension can be treated with radical surgery followed by pelvic radiation therapy and vaginal brachytherapy. Patients with extensive parametrial extension may be better treated with primary radiation therapy. IIIC:

 IIIC 1: Patients with positive pelvic nodes should receive complete debulking followed by pelvic radiation therapy.  IIIC 2: Patients with positive paraaortic nodes should receive complete debulking followed by pelvic and paraaortic radiation therapy. The benefit of adjuvant chemotherapy for women with stage III endometrial cancer is supported by a 2013 meta-analysis that included the data from two randomized trials comparing adjuvant chemotherapy with adjuvant RT (78). For women with stage III or respectable stage IV endometrial cancer, we recommend adjuvant chemotherapy. Chemoradiation has been shown to decrease the frequency of local recurrences relative to chemotherapy alone (but not recurrence-free survival), and we offer it to those at high risk of local relapse.

Radiation therapy for the inoperable patient

Patients that are not candidates for hysterectomy because of the high surgical risk (more than 10% to 15%) are usually treated with pelvic radiation therapy (71) or brachytherapy (80-82). Low grade tumors are commonly treated with brachytherapy since the risk of myometrial invasion and lymph node metastasis are low. For patients with grade III and stage II tumors, combined treatment with pelvic radiation therapy and brachytherapy is recommended (81). The use of high dose rate brachytherapy is an attractive option, since it reduces the risk of thromboembolic events (83-85).

Treatment of the recurrent disease

Patients with central or vaginal relapses without previous irradiation are treated with radiation therapy, commonly a combination of pelvic radiation followed by vaginal cuff brachytherapy (86).

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Radiation therapy techniques

 Pelvic Radiation Therapy: Patients are commonly treated in supine position using four-field box technique and the prescribed dose is 5040 cGy in 28 fractions. The dose can be reduced to 4500 cGy in 25 fractions if vaginal brachytherapy will be employed. Postoperative intensity-modulated RT (IMRT) is emerging for most patients with endometrial cancer who need pelvic RT to limit the dose in the small intestines.  Extended field radiation therapy: Used for positive paraaortic nodes, patients are commonly treated in supine position using AP/PA field technique from the top of L1 to the bottom of L5 and the prescribed dose is 4500 cGy in 25 fractions.

Brachytherapy

This treatment modality can deliver the highest radiation dose to the vaginal mucosa while limiting the dose to the surrounding normal structures such as the bladder, rectum, and small intestines. HDR brachytherapy using 192-Iradium sources is the preferred method of delivering vaginal RT. The type of applicator used is generally a vaginal cylinder. We commonly proceed with four insertions and the dose varies with the need of combine with pelvic radiation therapy and the surgical margin status.

 If brachytherapy is to be used as the sole treatment after surgery, we usually proceed with four vaginal insertions of 8.8Gy prescribed at the cylinder surface.  If brachytherapy is to be used after surgery and pelvic radiation therapy in a patient with negative surgical margins, we usually procced with four vaginal insertions of 6 Gy prescribed at the surface of the cylinder.  If brachytherapy is to be used after surgery and pelvic radiation therapy in a patient with positive surgical margins, we usually procced with four vaginal insertions of 5.5 Gy prescribed at 0.5cm of the cylinder surface.

In the inoperable patient, we usually procced with pelvic radiation therapy 4500 cGy in 25 fractions followed by four insertions of brachytherapy using an intrauterine device and two vaginal composters. The dose is 7 Gy prescribed at point A, as usual. CT or MRI can be used to optimize disease coverage.

Chemotherapy Chemotherapy starts its role in Stage III Endometrial Cancer. We believe that this group of patients, stages III and IV, are the patients that benefit the most from chemotherapy.

 Stage III:The benefit of adjuvant chemotherapy for women with stage III endometrial cancer is supported by a 2013 meta-analysis (updated in May 2014) that included the data from two randomized trials comparing adjuvant chemotherapy with adjuvant RT (89, 90). Further support for the incorporation of chemotherapy in the adjuvant management of these patients comes from preliminary data from PORTEC- Complimentary Contributor Copy 242 Neiro Waechter da Motta, Günther Alex Schneider, Carlos Eugenio Escovar et al.

3 (87, 88). In this trial, the subgroup of patients who had stage III disease experienced an improvement in five-year FFS with chemoradiation (69 versus 58 percent; HR 0.66, 95% CI 0.45-0.97) versus radiation alone.  Stage IV disease: Women with disease limited to the pelvis or abdominal carcinomatosis may be candidates for surgical cytoreduction and adjuvant chemotherapy (92, 93). However, upfront surgery may be challenging, and chemotherapy may instead be appropriate. For most women with high-risk endometrial cancer receiving chemotherapy, we suggest carboplatin and paclitaxel. This is based on the results of Gynecologic Oncology Group (GOG) 209, which were presented at the 2012 Society of Gynecologic Oncology Annual Meeting (93).

Treatment of recurrent or metastatic endometrial cancer Most patients with a diagnosis of recurrent or metastatic disease have poor prognosis, regardless of treatment. For women with metastatic endometrial cancer, surgical cytoreduction is a reasonable treatment option, particularly if they are newly diagnosed and a complete resection appears feasible. For women who undergo surgical cytoreduction of metastatic disease, we administer chemotherapy in the postoperative (or “adjuvant”) setting. The administration of postoperative chemotherapy in this setting is extrapolated from the benefits of treatment for women with newly diagnosed, high-risk endometrial cancer. Based on the results of the Gynecologic Oncology Group 209 (GOG 209) trial, our preferred regimen is six cycles of carboplatin and paclitaxel. Patients who are not surgical candidates should be offered medical therapy. Patients with metastatic disease who are not surgical candidates have a poor prognosis; in the Surveillance, Epidemiology and End Results database, the reported five-year relative survival for women presenting with distant disease (which encompasses stage IVB disease) is less than 20 percent (94). Therefore, the intent of treatment is generally palliative rather than curative. For women who develop metastatic endometrial cancer we typically administer a platinum-based combination regimen, provided patients are candidates for a combination regimen and understand the risks associated with treatment. The most commonly used regimen to treat metastatic endometrial cancer are carboplatin plus paclitaxel (95, 96). The benefit of multi-agent chemotherapy for advanced, recurrent, or metastatic endometrial cancer was shown in a 2012 meta-analysis of trials that compared administration of multi-agent combinations (“more intensive” regimens) with less intensive combinations (eg, three versus two-agent combinations, or two agents versus one agent) (97). Because of the toxicity associated with cisplatin-based combinations, carboplatin and paclitaxel is the preferred regimen for the first-line treatment of chemotherapy-naive recurrent metastatic endometrial cancer. The data to support carboplatin plus paclitaxel come from GOG 209 (95). Endocrine therapy can be used as initial treatment for patients in whom secondary cytoreduction or cytotoxic chemotherapy is not planned. It may also be an appropriate second-line option for certain patients. Response to endocrine therapy is expected to be more favorable in patients with any of the following characteristics:

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 Grade 1 or 2 endometrioid endometrial cancer.  Positive expression of estrogen (ER) and progesterone (PR) receptors. Several studies suggest that hormone receptor positive cancers are more likely to respond to endocrine treatment, though the data are not consistent (99-101).  Symptomatic or minimally symptomatic disease.

Endocrine therapy is well tolerated and lacks the usual toxicities associated with cytotoxic chemotherapy. Approximately 15 to 30 percent of women respond to endocrine therapy, with responses most frequent in low-grade tumors (99). While most remissions are partial and relatively brief, some patients may remain progression-free for extended periods of time (>2 years) (103).

 Progesterone: was first shown to be an effective anticancer agent for women with advanced disease in 1951 and contemporary trials report an overall response rate (ORR) between 15 and 20 percent (110). There is no evidence of a dose-response relationship with progestins. This was shown in a 2010 meta-analysis where medroxyprogesterone acetate at 1000 mg/day was associated with a higher risk of disease progression [hazard ratio (HR) 1.35, 95% confidence interval (CI) 1.07-1.71] and death (HR 1.31, 95% CI 1.04-1.66) compared with a lower dose (200 mg/day).  Tamoxifen: is the only selective estrogen receptor modulator that has demonstrated activity in this population. When used for women with hormone receptor positive tumors, response rates ranging from 10 to 46 percent have been reported (112-114).  Other commonly used agents administered to women with recurrent endometrial cancer include:  Paclitaxel (175 mg/m2 every three weeks): is an option in the second-line setting, particularly in patients who were not previously treated with this agent in the first- line setting. In one study, paclitaxel resulted in a 25 percent ORR among 48 paclitaxel-naive patients (120). However, weekly administration (80 mg/m2) is also a reasonable option, particularly in patients who were previously treated with paclitaxel. This is based on data showing activity with weekly treatment in women with platinum and paclitaxel-resistant ovarian cancer (121).  Ifosfamide (1.2 g/m2/day for five days, repeated every four weeks): resulted in an ORR of 15 percent in a study involving 52 women (122). Serious (grade 3/4) toxicity was limited to neutropenia in 53 percent and neuropathy in 11 percent.  Docetaxel (36 mg/m2 IV on days 1, 8, and 15 every 28 days): resulted in an ORR of 7.7 percent in a phase II GOG study involving 27 women (the majority of whom previously received paclitaxel) (123). The most frequently reported adverse events were leucopenia, neutropenia, gastrointestinal, constitutional, and peripheral neuropathy. Given the low response rate, the study was terminated early.  Topotecan:a prospective, phase II clinical trial of topotecan was suspended because of unexpected toxicities (ie, sepsis and bleeding), but was reopened using lower doses of 1.0 mg/m2 or 0.8 mg/m2 day one to five for patients with prior radiation therapy. The ORR among 44 patients was 20 percent (124). The median OS was 6.5 months. The major toxicities were hematologic and gastrointestinal.

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 Oral Etoposide (50 mg daily on days 1 through 21 on a 28-day schedule): was evaluated in a GOG trial that included 44 women (125). The ORR was 14 percent (including one complete remission). Toxicity included neutropenia, anemia, and nausea.  Pegylated liposomal doxorubicin: has limited activity in this setting, but is a well- tolerated agent in this population. In one study involving 46 patients treated at a dose of 50 mg/m2 on a four-week schedule, the ORR was 9.5 percent (126). However, it was generally well tolerated with limited myelotoxicity. The only grade 4 toxicities reported were esophagitis, hematuria, and vomiting which occurred in one patient each. For women with recurrent endometrial cancer, a dose of 40 mg/m2 is generally administered to reduce the treatment-related toxicities, particularly in those patients previously treated with a platinum agent.

CONCLUSION

The prognosis of women who experience disease progression following first-or second-line therapy is poor. These patients should be referred for palliative care, regardless of whether they desire further treatment. However, for women who maintain a good performance status, further treatment is reasonable. Yet, given that currently available treatments are palliative, we encourage the participation in clinical trials.

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Chapter 20

MANAGEMENT OF CERVICAL CANCER

Dolores de la Mata Moya1,, MD, PhD, Luisa María Catalina Tenorio Téllez1, MD, Fiona Lim2, MBBS, Bo Angela Wan3, MD(C) and Mauricio F Silva4,5,6, MD, PhD 1Department of Radiotherapy, American British Cowdray Medical Center, Mexico City, Mexico 2Department of Oncology, Princess Margaret Hospital, Hong Kong, PR China 3Odette Cancer Centre, Sunnybrook Health Sciences Centre, Toronto, Ontario, Canada 4Radiation Oncology Unit, Santa Maria Federal University, Santa Maria, Brazil 5Radiation Oncology Unit, Hospital de Caridade Astrogildo de Azevedo, Santa Maria, Brazil 6Latin America Cooperative Oncology Group, Porto Alegre, Brazil

ABSTRACT

This chapter is an overview of cervical cancer in Latin-American, where it is still the second most common cause of cancer death in women. New screening strategies and the human papilloma virus (HPV) vaccine campaign are the keys to detect cervical cancer in early stage. Also, MRI helps to improve staging in this disease and PET/CT is very useful as non-invasive tool in para-aortic node detection. In early stage disease, surgery is the most important treatment and fertility preservation techniques are considered whenever it is possible. Locally advanced cervical cancer is curable with multidisciplinary treatment with chemo-radiation followed by brachytherapy and new radiation technologies with 3D-HDR-brachytherpy decrease acute and chronic toxicity rates. In the metastatic setting chemotherapy is the recommended treatment but new targeted and immunotherapy drugs play a role in increasing time to progression. In the next decades an improvement in early detection and HPV vaccination should change the incidence of cervical cancer, leading to increasing rates of early stage and decreasing rates of cervical cancer deaths.

 Corresponding Author’s Email: [email protected]. Complimentary Contributor Copy 252 Dolores de la Mata Moya, Luisa María Catalina Tenorio Téllez, Fiona Lim et al.

INTRODUCTION

Cervical cancer (CC) is the second most common cause of female cancer deaths worldwide. In developed countries the incidence and deaths have decreased in the last decades, mainly related to implementation of screening and prevention programs, and advancement in science and technology applied to treatment. Unfortunately, these strategies have not arrived to developing countries and so they remain a public problem. In the last decade many developments on etiology and biology of CC has been made. Epidemiology has shown a relationship between CC and a sexually transmitted disease. Human papilloma virus (HP) is one of the most important etiology, and PVH-DNA is presented in CC. Early stage CC has higher rates of survival and similar rates of control with radical surgery or radical radiotherapy. Chemoradiotherapy followed by brachytherapy is the standard treatment option in locally advanced CC. Five years control rate in stage II are 65% and 35% in stage III.

EPIDEMIOLOGY

The CC is fourth cause of general mortality worldwide and the second cause of mortality in women 15 to 44 years old with over 528,000 new cases per year and 266,000 deaths in 2012. With almost 740 daily deaths, it is the second most common cause of female cancer deaths. And 88% new cases are diagnosticated in low-middle income countries, where mortality is 18 times higher (1, 2). In Latin-American, CC is second cause of cancer mortality in women, with annual rate of 21.2 in 100,000 women (74,488 cases in 2015) and approximately 8.7 deaths in 100,000 women (31,303 deaths in 2015). There is estimated to be an increase of around 45% mortality CC by 2030 in this region (3). Some factors related to this higher rate are a high prevalence HPV infection in this region, high cost of the HPV vaccine program in girls 9-11 years old, and difficulty due to cultural factors to screening programs and mistakes in operation of a screening program. Moreover, effective tertiary prevention is difficult due to resources and infrastructure (4).

ETIOLOGY

In the beginning of the 80s, several types of human papilloma virus (HPV) were associated with CC. Almost all CC has been related to persistent HPV infections. Currently there is at least 200 subtypes of HPV. The International Agency for Research on Cancer (IARC) described 12 types of carcinogenic HPV: HPV-16, -18, -31, -35, -39, -45, -51, -52, -56, -58, and -59. HPV-16 is the most oncogenic and associated with 50% of CC. HPV-18 is observed in 10% and it is associated with adenocarcinoma. The HPV-31, -33 and -45 are associated with 5% of CC. The HPV-18 and -45 are observed frequently in young patients with CC. In the early 80’s, different HPV varieties were identified as cervical cancer promotors. The HPV infection cause cancer through different mechanisms involving E6 and E7 Complimentary Contributor Copy Management of cervical cancer 253 oncogenes and p53 and pRb proteins. E6 and E7 protein activation/inactivation eliminates genetic control and promotes the cell cycle. The persistent infections induce cancer through different steps: initial infection in basal epithelial cells start an HPV chromosomic ring which elaborates carcinogenic proteins and in the maturation epithelium as virions are produced. The rupture of the chromosomic ring in E2 region allows integration of E6 and E7 in host cell genome. These mutations develop nuclear changes visible in high-grade intraepithelial tumors. Different mutations and methylation genes develop infiltration and metastasis, which develops into invasive cancer. Epidemiology has shown a relationship between CC and a sexually transmitted disease, but not all infected patients with pathogenic HPV serotypes (even HPV-16) develop cancer. These infections are eliminated by cell immunity mechanisms, as HPV is an epithelial virus. Around 50% of new infections are eliminated within 6 months and others within the first year of infection. Only 5-10% infected women by high-risk HPV serotype will present with chronic infection (5, 6). This chronic HPV infection is necessary for cancer progression and only one portion will progress to cancer. There are several cofactors that contributes to develop cancer: early age of sexual activity initiation, early age first pregnancy, high number of births, smoking, no prior cytology screening, contraceptive use for more than 5 years, multiple sexual partners, HIV or other sexually transmitted disease (herpes, chlamydia, gonorrhea), and immunosuppression. The time to develop cancer for chronic infection is slow in terms of several decades, so it tends to be diagnosed in women between 40 or 50 years old (7). The treatment of the HPV infection accelerates its elimination and reduces the risk of new HPV infections, but it is difficult to diagnose this infection because it is asymptomatic in women. Therefore, screening and regular consults are required for diagnosis and treatment.

PREVENTION AND SCREENING

There are differences in screening programs between developing countries and high-income countries. Developing countries had significant increases in incidence and mortality, from 230,000 in 2012 to 363,000 deaths in 2030, in comparison with high income countries from 36,000 in 2012 to 41,000 in 2030. According to the International Agency for Research on Cancer (IARC), 84% of new CC cases and 88% of deaths will be in developing countries. The reduction in high income countries is associated with better screening coverages and new diagnosis studies. The vaginal cytology (Papanicolaou test) in women over 25 years old every 3 years vital in the detection of early stage CC (IARC recommendation). There are differences in screening according to educational level and occupation: 51% of detection in educated women versus 5% in illiterate women; 68% working women versus 29% housewives (range of 2% in India to 60% in Mexico). Only 23% of women in Mexico has been screened. There is a clear difference between socioeconomical status and screening rates (8). On the other hand, it is referred that 44% women have had pelvic exploration in the last 3 years and only 55% tested with Papanicolaou. The grade A cervical cancer screening recommendations of United State Preventive Services Task Force (USPSTF) includes screening in women from 21 to 29 years old with

Complimentary Contributor Copy 254 Dolores de la Mata Moya, Luisa María Catalina Tenorio Téllez, Fiona Lim et al. vaginal cytology every 3 years, women from 30 to 65 years old vaginal cytology every 3 years or high-risk serotypes HPV test every 5 years (9). These recommendations are adapted to each country in different age ranges. In Mexico, vaginal cytology is recommended in women from 25 to 64 years old and HPV test can be use in women from 35 to 64 years old. Nevertheless only 3.3% women working in public institutions undergo screening (10).

PATHOLOGY AND DISSEMINATION PATHWAY

Almost 80 to 90% of CC cases are squamous, and are divided into large keratinize cells, large non-keratinize cells and small cell carcinoma. Only 10-20% are cervical cancer adenocarcinoma, which has increased lately in young woman. The cervix has rich lymphatic drainage across its mucosa, muscularis and serosa. There are three main lymphatic drainage systems: the superior with anterior and lateral cervix portion across uterine artery, the median portion drainage depth hypogastric (obturator nodes) and the inferior drainage of the common iliac, presacrum and subarotic. The incidence pelvic node affection is 15%, 30% and 50% in FIGO stage IB, IIB and IIIB, respectively. Also, para-aortic node affection is 5%, 20% and 30% in FIGO stage IB, IIB and IIIB, respectively (11).

Uterine preinvasive lesions

HPV infection precedes CC carcinogenic process. Most invasive lesions are preceded by an intraepithelial lesion or a Cervical Intraepithelial Neoplasia (CIN). Most CIN develop in the squamous-columnar junction between the endocervix columnar epithelium and the exocervix Squamous epithelium, the transformation zone. CINs consider changes in the cytoplasm, loss of nuclear polarity, pleomorphism and mitosis. There is a classification according to depth of epithelium affected: CIN1, only inferior third of the epithelium affected, CIN2, lesion extends up to the middle and CIN 3 the lesion has extended through the entire thickness. The mean time between CIN 3 or in situ carcinoma and initial HPV 16 infections is around 7 to 22 years, but in high risk HPV infection time to CIN1 is about six years (12). The most widely used screening tool is cervical-vaginal cytology. Colposcopy is not a screening method, given that it is only indicated when cytological abnormalities are found.

The treatment of premalignant lesions

Low grade squamous intraepithelial lesions (LG-SILs) and atypical squamous epithelium of undetermined significance (ASE-US) are considered premalignant lesions. The first may be kept under surveillance, because it can spontaneously resolve. Results of the HPV test showing high-risk predicts for the development of high-grade lesions (sensibility 90-100%) (13).

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Current recommendations include colposcopy of lesions and biopsy. An excisional procedure is recommended with a high-risk HPV test. Any CIN2 or CIN3 should be excised unless the patient is pregnant. When a malignant lesion is identified, it is necessary to complete staging and to review the signs and symptoms.

CLINICAL PRESENTATION

Women with premalignant lesions are asymptomatic. Lesions are detected with screening cytology or sometimes though testing of concomitant infections. Most patients are diagnosed in locally advanced stages with invasive cancer, as the most frequent sign in exophytic tumors is transvaginal hemorrhage, which is most often post-coital, intermenstrual or postmenopausal. Tumor necrosis produces a serosanguinous smelly fluid. Endocervical tumors may have subtle presentations. Locally advance tumours may present with the classical triad: sciatic pain, limb edema and hydronephrosis and is associated with extensive disease. It can also present as metastatic constitutional syndrome with weight loss, inguinal and/or supraclavicular node enlargement. Other presentations include bladder or rectal invasion with fistulae, hematuria, or hematochezia, pelvic pain, sciatic nerve pain, leg edema, lumbar pain, and due to contiguous extension sacral plexus affection and lymphatic, vascular or ureteral obstruction. External inspection and bimanual exploration are performed to evaluate the shape and mobility of the uterus, cervix and parametria. Uterus fixation due to tumor infiltration towards the pelvic wall, extension to parametria, bladder or rectum, and parametrium may be involved it is irregular, nodular and painful. In postmenopausal women, the clinical examination is more difficult. We need to remember that tumor size is an important prognostic factor, so this part of exploration is crucial. Lymphatic areas need to be explored, and supraclavicular and inguinal enlargements are suitable for biopsy. In locally advanced stages, poor prognostic indicators include pelvic nodes, low hemoglobin levels, and functional status.

DIAGNOSIS

Because the prognosis and management of these patients depends on stage, emphasis must be place on performing adequate staging. CC staging is mainly done clinically.

Clinical staging

In CC, clinical staging is the reference so gynecological exploration should be performed by a specialist, preferably under anesthesia (14). The currently used staging system is the International Federation of Gynecology and Obstetrics (FIGO) which consider clinical exploration the gold standard: tumor diameter,

Complimentary Contributor Copy 256 Dolores de la Mata Moya, Luisa María Catalina Tenorio Téllez, Fiona Lim et al. vaginal infiltration, tumor extension parametrium and septal. In 2009, FIGO revised the CC staging (15).

Surgical staging

If surgery is performed, histopathological findings can affect CC staging. TNM is considered by the American Joint Committee on Cancer (AJCC) with the 8th edition being the latest. All histologic types are included, and while grade is specified, it does not affect staging. The classification is described in Table 1 and Table 2 (16).

Table 1. FIGO 2009 / TNM 8th edition

FIGO 2009 /TNM 8th Description Primary tumor and FIGO TX: Primary tumor cannot be assessed stage: T0: No evidence of primary tumor T1 (FIGO I): Cervical carcinoma confined to uterus (extension to corpus should be disregarded) T1a (FIGO IA): Invasive carcinoma diagnosed by microscopy only; stromal invasion with a maximum depth of 5.0 mm measured from the base of the epithelium and a horizontal spread of 7.0 mm or less; vascular space involvement, venous or lymphatic, does not affect classification T1a1 (FIGO IA1): Measured stromal invasion of 3.0 mm or less in depth and 7.0 mm or less in horizontal spread T1a2 (FIGO IA2): Measured stromal invasion of more than 3.0 mm and not more than 5.0 mm, with a horizontal spread of 7.0 mm or less T1b (FIGO IB): Clinically visible lesion confined to the cervix or microscopic lesion greater than T1a2 / IA2; includes all macroscopically visible lesions, even those with superficial invasion T1b1 (FIGO IB1): Clinically visible lesion 4.0 cm or less in greatest dimension T1b2 (FIGO IB2): Clinically visible lesion more than 4.0 cm in greatest dimension T2 (FIGO II): Cervical carcinoma invading beyond the uterus but not to the pelvic wall or to the lower third of the vagina T2a (FIGO IIA): Tumor without parametrial invasion T2a1 (FIGO IIA1): Clinically visible lesion 4.0 cm or less in greatest dimension T2a2 (FIGO IIA2): Clinically visible lesion more than 4.0 cm in greatest dimension T2b (FIGO IIB): Tumor with parametrial invasion T3 (FIGO III): Tumor extending to the pelvic sidewall or involving the lower third of the vagina or causing hydronephrosis or nonfunctioning kidney T3a (FIGO IIIA): Tumor involving the lower third of the vagina but not extending to the pelvic wall T3b (FIGO IIIB): Tumor extending to the pelvic wall or causing hydronephrosis or nonfunctioning kidney T4 (FIGO IVA): Tumor invading the mucosa of the bladder or rectum or extending beyond the true pelvis (bullous edema is not sufficient to classify a tumor as T4) Regional lymph nodes (N) NX: Regional lymph nodes cannot be assessed N0: No regional lymph node metastasis pN0(i+): Isolated tumor cells in regional lymph node(s) no greater than 0.2 mm N1 (FIGO IIIB): Regional lymph node metastasis Modifier for regional lymph nodes: + (sn) + (sn)(i-) + (sn)(i+) Distant metastasis (M) M0: No distant metastasis M1 (FIGO IVB): Distant metastasis (including peritoneal spread, involvement of supraclavicular, mediastinal or paraaortic lymph nodes, lung, liver or bone) Complimentary Contributor Copy Management of cervical cancer 257

a. Ultrasound, b. CT scanner, c. MRI, d. PET/CT 18-FDG.

Figure 1. Diagnostic imaging cervical cancer.

Table 2. FIGO stage (2015 FIGO cancer report)

Stage I T1 N0 M0 Stage IA T1a N0 M0 Stage IA1 T1a1 N0 M0 Stage IA2 T1a2 N0 M0 Stage IB T1b N0 M0 Stage IB1 T1b1 N0 M0 Stage IB2 T1b2 N0 M0 Stage II T2 N0 M0 Stage IIA T2a N0 M0 Stage IIA1 T2a1 N0 M0 Stage IIA2 T2a2 N0 M0 Stage IIB T2b N0 M0 Stage III T3 N0 M0 Stage IIIA T3a N0 M0 Stage IIIB T3b Any N M0 T1 - 3 N1 M0 Stage IVA T4 Any N M0 Stage IVB Any T Any N M1 Notes:  All macroscopically visible lesions - even with only superficial invasion - are at least pT1b (FIGO IB)  Lower Anogenital Squamous Terminology (LAST) definition of superficial invasive squamous cell carcinoma (SISCCA) conforms to T1a1 (FIGO IA1)  For FIGO IA cancers, the depth of invasion should not be more than 5 mm taken from the base of the epithelium, either surface or glandular, from which it originates; vascular space invasion should not alter the staging  Pelvic sidewall is defined as the muscle, fascia, neurovascular structures and skeletal portions of the bony pelvis; on rectal examination, there is no cancer free space between the tumor and pelvic sidewall  FIGO no longer includes stage 0 (Tis). Complimentary Contributor Copy 258 Dolores de la Mata Moya, Luisa María Catalina Tenorio Téllez, Fiona Lim et al.

The pathological classification of TNM does not replace the TNM clinical classification, although it provides additional information. CC usually disseminates through the lymphatic system, first the pelvic nodes followed by the paraaortic nodes. Laparoscopy or laparotomy can be used for nodal evaluation in CC, keeping in mind that node affection is the most important survival prognosis factor (17).

Imaging studies

The revised FIGO staging guidelines recommend performing CT or MRI whenever such an imaging method is available (see Figure 1). In early stage IA, imaging studies are not useful, and surgery gives appropriate information on microscopic disease. However, in patients who desire to preserve fertility with trachelectomy, MRI is mandatory to select appropriate cases with tumor size < 2 cm., cervical length >2.5 cm. and the distance from the tumor to the internal cervical orifice >1 cm (17). Transvaginal ultrasound gives exact information about uterus and size of the tumor or infiltration, and transrectal ultrasound is superior to MRI for detecting tumor and calculating volume and parametrial invasion, but we need to remember it is operator dependent. Doppler ultrasound provides complementary information on the cell proliferation index (18). CT-scan has a sensitivity 32-80% in the evaluation CC; and parametrial invasion with a sensitivity of 64% and mean specificity of 81%. The positive predictive value (PPV) on evaluating nodal involvement is 51-65%, negative predictive value (NPV) is 86-96%, and sensitivity is 31-65%. However, ultrasound is better for parametrial evaluation (78% vs 50%, p=0.06) (19). Excretory urography is the study recommended for diagnosing ureteral obstruction according to FIGO, but it is expensive, and requires specific procedures. Chest X-ray is used to evaluate pleural effusions and metastatic disease but CT-SCAND chest is better.

Table 3. Devine MRI cervical cancer staging

Devine MRI Cervical Description Cancer staging Stage I Tumors in microinvasive stage IA are not observed in MRI, although they can be detected as early reinforcement foci in dynamic contrast images. Stage II Tumor invasion towards the vagina can be observed as T2 hyperintensity. It interrupts the vaginal walls, which are normally hypointense. It is important to keep in mind that physical exploration is more precise than MRI for observing vaginal fornices, and MRI is superior to gynecological exploration for detecting parametrial invasion (sensitivity, 69% and specificity, 93%). The precision of physical exploration is 50%. Stage III The internal obturator, the elevator ani, and the piriform muscles show hyperintense infiltration when a tumor is involved. Stage IV When there is invasion into adjacent organs, a separation plane loss can be observed in the fat between the cervix and the bladder or the rectum. The abnormally high signal intensity in the vesical wall is an indicator of tumor involvement, but is confirmed with cystoscopy as a bullous edema.

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MRI has higher sensitivity (66%) and specificity (98%) for gynecological exploration for local disease, 50% sensitivity and 97% specificity for detecting pelvic nodes, and 66% sensitivity and 100% specificity for detecting paraaortic nodes (20). The T2 sequences sagittal and oblique planes are optimal for evaluating the cervix area. Findings have been used for staging by Devine et al. in 2015 (see Table 3) (21). PET/CT is the most accurate diagnostic procedure for evaluating locoregional nodal involvement and extrapelvic disease in locally advanced CC, and surgical staging can be avoided due to the PPV, as the false positive rate in node less than 5mm is 12%. It is useful for discrimination of residual or recurrent disease from post-radiation fibrosis (22). These results can assist radiotherapy planning in locally advanced radical treatment and in using F- MISO (18-fluoromisonidazole) labelled hypoxic areas for radiotherapy planning (23).

TREATMENT OF CERVICAL CANCER

Surgery is the standard treatment for early stage cervix cancer, stages IA1, IA2, IB1, and IB2 less than four cm. There are several approaches that include radical hysterectomy and bilateral pelvic lymphadenectomy (BPL) to fertility sparing surgery or minimally invasive procedures. Between 25% and 40% of this early stage are in women of reproductive age. This group of patients need to be carefully selected, with criteria including: biopsy proven cervical cancer, FIGO stage IA1 with PVL, IA2, IB1, desire of fertility, tumor size <2 cm, limited endocervical affection (surgery margin >5mm), cervical length >1 cm, and negative pelvic nodes. Patients of stage IA1 can be operated with conization and sentinel lymph node biopsy. Stage IA2, IB1 <2cm can be treated with trachelectomy with BPL laparoscopy or laparotomy. Pregnancy rates of 52% can be achieved with this surgery (24). Nevertheless, the appropriate oncologic technique is radical hysterectomy type A (extrafascial) with bilateral lymphadenectomy for stage IA1. Stages IA1 with PVL, IA2 hysterectomy type B with BPL and para-aortic lymphadenectomy should be considered if positive nodes are suspected. In patients with stage IB1, IIA1 hysterectomy type C with BPL with /without para-aortic lymphadenectomy should be considered.

Table 4. Piver-Rutledge-Smith classification of radical hysterectomy

Classification Description Subtotal/Supracervical The uterus is removed. The superior portion of the cervix is amputated, and the remnant of the cervix is conserved. The uterosacral ligaments are conserved. Class I Extrafascial hysterectomy. The fascia of the cervix and the inferior segment of the uterus are removed. Class II Modified radical hysterectomy. The uterine artery is ligated where it bridges over the ureter, and the cardinal and uterosacral ligaments are cut in half at their insertion to the pelvic wall and the sacrum, respectively. One third of the vagina is cut. Class III Radical hysterectomy. The uterine artery is ligated at its origin to the superior vesical artery or to the iliac artery. The cardinal and uterosacral ligaments are cut at the pelvic and sacral walls. The superior third of the vagina is resected. Class IV Radical hysterectomy. The ureter is completely dissected from the vesicouterine ligament, the superior vesical artery is sacrificed, and three fourths of the vagina is resected. Class V Radical hysterectomy. In addition to the above, a portion of the bladder or the distal ureter is resected, followed by the reimplantation of the ureter to the bladder. Complimentary Contributor Copy 260 Dolores de la Mata Moya, Luisa María Catalina Tenorio Téllez, Fiona Lim et al.

Radical radiotherapy shows similar outcomes, but surgery is preferred in young women due to better long term quality of life. Radical hysterectomy techniques were first described by Wertheim in 1912. Later at Harvard Medical School, Meigs developed modifications to the hysterectomy procedure. In 1974, Piver, Rutledge and Smith established the first hysterectomy classification (see Table 4) (25), and in 2008 an update by Querleu and Morrow was published based on anatomic limits and margins of surgical resection, considering sympathetic and parasympathetic innervation of the female pelvis and anatomical retroperitoneum (see Table 5a, Figure 2) (26). It is also important to define references for trans-surgical report: anatomical limits of pelvic ganglion dissection, additional salpingo-oophorectomy or ovarian transposition, type of parametrectomy, and length of vaginal resection. BPL includes node dissection of level 1 external and internal iliac nodes, level 2 presacral and common iliac nodes, level 3 inframesenteric iliac nodes, and level 4 infrarenal aortic lymph nodes. EORTC-Gynecological Caner group defines 11 pelvic nodes as indicator of the quality of lymphadenectomy.

Table 5a. Radical hysterectomy classification system of Querleu and Morrow (2008)

Classification Description Type A Extrafascial The extent of paracervix resection is medial to the ureter but lateral to the cervix, and the hysterectomy or uterosacral and vesicouterine ligaments are not resected. The vaginal resection is minimal, and minimal paracervix trachelectomy is not performed. This technique includes palpation and observation, but not resection mobilization, of the uterus. Type B Radical B1: The paracervix is resected at the level of the ureteral tunnel, the uterosacral and modified vesicouterine ligaments are partially resected, and the neurological component of the paracervix hysterectomy or (caudal to the deep uterine vein) is not resected. At least 10 mm of vagina from the cervix to the paracervix resection at tumor is removed. A dissection is performed, and the ureter is lateralized without being the level of the ureter mobilized. B2: The lateral paracervical ganglia are dissected in addition to the procedures described for B1. The edge between the paracervical and parietal ganglia (iliac and obturator lymph nodes) is defined by the obturator nerve. Using this technique, the uterine artery is preserved Type C Radical The cardinal ligaments are resected from the pelvic wall and the uterosacral ligament is hysterectomy or resected at the level of the rectum, including a section of the vesicouterine ligament; a 15–20 paracervical resection mm segment of the vagina or the cervix tumor is removed. The ureter is completely mobilized. at the junction with the C1: With preservation of the autonomous nerves. vascular iliac system. C2: Without preservation of the autonomous nerves. Type D Laterally D1: The parametrium is resected from the pelvic wall with mobilization of the iliac vessels and extending resection with exposition of the sciatic nerve roots. D2: The parametrium is resected from the pelvic wall together with hypogastric vessels, muscular structures, and adjacent fascia. The ureter is completely mobilized

Table 5b. Groups of risk early stage cervical cancer and adjuvant treatment recommendations

Group of risk early stage cervical cancer Factors Adjuvant treatment Low None None Intermediate Deep stromal invasion Adjuvant radiotherapy Lymphovascular invasion Tumor size > 4cm. High Positive lymph node Adjuvant chemoradiation Positive margin Parametrial infiltration Complimentary Contributor Copy Management of cervical cancer 261

Figure 2. Radical hysterectomy classification system of Querleu and Morrow: type A: extrafascial hysterectomy or minimal paracervix resection; type B: radical modified hysterectomy or paracervix resection at the level of the ureter; type C: radical modified hysterectomy or paracervical resection at the level of vascular iliac system the ureter; type D: laterally extended resection.

Trachelectomy was described by Dragent in 1994, and involves resection of the cervix and 1 or 2 cm of the vagina, the parametrium, and the paracervical lymph nodes. The most common morbidity involves the urinary tract, with decreased bladder sensation and reduced filling capacity reported in 75-85% of patients receiving type III or C2 hysterectomy but with spontaneous recovery within 6-12 months after the surgery in 30% of patients.

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Severe bladder disfunction has been reported in 16% of patients, detrusor hypoactivity in 86%, and detrusor hyperactivity in 10%. The risk of bladder-vaginal or ureterovaginal fistula after hysterectomy has been reported in 0.9-2.7% (27), with higher risks in those with vesical damage, hemorrhage, obesity, diabetes, or post-surgical infection. In general, risk of complications is around 6%, transfusion related complication in 9%. and infections in 4%. Nerve lesions are related with anorectal dysfunction such as diarrhea, constipation, fecal incontinence, with higher risks after dorsal parametrial resection. Sexual dysfunction often has psychological and functional causes and anatomical changes, it is important to keep adequate lubrication, lymphoceles are rare and lymphedema has not been studied (28). Minimally invasive approaches with laparoscopy or robot-assisted surgery have become very popular lately without differences in pathological report, no differences in parametrial resection, or negative borders (96% vs. 91%, p=NS), and no difference in 5-year survival rate (92% vs. 93.6%, p=NS). The benefits with these procedures are smaller amount of bleeding (55mL vs. 145 mL, p=0.01), and less hospitalization time (4 days vs. 7 days, p<0.01) (29). The oncological results of fertility-sparing surgery with trachelectomy need to be similar to hysterectomy (recurrence rate form 1.2-6% vs 2.1%). Fertility preservation is obtained in 85-91% with a pregnancy rate of 16-24% (29). Sentinel lymph node biopsy is associated with short term and long-term decreases morbidity even it is not standard of treatment, with a sensitivity of 92% (95% confidence interval (CI): 84-88%) and detection rate of 97% (95% CI: 95-98%) (30). Morbidity of this procedure during surgery is 2% and acute postoperative morbidity of around 20%. Based on the final pathology report, adjuvant treatment with chemotherapy and/or radiotherapy is determined. New surgery techniques include minimally invasive methods, including using sentinel lymph nodes (28). In patients with locally recurrent cervical cancer, pelvic exenteration is a viable option with 17% of long-term survival, and 5-years survival rate 48-60%. This technique includes resection of multiple endopelvic organs, with posterior surgical reconstruction as colorectal anastomoses, urinary reservoirs and a neovagina. There are different types of exenteration: type I (supraelevator), type II (infraelevator) and type III (with vulvectomy) and other classifications are based on pelvic resected organs: anterior includes bladder, urethra and genital tract, posterior includes genital tract and rectum sigmoid, and the total includes genital tract, bladder, urethra and rectum sigmoid, with subtypes lateral endopelvic including resection of the internal obturator muscle, pubococcygeus and iliococcygeus muscles. This procedure should be performed by experienced surgeons (31, 32) (see Figure 3). This is an ultra-radical procedure mainly indicated in recurrent or persistent cervical cancer (70%), followed by advanced colorectal cancer (20%) with a curation rate of 45%, so it is very important to be able to consider resectability with negative margins, tumor localization and previous treatments. Absolute contraindications are pelvic wall involvement, sacral plexus or sciatic nerve involvement, large vessel affection, extrapelvic metastasis, or poor performance status. Good prognosis factors are recurrence with >12 months free time disease, tumor <3cm. with 5-year success rates of 50-60% (33). Palliative exenteration is controversial due to poor 2-years survival rates 10-47% (31).

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Figure 3. External radiotherapy 3D para-aortic and pelvis radiotherapy.

Radiotherapy

Cervical cancer (CC) is the most common gynecologic type of cancer. Unfortunately in Latin America, almost half of the cases are diagnosed at locally advanced stages. Radiotherapy is involved in different stages of disease.

Early stage cervical cancer

There are different treatment options for early stage CC, mainly different surgery techniques are used. Nevertheless, when radical radiotherapy is compared the surgery the data show that toxicity is lower with surgery, when it is not followed by radiotherapy and another advantage is surgery preserves ovaries and sexual functions, which improves quality of life. Retrospective studies comparing surgery vs. radical radiotherapy (RT) in early stage CC provided comparable local control and overall survival in a 5-year follow up (OS 80-90%). Complimentary Contributor Copy 264 Dolores de la Mata Moya, Luisa María Catalina Tenorio Téllez, Fiona Lim et al.

In 1997 first randomized trial surgery vs. radical RT in CC stages IB-IIA, in surgery arm postoperative RT was indicated for patients with >IIA, positive margins, positive lymph nodes or less 3cm., of non-compromised cervical stroma tissue. External beam radiotherapy (EBRT) consisted 47 Gy pelvic area followed by low-dose brachytherapy (LDR-BRT) for a total dose of 76 Gy (point A). Point A was defined as a point located 2 cm above and 2 cm lateral of an external cervical orifice. This point represents where the ureter crosses the uterine artery (see Figure 4) there was no significant difference in OS (83 vs. 83%), progression-free survival (PFS 74% vs. 74%) or local recurrence. The difference was higher morbidity 28% in the surgical group received adjuvant treatment. Based on these results, surgery is recommended for the treatment of early stage CC when is considered low risk of needing adjuvant treatment.

Figure 4. 2D LDR-Brachytherapy tandem plan.

Adjuvant treatment for cervical cancer

The treatment choice of early stage CC is surgery but one third of the patients have one or more high risk factors for recurrence in their pathology report. The GOG-49 Study showing tumor size >4 cm, lympho-vascular invasion or invasion into more than one-third of the cervical stroma, positive pelvic lymph nodes, positive surgical margins, parametrial involvement are predictive high-risk markers. Based on these results, GOG classified patients into three risk subgroups: low, intermediate, high-risk, the last of which carries a 41% risk of recurrence. To reduce risk, adjuvant radiotherapy only is recommended in intermediate risk patients (lympho-vascular invasion, tumor size > 4 cm and more than one-third of stromal invasion) and chemoradiotherapy recommended in high-risk patients (positive pelvic node, positive margins and positive parametrial invasion). Without macroscopic disease, 45-50 Gy to the pelvic area and brachytherapy boost must be individualized (34). The first trial considering this risk groups of patients was the GOG-92 trial randomizing pelvic radiotherapy versus observation after surgery. Local recurrence observed was (13% vs 21%), with higher toxicities in the radiotherapy group (6% vs 2%). An update with a 10 year Complimentary Contributor Copy Management of cervical cancer 265 follow up was in favor of radiotherapy progression-free survival (PFS) (hazard ratio (HR) = 0.58, p = 0.01), without differences in overall survival (OS) (35). Another randomized study GOG-109 included high risk patients who were randomized to RT (49.3 Gy to the pelvic area and 45 Gy to para-aortic area when the iliac node was positive), with or without chemotherapy (cisplatin and 5-fluouracyl-based) patients receiving combined treatment achieved better OS (81% vs 71%) and PFS (63% vs 80%). Several trials afterwards confirmed this data (36). Brachytherapy (BRT) is considered in margin positive patients or parametrial tissue affected, considering interstitial brachytherapy in the last situation.

Irradiation techniques

Early stage CC IA2 can be treated with radical radiotherapy; in this situation brachytherapy is the better option with less toxicity, considering low risk pelvic node affection. Selection of device depends on anatomy of the vagina (size, length, compliance) and the target volume that needs to be covered.

Figure 5. External radiotherapy 3D para-aortic and pelvis radiotherapy.

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Different brachytherapy schemes can be used. For LDR-BRT the dose prescription is around 65-75 Gy to the vaginal vault, with high dose rate brachytherapy (HDR-BRT) doses of 35-45 Gy is given in 6-7 Gy/3-5 fractions. GEC-ESTRO systems or Manchester system prescribe doses at a 5 mm depth form the vaginal mucosa (37) (Figure 4-7). For patients with stages IB and IIA disease, treatment consist of EBRT and BRT with a prescription point A for 3D planning; target GTV includes the primary lesion (defined with MRI if possible); CTV is the GTV + 0.5 mm and CTV intermediate risk node: common, external and internal iliac nodes, and presacral nodes. CTV high risk includes whole cervix, uterus, parametrial tissue from the cervix to the pelvic wall, uteral-sacral ligaments and the upper part of the vagina. The perirectal nodes should be covered if pelvic nodes were positive. The para-aortic lymph node should be included if pelvic nodes are positive and they extend above the renal vessels, approximately at the T12-L1 level (38) (see Figure 5). BRT can be admitted during or after treatment EBRT. The protocol varies according to oncologic center. In radical treatment, usually a uterine probe and ovoids (tandem) is recommended. In adjuvant treatment, cylinder or ovoids are recommended depending on anatomy and the volume that needs to be treated. Point A was defined as a point located two cm above and two cm lateral to an external cervical orifice. This point represents where the ureter crosses the uterine artery with Manchester system or GEC-ESTRO-PTV; dose prescription should be 65-75 Gy for stage IA1 and up to 85 Gy for stage IB or IIA (see Figure 6).

Figure 6. 3D HDR-Brachytherapy tandem plan.

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Figure 7. 3D HDR-Brachytherapy cylinder plan.

Locally advanced cervical cancer

Patients with stage IB2 or above are considered locally advanced stages and treatments consist of chemoradiotherapy followed by brachytherapy. This combined treatment has been shown to be beneficial in several studies and metanalyses, and there is an inverse relationship between size of the tumor and the probability of controlling the cancer. Radiotherapy in large tumors is affected by necrosis and decreased blood flow, which creates a hypoxic environment with less oxidation damage. These studies analyzed different chemotherapy drugs, the first being hydroxyurea. Later on, another study compared the results of treatment with pelvic radiotherapy (50 Gy in conventional fractioning, i.e., 2 Gy per fraction) combined with the following three chemotherapy agents: cisplatin, fluorouracil and hydroxyurea or with hydroxyurea alone. In all, 526 patients with stages IIB, IVA were included, and the results demonstrated that in both of the groups in which Cisplatin was administered, there was an improvement in OS and PFS, whereas more toxicity was observed in the group that received all three drugs than in the group that received cisplatin as the only drug. This is the reason the standard treatment for locally advanced cervical cancer is currently radiotherapy plus cisplatin, with both treatments used concomitantly. Another study supported the superiority of treatment results gained using pelvic radiotherapy (50 Gy mean dose) combined with chemotherapy compared with pelvic and para-aortic region radiotherapy treatment without chemotherapy. These results were confirmed in an updated publication on 2004. These studies are the basis for what is currently considered the standard treatment for locally advanced Cervical Cancer (see Figure 5) (39- 44). Treatment radiotherapy technique has been previously described (38) with EBRT pelvic area 45-50 Gy (e.g., 1.8 to 2 Gy per fraction), higher doses to positive nodes (image documented) of up to 60-70 Gy, with IMRT modality recommended in these cases (3D conformal RT with medial-Line structure blockade (e.g., of the rectum, vagina and intestine). IMRT is available around the world, due to latest results of randomized studies comparing 3D vs IMRT without differences in terms of local control, and slight differences in the gastrointestinal toxicity profile (45). Another option is boost situation using stereotaxic Complimentary Contributor Copy 268 Dolores de la Mata Moya, Luisa María Catalina Tenorio Téllez, Fiona Lim et al. radiotherapy (SBRT). This treatment consists of delivering high doses of radiation to a small target over a few sessions (usually no more than five), but results with this technique are still inconclusive (46).

Adjuvant treatment in locally advanced cervical cancer

Some patients are restaged after surgery; several factors led to stratified risk groups in other to indicate adjuvant treatment: low, intermediate, and high risk (see Table 5b). Approximately 20–25% will present with unfavorable prognostic factors that will dictate need for adjuvant treatment. The adequate selection of such patients, both before and after surgery, is extremely important so that we can always offer the best treatment options according to the clinical and pathological characteristics of each patient. This allows us to guarantee the best possible oncological outcomes.

Brachytherapy

Radiotherapy has been successfully used in cervical cancer for approximately a century. Cervical tissues are particular sensitive to radiation. A combination consisting of external radiotherapy and brachytherapy has been shown to be an effective treatment option. Several studies have reported that brachytherapy decreases the risk of recurrence and increases survival. In selected cases, it may be used as the only component of a treatment scheme during the early stages of cervical cancer, and is characterized by a close relationship between the radiation source and the tumor or vaginal vault. The ICRU 38 defines the brachytherapy dose rates as follows: low dose rate (LDR) 0.4–2 Gy/hr, medium dose rate (PDR) 2–12 Gy/hr, and high dose rate (HDR) over 12 Gy/hr (47, 48).

Low dose rate brachytherapy

This scheme has a long history as a treatment for cervical cancer. Initially, Radium 226 was used, but it was then replaced by Cesium 137, a radioisotope with similar physical characteristics, except that it has a lower half-life (30 years) than radium 226 (>1000 years) and results in health care providers being exposed to less radiation. According to ICRU 38, the permitted dose rate range for low dose brachytherapy is from 0.4 to 2 Gy/hr (47).

Pulsed dose brachytherapy

This is the most recent modality, and it was first used in San Francisco in 1992. It combines the physical advantages of a high dose rate and the radiobiological advantages of a low dose rate. It delivers radiation pulses in pre-established time intervals using Iridium 192 and the dose ranges described by the ICRU 38 are from 2 to 12 Gy/hr (47).

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High dose rate brachytherapy

This technique was first used on 1950, and the use of this treatment modality has increased considerably during recent decades. Currently, iridium 192 is used, and the ICRU 38 approves a dose from 12 Gy/hr. Among the advantages acquired with this kind of treatment in comparison with the low dose rate is that it avoids exposing the personnel in charge of patient care, allows dose optimization and higher reproducibility, and is an ambulatory treatment. Several studies and meta-analyses found no difference in oncologic results or toxicity between the low dose and high dose rates. Hence, independent of the absolute dose, the equivalent biological dose is the same for both modalities.

Applicators

Different applicator systems have been used to position the source of radiation inside the uterus and the vagina. These have included ovoids, a ring and a probe, a cylinder and a probe, and ovoids and a probe, but the most widely used ones are the Fletcher-Suit-Delclos. The position of the applicators is a critical determinant. Conditions required for an adequate intracavitary insertion include:

1) The geometry of the insertion should avoid sub-dosification around the cervix. 2) The parametrial tissue most receive an adequate dose. 3) Doses to the vaginal mucosa, bladder and rectum should be monitored and maintained as the lowest possible level to decrease the risk of toxicity.

During the patient’s initial evaluation, a determination is made regarding which applicators will be uses for the brachytherapy treatment, but the final evaluation will take place once external radiotherapy has concluded, and the ideal applicators will be selected based on the obtained response.

Table 6. Radiotherapy schedules in early stage cancer

External radiotherapy dose (Gy) Number of fractions (brachytherapy) Dose per fraction (brachytherapy) 20 6 7.5 20 7 6.5 20 8 6 45 5 6 45 6 5.3

Table 7. Radiotherapy schedules in locally advanced stage cancer

External radiotherapy dose (Gy) Number of fractions (brachytherapy) Dose per fraction (brachytherapy) 45 5 6.5 45 6 5.8 50.4 4 7 50.4 5 6 50.4 6 5.3

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Planning of the treatment

Diverse methods have been used to determine the prescription points in a 2D planning system with orthogonal radiographies based on the definition of Point A and dose restrictions for the bladder (absolute <75 Gy, relative <90%) and rectum (absolute of 70% Gy and relative <80%). This was the nomenclature that was approved by ICRU 38 (47) (see Figure 4). The American Brachytherapy Society (ABS) recognizes that the dose of external radiotherapy to the whole pelvis varies and the number of fractions of HDR-BRT will depend on the doses given before in radiotherapy to the whole pelvis. Usually, this is a 40–50 Gy dose of pelvic external radiotherapy, so the optimal high dose rate brachytherapy scheme remains undefined, and the dose per fraction may vary by +/− 0.25 Gy. If the HDR-BRT dose is up to > 7 Gy per fraction, special evaluations should be made of organs at risk (rectum and bladder) taking into consideration long-term complications. The ABS have a list of different schemes for BRT fractionation (see Tables 6 and 7) (47-51). Total treatment time should not exceed eight weeks, in order to achieve better results. Nowadays, 3D planning for HDR/PDR-BRT treatment is the best option. The GTV is defined and if MRI fusion is available, it allows better GTV definitions. In these cases, no maximum dose to organ at risk (OAR) is evaluated; instead, volumetric analysis (maximum prescribed dose (D2cc) rectum and bladder) and DVH are considered. In this situation, dynamic evaluation between fractions allows better optimization of the plan and total dose prescribed with protection of the OAR (53) (see Table 8).

Table 8. Dose constraints optimization brachytherapy plan

PTV Exclusive treatment: 65 Gy one fraction Combined treatment with EBRT: total dose 80 Gy to the target, one fraction. Rectum Total dose (RTE + BT) D2 cc < 75 Gy (< 130 Gy) Bladder Total dose (RTE + BT) D2 cc < 80 Gy (< 135 Gy) Urethra Total dose (RTE + BT) D1% < 80 Gy (< 135 Gy) Sigma, bowel Dose specification

The final dose of radiotherapy to point A or to the CTV (depending on the type of brachytherapy) will depend on the clinical stage and can vary from 65 to 75 Gy in stages IA1 and up to 85 Gy in locally advanced stages (51).

Re-irradiation

It is estimated that approximately 35% of all patients with a cervical cancer diagnosis who are treated with radiotherapy will experience cancer recurrence during the first 5 years after they finish treatment. In young patients with good status performance and small central recurrences, exenteration is the standard treatment and negative margins give better control of disease. Some patients with local recurrence close to the pelvic wall can be treated with intraoperative radiotherapy. When surgery is not suitable re-irradiation is an option in these patients (54). Whether external radiotherapy or brachytherapy is preferred generally depends on the dose distribution. There is currently not enough information available in the literature Complimentary Contributor Copy Management of cervical cancer 271 regarding the restriction of doses at OAR. In a previously published small retrospective series, a dose that included a total of +/−48 Gy in conventional fractionation was found to be safe. This study reported disease-free survival and 5-year local control rates of 46% and 45%, respectively. In multiple studies, a decrease in recurrence and an increase in survival have been reported when brachytherapy has been applied, given its capacity to deliver very high, localized doses while reducing the amount of radiation delivered to the surrounding tissues.

Toxicity and complications related to radiotherapy treatment in cervical cancer

In 1999, the National Cancer Institute (NCI) announced that the concurrent use of chemotherapy and radiotherapy improved OS in locally advanced cervical cancer, and it is the standard treatment option. Pelvic radiotherapy plays a definitive roll in patients, but we cannot ignore the toxicity that is often associated with it. Because complications normally arise between 3–5 years after treatment, there is still much to investigate regarding long-term morbidity in these patients. The definitions of acute and late toxicity vary in the literature: acute toxicity is defined as the presence of adverse effects that take place during treatment and up to 42, 60 and 90 days after radiotherapy is complete. Late toxicity refers to effects that present after 90 days or even years later. The incidence of late sequelae in patients with early-stage cervical cancer who were treated with radiotherapy is approximately 3.5%, whereas in patients with locally advanced disease, the rate of complications is reported to be slightly higher (10–15%). We can conclude that the probability of complications arising is directly related to the clinical stage, the volume of tissue being treated, the patient’s anatomy and the total dose administered to individual tissues (55-57).

Genitourinary toxicity

In cervical cancer, pelvic radiotherapy can result in complications in the lower urinary tract. Acute toxicity (G1–2) is relatively common following external beam radiotherapy (17–40%), depending on the report being described. The risk of developing adverse urinary effects (e.g., grade 3 or 4) is higher in the first 3 years but has an actuarial risk of 0.25% per year for the next 25 years incidence increases between 18 and 28% after 3- and 5- years post- radiotherapy, respectively. It is estimated that 44% of these patients will develop adverse acute urinary effects (<9 days post-radiotherapy), while only 7–9.5% will develop adverse late effects. However, the time required for these adverse effects to manifest can be substantial. From a physio-pathological point of view, this technique results in damage to the basal membranes of blood vessels, which can lead to occlusion, thrombosis, neo-vascularization and an increase in the proliferation of fibroblasts. These events can subsequently lead to lesions in the urinary tract, with the bladder and the point at which the ureter inserts into bladder being the most susceptible to damage, given their anatomical positions. Neo- vascularization is an important factor that contributes to radiation cystitis and the later Complimentary Contributor Copy 272 Dolores de la Mata Moya, Luisa María Catalina Tenorio Téllez, Fiona Lim et al. development of hemorrhagic cystitis. The most common urinary adverse effects (grade three or higher) are urethral stenosis, vesicle-vaginal fistula, ureter-arterial fistula and hemorrhagic cystitis. The risk of severe toxicity after radiotherapy is significantly associated with higher radiotherapy doses and the number of administered treatments. Urethral stenosis has been reported in 5% of pre-operative radiotherapy patients and in 25% of patients treated with definitive radiotherapy alone.

Gastrointestinal toxicity

Acute gastrointestinal toxicity can appear up to 90 days after radiotherapy treatment and is characterized mainly by diarrhea, tenesmus, and pain or hemorrhoids with rectal bleeding that can be controlled with symptomatic medication. Late toxicity could appear during the first 2 years or more after radiotherapy and is characterized mainly by proctitis, stenosis and rectal fistula. Several risk factors can increase the chances of a patient experiencing toxicity due to radiation. Prior abdominal or pelvic surgery can increase the risk of intestinal obstruction or adherence formation in patients treated with radiation therapy (> 50 Gy). Additionally, patients with coexisting comorbidities, including previous pelvic inflammatory disease, atherosclerosis, diabetes, vascular disease, collagen disease, tobacco consumption history or intestinal inflammatory disease, might have an increased risk of developing acute or long- term secondary effects following radiation therapy. Eifel et al. reported increase in toxicity and a higher risk of chronic adverse effects in patients with cervical cancer who were treated with radiotherapy. The risk was higher during the first three years of treatment, with 7.7% of patients presenting with G3 complications within 3 years. The incidence of rectal complications was 1% during the first two years and lowered to 0.68% from 2-25 years. The incidence of fistula was approximately twice as high in patients who were subjected to extrafascial hysterectomy and adjuvant treatment. These patients presented with this complication at rates of 5.3% and 2.3%, respectively, at 20 years post-radiation, and 5.2% and 2.9%, respectively, in patients who were previously subjected to laparotomy. The risk of intestinal obstruction is also increased in patients subjected to laparotomy (14.5% and 3.7%, respectively, after 10 years), and patients who weighted 70 kg (8.2% and 3.6%, respectively). The cumulative risk of complications was higher in young patients because they had a stronger probability of survival and were therefore exposed for a longer period of time. Mitchel et al. evaluated 398 patients with clinical stage I-III cervical cancer who were treated with definitive radiotherapy. The patients were divided into two groups, as follows: those who were 35–69 years old and those who were > 70 years old. The frequency and severity of acute and late adverse effects were equivalent in both groups. Age was therefore not associated with higher rates of acute or chronic toxicity. There is a direct correlation between the incidence of complications and the dose administered. Pérez et al. reported that with doses < 75–80 Gy the risk of G2–3 complications in the urinary tract and rectum is approximately 5%. However, this percentage increased >10% when higher doses of radiation were applied. In the small intestine, the incidence of morbidity was lower (2%) in patients treated with less than 50 Gy than in those treated with Complimentary Contributor Copy Management of cervical cancer 273

>50–60 Gy (5%). It has been demonstrated that patients who experienced treatment sequelae had slightly better survival rates than patients without complications. This result was associated with better tumor control when administering high doses of radiotherapy. The effects of the total dose of radiotherapy on the bladder, rectum and point A are also correlated with the severity of the complications. Eiffel et al. evaluated 1456 patients who were treated with external radiotherapy and LDR brachytherapy consisting of a total dose of 70–90 Gy. The frequency of G2 morbidity in these patients was 10–12%, and the frequency of G3 morbidity was 10%. The most important adverse effects ere cystitis and proctitis (G2) (0.7–3%), vesicle-vaginal fistula (G3) (0.6–2%), rectal-vaginal fistula (0.8–3%) and intestinal obstruction (0.8–4%). In the bladder, doses <80 Gy were correlated with a <3% incidence of morbidity, and this incidence increased to 5% with higher doses. In the rectal wall, the incidence of morbidity was <4% when <75 Gy was applied. In the small intestine, the incidence of morbidity was <1% when 50 Gy or less was administered, 2% for 50–60 Gy and 5% for higher doses. There are a variety of dosimetry parameters that are tightly correlated with the incidence of morbidity in patients who were treated with definitive radiotherapy. Hence, we should pay special care and attention to these related factors, which will help us reduce morbidity to a minimum without compromising tumor control. The correlation between tobacco and late complications following radiotherapy is of particularly interest. A significant difference has been observed in the incidence of intestinal complications between smokers and non-smokers, and this difference was associated with the intensity of tobacco consumption. These data provide evidence regarding a synergistic effect between tobacco use and the effects of normal tissue radiation.

Sexual function after pelvic radiotherapy

The most common gynecological complications following radiotherapy are ovarian insufficiency in pre-menopause patients and vaginal stenosis in patients that receive vaginal radiation. Vaginal stenosis is defined as a tightening or reduction of the vaginal canal that can interfere with a physical exam or sexual function. Its incidence varies between 20 and 88%. In patients who are initially subjected to surgery and then later receive vaginal HDR brachytherapy, the incidence is lower 2.5%. It is most common for this complication to occur during the first-year post-radiotherapy, but it has been observed at intervals ranging from 26 days up to 5.5 years. The risk factors associated with vaginal stenosis include high doses of radiation, patients who are >50 years old, insufficient use of the dilator, and concomitant chemo-radiotherapy. Doses >80 Gy have been associated with a 10–15% increase in the risk of G2 vaginal toxicity, including vaginal stenosis. Radiation-induced menopause generally occurs within six months after treatment.

Hematologic toxicity

High doses of radiation can induce chronic myelo-suppressive effects and lower tolerance to chemotherapy by damaging the bone marrow micro-environment. The results of prospective Complimentary Contributor Copy 274 Dolores de la Mata Moya, Luisa María Catalina Tenorio Téllez, Fiona Lim et al. studies have reported a 25% incidence of hematological toxicity > G3 when using cisplatinum-based chemo-radiotherapy. Irradiating an extended field that includes the covering over the para-aortic lymph nodes results in more irradiation of total bone marrow and therefore a higher rate of hematological toxicity. It is important to consider this complication and to monitor hematological toxicity because it predisposes patients to infections, frequent hospitalizations, multiple transfusions and delays in receiving chemotherapy.

Brachytherapy toxicity

In a meta-analysis published by Cochrane in 2010, LDR and HDR intracavitary brachytherapy were compared in locally advanced cervical cancer. All of the included studies, which involved 1,265 patients, provided detailed information regarding the complications that presented. The tissues found to be at risk of late complications were the bladder, sigmoid rectum and small intestine. The relative risk for late complications was 1.33 in the bladder, 1.0 in the sigmoid rectum and 3.37 in the small intestine. These results indicate that except for a slight increase in the complications that presented in the small intestine, there were no significant difference in complication in patients treated with a high dose.

Complications of concomitant radiotherapy/chemotherapy

Concerning the recent application of chemo-radiotherapy, it has been clearly demonstrated that this combination results in higher rates of acute toxicity, particularly hematologic and gastrointestinal complications, than radiotherapy alone. Kiran et al. carried out a review of acute and late toxicology following chemoradiotherapy in 1,766 patients. They found that G1 and G2 hematologic toxicity effects occurred more often in the chemo-radiotherapy group. A significant difference was observed in G3 and G4 hematological and gastrointestinal toxicity. Late toxicity has been described in eight assays, seven of which reported a significant difference. However, the survival benefit obtained from applying chemo-radiotherapy makes up for the toxicity observed in these patients, and this makes this strategy an acceptable option. In spite of the fact that there is not sufficient data on late toxicity to support its results, the data obtained from meta-analyses performed in the RTOG 9198 study suggests that there may not be any significant difference in the type or severity of the late effects produced by chemoradiotherapy or radiotherapy alone. Only a small percentage of women (1–3%) presented with severe late toxicity, and these complications primarily affected the rectum, bladder, intestines and vagina.

New radiation techniques aim to improve toxicity

As new radiation techniques have been developed, it has now become possible to minimize or substantially prevent G1 toxicity. The use of multiple fields avoids a lack of homogeneity in Complimentary Contributor Copy Management of cervical cancer 275 drug dose delivery. Additionally, the physical displacement of the intestines can be optimized by using a “belly board” while the patient lies in a prone position, and the procedure is now generally performed while the patient has a full bladder. Improved moderate radiotherapy treatment (IMRT) may contribute even further to reducing the rate of G1 toxicity. Moderate radiotherapy treatment is highly conformal and uses many angles to better adjust the treatment to the tumor’s geometry and minimize the dose applied to the normal surrounding tissues. The most recent technique, image-guided radiotherapy (IGRT), permits some adjustments during treatment and enables the practitioner to reduce the dose delivered to normal tissues by a higher percentage. Ghandi et al. published the results of a randomized study that evaluated toxicity and clinical results in 44 patients with locally advanced cervical cancer who received 3D pelvic radiotherapy vs IMRT with a dose of 50.4 Gy, which was delivered in 28 fractions that were administered concomitant with 40 mg/m2 cisplatin and followed by HDR intracavitary brachytherapy. IMRT was associated with a lower rate of acute G1, > G2 (63.3% vs 31.8%) and > G3 (27.3% vs 4.5%) toxicity in addition to a lower rate of late G1 toxicity (50 vs. 13.6%). In a dosimetry comparison between both groups, IMRT applied a significantly lower dose to the small intestine and rectum. New techniques that involve 3D imaging, either with TAC or with IMR, help us to better delimit the form of the surrounding tissues in patients who receive a high dose of brachytherapy, which allows us to achieve reductions in toxicity.

Systemic therapy

The systemic therapy in cervical cancer includes management in different stages with different roles: neoadjuvant, radical, palliative. The main role of chemotherapy is combined treatment of locally advanced CC with radiotherapy. There are some studies evaluating neoadjuvant chemotherapy in large tumors or hydronephrosis but it has not changed the standard of treatment. Angiogenesis inhibitors are an efficacious therapy in metastatic and/or recurrent diseases, and are one of the pathways in CC being targeted.

Chemoradiotherapy

Since 1990s combined chemoradiotherapy increases overall survival and the recurrence-free interval is the standard of treatment (58). They compared platinum vs non-platinum schemes and the schedule of application, also dose intensity (<25 vs >25 mg/m2/week cisplatin) (59) and the conclusions were cisplatin should be administered 40 mg/m2 on day 1 and weekly during radiotherapy (50 Gy) and total dose with BRT (85-90 Gy). Toxicity is manageable and toxicity grad is infrequent. Combination treatment with addition of other therapeutic agents has reported higher complete pathological response rates (77.5% vs 55%) with also higher rates of toxicity (60). There is a study comparing cisplatin and gemcitabine plus EBRT in 211 patients with IB2-IIB patients followed by brachytherapy vs hysterectomy and results showed no

Complimentary Contributor Copy 276 Dolores de la Mata Moya, Luisa María Catalina Tenorio Téllez, Fiona Lim et al. inferiority, so this could be an alternative in centers where brachytherapy systems ae unavailable (61).

Neoadjuvant or adjuvant therapy

There are some questions trying to increase survival and series of studies phase II reporting increase of overall survival around 19% whit chemotherapy is added to chemoradiation. Five of seven studies failed to demonstrate benefit of neoadjuvant therapy (59).

Chemotherapy in recurrent or persistent disease

Most recurrent disease occur within the first two years; 50-60% of recurrences are outside the pelvis and palliative chemotherapy is the most appropriate treatment option. If the recurrent disease is detected during the first 6 months, it is defined as a persistent disease. The percentage of recurrence by stage are: IB-10%, IIA 17%, IIB 23%, III 42% and IVA 74%. There are four different disease types: central lesion, pelvic wall recurrence, locoregional nodal recurrence, distant metastasis: supraclavicular (215), bone (16%), liver 8%), and lung (7%); biopsy is recommended for all (62-64). If recurrent disease is located in an unirradiated area, radiotherapy, or brachytherapy is the first option or exenteration. When platinum-based chemotherapy is used, 50% have a complete response after exenteration.

Chemotherapy in metastatic disease

Chemotherapy in metastatic disease has shown benefits in progression free survival and quality of life. It is important to evaluate patient condition. Various chemotherapy agents have demonstrated activity; cisplatin has reports 18-38% response rates. A randomized trial GOG compared different cisplatin dose schedule, established as 50mg/m2 every three weeks the standard regimen because higher doses were associated with increased toxicity without improved overall survival (65). Other drugs have been tested in recurrent setting including carboplatin, capecitabine, docetaxel, 5-fluoracil, gemcitabine, liposomal doxorubicine, pemetrexeb, topotecan and vinorelbine (66). GOG 169 and GOG 264 evaluated the value of adding paclitaxel 135 mg/m2 to the cisplatin standard schedule with better clinical response of 36% versus 19% (p=0.002), PFS 4.8 versus 2.8 m (p<0.0019) without differences in OS (9.4 m vs. 8.4m) or quality of life. In GOG 179, different drugs were evaluated. The addition of 0.75 mg topotecan to day 1-3 to standard cisplatin, had an OS 9.4 m versus 6.5 m (p=0.02), response rates 27% versus 13%, and no difference median OS 4.6 m versus 3 m (p=NS) (21), however the arm M-VAC was closed due to patient deaths. GOG204 tried to evaluate better doublets than standard cisplatin with palclitaxel (67) by looking at versus cisplatin + vinorelbine/ gemcitabine/ topotecan in 513 patients evaluated but did not show better outcomes compared to the original. The Japanese group (JCOG0505) (68) compared standard with paclitaxel 135 mg/m2 +5AUC Complimentary Contributor Copy Management of cervical cancer 277 carboplatin and it found non-inferiority, so it is an alternative when taking into consideration of the toxicity profile. Second or third lines of palliative chemotherapy should consider prior options described but the most important is patient performance status and potential benefits.

Targeted therapy

Patients with metastatic disease not suitable to chemotherapy treatment has poor prognosis (10-13 months). The introduction new molecular targeted therapies had great expectations; however only a small proportion of solid tumors had spectacular results. Novel biological agent include epidermal growth factor receptor (EGFR) and angiogenesis inhibitors (VEGF), and targets of cyclooxygenase-2 (COX-2), mTOR, etc. In CC, EGFR positivity overexpression is detected between 6-90% associated with poor prognosis. (69, 70) Also, tyrosine kinase inhibitors (TKI) can be an option. Goncalves et al. reports efficacy and tolerability of 500 mg/day gefitinib in second-third-line treatment in a multicenter study with metastatic CC, 20% has stable disease, median duration of 111 days. Erlotinib is another EGFR inhibitor 150 mg/day achieved 16% stable disease with well tolerated. In a phase II trial Erlotinib has been considered as radiosensitizer with chemoradiation standard treatment with same dose as metastatic treatment, with 91% complete response, longer follow-up is needed (only 9 m). Lapatinib and pazopanib are dual TKIs targeting HER-1 and HER-2, and a study with combined drugs was cancelled for toxicity reasons; response rates observed using only one agent are 5% and 9%, respectively, with median OS 39 weeks and 51 weeks, superior rates than VEGF therapy (71). Cetuximab was well tolerated and led to 14% stable disease in a phase II with double chemotherapy in combination but was stopped due to excessive toxicity. Nimituzumab in a phase II with or without gemcitabine in second or third line was effective with little toxicity (72). Antiangiogenic drugs have been widely studied in metastatic CC. Physiopathological studies shows upregulation production of VEGF via HPV direct stimulation, overexpression oncogenic protein E6 in an independent p53 pathway (73). In a phase II GOG trial bevacizumab 15 mg/kg every three weeks in 46 patients, five partial responses and 11 cases of stable disease, average PFS 3.4 m. In a phase II, 240 patients compared: group 1- cisplatin + paclitaxel, group 2- cisplatin + paclitaxel followed bevacizumab, group 3- paclitaxel + topotecan and group 4- paclitaxel topotecan followed bevacizumab; increase OS 17m. vs 13.3 m, PFS 8.2 vs 5.3 m, with a tolerable increase of toxicity, in favor bevacizumab group (74). A phase II RTOG study evaluated bevacizumab as a radiosensitizer found OS rates of 81% and DFS of 68% 3 year, with tolerable toxicity, although thrombotic or fistulae events were not mentioned (75). Epigenetic therapy relies on the use of DNA methyltransferase (DNMT: decitabine, azacitdine) and histone deacetylase inhibitors (HDAC: vorinostat and depsipeptid) approved in different types of lymphoma. The interaction between HPV E6 and E7 proteins are considered in pilot study with hydralazine with cisplatin with 100% response. There is a randomized trial with preliminary good PFS and well tolerated, so these epigenetic targeted treatments could play a role in metastatic CC (76).

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Systemic therapy in special histologies

Small cell cervical carcinoma: Annual incidence small cell CC is 0.6 in 100,000 compared with 6.6. or 1.2 in squamous cell or adenocarcinoma types, respectively (77). This subtype is worse prognosis with higher lympho-vascular invasion, nodal and hematogenous dissemination, early metastasis, shorter 5-year OS 36% compared to 61-70% squamous cell (78). Treatment strategies are based on case reports, Zivanovic et al. studied chemotherapy the benefit even in early stages with good response 3-year DFS 83% vs 0% without chemotherapy. Cohen et al. analyzed 188 patients from different series using adjuvant chemotherapy in locally advanced stages was associated with better survival 18% vs 6%, p=0.04. The most frequently regimen was cisplatin+etoposide, VAC, carboplatin+placlitaxel (79, 80). Clear cell carcinoma only represents 4-9% of CC, mostly in young women and it is associated to in utero exposure of diethylstilbestrol, microsatellite instability, HPV infection, BCL-2 overexpression, and p53 mutation. There is no evidence in literature of worse prognosis and specific therapy are not being pursued (81, 82). Glassy cell carcinoma represents 1-5% of CC and is a poorly differentiated variant of adenosquamous presenting in young patients, with 45% having HER-2 overexpression and often recurrence at 2 years.

Follow-up

After treatment, it is very important to propose a follow-up plan with periodic consultations. The risk of recurrence is 70% in the first 2.3 years after diagnosis for locally advanced disease, even though probability decreases, it never reaches zero. Table 9 summarize the plan.

Table 9. Recommendations for patient follow-up

Procedure Frequency Patient orientation about signs and symptoms of recurrence At the end of the initial treatment Physical examination by an oncologist or a gynecologic oncologist Every 3 months during the first 2 years Every 6 months from years 3–5 Annually beginning in year 5 Tomography, bone scintigraphy, PET, PET/CT or MRI Only when symptoms are present Laboratory tests: complete blood count, blood chemistry, creatinine, Only when recurrence is suspected blood urea nitrogen and LFT Tumor markers Not recommended Scrutiny for other neoplasias, such as endometrial, ovarian or colon Annually cancer Patient education regarding symptoms of potential recurrence, After treatment and every 3 or 4 months as lifestyle, obesity, exercise, smoking cessation and nutrition necessary counseling Patient education regarding sexual health, vaginal dilator use, and After treatment and every 3 or 4 months as vaginal lubricants/moisturizers (e.g., estrogen creams) necessary

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Chapter 21

MANAGEMENT OF PROSTATE CANCER

Camila Casadiego Peña1,, MD, Maribel Bruna Figueroa1, MD, Hugo Marsiglia1, MD, Fiona Lim2, MBBS, Bo Angela Wan3, MD(C) and Maurício F Silva4,5,6, MD, PhD 1Radiation Oncology Fundacion, Arturo Lopez Perez, Santiago, Chile 2Department of Oncology, Princess Margaret Hospital, Hong Kong, PR China 3Odette Cancer Centre, Sunnybrook Health Sciences Centre, Toronto, Ontario, Canada 4Radiation Oncology Unit, Santa Maria Federal University, Santa Maria, Brazil 5Hospital de Caridade Astrogildo de Azevedo, Santa Maria, Brazil 6Latin America Cooperative Oncology Group

ABSTRACT

According to Globocan 2018, prostate cancer has the second cause incidence among all cancers in men and is the fourth cause of mortality. The treatment of prostate cancer should be done in a multidisciplinary manner and to define the best treatment strategy, the risk should be taken into account. Currently there are different therapeutic modalities for the integral management of prostate cancer, including active surveillance, wait and see, surgery, radiation therapy, hormone therapy, chemotherapy, and other novel treatments currently under study. With these different therapeutic modalities, good long- term oncological results have been achieved and adequate management in metastatic patients with an adequate quality of life. Since the treatment of prostate cancer is very extensive, this chapter will be divided into two, the first part will talk about prostate cancer as a primary treatment and the second part of the treatment of prostate cancer in the postoperative and metastatic context.

 Corresponding Author’s Email: [email protected]. Complimentary Contributor Copy 286 Camila Casadiego Peña, Maribel Bruna Figueroa, Hugo Marsiglia et al.

INTRODUCTION

According to Globocan 2018, prostate cancer has the second highest incidence in men and is the fourth cause of mortality. In Latin America, prostate cancer had an incidence of 60.4 per 100,000 inhabitants and a total of 14 per 100,000 inhabitants (1). There are several therapeutic modalities available for the management of prostate cancer, including active surveillance, wait and see, surgery, radiation therapy, hormone therapy, chemotherapy, and other novel treatments currently under study. We list and illustrate below each of these treatment modalities according to patient risk in prostate cancer as a primary treatment.

ACTIVE SURVEILLANCE

Active surveillance is defined as close follow-up, which aims at avoiding unnecessary treatments for patients who do not require immediate treatment while helping to choose the best moment in time to start curative treatment (4). It is recommended for patients with very low to low risk disease, but can also be considered for low-intermediate risk patients with a life expectancy of over 10 years. Follow up requires rectal examination at least once a year, Prostate-Specific Antigen (PSA) test at least every 6 months, yearly biopsies and multiparametric Magnetic Resonance Imaging (MRI), when available; the latter is useful to determine when the patient is facing radiological recurrence, although it is not considered an independent tool to decide whether a follow-up biopsy is needed, (2, 3). To date, there are no randomized clinical trials comparing this modality with standard threatment. Patients enrolled in the Prostate Testing for Cancer and Treatment (ProtecT) trial did not undergo active surveillance but Active Monitoring, with only PSA tested. When a > 50% elevation over twelve months was observed, a biopsy was repeated, but neither biopsies at fixed intervals nor basal or follow-up multiparametric MRI were performed. For these reasons, it was not considered to be active surveillance. Fifty-six per cent of patients enrolled in the study had low-risk disease. After 10-year follow-up, cancer-specific mortality was the same for patients receiving active monitoring and active treatment (99% and 98.8%, respectively) (5). Similar results were reported for overall survival. However, patients undergoing active monitoring had a higher rate of distant metastases compared to the group who received active treatment (6% vs 2.6% respectively). Nevertheless, it should be noted that postponed active treatment (either with active surveillance or active monitoring) is considered the standard treatment for very-low-risk and low-risk patients, thanks to the results of this study (5). Several cohort studies, a systematic review and a prospective series of active surveillance in men with low-risk prostate cancer showed that active surveillance yields good results both for overall and cancer-specific survival rates. However, it should be pointed out that over a third of the patients had to be restaged during follow up; of these, most needed active treatment, either for localized disease or progression of local and/or distant disease. For this reason any time a patient is offered this treatment strategy, he should be clearly informed of its risks and benefits. Furthermore, only patients who will really comply with the prescribed follow-up schedule should be chosen for this strategy (6-14).

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WATCHFUL WAITING

Watchful waiting is a valid alternative for prostate cancer patients who have less than 10 years’ life expectancy, regardless of disease risk or stage. It entails administering symptomatic treatment only, on areas that are causing some discomfort that affects the patient’s quality of life; it is therefore considered a treatment with palliative intent. This method aims at avoiding toxicity to patients who will die of other causes than prostate cancer (15). The difference between active surveillance and watchful waiting is that active surveillance is performed with curative intent in patients who have very-low- or low-risk and some low-intermediate-risk prostate cancer, applying a very strict follow-up to define what is the best time to start active treatment, while watchful waiting has palliative intent and is performed on any patient who has life expectancy of less than 10 years regardless of risk. Wait waiting studies have enrolled patients with up to 25-year follow up. Data analyzed by outcomes show that 10-year cancer-specific survival varies between 82-87% in some series, to 80-95% for T1/T2, grade <2 in others. A study also evaluated cancer-specific survival by differentiation grade; patients with well-, moderately- and poorly-differentiated cancer showed 10-year cancer-specific survival rates of 91%, 90% and 74%, respectively. Three studies with data collected over more than fifteen years showed disease-free survival rates of 80%, 79% and 58% respectively, with two of them reporting 20-year cancer-specific survival rates of 57% and 32%. The wait-and-see method was more effective in men aged 65 to 75 with low-risk prostate cancer (16-23). The ten-year results of 19,639 prostate-cancer patients aged over 65 who received no curative treatment were analyzed. Charlson’s comorbidity index was >2 in most patients, and < 1 in a minority of them. The results showed that most patients who had a comorbidity index >2 died of other causes than prostate cancer; tumor aggressiveness did not affect overall survival, showing that these patients could have avoided being biopsied for and diagnosed with cancer, while the men who had Charlson comorbidity index <1 had a low risk of death at ten years, especially those who had well- or moderately-differentiated lesions (24). These results show that avoiding biopsy could be considered for patients with a high comorbidity index. The SPCG-4 study, performed in the pre-PSA era, randomized patients to wait and see vs radical prostatectomy (25). With a median follow up of 13.4 years (range 3 weeks-23.2 years), the results showed that radical prostatectomy is superior in both overall and disease- free survival. Another trial that also compared these two treatment modalities was the PIVOT study, which randomized 731 men (50% with non-palpable disease). Unlike the SPCG-4 trial, this study found no benefit for radical prostatectomy, with mean follow up of 12.7 years (interquartile range, 7.3-15.5 years). Patient analysis showed that only patients with serum PSA >10 ng/ml or with high-risk prostate cancer received a benefit in terms of overall survival with prostatectomy, reducing mortality by 33% and 31% respectively. Likewise, it was reported that patients who underwent radical prostatectomy also showed a lower incidence of bone metastases (4.7% vs 10.6%). However, a strong criticism to the PIVOT trial is the high mortality rate (almost 50%) registered in the wait-and-see group, over a median ten-year period (26, 27). For this reason, this treatment modality should be reserved to

Complimentary Contributor Copy 288 Camila Casadiego Peña, Maribel Bruna Figueroa, Hugo Marsiglia et al. well-selected patients ascertaining by comorbidity index that the patient really has a short life expectancy.

SURGERY

The surgical treatment planned for prostate-cancer patients is radical prostatectomy, first described by Young in 1905. It consists of an excision of the entire prostate with its capsule in one piece and of the seminal vesicles, followed by vesicourethral anastomosis, and, for some patients, by nodal dissection (28, 29). There are three techniques open, laparoscopic or robot-assisted to perform a prostatectomy. The surgical approach for open prostatectomy can be either retropubic or perineal. The procedure is the same for both approaches and consists of the resection of the prostate and its surrounding capsule together with seminal vesicles, ampulla and vas deferens. The prostate should be completely resected by excising the urethra in the prostatic membranous junction without leaving any residual prostatic tissue at the apex (29). Over the last few years the use of laparoscopic or robot-assisted prostatectomy has been increasing. A three-arm robot is used: one arm controls the binocular endoscope and the other arms control small-doll tools. The entire system is controlled by the surgeon, who can be positioned away from the patient. The surgeon has a stereoscopic view of the operating field, which offers a tridimensional tenfold vision, and more precise movements, while eliminating physiologic trembling (29). The literature comparing these three surgical methods reports contradictory results. A phase-III randomized trial proved that robotic prostatectomy decreased hospitalization length and blood loss, but early oncological and functional results assessed 12 weeks after surgery were similar to those reported with open prostatectomy (30). A later analysis after 24 months did not show different functional results (31). There are two metanalyses that assess the different treatment techniques. A metanalysis of non-randomized controlled trials showed that robotic prostatectomy had lower peroperative morbidity and lower risk for positive surgical margins compared to laparoscopic prostatectomy, but there was no difference regarding 12-month urinary incontinence (32). The other metanalysis included two small randomized clinical trials that compared robotic versus laparoscopic prostatectomy, showing higher recuperation rates for erectile function (Relative Risk [RR]: 1.51; Confidence Interval [CI] 95%: 1.19-1.92) and urinary continence (RR: 1.14; CI 95%: 1.04-1.24) for the robot-assisted procedure (33). However, a recent Cochrane review comparing robot-assisted or laparoscopy-assisted prostatectomy versus open prostatectomy that included two randomized clinical trials did not find any significant differences with regards to urinary or sexual functions, while confirming that patients undergoing robot-assisted or laparoscopy-assisted prostatectomy had shorter hospital stays and needed fewer transfusions compared to those who received open prostatectomy (34). Studies comparing long-term results with these three methods are needed. Reports comparing surgical techniques further noted that the surgeon’s experience can also affect oncological results (35-41). Table 1 summarizes the main articles on prostatectomy.

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Table 1. Randomized studies on prostatectomy

Author Acronym Median Risk group Arms Outcome follow up (months) Bill-Axelson SPCG-4 283 Low and Surgery  Death of prostate cancer at 18 years:17.7% et al. 2018 intermediate (n=347) vs surgery vs 28.7% wait and see (p=0.001) (39) wait and see  Distant metastases: 26.1% surgery vs 38.3% (n=348) wait and see (p=<0.001)  Disease progression:40% surgery vs 60% wait and see  Larger recourse to palliative care in the wait-and-see arm than in the surgery arm Wilt et al. PIVOT 152 All groups Surgery  Death of prostate cancer at 19.5 years:7.4% 2017 (40) (n=364) vs surgery vs 11.4% wait and see (p=0.06) wait and see  Lower mortality by all causes: Only in the (n=367) intermediate-risk group CI 95%, 2.8 to 25.6  Fewer treatments for disease progression in the surgery arm (CI 95%, 19.0-32.9)  Higher 10-year urinary-incontinence and erectile-dysfunction rates in the surgery arm  Daily activities were more limited in the surgery arm up to 2 years after

A systematic review on pelvic lymph nodes dissection showed that it has a role in the adequate staging and prognosis of patients, although it does not improve oncological results (42). There are several nomograms that help predict which patients may have positive nodes before surgery is performed, among them those by Briganti, Partin and the Memorial Sloan Kettering Cancer Center (MSKCC) (43). These nomograms were evaluated in a systematic review and a metanalysis; their precision in diagnosing nodal involvement was similar to that of surgery. When these nomograms are measured preoperatively and the patient has a >5% risk of nodal metastases, nodal dissection is indicated (44-46) When indicated, nodal dissection should be extended to include external iliac, internal iliac and obturator nodes, as this leads to correct staging in 94% of patients (47). There is at present no consensus on the recommended minimum number of nodes to be removed. Sentinel node biopsy could be a good solution to avoid nodal dissection. However, there are no quality proofs as yet to confirm its oncological efficacy in the nodal staging of prostate cancer and it is therefore not considered a standard procedure (48).

Complications of surgery

The most common postoperative complications are incontinence and erectile dysfunction. When comparing complication rates with different treatment techniques, a systematic review reported 12-year mean continence rates of 89-100% for robot-assisted procedures and of 80-97% for non-robotic prostatectomy. However, most of these studies were retrospective. A non-randomized controlled prospective study assessed urinary incontinence and erectile dysfunction in fourteen centers performing open or laparoscopic prostatectomy. Twelve-month urinary incontinence was similar with both procedures, 21.3% with Complimentary Contributor Copy 290 Camila Casadiego Peña, Maribel Bruna Figueroa, Hugo Marsiglia et al. laparoscopy-assisted and 20.2% with open prostatectomy. Adjusted Odd Ratio (OR) was 1.08 (CI 95%: 0.87-1.34). Erectile dysfunction rates were 70.4% and 74.7%, respectively, with an adjusted OR of 0.81 (CI 95%: 0.66-0.98) (49). Complications after dissection have been reported to increase morbidity for prostate cancer treatment, with higher complication rates in patients undergoing dissection compared to those who do not (19.8% vs. 8.2%), lymphocele being the main complication (42).

HORMONE THERAPY

Hormone therapy plays a very important role in prostate cancer treatment, since it helps decrease the size of the prostate and can improve oncological outcomes although its use alone is not curative, as explained later on. There are two modalities to achieve androgen deprivation: suppression of testicular androgen production and inhibition of circulating- androgen activity at receptor level. These two methods can be used together to achieve a state known as combined androgen blockade (50). It is important to define when the patient reaches castration levels, since this can help determine which patients are to be considered castration-resistant. In order to achieve castration, a patient’s testosterone level has to be <50 ng/dL (1.7 nmol/L). Current methods, however, have shown that the mean value after surgical castration is 15 ng/dL (51), therefore, a more appropriate level should be defined as <20 ng/dL (1 nmol/L). Clinical trials, however, accept castration testosterone levels of <50 ng/dL (1.7 mmol/L) (52-54).

HOW TO ACHIEVE CASTRATION

Castration can be obtained either by surgical procedure or through drugs.

Surgical procedures

Bilateral orchiectomy is a simple, inexpensive complication-free surgical procedure . It consists of the removal of both testicles while preserving the scrotum. It can be performed under local anesthesia and it is the quickest way to obtain some level of castration, usually within twelve hours. It is considered an irreversible method (55).

Drugs

1) Estrogens: When castration is achieved with estrogens, these cause testosterone suppression not associated with bone loss. However, patients can manifest serious side effects, thromboembolism being the most common one. For this reason, they are not used as first-line treatment (56-59). 2) Luteinizing-Hormone Releasing-Hormone Agonists: Luteinizing-Hormone Releasing-Hormone (LHRH) agonists are drugs that act at central level Complimentary Contributor Copy Management of prostate cancer 291

(hypothalamus-hypophysis axis). They achieve their effect by way of a negative regulation of LHRH receptors and their continuous administration suppresses the secretion of Luteinizing Hormone (LH), testosterone, estrogens and serum alkaline phosphatase (60). However, it is important to remember that at the start of treatment there is a peak in the secretion of LH, testosterone, acid phosphatase and PSA (during the first two or three weeks of treatment), which can exacerbate symptoms and increase the risk of complications secondary to prostate growth or metastases (e.g., a patient with medullary compression secondary to testosterone blockade) (17). For this reason, the patient should receive antiandrogens for at least a month before starting LHRH-analogue treatment, in order to avoid these complications (61). Long-acting LHRH agonists are currently the main form of Androgen Deprivation Therapy (ADT). These synthetic LHRH analogues are injected every 1, 2, 3, 6 or 12 months and castration is achieved approximately after two to four weeks (62, 63). Although no formal direct comparison between the different compounds has been made, they are considered equally effective and at least comparable to orchiectomy (64, 65). These drugs include goserelin acetate, histrelin acetate, leuprolide acetate, and triptorelin pamoate, among others (66). 3) Luteinizing Hormone Releasing-Hormone antagonists: These drugs link immediately to LHRH receptors, causing a fast decrease in LH, Follicle-Stimulating Hormone (FSH) and testosterone levels. These drugs do not cause a LH-secretion peak and castration is achieved by the third day of administration. A drug listed in this group, Degarelix, is administered intravenously; its major disadvantage is that there is no prolonged-action formulation; so far only monthly formulations exist. A systematic review did not show any differences between LHRH agonists and antagonists. (67). 4) Anti-androgens: This type of hormone therapy antagonizes androgens at receptor level through a competitive-antagonism mechanism. They are oral drugs classified as steroidal and non steroidal (66). 5) Steroidal Antiandrogens: These compounds are synthetic derivatives of hydroxyprogesterone. They have a double effect, since they can act at peripheral level, by interfering with the activation of androgenic receptors, and at central level, by blocking the secretion of gonadotropins through negative feedback, since they have a progesterone-like action (68). Their main side effects are gynecomastia (rare occurrence) and problems to the liver and cardiovascular systems. Patients may manifest up to 40% risk of liver alterations; for this reason, they are not habitually used. Among the drugs in this group is cyproterone acetate, which achieves castration in 14 days (66). 6) Non-steroidal Anti-androgens (Gonadotropin Releasing Hormone [GnRH]- analogues): This treatment has the advantage that it does not suppress testosterone secretion, thus there is no sexual deficiency, nor alterations of bone density or physical performance. The main non-steroidal antiandrogen is bicalutamide, which is administered at a dose of 50 mg/day to manage the initial effect achieved with luteinizing hormone releasing hormone agonists and at a dose of 150 mg as monotherapy for prostate-cancer patients where castration is the expected outcome. The main side effects are gynecomastia (70%) and breast pain (68%), but it has been

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reported to offer an important bone protection compared to LHRH analogues and probably to LHRH antagonists as well (69, 70). 7) Steroidogenesis inhibitors: These drugs inhibit cytochrome p450, interfer ing with androgen synthesis in the adrenal gland. They are used assecond-line treatment; the main compounds in this group are ketoconazole and aminoglutethimide (66).

When administering hormone treatment, castration-resistant patients should be taken into account. They are defined as patients who, while receiving hormone therapy and achieving testosterone castration levels of <50 ng/dL, present either biochemical progression, measured in three different tests taken a week apart from each other or radiological progression. The latter is the appearance of new lesions either detected on a bone scan or a soft-tissue lesion defined according to RECIST (Response evaluation criteria in solid tumors) criteria (51-54, 71). In order to offer alternative treatments for these patients, new compounds have been found for their condition, among them:

1) Abiraterone Acetate: It is a CYP17 inhibidor that significantly decreases testosterone intracellular levels by suppressing its synthesis at adrenal level. It is a drug that should be prescribed in association with prednisone/prednisonlone to avoid drug- induced hyperaldosteronism (48). 2) Enzalutamide: It is a new anti-androgen characterized by a higher affinity for androgen receptors than bicalutamide. This drug competitively inhibits the binding of androgens to androgen receptors, the nuclear translocation of activated receptors and the association of the activated androgen receptor with DNA (48).

Table 2. First- and second-line treatments (48)

First-line treatment Second-line treatment  Orchiectomy  Steroidogenesis inhibitors  Luteinizing-Hormone Releasing-Hormone Agonists  Abiraterone Acetate  Luteinizing-Hormone Releasing-Hormone  Enzalutamide Antagonists

Table 2 shows which drugs are used as first-line hormonal treatment and which are used as second-line treatment.

Ways of Administration of Hormone Therapy

1) Continuous: Hormone therapy is administered without interruptions from diagnosis through disease evolution, until the patient progresses to a hormone-resistant stage or dies (66). 2) Intermittent: It is characterized by periods with and without treatment. When this kind of blockade is administered, every 3 to 6 months the patient undergoes blood tests for PSA and testosterone, as well as an assessment of his clinical symptoms for the early detection of any disease progression (72).

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The main objective of this modality is to reduce the toxicity induced by hormone therapy since, when hormonal blockade is suspended, testosterone levels increase, thus improving quality of life for a while. This hormone blockade is obtained by continuous administration of the treatment for nine months, followed by a suspension of the hormone therapy, during which tests are repeated every 3-6 months.When there is a PSA increase of > 4 ng/mL (range, 4-15 ng/mL) in non-metastatic disease, or > 10 ng/mL (range 10-20 ng/mL) in metastatic disease, the hormonal treatment should be reinstated (48, 73). It is important to remember that patients with extensive metastatic disease are not eligible for this treatment, since they will progress rapidly (48).

RADIOTHERAPY

External-beam radiotherapy

There are different techniques for the administration of external-beam radiotherapy for prostate cancer, the gold standard being IMRT (Intensity-Modulated Radiation Therapy). When using this technique, the movement of the prostate should be taken into account, since it can increase toxicity due to the possibility that the treatment is not administered where it should. For this reason, IMRT for prostate cancer is administered as image-guided radiotherapy (IGRT), which allows the visualization and real-time correction of organ movements (48, 73).

IGRT

Image-guided radiotherapy (IGRT) resulted from different doubts arisen during radiotherapy treatments for prostate-cancer patients regarding volume contouring due to the patient’s change of position and tumor variation. Image-guided radiotherapy identifies daily where the tumor is, allowing for positioning corrections during treatment, which is very important in prostate cancer. Because of the localization of the prostate, it has been reported that it can change position due to anatomical changes. This should be taken into account since complication rates during radiotherapy can increase, the position of the prostate varying so much. Healthy gastrointestinal and urinary tissues may be irradiated instead of the tumor, which increases toxicity and reduces local control. Two concepts should be remembered: interfraction movement, which is the movement of the prostate during the days of treatment, and intrafraction movement, which is the movement of the prostate during treatment administration. It has been reported that IGRT can solve all these problems, therefore smaller planning margins can be used while guaranteeing higher safety with the use of modern radiation (74). One of the most common ways to use IGRT in prostate cancer is by radio-opaque intraprostatic markers, whose use has become increasingly important thanks to their low cost, easy usage and limited interobserver variability (75). It is recommended to implant three radio-opaque markers, such as gold seeds or coils, at the periphery of the prostate two at the

Complimentary Contributor Copy 294 Camila Casadiego Peña, Maribel Bruna Figueroa, Hugo Marsiglia et al. base and one at the apex, via a transrectal or transperineal approach. It has been reported that these markers stay stable inside the prostate with a mean shift of 1.01-2.8 mm (76-79). Daily IGRT is performed by taking either portal or volumetric images. When portal images are used, corrections can be made to match the position of the markers with digitally- reconstructed radiograms, while volumetric images require corrections by displacing the mass based on the position of three-dimensional markers, thus decreasing interobserver variability (80). The most common imaging system is Cone Beam Computed Tomography (CBCT), provided that the accelerator has it. It offers excellent space resolution, which helps to carry out a daily evaluation and correction of the positioning, identifying tumor-related anatomical changes and organs at risk during treatment fractionation (74). It has been reported that in prostate cancer the administered dose plays a very important role in terms of oncological outcomes, as a higher dose yields fewer biochemical recurrences. It has also been reported that, due to its characteristics, the prostatic tissue responds better to a hypofractionated treatment. Dose escalation and hypofractionation are discussed below.

Table 3. Randomized trials of dose escalation in prostate cancer

Study Arms Patient Follow up Outcomes characteristics (mean) PROG 95-09 70.2 GyE (n=196) All 8.9 years  Allpatients: biochemical failure 32% with 2010 (83) vs 70.2Gy vs 17% with 79.2Gy (p<0.0001) 79.2 GyE (n=195)  Low-risk patients: Bio-chemical Proton study failure28% with 70.2Gy vs 7% with 79.2 (p<0.0001) MD 70Gy (n=150) All risk groups 9 years  High risk/PSA> 10 Anderson vs  Cancer specific mortality: 16% with 70 2011 (82) 78Gy (n=151) Gy vs 4% with 78 Gy (p = 0.05)  Patients with initial PSA > 10 ng/mL had significantly more PSA (p= 0.013), nodal (p= 0.030) and distant (p= 0.016) failureswhen receiving 70 Gy than 78 Gy GETUG 06 70 Gy (n=153) All risk groups 6 months  5-year biochemical recurrence rate was 2011(86) vs 39% and 28% in the 70Gy and 80Gy 80 Gy (n=153) arms, respectively  (p = 0.036) MRT RT01 64Gy (n= 421) All risk groups 10 years  Biochemical recurrence free survival 43% 2014 (103) vs with 64 Gy vs 74 Gy (n= 422)  55% with 74 Gy  (p = 0.0003)  Overall survival: 71% in both groups (p = 0.96) Dutch 2014 68 Gy (n=332) vs All risk groups 110 months  No biochemical or clinical failure 43% (87) 78 Gy (n=337) with 68 Gy vs49% with 78 Gy (p= 0.045) RTOG 0126 70.2 Gy (n 751) vs All risk groups 100 months  Overall survival: 75% with 70.2 Gy vs 2018 (81) 79.2 Gy (n= 748) 76% with 79.2 Gy (ns)  Distant metastases: 6% with 70.2 Gy vs 4% with 79.2 Gy (p = 0.05)  Biochemical progression free survival: 47% with 70.2 Gy vs 31% with 79.2 Gy (p <0,001)  Phoenix, p <0.001

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Dose escalation

The optimal dose for the management of prostate cancer has been studied in several studies. Seven randomized clinical studies showed that dose escalation, defined as a maximum dose to the prostate between 74 and 80 Gy has a statistically-significant impact on 5-year biochemical recurrence. It is important to bear in mind that these studies included patients of any risk group, receiving different kinds of hormonal treatment (see Table 3) (81-87). There is no randomized clinical trial showing that dose escalation impacts outcome; however, a population retrospective study carried out in the US on 42,481 patients showed that high-intermediate-risk patients may benefit from dose escalation (88). It has been reported that when dose-escalation IMRT and IGRT external-beam radiotherapy (EBRT) is performed, > grade 3 rectal toxicity is possible in 2-3% of cases and some genitourinary toxicity in 2-5% of cases (84, 87, 88-103). It should be remembered that any time dose escalation is considered, it should be performed together with IMRT and IGRT (48).

Hypofractionation

Several studies have been performed on prostatic cancer, and it has been observed that it is a slowly-proliferating tumor. This finding led to studies on whether an increase in the dose per fraction may yield better oncological outcomes, since slowly-growing tumors respond better when receiving high fractions (29, 104). This theory was assessed in a meta-analysis of 25 studies with >14,000 patients. It concluded that hypofractionation may be more effective than conventional fractionation, prostate cancer being a tumor with as low proliferation rate (105). Several studies have demonstrated the role played by hypofractionation in prostate cancer; these studies are listed in Table 4. Since it has been reported that hypofractionation is a safe treatment yielding oncological outcomes similar to those observed with conventional dose per fraction, a systematic review assessed an increase in the dose per fraction using a moderate dose between 2.5-4 Gy per fraction. The review that revised the studies showed that, although this dose per fraction may be safe, there are still not enough data on long-term follow-up to evaluate its full effectiveness. It is important to keep in mind that when moderate hypofractionation is performed, IGRT and IMRT should always be used and patient should be accurately selected, who meet the characteristics of the patients included in the phase-III studies listed in Table 4 (106-112). Stereotactic radiotherapy (SBRT) is becoming more and more popular. This treatment entails a dose per fraction of over 3.4 Gy (113). When this treatment is administered, it shoud be performed with daily IGRT. As for oncological outcomes, biochemical control is similar to that achieved with conventional fractionation, while a study with a 10-year follow up showed low toxicity in low-risk prostate-cancer patients treated with SBRT (114). Similarly to moderate hypofractionation, SBRT should be administered selecting patients according to the criteria established in the studies carried out with this technique, in order to avoid unwanted negative outcomes; these are shown in Table 5. To date, it is considered a definitive treatment option for very low- to low-risk prostate-cancer patients who do no wish or are not considered eligible for active surveillance, provided the radiotherapy center has the necessary tools for Complimentary Contributor Copy 296 Camila Casadiego Peña, Maribel Bruna Figueroa, Hugo Marsiglia et al. the procedure. In intermediate- or high-risk patients it is only considered as boost to the prostate, while SBRT as definitive treatment in this group of patients can only be considered within a clinical trial (48, 115-117).

Table 4. Randomized clinical studies of moderate hypofractionation for prostate cancer

Study Arms Patient Hormone RT/BED Follow up Outcomes characteristics therapy (mean) Aluwini, et al. 39 fractions of 2 Intermediate LHRH Total dose 78 Gy 60 months 5-year biochemical 2015, 2016 Gy (n=391) vs and high risk analoguein (BED:78Gy) vs recurrence free HYPRO (106- 19 fractions of most cases 64.6 Gy (BED: survivalwas 80.5% 108) 3,4 Gy with a 90.4 Gy) with median of 32 hypofractionation months and 77.1% with conventional fractionation

Toxicity: acute gastro-intestinal toxicity higher with hypofractionation, no difference in chronic toxicity Lee,et al. 2016 41 fractions of Low risk No Total dose: 73.8 70 months 5-year progression (109) 1.8 Gy vs 28 Gy (BED=69.3 free survivalwas fractions of 2.5 Gy) vs 70 Gy 86.3% vs 85.3% Gy (BED=80Gy) (ns) Dearnaley et al. 37 fractions of 2 All risk groups 3 to 5 Total dose: 74Gy 62 months 5-year clinical- or CHHiP 2012 Gy (n=153) vs months (BED= 74 Gy), biochemical-failure and 2016 (110, 20 fractions of 3 before and 60 Gy (BED= free survival 85.9% 111) Gy (n= 153) vs duringextern 77.1 Gy) 57 Gy (19 fractions) 90.6% 19 fractions of 3 al-beam (BED73.3 Gy) (20 ff) and 88.3% Gy (n= 151) radiation (37 ff) (ns) No difference in acute or late toxicity Catton et al. 39 fractions of 2 All risk groups No 78Gy (BED: 78 72 months 5-year biochemical 2017 (112) Gy (n=598) vs Gy) vs 60 Gy recurrence free 20 fractions of 3 (BED= 77.1 Gy) survival 85% in Gy (n=608) both groups (p=0.96)

Table 5. Randomized clinical studies on extreme hypofractionation in prostate cancer

Study Patients Patient characteristics Radiotherapy Follow up Results Freeman, et 1743 41% low risk 35-40 Gy/4-5 - 92% Free of biochemical al. 2014 (116) 42% intermédiate risk fractions recurrence after 2 years. 10% high risk (8% SBRT-boost 99% low-risk group 7% missing data 19.5-21.8 Gy/3 97-85% intermediate risk group fractionsafter 45- 87% high risk group 50 Gy EBRT) Katz et al. 515 63% low risk, 30% 35-36,25 Gy in 5 72 months Free of biochemical recurrence 2014 (117) intermediate risk fractions after 7 years: and 7% high risk 96% low risk group, 89% intermediate riskgroup and 69% high risk group

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Table 6. Randomized clinical studies on the use of hormone therapy with radiotherapy

Study Arm Patient characteristics Results Mottet N, et al. 70 Gy 3DCRT with hormone T3-T4N0M0 Significant decrease in5-year clinical 2012 (118) therapy vs hormone therapy progression rate. OS: 71.4% vs. 71.5% with LHRH agonist alone for 3 years PRO7/NCIC 65-70 Gy 3DCRT T3-T4, PSA > 20 10-year OS: 49% vs 55% in favor of 2011 and 2015 +continuous LHRH agonist ng/dl, Grade group 4- combined treatment (p<0.001) (119, 120) vs hormone therapy alone 5 N0M0 SPCG-7/SFUO-3 70 Gy 3DCRT with LHRH T1b-2 OMS Grade 1- Cancer-specific mortality: single 2016 (121) agonist during 3 months 3, T3 N0 M0 treatment 34% (CI 95%: 29-39%) vs. +continuous flutamide vs combined 17% (CI 95%: 13-22% at 12 hormone therapy alone years (p <0.0001 for 15 year results)

Hormone therapy and radiotherapy

Table 7. Randomized clinical studieson the use and duration of the hormone therapy

Study Arms Patient characteristics Results RTOG 85-31 2005 (122) 65-70 Gy +hormone therapy with T3 or N1M0 The significant benefitfor the orchiectomyorLHRH agonist vs combined treatment is higher RT alone in patients with grade groups 2-5 (p = 0.002) RTOG 9413 2007 (123) 2 months of neoadjuvant + T1c-4N0-1M0 No significant differences concomitant treatment vs 4 months adjuvant treatment. All received 70.2 Gy RT to pelvis and prostate RTOG 86-10 2008 (124) 65-70 Gy concomitant with T2-4 N0-1 No significant differences at Gosereline + flutamide 2 months 10 years vs RT alone D’Amico 2008 (125) Hormone therapy with LHRH T2N0M0 Significant benefit for the agonist + 70 Gy 3D CRT vs RT combined treatment (p=0.01) alone RTOG 92-02 2008 (126) Short vs prolonged hormone T2c-4 N0-1 M0 Only significant benefit in therapy with LHRH agonists. All grade 4 and 5 groups(p = pts received 65-70 Gy 0.044) (p = 0.0061) EORTC 22961 2009 Short (6 months) vs prolonged (3 T1c-2ab N1 M0, T2c-4 Betterresults with three years (127) years) hormone therapy with N0-1M0 of treatment with a 3.8% LHRH agonists. All pts received improvement in 5-year OS 70 Gy EORTC 22863 2010 LHRH agonist for 3 years + 70 Poorly-differentiated Significant benefit at 10 years (128) Gy RT vs RT alone T1-2 M0, or T3-4 N0-1 for the combined treatment M0 (HR: 0.60, CI 95%: 0.45- 0.80, p = 0.0004). TROG 9601 2011 (129) Neoadjuvant and T2b-4 N0M0 No benefit in OS, benefit in concomitantGoserelin + cancer-specific survival flutamidefor 2 or 6 months. All (p=0.004) pts received66 Gy with 3D CRT RTOG 99-10 2015 (130) LHRH agonist 8 + 8 vs. 8 + 28 Intermediate-risk (94% No significant differences wees. All pts received70.2 Gy T1-T2, 6% T3-4) 2D/3D

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Several phase-III randomized clinical studies have been performed, showing the superiority of radiotherapy with hormone therapy compared to radiotherapy alone in terms of biochemical recurrence. These studies are listed in Table 6. The duration of hormone therapy was also assessed in phase-III randomized clinical studies; the results were that low-risk patients do not need hormone therapy, intermediate-risk patients should receive hormone therapy for 6 months, while high-risk patient should be treated for 2-3 years. Table 7 summarizes these studies (118-130). Based on what previously discussed, the potential results of dose escalation with hormone therapy were evaluated. Three randomized clinical studies listed in Table 8 were performed to answer this question. They showed that hormone therapy offers a benefit in the treatment of prostate-cancer patients independently of dose escalation, but hormone therapy does not balance out with low-dose radiotherapy (31, 32, 94).

Table 8. Randomized clinical studies on the use of hormone therapy and dose escalation

Study Results GICOR (94) Better biochemical-recurrence free survival in high-risk patient who received a dose >72 Gy and long-term hormone therapy DART01/ 05GICOR (131) 2-year adjuvant hormone therapy combined with high-dose RT improved biochemical control and overall survival in high-risk patients EORTC 22991 (132) 6-month hormone therapy improved clinical and biochemical-recurrence free survival independently of the dose (70, 74, 78 Gy) in high-risk and intermediate-risk patients

Therapy with proton beam irradiation

To date, one randomized clinical trial has been carried on to evaluate the benefit of increasing the dose using protons (70.2 vs. 79.2 Gy). This trial shows that so far protons are not superior to photons (82). As for toxicity, two studies have not shown protons superiority to photons either (133, 134). There are several trials currently ongoing comparing protons to IMRT; it is necessary to wait for the results of these trials to draw any solid conclusions.

Brachytherapy

Brachytherapy in prostate cancer can be administered using either low-dose-rate or high- dose-rate sources.

Low-Dose-Rate (LDR) Brachytherapy When planning this treatment, radioactive seeds are used that are permanently implanted inside the prostate. It is important to remember that this type of treatment cannot be administered to all patients therefore an adequate selection is needed. Patients eligible for this type of treatment are patients with tumors stages cT1b-T2a N0, M0; grade group 1 with <50% of biopsy nuclei positive for cancer or grade group 2 with <33% of the nuclei involved; an initial PSA level of <10 ng/mL; a prostate volume of <50 cm3; an international prostatic

Complimentary Contributor Copy Management of prostate cancer 299 symptom system (IPSS) score of <12 and a maximum flow rate > 15 ml/min in urinary flow tests (135, 136). There is a growing series of large cohort studies with long-term follow up assessing this treatment. They show that the dose administered relates to biochemical control, so that if D90 (the dose covering 90% of the prostate volume) is > 140 Gy, a significantly higher biochemical control (PSA <1.0 ng/mL) is achieved after four years (92 vs. 68%) (136-144). The addition of hormone therapy has been studied to asses if it improves oncological outcomes but so far no benefits have been found (137). Low-dose-rate brachytherapy can be combined with EBRT in intermediate/high-risk patients.

High-dose-rate brachytherapy High-dose-rate (HDR) brachytherapy uses a radioactive source temporarily introduced in the prostate to adminster the radiation. High-dose-rate brachytherapy can be administered either as a single fraction or in multiple fractions and it is often combined with external-beam radiotherapy (146). Just like LDR, HDR brachytherapy should be administered to well- selected patients applying the same criteria mentioned above for LDR brachytherapy. To date, there is only one randomized clinical trial of external-beam radiotherapy (55 Gy in 20 fractions) versus external-beam radiotherapy (35-75 Gy in 13 fractions) followed by HDR brachytherapy (17 Gy in two fractions for 24 hours) (147), which enrolled 218 patients with prostate cancer limited to the organ. The results showed that external-beam radiotherapy with brachytherapy significantly improves biochemical-recurrence-free rates (p = 0.04) both after five and ten years (75% and 46% compared to 61% and 39%) (147). A systematic review of non-randomized clinical studies showed that patients treated with external-beam radiotherapy plus HDR brachytherapy have better results than patients treated with brachytherapy alone, however, randomized clinical trials needed to confirm these results (148). It is possible to offer fractionated HDR brachytherapy as monotherapy to low- and intermediate-risk prostate-cancer patients. However, it is important to remember that only limited series from very experienced centers have been published. With regards to oncological outcomes, 5-year PSA-control rates over 90% have been reported, with grade-3+ late genitourinary toxicity rates <5% and little to no grade-3+ gastrointestinal toxicity rates (149, 150).

How to perform brachytherapy (48) First of all, a transrectal ultrasound is taken, which will help decide whether the prostate size is ideal for brachytherapy. Ideally, a pre planning should be performed, to identify the tumor location and the characteristics of the patient’s prostate, as well as to evaluate where to position the needles for interstitial brachytherapy, so as to offer the patient the better treatment plan. When everything is ready, interstitial needles are positioned under ultrasound guidance using a trans-perineal template based on the pre planning coordinates. In order to define how the radiation is going to be administered, it is important to bear in mind that it depends on the brachytherapy equipment available: LDR or HDR (48). LDR:

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 Permanently-implanted seeds.  Irradiation dose administered over weeks or months.  Acute side effects solved over a period of a few months.  Radiological-protection problems, both for the patient and his caregivers.

HDR:

 Temporary implantation  Irradiation dose administered in a few minutes.  Acute side effects solved over a period of a few weeks  No radiological-protection problems, for either the patient or his caregivers.

Side effects of external-beam radiotherapy and brachytherapy

The most common side effects when external-beam radiotherapy is performed in combination with brachytherapy are at gastrointestinal and urinary levels. With regards to external-beam radiotherapy, EORTC trial 22991 showed that approximately 72% of patients complained of acute genitourinary toxicity (grade 1 50%, grade 2 20%; grade 3 2%) (94). The same trial showed approximately 30% grade-1, 10% grade-2 and less than 1% grade-3 gastrointestinal toxicity. As for brachytherapy, a randomized clinical trial showed that the incidence of acute proctitis decreased in the LDR-brachytherapy arm, but other acute toxicities were equivalent (151). There are no randomized clinical studies on acute toxicity for HDR brachytherapy, but retrospective reports confirmed that gastrointestinal toxicity rates are lower than those for external-beam radiotherapy and grade-3 genitourinary toxicity only occurs in 10% of patients or less (152).

Radiotherapy techniques

All patients should be positioned fiducial markers for IGRT (if the hospital does not have IGRT, fiducial markers can be dispensed with) and approximately a week (7 to 10 days) later CT simulation should be carried out. The night before CT simulation, the patient should prepare his intestines, emptying his rectum, thus avoiding a larger prostate movement and at the same time trying to reduce rectal toxicity. This preparation should be established in a protocol for each center. The bladder, on the other hand, should be comfortably full, to reduce the prostate movement and avoid urinary toxicity (29). During simulation, the patient lies supine, with his arms overhead, wearing a knee brace to avoid pelvic movement. The simulation position should be comfortable, since it is the same the patient will stay in during the entire treatment and if it is not comfortable for the patient the treatment will not be reproducible. A simulation CT scan is taken leaving 20 to 30 extra cm around the prostate, with an image thickness of 3 mm (29).

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Volume delimitation depends on the patient’s risk group, and the margins for the planning target volume (PTV) depend on whether fiducial markers were placed. The following Table 9 is a description of how volume contouring should be (29).

Table 9. Treatment volumes by risk

Risk Volumes Very low risk, low Only the prostate is contoured, without the seminal vesicles risk Intermediate risk The entire prostate is contoured and half of the seminal vesicles High risk The entire prostate is contoured, all seminal vesicles and the pelvis PTV In order to define the margins the above-mentioned volumes will be given to create the PTV the presence or absence of fiducial markers should be taken into account:  Without fiducial markers: 1 cm all around (it can be reduced to 0.8 or 0.5cm on a case-by- case basis) and 0,5 around the rectum  With fiducial markers: 0,5 in all directions (it can be reduced to 0.3cm at the back, to protect the rectum, if intrafraction follow up is used) It is important to remember that these margins may change according to each institution’s protocol SBRT with  Fiducial markers are placed in the prostate intrafraction  GTV (Gross Tumor Volume): Only the prostate follow up  CTV (Clinical Tumor Volume): Ideally no safety margin should be give to the CTV, unless this is considered the GTV itself, thus avoiding dose delivery to healthy tissues. This is important since the dose delivered with SBRT is very high. In case of intermediate risk, irradiating the proximal third of the seminal vesicles should be evaluated, while in case of extracapsular involvement, the area at risk should be added  PTV: A small margin should be given to the PTV according to institutional protocols, ideally it should be 3-5 mm NOTE: If a high-risk of uncertainty is suspected, it is better to avoid using this technique Organs at risk Femoral heads To determine the constraints to be used, an institutional protocol should establish the dose to be Rectum delivered, keeping in mind the type of technique: hypofractionation, dose escalation or SBRT. Bladder Based on this, a guideline should be chosen to establish the constraints to be used in the different Intestinal bowel organs at risk. Bulb of the penis

Nodal drainage

Prophylactic nodal irradiation in prostate-cancer patients with negative nodes is controversial, since randomized clinical trials have not proved a benefit of the procedure (46-50 Gy) (153- 154). However, it is important to remember that, in most studies on high-risk prostate-cancer patients, pelvic irradiation is considered a standard. The same nomograms used for nodal surgical dissection can be of use in defining which patients should receive prophylactic radiotherapy to the pelvis, applying the score used by RTOG study 9413. The pelvis can be irradiated in all the patients who have an estimated >15% risk of nodal involvement and the patients who are at high and very high risk of recurrence (156). When including the pelvis, the RTOG guideline can be applyied, showing how the drenaje should be contoured in prostate-cancer patients. Based on this guideline, the nodal chains to be included are the external and internal iliac chains (starting from L5-S1), presacral nodes up to S3 and obturator nodes. A 7-mm margin around the vases should be left (157). Complimentary Contributor Copy 302 Camila Casadiego Peña, Maribel Bruna Figueroa, Hugo Marsiglia et al.

Treatment for patients with positive nodal disease who do need nodal radiotherapy includes the same nodal chains mentioned above with a boost to the positive nodes (48). Once the medical physicist or the dosimetrist have finished the treatment plan it has to be revised by a radiation oncologist who, in order to evaluate how good the plan is, should bear in mind the technique used, if dose escalation is planned with or without SBRT. Based on this, they should apply an institutional protocol to set the parameters to be taken into account, in order to define when a treatment plan can be approved or not. Different guidelines used in published studies are available, on which to base the protocol for prostate-cancer treatment in each institution. It is also mandatory to ascertain the correct application of constraints to the organs at risk (28). Based on what said above, sometimes a question comes to mind: which treatment is the best? The only study comparing these modalities was the ProtecT trial, which, beside radical prostatectomy and radiotherapy with six months of hormone therapy, also compared active monitoring. With a median follow up of ten years, there were no differences between surgery and EBRT for all oncological outcomes (5).

CHEMOTHERAPY

Chemotherapy is a subject that will be studied in depth later on, in the section reserved to metastatic disease. However, the treatment schedule currently used in prostate-cancer patients eligible for chemotherapy is docetaxel.

NOVEL TREATMENTS

In this section, new treatment modalities are presented, that have been proposed as possible therapeutic options in patients with clinically-localized prostate cancer (158-161).

Cryotherapy

This type of treatment is used either as primary or salvage treatment for prostate cancer. Freezing techniques are used to cause cellular death by dehydration, producing protein denaturation, direct rupture of cellular membranes by ice crystals, and vascular stasis and microthrombi, which leads to microcirculation blockade with ischemic apoptosis (158-161). The operator places 17-gauge cryogenic needles inside the prostate via transrectal ultrasound, thermal sensors at the external sphincter and rectal wall, and a urethral heater. Two freezing-unfreezing cycles are applied under transrectal-ultrasound guidance, achieving a temperature of -40°C to the mid gland and neurovascular bundle. The main adverse effects are erectile dysfunction (18%), urinary incontinence (2-20%) and urethral leakage (0-38%). There are no randomized clinical studies in literature supporting this treatment in prostate cancer, as most published studies are non-comparative case series with a single arm and short follow up (162).

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High-intensity focused ultrasound

It consists of applying a high-frequency, high-energy ultrasound beam to induce cellular destruction or necrosis of tumor cells, by increasing the temperature to 55-100 C (thermal ablation). It offers the advantage of not affecting surrounding tissues. It is a procedure performed under general or spinal anesthesia, with the patient lying in a lateral or supine position. The main adverse effects are acute urinary retention (10%), erectile dysfunction (23%), uretral stenosis (8%), rectal pain or bleeding (11%), recto-urethral fistula (0-5%) and urinary incontinence (10%). This procedure presents a drawback, as it may be difficult to achieve complete ablation of the prostate, especially when the patient has a prostate over 40 ml big. There are at present no long-term prospective studies supporting this procedure as a standard treatment for prostate cancer (162).

TREATMENT ACCORDING TO PROSTATE-CANCER RISK

In order to decide the better therapeutic option in prostate cancer, the patient should be staged by risk group, which is determined according to the guidelines established by the American Urological Association (AUA)/American Society for Radiation Oncology (ASTRO)/Society of Urologic Oncology (SUO), with the support of the American Society of Clinical Oncology (ASCO), and the National Comprehensive Cancer Network (NCCN) (115, 163-165). It is important to remember that, ideally, the treatment decision should be made by a multidisciplinary team (including urologists, medical oncologists, radiation oncologists, pathologists, palliative care experts, radiologists, nurses, psychologists and social workers), in order to choose the best personalized treatment benefiting each patient, who should be informed of the advantages and disadvantages of each treatment option as well as of the possible toxicities he may present. The best therapeutic modalities for prostate cancer by risk group are shown below in Table 10.

Table 10. Treatment according to risk

Risk Treatment Very low risk  Standard treatment: Active surveillance  T1c  Options of treatment  Grade group 1  Radical Prostatectomy without nodal dissection, as the estimated risk  PSA< 10 ng/ml for nodal involvement is less than 5%  <2-3 positive nuclei with<50%  Intensity-modulated EBRT at a total dose of 74-80 Gy or moderate of the cores positive for prostate hypofractionation (60 Gy/20 fractions in four weeks or 70 Gy/28 cancer fractions in six weeks) without hormone therapy or SBRT  PSA density <0.15 ng/ml/  Brachytherapy as monotherapy Low risk  Standard treatment: Active surveillance  T1-T2a  Options of treatment:  Grade group 1  Radical Prostatectomy without nodal dissection, as the estimated risk  PSA< 10 ng/ml for nodal involvement is less than 5%  Intensity-modulated EBRT at a total dose of 74-80 Gy or moderate hypofractionation (60 Gy/20 fractions in four weeks or 70 Gy/28 fractions in six weeks) without hormone therapy or SBRT  Brachytherapy as monotherapy Complimentary Contributor Copy 304 Camila Casadiego Peña, Maribel Bruna Figueroa, Hugo Marsiglia et al.

Table 10. (Continued)

Risk Treatment Intermediate-low risk  Active surveillance  T2b-T2c  Radical prostatectomy with nodal dissection if the estimated risk for  Grade group 1 or 2 positive nodes is more than 5%  PSA 10-20 ng/ml  Intensity-modulated EBRT at a total dose of 76-78 Gy or moderate  <50% of the cores positive for hypofractionation (60 Gy/20 fractions in four weeks or 70 Gy/28 prostate cancer fractions in six weeks) with hormone therapy for 6 months. If the patient refuses hormone therapy, he should receive a higher dose of EBRT (76-78 Gy) or a Brachytherapy boost,  Brachytherapy as monotherapy Intermediate-high risk  Radical prostatectomy with nodal dissection if the estimated risk for  T2b-T2c positive nodes is more than 5%  Grade group 3 Intensity-modulated EBRT at a total dose of 76-78 Gy or moderate  PSA 10-20 ng/ml hypofractionation (60 Gy/20 fractions in four weeks or 70 Gy/28 fractions in  ≥50% of the cores positive for six weeks) with hormone therapy for 6 months. If the patient refuses hormone prostate cancer therapy, he should receive a higher dose of EBRT (76-78 Gy) or a Brachytherapy boost. It is necessary to use nomograms to assess the need of prophylactic pelvic radiotherapy. Treatment is mandatory when the patient has a >15% risk for nodal involvement High-risk  Intensity-modulated EBRT at a total dose of 76-78 Gy including pelvic  T3a OR drainage with hormone therapy for 2 years**.  Grade group 4 or 5 OR  EBRT + Brachytherapy boost, and hormone therapy for 2 years is a  PSA > 20 ng/ml possible option.  Radical prostatectomy with nodal dissection; generally these patients will require adjuvant radiotherapy, as there is a risk for recurrence after surgery Very high-risk  Intensity-modulated EBRT at a total dose of 76-78 Gy including pelvic  T3b-T4 OR drainage with hormone therapy for 2 years**.  Grade group 5  EBRT + brachytherapy boost, and hormone therapy for 2 years is a  >of 4 cores with grade group 4 possible option. or 5  Radical prostatectomy with nodal dissection; generally these patients will require adjuvant radiotherapy, as there is a risk for recurrence after surgery N+  The pelvis should always be included, with a possible boost to the adenopathy level. Patient with <10-year life expectancy  Wait and see, according to the patient’s symptoms; if a patient is at high whatever the risk risk, hormone therapy can be considered. ** In this group of patients prophylactic pelvis irradiation is mandatory because all published randomized studies irradiated the pelvis in high-risk patients.

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[82] Kuban DA, Levy LB, Cheung MR, Lee AK, Choi S, Frank S, et al. Long-term failure patterns and survival in a randomized dose-escalation trial for prostate cancer. Who dies of disease? Int J Radiat Oncol Biol Phys 2011;79(5):1310-7. [83] Zietman AL, Bae K, Slater JD, Shipley WU, Efstathious JA, Coen JJ, et al. Randomized trial comparing conventional-dose with high-dose conformal radiation therapy in early-stage adenocarcinoma of the prostate: long-term results from proton radiation oncology group/american college of radiology 95-09. J Clin Oncol 2010;28(7):1106-11. [84] Viani GA, Stefano EJ, Afonso SL. Higher-than-conventional radiation doses in localized prostate cancer treatment: a meta-analysis of randomized, controlled trials. Int J Radiat Oncol Biol Phys 2009;74(5):1405-18. [85] Peeters ST, Heemsbergen WD, Koper PC, van Putten WL, Slot A, Dielwart MF, et al. Dose-response in radiotherapy for localized prostate cancer: results of the Dutch multicenter randomized phase III trial comparing 68 Gy of radiotherapy with 78 Gy. J Clin Oncol 2006;24(13):1990-6. [86] Beckendorf V, Guerif S, Prise EL, Cosset J, Bougnoux A, Chauvet B, et al. 70 Gy versus 80 Gy in localized prostate cancer: 5-year results of GETUG 06 randomized trial. Int J Radiat Oncol Biol Phys 2011;80(4):1056-63. [87] Heemsbergen WD, Al-Mamgani A, Slot A, Dielwart MF, Lebesque JV. Long-term results of the Dutch randomized prostate cancer trial: impact of dose-escalation on local, biochemical, clinical failure, and survival. Radiother Oncol 2014;110(1):104-9. [88] Kalbasi A, Berman A, Swisher-MeClure S, Smaldone M, Uzzo RG, Small DS, et al. Dose-escalated irradiation and overall survival in men with nonmetastatic prostate cancer. JAMA Oncol 2015;1(7):897-906. [89] Zietman AL, Desilvio ML, Slater JD, Rossi CJ Jr, Miller DW, Adams JA, et al. Comparison of conventional-dose vs high-dose conformal radiation therapy in clinically localized adenocarcinoma of the prostate: A randomized controlled trial. JAMA, 2005;294(10):1233-9. [90] Peeters ST, Heemsbergen WD, van Putten WL, Slot A, Tabak H, Mens JW, et al. Acute and late complications after radiotherapy for prostate cancer: results of a multicenter randomized trial comparing 68 Gy to 78 Gy. Int J Radiat Oncol Biol Phys 2005;61(4):1019-34. [91] Dearnaley DP, Sydes MR, Langley RE, Graham JD, Huddart RA, Syndikus I, et al. The early toxicity of escalated versus standard dose conformal radiotherapy with neo-adjuvant androgen suppression for patients with localised prostate cancer: results from the MRC RT01 trial (ISRCTN47772397). Radiother Oncol 2007;83(1):31-41. [92] Kuban DA, Tucker SL, Dong L, Starkschall G, Hang EH, Cheung MR, et al. Long-term results of the M. D. Anderson randomized dose-escalation trial for prostate cancer. Int J Radiat Oncol Biol Phys 2008;70(1):67-74. [93] Matzinger O, Duclos F, van den Bergh A, Carrie C, Villa S, Kitsios P, et al. Acute toxicity of curative radiotherapy for intermediate- and high-risk localised prostate cancer in the EORTC trial 22991. Eur J Cancer 2009;45(16):2825-34. [94] Zapatero A, Valcarcel F, Calvo FA, Algas R, Bejar A, Maldonado J, et al. Risk-adapted androgen deprivation and escalated three-dimensional conformal radiotherapy for prostate cancer: does radiation dose influence outcome of patients treated with adjuvant androgen deprivation? A GICOR Study. J Clin Oncol 2005;23(27):6561-8. [95] Zelefsky MJ, Chan H, Hunt M, Yamada Y, Shippy AM, Amols H. Long-term outcome of high dose intensity modulated radiation therapy for patients with clinically localized prostate cancer. J Urol 2006;176(4 Pt 1):1415-9. [96] Vora SA, Wong WW< Schild SE, Ezzell GA, Hhalyard MY. Analysis of biochemical control and prognostic factors in patients treated with either low-dose three-dimensional conformal radiation therapy or high-dose intensity-modulated radiotherapy for localized prostate cancer. Int J Radiat Oncol Biol Phys 2007;68(4):1053-8. [97] Kupelian PA, Willoughby TR, Reddy CA, Klein EA, Mahadevan A. Hypofractionated intensity- modulated radiotherapy (70 Gy at 2.5 Gy per fraction) for localized prostate cancer: Cleveland Clinic experience. Int J Radiat Oncol Biol Phys 2007;68(5):1424-30.

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[98] Gomez-Iturriaga Pina A, Crook J, Borg J, Lockwood G, Fleshner N. Median 5 year follow-up of 125iodine brachytherapy as monotherapy in men aged

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[134] Sheets NC, Goldin GH, Meyer AM, Wu Y, Chang Y, Sturmer T, et al. Intensity-modulated radiation therapy, proton therapy, or conformal radiation therapy and morbidity and disease control in localized prostate cancer. JAMA 2012;307(15): 1611-20. [135] Ash D, Flynn A, Battermann J, de Reijke T, Lavagini P, Blank L. ESTRO/EAU/EORTC recommendations on permanent seed implantation for localized prostate cancer. Radiother Oncol 2000;57(3):315-21. [136] Martens C, Pond G, Webster D, McLean M, Gillan C, Crook J. Relationship of the International Prostate Symptom score with urinary flow studies, and catheterization rates following 125I prostate brachytherapy. Brachytherapy 2006;5(1):9-13. [137] Machtens S, Baumann R, Hagemann J, Warszawski A, Meyer A, Karstens JH, et al. Long-term results of interstitial brachytherapy (LDR-Brachytherapy) in the treatment of patients with prostate cancer. World J Urol 2006;24(3):289-95. [138] Grimm P, Billet I, Bostwick D, Dicker AP, Frank S, Immerzeel J, Keyes M, et al. Comparative analysis of prostate-specific antigen free survival outcomes for patients with low, intermediate and high risk prostate cancer treatment by radical therapy. Results from the Prostate Cancer Results Study Group. BJU Int 2012;109 Suppl 1:22-9. [139] Potters L, Klein EA, Kattan MW, Reddy CA, Ciezki JP, Reuther AM, et al. Monotherapy for stage T1-T2 prostate cancer: radical prostatectomy, external beam radiotherapy, or permanent seed implantation. Radiother Oncol 2004;71(1):29-33. [140] Sylvester JE, Grimm PD, Wong J, Galbreath RW, Merrick G, Blasko JC. Fifteen-year biochemical relapse-free survival, cause-specific survival, and overall survival following I(125) prostate brachytherapy in clinically localized prostate cancer: Seattle experience. Int J Radiat Oncol Biol Phys 2011;81(2):376-81. [141] Potters L, Morgenstern C, Calugaru E, Fearn P, Jassal A, Presser J, et al. 12-year outcomes following permanent prostate brachytherapy in patients with clinically localized prostate cancer. J Urol 2005;173:1562-66. [142] Stone NN, Stock RG, Unger P. Intermediate term biochemical-free progression and local control following 125iodine brachytherapy for prostate cancer. J Urol 2005;173(3):803-7. [143] Zelefsky MJ, Kuban DA, Levy LB, Potters L, Beyer DC, Blasko JC, et al. Multi-institutional analysis of long-term outcome for stages T1-T2 prostate cancer treated with permanent seed implantation. Int J Radiat Oncol Biol Phys 2007;67(2):327-33. [144] Lawton CA, DeSilvio M, Lee WR, Gomella L, Grignon D, Gillin M, et al. Results of a phase II trial of transrectal ultrasound-guided permanent radioactive implantation of the prostate for definitive management of localized adenocarcinoma of the prostate (radiation therapy oncology group 98-05). Int J Radiat Oncol Biol Phys 2007;67(1):39-47. [145] Stock RG, Stone NN. Importance of post-implant dosimetry in permanent prostate brachytherapy. Eur Urol 2002;41(4):434-9. [146] Galalae RM, Kovacs G, Schultze J, Loch T, Rzehak P, Wilhelm R, Bertermann H, et al. Long-term outcome after elective irradiation of the pelvic lymphatics and local dose escalation using high-dose- rate brachytherapy for locally advanced prostate cancer. Int J Radiat Oncol Biol Phys 2002;52(1):81- 90. [147] Hoskin PJ, Rojas AM, Bownes PJ, Lowe GJ, Ostler PJ, Bryant L. Randomised trial of external beam radiotherapy alone or combined with high-dose-rate brachytherapy boost for localised prostate cancer. Radiother Oncol 2012;103(2):217-22. [148] Pieters BR, de Back DZ, Koning CC, Zwinderman AH. Comparison of three radiotherapy modalities on biochemical control and overall survival for the treatment of prostate cancer: a systematic review. Radiother Oncol 2009;93(2):168-73. [149] Hauswald H, Kamrava MR, Fallon JM, Wang PC, Park SJ, Van T, et al. High-Dose-Rate Monotherapy for Localized Prostate Cancer: 10-Year Results. Int J Radiat Oncol Biol Phys 2016;94(4):667-74. [150] Zamboglou N, Tselis N, Baltas D, Buhleier T, Martin T, Milckovic N, Papaioannou S, et al. High- dose-rate interstitial brachytherapy as monotherapy for clinically localized prostate cancer: treatment evolution and mature results. Int J Radiat Oncol Biol Phys 2013;85(3):672-8. Complimentary Contributor Copy Management of prostate cancer 313

[151] Hoskin PJ, Motohashi K, Bownes P, Bryant L, Ostler P. High dose rate brachytherapy in combination with external beam radiotherapy in the radical treatment of prostate cancer: initial results of a randomised phase three trial. Radiother Oncol 2007;84(2):114-20. [152] Hoskin P, Rojas A, Ostler P, Hughes R, Alonzi R, Lowe G, et al. High-dose-rate brachytherapy alone given as two or one fraction to patients for locally advanced prostate cancer: acute toxicity. Radiother Oncol 2014;110(2):268-71. [153] Leibel SA, Fuks Z, Zelefsky MJ, Whitmore WF. The effects of local and regional treatment on the metastatic outcome in prostatic carcinoma with pelvic lymph node involvement. Int J Radiat Oncol Biol Phys 1994;28(1):7-16. [154] Asbell SO, Krall JM, Pilepich MV, Baerwald H, Sause WT, Hanks GE, et al. Elective pelvic irradiation in stage A2, B carcinoma of the prostate: analysis of RTOG 77-06. Int J Radiat Oncol Biol Phys 1988;15(6):1307-16. [155] Pommier P, Chabaud S, Lagrange JL, Richaud P, Lesaunier F, Le Prise E, et al. Is there a role for pelvic irradiation in localized prostate adenocarcinoma? Preliminary results of GETUG-01. J Clin Oncol 2007;25(34):5366-73. [156] Roach M, Moughan J, Lawton CA, Dicker AP, Zeitzer KL, Gore EM, et al. Sequence of hormonal therapy and radiotherapy field size in unfavourable, localised prostate cancer (NRG/RTOG 9413): long-term results of a randomised, phase 3 trial. Lancet Oncol 2018;19(11):1504-15. [157] Lawton CAF, Michalski J, El-Naqa, I. Pelvic nodal consensus CTV contours: High risk/locally advanced adenocarcinoma of the prostate. Philadelphia: Radiation Therapy Oncology Group, 2008. [158] Fahmy WE, Bissada NK. Cryosurgery for prostate cancer. Arch Androl 2003;49(5):397-407. [159] Rees J, Patel B, MacDonagh R, Persad R. Cryosurgery for prostate cancer. BJU Int 2004;93(6):710- 14. [160] Han KR, Belldegrun AS. Third-generation cryosurgery for primary and recurrent prostate cancer. BJU Int 2004;93(1):14-8. [161] Beerlage HP, Thuroff S, Madersbacher S, Zlotta AE, Aus G, de Reijke TM, et al. Current status of minimally invasive treatment options for localized prostate carcinoma. Eur Urol 2000;37(1):2-13. [162] Ramsay CR, Adewuyi TE, Gray J, Hislop J, Shirley MD, Jayakody S, et al. Ablative therapy for people with localised prostate cancer: a systematic review and economic evaluation. Health Technol Assess 2015;19(49):1-490. [163] Bekelman JE, Rumble RB, Chen RC, Pisansky TM, Finelli A, Feifer A, et al. Clinically localized prostate cancer: ASCO clinical practice guideline endorsement of an American Urological Association/American Society for Radiation Oncology/Society of Urologic Oncology Guideline. J Clin Oncol 2018;36(32):3251-8. [164] Sanda MG, Cadeddu JA, Kirkby E, Chen RC, Crispino T, Fontanarosa J, et al. Clinically localized prostate cancer: AUA/ASTRO/SUO Guideline. Part I: Risk stratification, shared decision making, and care options. J Urol 2018;199(3):683-90. [165] Sanda MG, Cadeddu JA, Kirkby E, Chen RT, Crispino T, Fontanarosa, et al. Clinically localized prostate cancer: AUA/ASTRO/SUO guideline. Part II: Recommended approaches and details of specific care options. J Urol 2018;199(4):990-997.

Chapter 22

MANAGEMENT OF PROSTATE CANCER IN THE POSTOPERATIVE CONTEXT AND IN METASTATIC DISEASE

ABSTRACT

According to Globocan 2018, prostate cancer has the second highest incidence in men and is the fourth cause of mortality. The treatment of prostate cancer should be done in a multidisciplinary manner, in the postoperative context there are different therapeutic modalities including radiation therapy, hormone therapy or surgery, and the treatment can be administered in the adjuvant or biochemical recurrence context. In metastatic disease also there are different therapeutic modalities with good long-term oncological results, like hormonotherapy, chemotherapy and others.

INTRODUCTION

According to Globocan 2018, prostate cancer has the second highest incidence in men and is the fourth cause of mortality. In Latin America, prostate cancer had an incidence of 60.4 per

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100,000 inhabitants and a total of 14 per 100,000 inhabitants (1). In the postoperative context there are different therapeutic modalities including radiation therapy, hormone therapy or surgery, and the treatment can be administered in the adjuvant or biochemical recurrence context. In metastasis disease also there are different therapeutic modalities with good long- term oncological results, like hormonotherapy, chemotherapy and others.

Table 1. Risk factors for recurrence (2, 3)

Local Nodal  Positive margins  Extracapsular involvement  Extracapsular involvement  Nodal density (defined as the percentage of positive nodes in relation with the  Vesicle involvement total of analyzed nodes) over 20 is associated to poor prognosis

ADJUVANT TREATMENT AFTER RADICAL PROSTATECTOMY

The term adjuvant treatment refers to the need for further treatment after primary management, aimed at decreasing the risk for recurrence (see Table 1) (2, 3). It is important to bear in mind that adjuvant treatment requires negative postoperative PSA levels (4). Immediate postoperative external-beam radiotherapy is a viable alternative in the adjuvant treatment of patients at high risk for recurrence. Three prospective randomized clinical studies assessed the role played by immediate radiotherapy. However, the ARO 9602 study was the only trial that enrolled patients with undetectable PSA. This shows an important limitation when interpreting studies, since when postoperative PSA is detectable, we are in a setting of persistent disease (5). Table 2 lists the main studies in the adjuvant setting (5-7).

Table 2. Randomized clinical studies on adjuvant treatment for prostate cancer

Study Arms Patient characteristics postoperative Follow Results PSA up SWOG 60-64 Gy vs pT3 cN0 ± surgical > 0.4 156 10-year biochemical-recurrence- 8794 2009 Surveillance margin free survival: 53% vs. 30% (5) (p <0.05) 10-year OS: 74% vs. 66% Mean time follow up: 15.2 vs. 13.3 years. p = 0.023 EORTC 60 Gy vs pT3 N0 any margins, > 0.2 127 10-year progression free survival: 22911 2012 surveillance pT2 N0 with positive 60,6% vs 41% (p <0,001) and OS (5) margins 81% vs 77% not significant ARO 96-02 60 Gy vs. pT3 pN0 post- > 0.05 112 10-year progression free survival: 2014 (7) surveillance surgery PSA 56% vs. 35% undetectable (p = 0.0001) OS: Not significant

A systematic review of adjuvant hormonal therapy in N0 patients showed a possible benefit for progression-free survival but no for overall survival, therefore in this setting, treatment should be personalized for each case. Keeping in mind the patient’s risk group and possible risk factors, the treating physician will decide whether to add hormone therapy. Complimentary Contributor Copy Management of prostate cancer in the postoperative context … 317

Using nomograms can also be useful in these cases. In N1 patients, where the use of hormone therapy has been proved to yield an 80% 10-year cancer-specific survival rate, two studies showed that not only cancer-specific survival but also overall survival can improve. However, they enrolled mostly patient with high nodal-tumor burden and multiple factors for poor prognosis and their results cannot therefore be applied to the general prostate-cancer population (8-10). A phase-III randomized clinical trial comparing adjuvant docetaxel to active surveillance after prostatectomy in patients with advanced disease showed no oncological benefit with the use of docetaxel. Another study, TAX3501, that was supposed to compare hormonal treatment with leuprolide acetate for 18 months with or without docetaxel was closed early for lack of recruitment (11, 12).

Persistent PSA after prostatectomy

Prostate-Specific-Antigen persistance is defined as PSA levels > 0.1 ng/ml within four to eight weeks after surgery which can be due to the presence of persistent local disease, disease metastases, or residual benign prostatic tissue. This condition can occur in 5% to 20% of men. The studies assessing persistence after prostatectomy show that this condition manifests in patients with more advanced disease, as is the case with patients with positive margins, pathological stage >T3a, positive nodal involvement and/or pathologicalgrade group > 3; it generally has poor prognosis. It has been related to one- and five-year biochemical- recurrence-free survival rates of 68% and 36%, in comparison with 95% and 72% in men without persistence. It has a negative impact on overall survival, which is 63% at 10 years in patients presenting disease persistence in comparison with 80% in patients who do not (5, 13- 15). When predictors of disease persistence were assessed, it was found that a high Body Mass Index (BMI), together with higher preoperative PSA and grade group >3, may be related to this outcome (15). Patients with high persistent PSA after prostatectomy, usually have a poor prognosis. It has been reported that it is not recommended to prescribe bone scan or magnetic resonance imaging (MRI) when PSA is lower than 2 ng/ml, but prostate-specific membrane antigen positron emission/computer-aided tomografy (PSMA PET/CT) can identify residual tumor in 15-58%, 25-73%, 69-100% and 71-100% of cases, with post-surgery PSA ranging between 0.2-0.5 ng/mL, 0.5 -1 ng/ml, 1-2 ng/ml and> 2 ng/ml, respectively. This scaB can be of major help, since it is used to identify the site of the disease that causes high PSA values (16-22). There are no clinical trials supporting a role for radiotherapy in this setting. However, it is considered a viable treatment option. In this setting hormone therapy has been reported to improve progression-free survival (23). Among clinical trials that included patients with disease persistence, the ARO 96-02 study, enrolled 74 patients with persistent PSA (20%) who received 66 Gy external-beam radiotherapy without hormone therapy and had a 63% ten-year clinical-recurrence-free survival rate (5). The GETUG-22 trial, comparing external-beam radiotherapy alone versus external-beam radiotherapy with short-term hormone therapy in patients with elevated persistent PSA (0.2-

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2.0 ng/mL) after prostatectomy, reported good tolerance; oncological outcomes are currently pending and will help determe future conduct in this setting (24).

Biochemical recurrence

It has been reported that between 27% and 53% of all intermediate or high-risk patients will manifest an increase in PSA at some time after radical prostatectomy or radiotherapy. When this occurs, the physician should evaluate the reason for this new increase and investigate where the disease causing PSA rise may be located (4). In order to define when an increase in PSA is considered a biochemical recurrence, the primary treatment the patient received should be taken into account. When the initial treatment was radical prostatectomy, a patient with PSA >0.4 ng/mL is considered to present a biochemical recurrence (25, 26). However, it is important to remember that the lower is the PSA value when the recurrence is detected, the better is the patient’s oncological outcome. For this reason, a patient is now considered to manifest biochemical recurrence with PSA levels of 0.2 ng/mL or more and should receive treatment (27). When the primary treatment was radiotherapy, with or without hormone therapy, the RTOG-ASTRO Phoenix Consensus Conference defined biochemical recurrence as a patient with PSA > 2 ng/mL than his nadir value (nadir is the lowest PSA value the patient showed after radiotherapy), with a precision of > 80% for initial failure (28). However, it is important to bear in mind that once the patient ends radiotherapy he can have a slight PSA elevation and it is therefore necessary to start evaluating PSA 18 months after the end of radiotherapy, in order to establish its nadir and thus detect PSA increase (29). Once it has been establish that the patient has biochemical recurrence, it is important to determine where the recurrence is and if it is local or metastatic, since this can help us determine the patient’s prognosis. Some factors have been established to have poorer prognosis and to be more often related with metastatic disease. They are: PSA doubling time <1 year, pathological-grade group 4-5 and biochemical recurrence within 18 months after treatment (radical prostatectomy) (30). In order to decide which imaging tests should be prescribed to find the recurrence site, the following recommendation should be kept in mind:

1) Bone scan and abdomino-pelvic computer-aided tomography (CT): It has been reported that these are not exams of choice for patients presenting biochemical recurrence. Bone scan has been reported positive in < 5% of cases when PSA level is < 7 ng/ml, while CT scan is positive in only 11-14% of patients with biochemical recurrence (31, 32). 2) Positron emission tomography/Computer-aided tomography (PET/CT) 3) Choline: Two metanalyses showed that the sensitivity and specificity for all sites of recurrence in patients with biochemical recurrence is 86-89% and 89-93%, respectively (33, 34). It can detect multiple bone metastases in patients with a single metastasis at the bone scan and can be positive for bone metastases in up to 15% of patients with negative bone scans (35, 36). The specificity of choline PET/CT is also higher than that of bone scan, with fewer falsely-positive or indeterminate results (37). However, it has low sensitivity for the detection of nodal metastases (38-40). Complimentary Contributor Copy Management of prostate cancer in the postoperative context … 319

In patients with biochemical recurrence after prostatectomy, the detection rate of choline PET/CT depends on PSA kinetics, i.e.5-24% of patients may have a positive PET scan with PSA levels<1 ng/mL, but the percentage increases to 67-100% with PSA levels > 5 ng/mL. After radical prostatectomy, a choline PET/CT should be prescribed when the patient has a PSA value between 1 and 2 ng/ml. It has been reported that this type of scan can change medical treatment in 18-48% of patients (41-43). 4) PSMA PET/CT: It has been reported that detection rates are also dependent on PSA levels, the disease being detected in 15-58%, 25-73%, 69-100% and 71-100% of patients for PSA levels of 0.2-0.5 ng/mL, 0.5-1 ng/mL, 1-2 ng/mL and> 2 ng/mL, respectively (16-21). It is considered to be more sensitive than choline PET/CT, especially for patients with PSA levels <1 ng/mL (18, 44). It has been reported that it can lead to a change in treatment intent in 62% and in treatment conduct in 30.2% of cases (45). 5) Magnetic resonance imaging (MRI): The role this exam plays in patients with biochemical recurrence is unclear. Multiparametric MRI has been reported to detect local recurrences to the prostatic bed, but its sensitivity in patients with PSA levels <0.5 ng/ml is still controversial (46, 47). 6) Biopsy: It has been reported to have low sensitivity in patients who underwent prostatectomy, especially for PSA levels<1 ng/ml; for this reason salvage radiotherapy (RT) should start straightaway when a PSA increase is detected, without the need for pathological results. In patients who received radiotherapy as primary management, however, biopsy does play an important role as a predictive factor and should be performed 18-24 months after treatment. Multiparametric MRI is a viable alternative to detect where the lesion is and can therefore be a useful tool to decide the point where to take a biopsy (46-51).

Table 3. Clinical trials on radiotherapy management of prostate-cancer patients with biochemical recurrence after prostatectomy

Study Follow up pre-RT RT and ADT 5-year Results in months PSA Bartkowiak et al., 71 0.31 66.6 Gy 73% vs 56%;PSA 2017. (53) < 0.2 vs. >0.2 ng/mL p < 0.0001 Soto et al., 2012. 36 <1 68 Gy 24% ADT 44 vs 40% with and without ADT (54) (58%) p <0.16 Stish et al. 2016. 107 0.6 68 Gy 16% ADT 44% vs 58%; PSA (55) <0.5 vs.> 0.5 ng/mL p <0.001 Tendulkar, 60 0.5 66 Gy 16% ADT Salvage radiotherapy; PSA <0.2 ng/mL et al., 2016. (56) 71% 0.21-0.5 ng/mL, 63% 0.51-1.0 ng/mL, 54% 1.01-2.0 ng/mL, 43% > 2 ng/mL 37% p < 0.001

Treatment of biochemical recurrences after prostatectomy The treatment of biochemical recurrences either after radical prostatectomy or radiotherapy is still controversial. A systematic review and a metanalysis on the impact of biochemical recurrence after radical prostatectomy report that salvage radiotherapy improves overall survival and cancer- specific mortality. Salvage radiotherapy should be performed in patients with PSA increase; it Complimentary Contributor Copy 320 Camila Casadiego Peña, Maribel Bruna Figueroa, Hugo Marsiglia et al. has been reported that the sooner the treatment starts, the better is its oncological outcome (52). Table 3 summarizes the results of recent studies on salvage radiotherapy (53-56).

Table 4. Randomized clinical studies evaluating hormone therapy in biochemical recurrence

Study Arms Patient characteristics Results GETUG-AFU 16 66 Gy + o - GnRH Grade group<2/3 89%, 5-year biochemical-recurrence-free survival Carrie et al., analoguefor 6 months Grade group>4 11% 80% vs 62% 2016. (57) cN0 p <0.0001 RTOG 9601 64.8 Gy + bicalutamide pT2 R1, pT3 cN0  12-year distant metastases 14% vs Shipley et al., 24 months vs 64.8 Gy + 23% (p = 0.005) 2017. (58) placebo  12-yearOS 76% vs 71% (p = 0.04)  12-year cancer-specific mortality 5.8% vs 13.4% (p <0.001)

Table 5. Guidelines for volume contouring to determine volume limits

Guideline Volumes Australian  Inferior: The inferior border of the CTV will be 5-6 mm below the vesicourethral anastomosis (59) (depending on CT slice thickness), but should be extended lower to include all surgical clips inferiorly. The anastomosis can be identified on axial, coronal and sagittal reconstructions as the first slice below where urine is last visible. When the anastomosis is not clearly defined, the inferior border will be the slice above the penile bulb.  Anterior: (i) From the lower border of the CTV to 3 cm superior, the anterior border of the CTV is the posterior aspect of the symphysis pubis. (ii) More superiorly, the anterior border of the CTV encompasses the posterior 1.5 cm of the bladder.  Posterior: The space delineated by the levator ani and anterior rectal wall is at risk for recurrence and should be encompassed in the CTV if rectal dose constraints allow. Ensure a minimum 2 cm margin from the posterior extent of the CTV to the posterior rectal wall to prevent the entire circumference of rectum receiving the full radiation dose. More superiorly, the posterior border of the CTV is the anterior mesorectal fascia  Lateral: The medial border of the levator ani muscle or obturator internus muscle  Superior: (i) The superior border should encompass all of the seminal vesicle bed as defined by non- vascular clips and should include the distal portion of the vas deferens. The vas deferens is usually visualised superiorly as thin, horizontal cylindrical structures. (ii) If the seminal vesicles are pathologically involved by tumour, ensure any residual seminal vesicles are also included in CTV. EORTC  Central: Vesico-urethral anastomosis (60)  Cranial: Bladder neck  Posterior: Up to but not including the outer rectal wall, cranially including the most posterior part of the bladder neck  Lateral: Neurovascular region or ileopubic muscle  Anterior: Includes the anastomosis RTOG (61) BELOW THE UPPER LIMIT OF THE PUBIC SYMPHYSIS  Anterior: Posterior limit of the pubic bone  Posterior: Anterior region of the rectal wall  Lower: 8-12mm below the vesico-urethral anastomosis  Lateral: Levator ani and internal obturator muscles ABOVE THE UPPER LIMIT OF THE PUBIC SYMPHYSIS  Anterior: 1-2 cm from the posterior part of the bladder  Posterior: Mesorectal fascia  Upper: Point where the vas deferens ends or 3-4 cm above the upper part of the synphysis  Lateral: Sacrorectogenitopubic fascia

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Two studies (see Table 4) reported the benefit of administering hormone therapy to the patients who will receive salvage radiotherapy. The RTOG 9601 study (57) suggested that hormone therapy for two years yields a benefit in both overall and cancer-specific survival for all groups. GETUG-AFU 16 study also showed better results with six months of hormone therapy (58). Bearing this in mind, the obvious question arises: how long should hormone therapy be administered in the salvage setting? Independently of risk, the two above- mentioned studies showed a benefit in the oncological outcomes of patients with biochemical recurrence with either 6 or 12 months of treatment. A viable alternative to determine the length of hormonal treatment is to assess the patient’s risk factors, so that high-risk patients can receive hormone therapy for 2 years and low-risk patients can be treated for six months (4). There are three guidelines for volume contouring which can help determine the limits of the volume and how to contour it: the RTOG, EORTC and Australian guidelines (59-61). Table 5 shows the anatomical limits of each guideline; we invite readers to check the original guidelines for indications on how to deliver radiotherapy. With regards to the inclusion of the nodal drainage, the ongoing RTOG 0534 study is enrolling patients who received primary prostatectomy for T2-3N0/Nx prostate cancer, with initial PSA levels of ≥0.1-<2.0 ng/mL, with or without positive margins and a Gleason score ≤9. Preliminary results show that patients who received pelvic radiotherapy and hormone therapy for six months have better disease-free survival. However, the final results of the study have not been published yet. Irradiating the pelvis in patients who show risk factors for poor prognosis is a viable option. Contouring is the same as for patients who receive radiotherapy as primary treatment (4). The recommended dose of radiotherapy is at least 66 Gy to the prostatic bed (including or not the base of the seminal vesicles according to the pathology result after prostatectomy) (62, 63). In a systematic review, both PSA levels before salvage radiotherapy and the dose of radiotherapy correlated to oncological outcomes, showing that recurrence-free survival decreased by 2.4% for each 0.1 ng/ml of PSA and increased by 2.6% for each Gy delivered, suggesting that a treatment dose over 70 Gy should be administered, with PSA level as low as possible (64). The organs at risk are the same as for primary external-beam radiotherapy. However, it is important to remember that, since the patient underwent previous surgery, the toxicity may be higher. In a randomized clinical trial evaluating dose escalation for salvage radiotherapy in 350 patients, grade-2 and -3 acute genitourinary toxicity was registered in 13.0% and 0.6% of patients, respectively, with 64 Gy irradiation, and in 16.6% and 1.7%, respectively, with 70 Gy. Grade-2 and -3 gastrointestinal toxicity was observed in 16.0% and 0.6% of cases, respectively, with 64 Gy, and in 15.4% and 2.3%, respectively, with 70 Gy. Late toxicity rates have not been published as yet (65, 66). With a dose over 72 Gy up to a median of 76 Gy, severe side effects clearly increase, especially genitourinary symptoms, even with the newest planning and treatment techniques, therefore the recommended dose is 70 Gy (67, 68). An obvious question arises: in a post-operative patient with poor prognostic factors for recurrence but negative PSA, what is the better option, to deliver adjuvant radiotherapy straight away or to wait for PSA to increase and to treat the patient with biochemical recurrence? The answer often depends on the protocols established by each center. Some centers prefer to administer the treatment when the patient has developed a biochemical Complimentary Contributor Copy 322 Camila Casadiego Peña, Maribel Bruna Figueroa, Hugo Marsiglia et al. recurrence, because approximately 50% of patients will have a new PSA increase independently of their risk factors. There are several phase-III studies currently ongoing, comparing these two treatment modalities.

Treatment of biochemical recurrence after radiotherapy The therapeutic options for these patients are surveillance, hormone therapy, salvage prostatectomy, cryotherapy, interstitial brachytherapy and high-intensity focused ultrasound (69-78). As there is only low-quality evidence available for these treatment options, it is not possible to recommend any of them with certainty. Salvage prostatectomy after radiotherapy has the better probability to achieve local control compared with other salvage treatments. However, it has to be weighed against possible adverse events the patient may have. A systematic review showed that salvage prostatectomy yields five- and ten-year biochemical recurrence-free survival rates of 47-82% and 28-53%, respectively. Ten-year cancer-specific and overall-survival rates vary between 70-83% and 54-89%, respectively. Pre-surgery PSA value and grade group of the prostatic biopsy were the factors most correlated with oncological outcome (79). It is important to bear in mind that salvage prostatectomy relates to a higher risk of posterior anastomotic stenosis, urinary retention, urinary fistula, abscess, rectal lesions (80), urinary incontinence and erectile dysfunction in almost all patients (79). The surgical treatment of (recurrent) nodal metastases within the pelvis has been studied in several retrospective analyses (80-82). Most patients treated for this condition had over 70% 10-year disease-free and cancer-specific survival; however, the real efficacy of this salvage procedure has not been proved, nor has its impact on survival (83-85). Brachytherapy is a therapeutic option for carefully-selected patients with good life expectancy, localized prostate cancer and histologically-proven local recurrence, with an aceptable toxicity profile (28, 86-88). However, published series are relatively small and, consequently, this treatment should be offered only in experienced centers. The role of hormone therapy as single treatment in this setting was assessed in a systematic review that showed contradictory results on clinical effectiveness when patients received previous curative therapy for the primary tumor. Some studies reported a favorable effect of hormone therapy, including the only randomized clinical trial studying this specific subject, which showed an improvement in overall survival with the use of early hormone therapy (86% vs 79%) (89). However, a study had worse oncological outcomes with early hormone therapy. It has been determined that there are some predictive factors for negative results, such as castration-resistance, presence of distant metastases, short doubling time, high grade group, high PSA, advanced age and comorbilities (90). Hormone therapy as single treatment in the management of biochemical recurrence aims at prolonging overall survival, decreasing the risk of distant metastases and improving quality of life. However, it has not been proved that this management alone yields these clinical benefits in the entire population; e.g., in elderly patients and in patients with comorbidities, the side effects of hormone therapy may even shorten life expectancy (91, 92). Early hormone therapy should therefore be reserved for patients at higher risk of disease progression, due to a short doubling time (> 6-12 months) or a high initial grade group (>2/3), with long life expectancy (4).

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As for surveillance, it is only considered a treatment alternative in asymptomatic patients with life expectancy shorter than 10 years and in patients who do not wish any active treatment (93).

Treatment of metastatic disease It is important to keep in mind that even if mean survival for a recently-diagnosed patient with metastatic disease is approximately 42 months, this is a very heterogeneous group, for whom several prognostic factors can impact survival, such as the number and site of bone metastases, the presence of visceral metastases, grade group, initial PSA and alkaline phosphatase levels (94- 98).

Table 6. SWOG 9346 Impact of PSA value on mean survival (99)

PSA after 7 months of castration Mean survival < 0.2 ng/mL 75 months 0.2 < 4 ng/mL 44 months > 4 ng/mL 13 months

Based on these premises, SWOG 9346 study evaluated the impact of PSA levels after seven months of hormone therapy on mean survival and a prognostic scale was created to predict mean survival in months based on PSA value after 7 months of hormone therapy (see Table 6). It should be noted that, in the CHAARTED study, patients with metastatic disease with PSA <0.2 ng/ml after seven months of hormone therapy showed better oncological outcomes, independently of the addition of docetaxel (99, 100).

Table 7. Definitions of tumor volume and risk according to the CHAARTED and LATITUD studies

High Low CHAARTED >4 bone metastases including >1 outside or inside the spine Different from high (volume) (100) OR Visceral metastases LATITUD >2 high-risk characteristics Different from high (risk) (101)  3 bone metastases  Visceral metastases  Grade group >4

The CHAARTED (see Table 7) study also introduced another predictive factor, i.e., tumor “volume”: patients can be classified in two groups, high and low tumor burden, depending on the volume of their metastatic disease. This was an important finding because a subgroup analysis showed that disease volume is a factor that can predict the benefit of adding radiotherapy with hormone therapy in patients with high tumor volume (100). The LATITUDE (see Table 7) study classified patients as high and low risk, according to the characteristics of their metastases (101).

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HORMONAL TREATMENT

Primary management with hormone therapy has been the standard treatment in metastatic prostate-cancer patients for over 50 years (102). To date, there is no study with high enough statistical value to indicate which is the best hormonal management, except for patients who present an immediate risk of medullary compression, where the preferred hormonal management is orchiectomy or LHRH antagonists. A systematic review including studies with moderate quality evidence showed that monotherapy with non-steroidal anti-androgens was less effective in terms of overall survival, clinical progression, treatment failure and discontinuation due to adverse events (103). However, it is useful to repeat that to date there is no study with enough statistical value to help us decide which the best option for hormonal therapy is. In order to choose the drug to be administered, it may be useful to evaluate the patient’s conditions, his functional status, the location and grade of his metastases and also to take into account the side effects of each drug used as hormonal therapy and, based on all of this, to define which is the most adequate treatment for each patient. Another open issue is the way of administration for hormone therapy, intermittent (i.e., to administer hormone therapy for a while and then suspend it) or continuous (without interruptions). Three independent reviews (104-106) and two metanalyses (107, 108) assessed the clinical efficacy of intermittent hormonal therapy. All the reviews included eight randomized clinical studies, only three of which enrolled patients with metastatic disease only. The other five trials enlisted different groups of patients, mainly patients with locally-advanced and metastatic recurrence. The SWOG 9346 trial is so far the largest study to assess intermittent hormonal therapy in M1b patients. This study enrolled patients with recently-diagnosed metastatic prostate cancer who had good ECOG status and PSA levels of 5 ng/ml or more. After seven months of hormone therapy the patients whose PSA decreased to 4 ng/ml or less were divided into two groups: one to intermittent and one to continuous hormone therapy. It is important to bear in mind that 3,040 patients were selected, but only 1,535 of then complied with inclusion criteria. This proves that only 50% of patients with M1b disease would be eligible for hormone therapy, i.e., PSA better responders. The results of this trial did not show statistically-significant differences between continuous or intermittent hormone therapy. The only statistically-significant result was that intermittent therapy gave patients better mental health and better erections (P <0.001 and P = 0.003 respectively) but only at three months, in the remaining months no difference was registered (109). No trial showed any difference in overall survival between the two administration modalities (104). These reviews and metaanalyses concluded that is it improbable that there is a difference in terms of overall or cancer-specific survival between the two ways of administration. A recent review of available phase-III trials showed the limitations of most trials and suggested a prudent interpretation of non-inferiority results. None of the trials studying intermittent or continuous hormone therapy in metastatic patients proved a benefit in terms of survival, but they did show a trend to better overall and progression-free survival with the use of continuous hormone therapy. In terms of quality of life, however, the trend favors intermittent hormone therapy, since it relates with fewer side effects. It was also observed that

Complimentary Contributor Copy Management of prostate cancer in the postoperative context … 325 intermittent hormone therapy may yield long-term benefits in terms of bone loss, metabolic syndrome and cardiovascular problems (110-113). The veracity of these results was verified through a detailed analysis of the SWOG 9346 trial, showing a higher risk of thrombotic and ischemic events in patients who received intermittent hormone therapy (24% vs 33%) but no difference was found in terms of endocrine, psychiatric, sexual and neurologic side effects. As for testosterone recuperation, patients with intermittent castration were reported to achieve normal levels after treatment interruption (114, 115). For all the above, intermittent hormone therapy is only recommended for well-informed metastatic patients who perfectly understand what the treatment entails and accept it, committing to strict follow up, and who also show some symptoms from the side effects of the hormone therapy.

How is intermittent castration achieved? (4)

 Firstly, hormone therapy is administered for nine months, as a longer administration may hinder testosterone recuperation.  Androgen deprivation therapy should be interrupted only if all the following criteria are met:  The patient is well informed and compliant  There is no clinical progression  There was a clear PSA response, empirically defined as PSA <4 ng/ml in metastatic disease.  Strict follow up including a clinical exam every three to six months is mandatory.  PSA should always be assessed by the same laboratory.  The treatment restarts when the patient presents clinical progression or a PSA elevation over a predetermined threshold (empirically established): generally 10-20 ng/mL in metastatic patients.  The same treatment is repeated for at least three to six months.  If the patient requires to repeat hormone therapy, the same treatment can be used until the first signs of castration-resistance appear.

Patients who can benefit from intermittent hormone therapy have not been defined yet, but the most important factor is a good PSA response to the first cycle of hormone therapy, otherwise other therapeutic options should be evaluated (116).

Immediate vs postponed hormone therapy In symptomatic patients immediate treatment is mandatory. However, it is still controversial for asymptomatic patients. A Cochrane review found four randomized clinical studies carried out before the PSA era, which included patients with advanced, metastatic or non metastatic prostate cancer. They compared immediate vs delayed hormone therapy. No improvement in cancer-specific survival was found, although immediate hormone therapy significantly reduced disease progression (117).

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Combined therapies

Complete blockade To date, there is only one randomized clinical trial conducted on 1,286 M1b patients, where no difference was found between complete blockade vs surgical castration. Systematic reviews on the subject showed that complete hormonal blockade with LHRH antagonists can offer a small advantage in survival (<5%) in comparison with monotherapy (surgical castration or LHRH agonists). However, this minimal advantage is only seen in a small subgroup of patients and it should be weighed against the increase in side effects associated with the long-term use of antagonists (118-121).

Hormonal Blockade combined with other agents Combination with abiraterone acetate: Abiraterone acetate is a treatment used as second-line hormonal therapy. Two randomized clinical studies (STAMPEDE, LATITUDE) evaluated the addition of abiraterone acetate (1000 mg/day) plus prednisone (5 mg/day) to first-line hormonal therapy in men with hormone-sensitive prostate cancer (101, 122). The results of both studies showed a significant benefit in terms of overall survival. However, the patients who received both drugs had more treatment interruptions for toxicity, 20% in the STAMPEDE study (101) and 12% in the LATITUDE study (122). Based on the results of these two trials, the use of abiraterone acetate and prednisone combined with first-generation hormone therapy should be considered the standard treatment for men presenting metastases at diagnosis (123). Combination with chemotherapy: Three randomized clinical studies, GETUG-QFU 15, CHAARTED and STAMPEDE trials, compared the use of hormone therapy alone to hormone therapy with docetaxel (75 mg/m2, every three weeks) within three months after starting hormone therapy (97, 98, 123). Based on the results of these studies, docetaxel can be used in combination with hormone therapy for men presenting metastases at diagnosis, provided they are sufficiently fit to receive the drug (122). However, it is important to remember that, in the subgroup analyses of the GETUG-AFU 15 and CHAARTED studies, the benefit of adding docetaxel to hormone therapy is higher in men with de-novo high-volume metastatic disease (97, 100). There are no comparative data between the two treatments to determine whether docetaxel or abiraterone acetate plus prednisone is the better alternative for recently- diagnosed hormone-sensitive metastatic prostate-cancer patients. However, the patients from the STAMPEDE study received either abiraterone or docetaxel, and the results do not show any advantages in terms of survival between the two. The results, however, were not published, since the comparison had not been one of the protocol endpoints. Similarly, a meta-analysis also comparing the two drugs did not find any significant benefit in overall survival for either drug (125). The STOPCAP systematic review reports that abiraterone acetate plus prednisone has a higher probability of being the more effective treatment (126). In order to define which treatment should be used, it is important to bear in mind that, although neither treatment seems better than the other, both modalities present different side

Complimentary Contributor Copy Management of prostate cancer in the postoperative context … 327 effects. The choice, therefore, will probably depend on the patient’s preference and performance status as well as on the specific side effects, availability and cost of each drug.

DELAYED TREATMENT FOR METASTATIC PROSTATE-CANCER PATIENTS

The only patients who can be considered eligible for delayed treatment in the metastatic setting are asymptomatic ones who want to avoid the side effects of treatment (127, 128). Patients opting for this modality are those who can be followed closely, so as to detect any symptoms, and consequently start their treatment, as early as possible.

TREATMENT OF PRIMARY TUMOR METASTATIC AT DIAGNOSIS

The first trial to study the possible role of irradiating the prostate in castration-sensitive patients metastatic at diagnosis was the HORRAD trial, where no difference was observed in overall survival for metastatic patients sensitive to hormone therapy treated with hormone therapy alone or hormone therapy plus radiotherapy to the prostate (129). The STAMPEDE study evaluated 2,061 men with prostate cancer metastatic at diagnosis who received hormone therapy alone or hormone therapy with radiotherapy to the prostate, confirming that radiotherapy targeted to the primary tumor did not improve overall survival. However, this study classified patients between high and low tumor volume, as did the CHAARTED study, and a subgroup analysis with high statistic value observed that low- volume patients (n = 819) did received a statistically-significant benefit in overall survival from hormone therapy and radiotherapy to the prostate. Therefore, radiotherapy to the prostate should be considered for patients with low-volume metastatic disease (94, 100).

Treatment for castration-resistant patients

A patient is considered castration-resistant when, despite castration serum levels of testosterone (<50 ng/dL or 1.7 nmol/L), he presents either biochemical or radiological progression. The former is defined as the increase of three consecutive PSA samples taken a week apart from each other, i.e.two 50% increases above nadir, and a PSA value of >2 ng/ml. The latter is considered the appearance of two or more new bone lesions in a bone scan or a soft-tissue lesion assessed by RECIST criteria appearing on other imaging tests (130). A symptomatic progression alone is not considered a definitive criterion to determine castration- resistance.

Non-metastatic castration-resistant patients

Patients with biochemical progression are nowadays detected earlier, and approximately a third of them will develop bone metastases detectable at bone scan within two years (128). Complimentary Contributor Copy 328 Camila Casadiego Peña, Maribel Bruna Figueroa, Hugo Marsiglia et al.

Some men may have hormone-resistant prostate cancer and undetectable clinical metastases. In order to determine which patients have a higher risk for metastases, certain factors may be taken into account, such as PSA basal levels, PSA velocity and PSA doubling time, which may help determine when a patient has a higher risk for metastases and/or for shorter overall survival (131-133). An important issue is to decide when to prescribe imaging studies for bone and/or visceral metastases. A consensus of the group on Radiographic Assessments for the Detection of Advanced Recurrence (RADAR) suggested that bone and CT scans should be prescribed when PSA value is ≥2 ng/mL. If imaging results are negative at this time, PSA sampling should be monitored and when it reaches 5 ng/mL imaging tests are repeated. If these are still negative, they should be repeated after each PSA doubling, which should be tested every three months in asymptomatic men. If the patient shows any symptom, a PSA test should be performed at once and a PSMA PETCT or an MRI scans should be performed depending on PSA levels, in case castration-resistence is suspected. Ideally, the diagnosis should be achieved as soon as possible in order to start a new treatment regimen (133). Two large randomized phase-III controlled trials, the PROSPER and SPARTAN studies, assessed metastasis-free survival in non-metastatic, castration-resistant prostate-cancer patients treated with enzalutamide versus placebo (PROSPER) or apalutamide versus placebo (SPARTAN). In order to determine that patients really were non metastatic, CT and bone scans were performed. Only patients at high risk for metastases were included, choosing patients with a short, i.e., ten months or less, PSA doubling time. Both trials showed a significant benefit in terms of metastasis-free survival. The PROSPER study had median metastasis-free survival of 36.6 months in the enzalutamide group versus 14.7 months in the placebo group (HR for metastases or death, 0.29; CI 95%: 0.24-0.35, p <0.001]. For the SPARTAN study, median metastasis-free survival was 40.5 months in the apalutamide group versus 16.2 months in the placebo group (HR for metastases or death, 0.28; CI 95%: 0.23- 0.35, p <0.001]). The time to systematic progression was significantly longer with apalutamide versus placebo (HR 0.45; CI 95%: 0.32-0.63, p <0.001). Severe toxicity was low in both trials (134, 135). Based on the results of these two trials, for castration-resistant, non-metastatic patients the use of hormone therapy is recommended, since the results show that this treatment helps to prolong metastasis-free survival and to shorten symptomatic progression.

FIRST- AND SECOND-LINE TREATMENT FOR CASTRATION-RESISTANT, METASTATIC PROSTATE-CANCER PATIENTS

There are a number of drugs available for the treatment of castration-resistant, metastatic prostate-cancer. Most of them can be used either as first- or second-line treatment at the discretion of the attending physician, swiching to other drugs when failure to first-line treatment occurs. The possible combinations of these drugs are shown in Tables 8 and 9 (136- 149).

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Table 8. First-line phase-III randomized controlled trials (47)

Author Intervention Comparison Patient characteristics Main results Docetaxel SWOG 99-16 Docetaxel every 3 weeks,60 Mitoxantrone OS: 17.52 vs. 15.6 Petrylak DP et mg/m2 +estramustine3x280 every 3 weeks, months. (p = 0.02, HR: al., 2004. (136) mg/day 12 mg/m2 0.80; CI 95%: 0.67- prednisone 5mg 0.97) DFS: 6.3 vs 3.2 b.i.d. months(p <0.001) TAX 327 2008 Docetaxel, every 3 weeks, 75 Mitoxantrone OS: 19.2 por 3 weekvs. (137, 138) mg/m2 prednisone 5 mg b.i.d. every 3 weeks, 17.8 months. Weekly vs OR weekly docetaxel, 30 12 mg/m2 16.3 in the controlgroup. mg/m2 prednisone 5mg (p = 0.004, HR: 0.79; CI prednisone 5 mg b.i.d. b.i.d. 95%: 0.67-0.93) Abiraterone COU-AA-302 Abiraterone + Placebo + - No previous docetaxel OS: 34.7 vs. 30.3 Ryan CJ et al., prednisone prednisone - ECOG 0-1. months. (HR: 0.81, 2013. (139, 140) - PSA or imaging p = 0..0033).Survival progression without imaging - No or mild symptoms changes: 16.5 vs. 8.3 - No visceral metastases. months. (p <0.0001) Enzalutamide PREVAIL Beer Enzalutamide Placebo - No previous docetaxel OS: 32.4 vs. 30.2 TM et al., 2014. - ECOG 0-1. months. (p <0.001). (p (141) - PSA or imaging <0.001 HR: 0.71; CI progression 95%: 0.60-0.84) - No or mild symptoms Survival without - 10% had visceral imaging changes: 20.0 metastases. months vs5.4 months. HR: 0.186 (CI 95%: 0.15-0.23)p <0,0001) SIPULEUCEL-T Sipuleucel-T Placebo - Some with prior OS: 25.8 vs. 21.7 Kantoff PW et docetaxel months.(p = 0.03 HR: al., 2010. (142) - ECOG 0-1. 0.78; CI 95%: 0.61- - No or mild symptoms 0.98). DFS: 3.7 vs. 3.6 months. (n.s.) Small EJ et al., Sipuleucel-T Placebo - ECOG 0-1. OS: 25.9 vs 21.4 2006. (143) - No visceral metastases. months.(p = 0.1). DFS: - No corticoids 11.7 vs. 10.0 weeks.

Table 9. Second-line phase-III randomized controlled trials (47)

Author Arms Comparison Patients’ characteristics Mainresults Abiraterone Fizazi et al., 2012. abiraterone + placebo + Previous Docetaxel OS: 15.8 vs. 11.2 months (144) prednisone prednisone ECOG 0-2. (p <0.0001) Imaging- PSA or progression free survival: no imagingprogression changes de Bono et al., 2011 OS: 14.8 vs. 10.9 months. .(145) (p <0.001 HR: 0.65; 95% CI: 0.54-0.77) withoutimaging changes: imagingPFS: 5.6 vs. 3.6 months.

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Table 9. (Continued)

Author Arms Comparison Patients’ characteristics Mainresults Radium-223 Parker et al., 2013 radium-223 placebo With or without OS: 14.9 vs. 11.3 months. (146) previous docetaxel (p = 0.002, HR: 0.61; 95%CI: ECOG 0-2. 0.46-0.81). ≥2 symptomtic bone metastases No visceral metastases. CABAZITAXEL Bahl et al., 2013 cabazitaxel + mitoxantrone + Previous docetaxel OS>2years 27% vs. 16% (147) prednisone prednisone ECOG 0-2. deBono et al., 2010. OS: 15.1 vs. 12.7 months. (148) (p <0.0001, HR: 0.70; 95% CI: 0.59-0.83). PFS:2.8 vs. 1.4 months.(p <0.0001, HR: 0.74; 95%CI: 0.64-0.86) ENZALUTAMIDE Scher et al., 2012. Enzalutamide placebo Previous docetaxel OS: 18.4 vs. 13.6 months. (149) ECOG 0-2 (p <0.001 HR: 0.63; 95% CI: 0.53-0.75). Survival without imaging changes 8.3 vs. 2.9 months.(HR: 0.40; CI 95%: 0.35-0.47 p <0.0001)

Follow up of castration-resistant patients with prostate cancer

First of all, the patient’s complete clinical history should be collected and an accurate clinical exam should be performed. Routine exams include PSA test, renal function tests, bone scan and chest-abdomen-pelvis CT scan. A significant role of PET CT scan in the study of castration-resistant prostate-cancer patients has not been defined. For an appropriate follow up, it is recommended that blood samples should be tested every two to three months and imaging exams repeated at least every six months, even when the patient is asymptomatic. In order to determine if a patient presents disease progression, PSA and/or imaging progression and/or clinical decline should be present. The disease is considered to be progressing when two out of three of these conditions are met, when a treatment modification is necessary (150, 151).

When to switch treatment The treatment for castration-resistant prostate-cancer patients should switch when the patient has a progressing metastatic disease. The progression is evaluated through changes in PSA and/or imaging and/or through clinical decline, and the patient should present changes in two out of three of these conditions. The treatment to be chosen depends on the patient’s functional status, the symptoms he presents and the toxicities each treatment may cause him (150, 151).

Management of symptomatic castration-resistant prostate cancer In order to choose the best symptomatic management, it is important to remember that the castration-resistant patient with metastatic disease is often an elderly man in normal general Complimentary Contributor Copy Management of prostate cancer in the postoperative context … 331 condition. It is therefore necessary that decisions are made by a multidisciplinary team comprising urologists, medical oncologists, radiation oncologists, pathologists, palliative care experts, nurses, psychologists and social workers, who discuss all available therapeutic options and choose the best one for each patient (152).

Frequent complications due to bone metastases The main complication that patients with bone metastases present is pain, where the use of external-beam radiotherapy is highly effective (153, 154). If radiotherapy is not available, a single shot of third-generation bisphosphonates could be a viable option (155). The most common complications caused by bone metastases are pathological fractures, medullary compression and vertebral collapse. Cementing can be an effective alternative for painful fractures, improving pain and quality of life (156). Medullary compression is considered an oncological emergency and should therefore be diagnosed and treated as soon as possible to avoid any neurological damage. If suspected, an MRI should be prescribed to confirm the diagnosis and treatment with corticoids started immediately. When the diagnosis is confirmed, a neurosurgeon or an orthopedist should see the patient to determine if surgery is feasible, followed by radiotherapy, unless radiotherapy is the better option. There are different ways to avoid bone complications (4):

 Bisphosphonates: A study with zoledronic acid showed that at 15 and 24 months of follow up, patients treated with 4 mg of zoledronic acid had fewer bone events in comparison with the placebo group (44 vs. 33%, p = 0.021), fewer pathological fractures (13.1 vs. 22.1%, p = 0.015). The time to first bone event was longer in the zoledronic acid group. No benefit in overall survival was observed (4).  RANK-ligand Inhibitors: Denosumab is a monoclonal antibody targeting RANKL (Receptor activator of nuclear factor kappa-Β ligand), a key mediator of the formation, function and survival of osteoclasts. The efficacy and safety of denosumab (n = 950) in comparison with zoledronic acid (n = 951) for metastatic castration-resistant prostate-cancer patients was evaluated in a Phase-III trial. Denosumab yielded better results than zoledronic acid in delaying or preventing bone changes. Pathological fractures, the need for bone irradiation or surgery and spine compression occurred at 20.7 vs. 17.1 months in favor of denozumab (HR: 0.82, p = 0.008). Decrease in both urinary N-terminal telopeptide and bone-specific alkaline phosphatase was significantly higher in the denosumab arm in comparison with the zoledronic acid arm (p <0.0001 for both). However, these findings did not correlate to a benefit in overall survival.

The drug toxicity should be assessed, as one of its main complications is osteonecrosis to the mandible which can get more frequent when increasing the duration of its administration (4).

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Chapter 23

BLADDER CANCER: EPIDEMIOLOGICAL STUDY IN LATIN AMERICA, TRENDS AND REVIEW OF SURGICAL ASPECTS FOR THE TREATMENT OF THE DISEASE

Paulo Rodrigues1,2, MD, PhD, MBA, Eduardo Barbieri2, MD, Angelo Bezerra de Souza Fede3, MD, Fiona Lim4, MBBS, Bo Angela Wan5, MD(C), and Mauricio F Silva6,7,8, MD, PhD 1Hospital Santa Catarina de São Paulo e Hospital Albert Einstein de São Paulo, Brazil 2Hospital Santa Catarina de São Paulo, Brazil 3University of São Paulo, São Paulo, Brazil 4Department of Oncology, Princess Margaret Hospital, Hong Kong, PR China 5Odette Cancer Centre, Sunnybrook Health Sciences Centre, Toronto, Ontario, Canada 6Radiation Oncology Unit, Santa Maria Federal University, Santa Maria, Brazil 7Radiation Oncology Unit, Hospital de Caridade Astrogildo de Azevedo, Santa Maria, Brazil 8Latin America Cooperative Oncology Group, Porto Alegre, Brazil

ABSTRACT

Bladder cancer is an emerging complex and lethal disease in Latin America. Due to the inherent economic and social difficulties in this subcontinent, poor attention has been paid to the disease, hindering progress on its management and on policies that could mitigate its effects. With an increasing population, better public information and social demands, Latin America is expected to be forced to build new policies on cancer registries and control, as the trend is that the bulk of diseases are migrating from infectious to neoplastic in nature. It is expected that this shift will pose huge stresses on the public health care system. This chapter is a critical and updated review on the epidemiology of bladder cancer in the South American continent with a critical view and discussion of limitations on the data available for the region, with the recognition that

 Corresponding Author’s Email: [email protected]. Complimentary Contributor Copy 342 Paulo Rodrigues, Eduardo Barbieri, Angelo Bezerra de Souza Fede et al.

despite the unique regional difficulties, the practiced management is very similar to the worldwide practice.

INTRODUCTION

Bladder cancer is a very complex disease as initial presentations can differ clinically, and with different histology and stages. Between 40% to 80% of patients with superficial bladder cancer will experience recurrent disease after minimally invasive primary endoscopic resection. Of the recurrent cases, in 10-25% of patients the superficial cancer will evolve to become invasive, leading to modification of the management of the disease requiring adding radiotherapy, chemotherapy and/or radical surgical resection. Fifty percent of patients with bladder cancer were diagnosed with the disease in its muscle-invasive form (1). This requires more expensive treatments as determined by the contemporary evidence that multimodality treatments results in better overall survival rates as compared to single modality treatments (2). Latin America presents as a case study of bladder cancer due to the lack of aggressive policies on smoking and its relationship to the disease and other maladies stressing more the governmental expenditures.

OUR SEARCH

Records identified through Database Searching Multiple combinations of search words

(n=95,245) Identification

Identified articles crossing with each of the 28 countries names in Title, origin of authors mentioned in the authorship or academic allotment Screening (n=38)

Studies included in the critical Review

(n=34) Included

Figure 1. PRISMA diagram of study selection. Complimentary Contributor Copy Bladder cancer 343

A Medline search was conducted of the manuscripts published in the last 15 years (January 2003 to October, 2018) with the search words: “1-Bladder cancer,” “2-Bladder Neoplasms,” “3-Latin America,” “4-Epidemiology,” “5-Risk-factors,” “6-Causes,” and “7-Cancer.” Collating search terms 1+ 3; 1 + 4; 1 + 5; 1 + 6; 2 + 3; 2 + 4; 2+ 5; 2 + 6; 3 + 7; resulted in 95,245 hits of papers in English, Spanish and Portuguese. These same search combinations were repeated using each of the 28 individual countries of Latin America. allowing to filter out eventual mention of the name of the countries crossed because one or more authors were related in the paper as author or co-author because they were established in an non-Latin America Academic position with dual duty or appointment that referred to the born country causing the mismatch of the crossing although the research itself was not related to bladder cancer in Latin America but related to other regions in the Globe, basic research on its causes and/or risk-factors studies not specifically related to Latin America. After careful readings of the title, abstract and finally full text, 8 papers were consider eligible as being truly studying bladder cancer in Latin America, while 26 were epidemiological studies on cancers comprising global or regional data where Latin America data were also included (see Figure 1).

FINDINGS

Despite the scarcity of the content truly dedicated to Latin America for bladder cancer, additional information applicable to the issue was carefully reviewed from other sources to build a contemporary and comprehensive review of bladder cancer and its epidemiological implications for the region.

Regional difficulties in the management of bladder cancer

Epidemiological studies in general and for bladder cancer in particular in the 41 countries that composes Latin America and Caribbean (LAC) is a challenge. With 8.5% of the world population, LAC also had complex modification of its population profile in the last 60 years. Tripling its population from 167 million in 1950 to 588 million in 2010, LAC now has 81% of its population in the urban area. At the same time, they experienced an increase in the gross domestic product (GDP) per capita of 30 times (USD $372 in 1950 to USD $7623 in 2010) while fertility rates decreased from 6 to 2.2 (3). Social inequalities in LAC remained the same as in 1970 according to United Nations Development Program (UNDP) report 2010 and the average GINI index (0.53) is worse than that of Africa (0.43). The 3-dimensional Human Development Index proposed by the UNDP (life expectancy, schooling and income per capita) rose in LAC from 0.573 to 0.704, but is far from the developed countries, which scored a 0.754 in 1980. Brazil, Mexico and Colombia, the most populous countries in LAC, have multidimensional poverty rates of 8.5, 4 and 9.2%, respectively (5). The urbanization drive and general ageing of the population associated with inequalities by government agencies and private health sector deforms the homogenization for non-communicable diseases and injuries, making the panoramic view of diseases in LAC inaccurate and demanding attention from authorities. This is better realized when faced that direct out-of-

Complimentary Contributor Copy 344 Paulo Rodrigues, Eduardo Barbieri, Angelo Bezerra de Souza Fede et al. pocket expenditures and voluntary payment to private health sector accounts to 66% in Brazil and to 50% in Ecuador, Jamaica and Peru. Studying cancer in the underdeveloped world is challenging as official documentation of the causes of death might be far from desired, complicating mortality data analysis as some cases of death certification stating 'senility' adds imprecision on the nomenclature for cancer. It is estimated that only 8% of the population in Latin America is covered for the high- quality data according to the Cancer in five-Continents (CI5) series while 96% of the US population is covered by the same account (5). This may certainly account for the higher cancer mortality rates in Latin America despite the lower incidences of detection when compared to developed countries (6). With an estimated 435,000 new cases per year, bladder cancer positions itself as the 9th cause of death by cancer worldwide being 7th in occurrence for men and 9th for women. Chile has presented the highest incidence rate (Age Standardized Rate (ASR) = 17.6/100,000 men and ASR = 9.8/100,000 women) with an overall incidence in Latin America stable since 1993, although mortality was still in elevation in Cuba and Brazil (7). Until recently, the International Codification of Disease (ICD-7) had not distinguished the non-invasive version of bladder cancer from the lethal invasive version. The ICD-10 or International Classification of Diseases for Oncology (ICD-O) was a fruitful attempt to distinguish cases in the nomenclature.

Disposition factors for bladder cancer

The relationship between cancer and diet has had passionate discussion for a long time. One case-control study showed that total meat consumption (OR 1.47, 95% CI 1.02-2.11), total processed meat (OR 1.57, 95% CI 1.08-2.27), frankfurters (hot dogs) (OR 2.03, 95% CI 1.28- 3.21), ham (OR 1.79, 95% CI 1.21-2.67) and salted meat (OR 2.73, 95% CI 1.78-4.18) were associated with a higher risk for bladder cancer. Surprisingly, not only meat but cheese, milk and eggs were also linked to higher rate of bladder cancer (8). While there are studies denying this association in Spain (OR 0.8), others reinforced the linkage for bacon consumption and its high content of N-nitrosamines derivatives (9, 10). While larger fluid intake could protect people from bladder cancer by diluting the carcinogens such as arsenic, very few studies on this matter claim that fluid intake decreases the risk for bladder cancer when the author compared 1.4 L/day to 0.4 L/day of drunk fluid (HR 0.47, 95% CI 0.33–0.66) (11). Fluids resulting from chlorination of tap water and trihalomethanes were found to increase the rate for bladder cancer (12) although a prospective study with 250,000 dwellers found none after a 9 year-follow-up study (HR 1.12, 95% CI 0.86–1.45) (13). Controversial results can also be observed for coffee and alcohol ingestion as there are strong confounders for this population such as smoking (14).

Family history While family history increases the risk for bladder cancer by 2 to 6-fold, this particular subset of cases accounts for only 2% of the whole and seems too low to warrant screening (15).

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Medical radiation Bladder cancer secondary to medical radiation accounts for 2-3% of all cases of bladder cancer (16). Age-standardized incidences secondary to external beam-radiotherapy in prostate cancer treated men may be increased by 1.7 times (17).

Thiazolidinediones In general, patients with diabetes mellitus was observed to be have a greater incidence of bladder cancer than the general population and greater yet if associated with oral hypoglycemic drugs (HR 2.2; 95% CI 1.3–3.8) (18). Chronic use of thiazolidinediones for diabetes increases the relative risk for bladder cancer 2-3 fold and represent an exclusive group for screening (19).

Source: Ploeg M, Aben KK, Kiemeney LA. The present and future burden of urinary bladder cancer in the world. World J Urol 2009;27(3):289-93.

Figure 2. Prevalence of smoking and smoking-related deaths by gender (121).

Smoking Smoking was reported to be the number one preventable cause of cancer. WHO claimed that 6,000,000 people die as a result of tobacco usage, with numbers expected to rise to 7,500,000 by 2020. Brazil has a population of 200 million and a corresponding 200,000 deaths related to tobacco usage/year. As Figure 2 shows, Brazilian prevalence of smoking is 34.8% (43.3% among men and 27% among women). Anti-smoking governmental policy in Brazil led to a 50% decline in the incidence of new smoking-persons in the last 2 decades (20). It is expected that a reduction in smokers will occur in the future. The relationship between smoking and bladder cancer involves a latency of 20-40 years, with the same effect observed for those who stopped smoking regarding previous recurrence, multiplicity of lesions, and recurrence-free survival of patients with non-muscle invasive or muscle invasive bladder cancer. As in other countries, the anti-smoking policies affect the magnitude of bladder cancer in their Complimentary Contributor Copy 346 Paulo Rodrigues, Eduardo Barbieri, Angelo Bezerra de Souza Fede et al. populations and the four stages of populational effect of smoking can be observed on the epidemic of smoking, reflecting deaths related to cancer-induced tumor, as in bladder cancer. Given the non-smoking government policy wave observed in recent years in many developed countries and similar trend in developing ones, it is expected a reduction in bladder cancer incidences would be found in USA and Spain since they have smoking prevalences of respectively 63% and 42% in the 70's and 60's. Although declining in LAC, recent studies show that 17% of women in LAC smoke with a distinct prevalence of 30% for the Southern Cone. While 31% of men smokes in LAC overall, 44% of men in Southern Cone do (22).

Agents and genetic predisposition

Naphthylamine and polycyclic aromatic hydrocarbons are aromatic amines derivatives from smoking, and are related to bladder cancer. Being renally excreted, they have carcinogenic effects all over the urinary tract and not solely restricted to the bladder. In particular, blond tobacco seems to have higher concentration of N-nitrosamine and 2-naphtylamine than black- tobacco, with increased risk of urothelial cancer. It is hard to argue that the amount of aromatic amines determines the chance of bladder cancer because idiosyncratic factors may also weigh in. Differential expression of the isoforms of the enzyme 5'-diphosphogluc- oronosyltransferase (UGT) among people may determine different susceptibility to urothelial cancer as the aromatic amine clearance is determined by the amount of the enzyme in the liver and determines the its clearance rate (23). Surprisingly, UGT seems to be downregulated by androgen receptors, possibly explaining the observed contemporary differences among bladder cancer in men and women (1:4) despite women increasingly smoking more. Similarly, bladder cancer seems to be increased in persons with null or reduced concentration of the enzyme glutathione-S-transferase M1 (GSTM1) which helps clear foreign substances by reducing glutathione (OR 1.7, 95% CI 1.0-3.0). Interestingly, the higher risk of bladder cancer with the lack of this enzyme was observed for women but not for men (24).

Environment contribution to bladder cancer

Populational studies clearly showed a correlation between bladder cancer and arsenic exposure mostly from water intake from wells. Of attention, certain regions of Chile seemed to be more exposed to arsenic in well water showing a higher rate of bladder cancer mortality even after 20 years on policies to decrease that exposure (HR 3.6, 95% CI 3.0–4.7) (25).

Gender disparities in bladder cancer diagnosis

The observed gender disparities between males and females in bladder cancer with women presenting with more advanced stages and worse mortality might be related to the fact that women who present with hematuria may ultimately be diagnosed as bladder cancer later than men (26). UTI in women was less likely to undergo imaging exams (OR 0.8).

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This finding reflects the distinct time-frame between the initial episode of hematuria and the final diagnosis of bladder cancer on men (73.6 days) and women (85.4 days) (27). Similarly, without the confounding factor of UTI observed in women, men are more promptly referred to an urologist than women (28) with only 8% of women with hematuria being referred to an urologist (29). Furthermore, men are more fully studied for hematuria than women who in turn received more treatments without further workup than men (19% versus 47%) despite the absence of clinical presentations for both genders (30). Despite male prevalence for bladder cancer being three times higher than for females, the cancer-specific mortality is only twice as high (30). The reasons for this has to be explored but even across all the stages, women seem to have a poorer outcome with 5-years survival for stage I (93.7% vs. 96.5%), stage II (59.6% vs. 65.5%), stage III (49.6% vs. 58.8%) and stage IV (15.2% vs. 27.1%) (31).

Screening

Despite muscle-invasive bladder cancer being a fatal disease, they represent 25% of bladder cancers and benefit from populational screening is still lacking and therefore not regularly practiced. While the direct-screening diseases aim at early detection and enhance cure rates, these programs may lead to overdiagnosis, increased costs and harm to patients. Familial history of bladder cancer increases the relative-risk to 2-6 times and smokers (>10 cigarettes/day) increases the odds by 4-5 times persisting for their lifespan (1.3-3.8 times) (32) These groups are of particular interest. Urinary molecular markers (NMP22, FGFR3, microsatellite and methylation analysis) seemingly reduces the number of necessary cystoscopies to diagnose one case of bladder cancer by 82%, but may still be costly in comparison to urine dipstick (79%) although their specificity is not high (75-88%). Moreover, 10-20% of the population would still need to undergo to invasive cystoscopy due to positive exams, which is very limiting on screening programs (33). While the debate is raging it seems more productive to screen populations of interest such as high smokers of over 40 pack-years, although the detection rate was still only 1.6%. The predicament of screening for bladder cancer still remains with an estimated cost of $400,000 per detected case on using NMP22 followed by cystoscopy (35). If the incidence of bladder cancer were 6% (comparable to prostate or breast cancer) in the general population the detection cost could be reduced to $3310 per case.

Hematuria

Macroscopic hematuria must promptly trigger a full evaluation on any patient, but microscopic hematuria is more difficult to analyze. With a sensitivity of 0.91 and specificity of 0.99, dipstick tests for hemoglobin detection is perfect for screening. However, the presence of positive test does not guarantee the presence of bladder cancer as 16-24% of healthy persons present with a positive dipstick while 32% of bladder cancer does not (37).

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Aging and bladder cancer

Enormous attention was drawn for bladder cancer in the older population. Social and economic interest in the matter is related to the median age for the disease which is about of 73 years. In particular, a subclass of clinical condition recently named frailty was defined not by the presence of any disease but by the natural decrease in physiological reserve which is subjected to related problems. This can occur after an ordinary disease or surgical manipulation accompanied by higher rates of postoperative complications and mortality (37). In this regard, patients who regularly exercise do better than sedentary patients on cancer- mortality rates (38). Pearl et al. (39) studied 4,330 cystectomies from the American College of Surgeons' National Surgical Quality Improvement Project with modified Frailty Index dividing patients into robust, pre-frail and frail cases and verified that female sex, smoking status, age and BMI, time at ICU and pre-operative acetylsalicylic acid were less related to be discharged to home (39).

Superficial bladder cancer

Many bladder cancer cases are first diagnosed as superficial cancers, meaning there is no invasion of the muscular layer (77%). While 30% of the overall cases are primarily diagnosed as muscle-invasive bladder cancer (stages T2 to T4) 45% of the non-muscle invasive cases (superficial) will evolve to recurrent muscle-invasive cases (40). During bladder endoscopy, tumours can be characterized by tumor size (> 3 cm in diameter), number of recurrences and concomitant presence of in situ bladder tumor to predict the chance of recurrence (41). Based on these factors the 5-year recurrence risk after endoscopic resection of superficial bladder cancers ranges from 31 to 78% while the progression rate to muscle-invasive bladder cancer ranges from 1 to 45%. Therefore, surveillance with at least 4 cystoscopies and 4 cytology exams in the first 2 years for patients at higher risk of recurrence showed lower risk of death from the disease (42). Surprisingly, analysis from the SEER Medcare showed that only 40% of the cases received the consensual standard of care for follow-up (43) and only 42% of the high-risk cases received bladder instillations (44).

Muscle invasive bladder cancer

Patients with muscle invasive bladder cancer rarely, if ever, are cured by endoscopic resection. Transurethral Endoscopic resection (TUR) of the bladder tumor is the first step in the treatment of the disease allowing histological staging and sampling of the tumor. Both have capital importance on the way the disease will be managed. In a seminal study, Herr evaluated the importance of the second TUR (reTUR) in 96 cases showing that 55% of cases had viable residual bladder tumor while 20% were upstaged to T2. Likewise, of the 54 cases diagnosed with muscle-invasive bladder cancer, 22% had no residual tumor (cured) and 56% still had muscle-invasive residual disease (45). Recognizing the possibility of complete resection in muscle-invasive bladder cancer confirmed by no tumor (pT0) residual carcinoma in situ or non-muscle invasive (T1) in the reTUR, Herr reported his 10-year experience in 52 patients who elected to have immediate Complimentary Contributor Copy Bladder cancer 349 radical cystectomy despite having no firm indication for that in the re-TUR. He observed that 35% were upstaged to pT2, pT3 or N+ on final pathology. 24% of 99 cases of parallel patients who preferred to preserve their bladder died of the disease while 29% of those treated with immediate radical cystectomy died of the disease (46). Moreover, 18% of those who had T0 on re-TUR died of bladder cancer while 42% of those who had T1 on reTUR died of the disease suggesting that those who still present with T1 at reTUR are not good candidates to bladder preservation. In this scenario, the use of platinum-based neoadjuvant chemotherapy has been demonstrated to substantially improve overall survival and disease-free survival as well as decrease in local recurrence rates (47). MVAC (methotrexate, vinblastine, cisplatin and doxorubicin) in its conventional form or dose density as well as the association of cisplatin and gemcitabine are the most used regimens in the neoadjuvant setting. No prospective randomized study demonstrated any superiority of one chemotherapy regimen over the other and the choice should be based on patients’ tolerability and preference (48). Due to toxicities, a randomized phase III study was conducted, modifying the regimen for every 14 days with support of granulocyte factors, and obtained superior results in disease-free survival (49). While neoadjuvant chemotherapy was demonstrated to add benefit to cancer-specific survival, as low as 3.0% of Canadian cases, 3.6% of Danish cases and 11% of the T3 cases in USA received it (50-53). Multi-institutional studies contain the faults of different approaches had difficulties in enrollment while single-institution series such as that in Ontario, Canada with 5259 radial cystectomies (54) or the SEER database analysis gathering 26,851 cases (55) had showed superiority of radical cystectomies over radiotherapy, although patients who were surgery candidates were fitter than those who underwent radiotherapy, possibly affecting the end- results. Similarly important was the demonstration that hospital and surgeon cystectomy volume influences the post-operative mortality and long-term survival rates, possibly reflecting improvements in technique and comfort with the procedure (56). Surprisingly, low- volume hospitals might also offer cystectomies to their patients less frequently than high- volume hospitals (34% vs. 42%) (57).

Table 1. Analysis of mortality in 5207 radical cystectomies

Age Mortality 65-69 years 6.4% 70-79 years 10.1% > 80 years 14.8% Adapted from Schiffmann J, Gandaglia G, Larcher A, et al. Contemporary 90-day mortality rates after radical cystectomy in the elderly. Eur J Surg Oncol. 2014;40(12):1738–45.

Radical cystectomy

Radical cystectomy is still the gold-standard treatment for muscle-invasive bladder cancer (58) despite mortality varying from 3 to 7% as shown in Table 1 (59).

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Redirection of urine after bladder removal

After bladder removal urine can be directed to incontinent (as provided by the ileal conduit) or continent (as provided by cutaneous heterotopic neobladder or urethral orthotopic neobladder) ways. The two main techniques distinguish themselves by the unappealing construction of an incontinent stoma in the abdomen demanding external appliance or by the construction of a heterotopic neobladder using GI segments. In a continent cutaneous reservoir, a low-pressure reservoir of urine is externalized by a continent mechanism in the abdomen constructed from detubularised segments of the bowel. This provides a mechanism where urine can be stored without the use of external appliance. This basic design was many times modified by different authors naming their specific modification or the place where it was adopted, such as Kock pouch, Indiana, Padova, Mainz or Miami pouches. Along the development of cystectomy operations, the more attractive orthotopic neobladder supplanted the heterotopic version. In a unique study from India with 24 institutions, 12 of them (50%) elected the neobladder as the preferred option of urinary reconstruction with ileum as the preferred intestinal segment (66%) used for reconstruction followed by ileocecum (16%) (60). Long-term functional outcome may also weigh in as deciding what to use to derive the urinary tract. The ileum is more distensible and favors urine low-pressure storage compared to a colonic segment which is restricted by the colonic taenias. Ileal segments also present a more marked flattening of the mucosa with no or minimal interference in metabolic alterations, promoted by intestinal absorption of the urinary content inside the hollow neobladder as well as a larger reservoir capacity - average sigmoid neobladder capacity of 296 ml in comparison to 546 ml measured in the ileal neobladder (61). Relevant to the matter, as urine is very rich in potassium and chloride, absorption by the intestinal mucosa in exchange for sodium may lead to hyperchloremic-hyperkalemic metabolic acidosis associated with sodium wasting that aggravates the acidosis due to dehydration in colonic segments for reconstruction, with a especial interest for the pediatric population. Many studies showed daily continence around 80 to 100% with night-time continence rates from 66% to 97% (63-65). It was also demonstrated that ability to spontaneous voiding changes along the longer follow-up as demonstrated by Madersbacher et al. (66) in Table 2.

Table 2. Categorical voiding pattern from different types of Neobladders reconstructions

Type of Neobladder Voiding with no assistance (%) Voiding with assistance of catheter (%) Modified Studer (n=36) 27 (75%) 7 (19.4%) Hautmann (n=9) 7 (77.8%) 1 (11.1%) Mainz type (n=15) 10 (66.7%) 3 (20%) Goldwasser type (n=10) 7 (70%) 2 (20%) Reddy type (n=19) 16 (84.2%) 2 (10.5%) OVERALL (N=89) 67 (75.3%) 15 (16.8%)

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Lymphadenectomy in radical cystectomy

At the time of diagnosis approximately 25% of the cases of muscle-invasive bladder cancer will harbor lymph nodal cancer exposing the early extravesical tumor involvement and the low sensitivity of pre-operative evaluation, thereby posing lymphadenectomy as a key strategy to cure (58). Historically, limited lymphadenectomy to the obturator fossa was proven to improve survival but Pulsen et al. demonstrated that extended lymphadenectomy enhanced the advantage to 21% (67-68). It is now consolidated that lymphadenectomy must be done in any circumstance as clinical stage and pathological samples obtained through endoscopic resections underrepresent the tumor, with 42% being upstaging at final pathology (69-70). Few articles looked at this issue but a striking difference in survival was observed when lymphadenectomy was routinely added to the cystectomy as compared to cystectomy alone. Although the survival rate was higher for lymphadenectomized cases, the difference was remarkable for patients <75 year-old with no morbidity (Charlson’s Comorbidity Index =0). It is hard to establish the minimum threshold for standard-quality on the number of dissected nodes but higher numbers seem to positively affect the survival rate and some authors adopted 10 nodes as the minimum adequate although cadaveric studies on cystectomy showed a presence of 22.7 +/- 10.2 nodes (71-72). It is still surprising that despite this knowledge, only 53% of 16,505 studied cystectomies have had >10 nodes removed which was reflected on cancer-specific survival (60.0 vs 46.8 months) and is also dependent by surgeon effort (73-74).

Radical cystectomy in women

First introduced for men, radical cystectomy was rapidly extended to women after recognition that the tubular urethra could be functionally preserved with oncological safety with the 5- year survival rate of 60-83% (75). Largely feared in the first series, 57% of women with cystectomies retained continence while 24% developed urinary retention (76). Preservation of the uterus and adnexal elements clearly helped in the preservation of the neural network by preserving the urethral closing pressure (77). Counterintuitively, the preservation of uterus and adnexal organs do not compromise the oncological outcome but raised the daytime continence rate to 80% (78).

Radical cystectomy in advanced stage

Radical cystectomy is often taken as a gold-standard in the treatment of bladder cancer but in the event of unresectable advanced disease, the protocol is yet undefined. In a recent survey with 896 patients with advanced disease (cT4b), 20.6% underwent chemotherapy only, 8.9% chemo-radiation, 18.9% radical cystectomy, 27.8% observation and 24.7% other treatment. Chemo-radiation modality presented the longest overall survival (10.5 vs. 12.1 months, p=0.004) comparable to radical cystectomy (79).

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Urodynamic findings in neobladder

Any inventive bladder substitution or drainage system must comprise adequate volume capacity to store urine at low pressure in order to preserve the low glomerular filtration pressure. Additionally, bladder substitutes must have a volume capacity that allows daytime and nighttime continence, while preserving body image esteem. As neobladers are constructed from isolated segment of the intestines, most of them keep peristaltic contractions active despite new designations to store urine, resulting in incomplete continence recovery (80). The storage capacity largely depends on the intestinal length but as a rule daytime continence is accomplished in 70 to 100% while nighttime from 60 to 80% (81-83). The capacity to empty the reservoir is also important. The majority (>83%) of patients with neobladders use abdominal straining with 52% of them also activating the pelvic floor during the expelling phase. The undesired activation of the pelvic floor during voiding is called pseudo-dyssynergia and straining is a way to overcome the resistant outlet. There is a scarce number of studies for long term results but they can be classified in poor voiders that show peaked flow rate at 9.4 ± 0.9 mL/s and strained 7.0 ± 6.3 times during emptying while fine voiders peaked 26.2 ± 8.7 ml/s and strained 1.5 ± 0.9 times to void (84).

Short-term and surgical complications of cystectomies

Cystectomy is a very complex procedure; it is important to understand its 90-day complications. Observed mortality rate on 823 operated cases in 39 different hospitals were 5.4, 6.9 and 8.4% respectively for low, intermediate or high-volume hospitals, a very different rate when only 30 days were analysed at referral centres - 0.6 to 0.8% (85-86). In the study by Novotny et al. on 830 cystectomies, hypertension (57.3% vs. 38.5%), coronary heart disease (27.1% vs. 14.8%) and diabetes (25.5% vs. 14.6%) were more prevalent in the elderly (>70 years old) and reflected on perioperative complications (31.0% vs. 21.5%, p=0.002), although the ASA score also kept a clear relationship with complications rates (score ≥3 (37.0%) vs score ≤2 (25.0%), P<0.02) with mortality rates comparable between younger and older cases (0.6% (elderly) vs 0.5% (younger)) (86). Readmission was another dimension of interest and fever was the most frequent reason for hospital readmission (57%) followed by abdominal pain (25%) and dyspnoea, and urinary retention or chest pain combined (18%). Hospital readmission was influenced by how the patient approached the health system. Krishnan et al. showed that readmitted patients more often used the emergency department to be reevaluated by any supposed complication (27% vs. 1%) than patients not-readmitted (87). Being a burden to the society, bladder cancer is estimated to cost up to USD $200,000 per patient (88) with an observed 90-days complication in roughly 50% of the cases (88-91). Readmitted cases who did not have an index complication cost USD $45,487 while those who had complication during index hospitalization and were posteriorly readmitted cost USD $54,934 (p<0.001).

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Quality of life after cystectomies

Quality of life (QoL) has drawn attention as it is an important dimension in any cancer care program. In general, the tools measuring different life dimensions are subjective and are gauged by metrics containing specific questions. As long as it can be understood, incontinent urinary diversion reaches similar rates of quality of life as those reconstructed as neobladders in many social domains after a while, surprising and opposing the concept that incontinent diversion would gave worse quality of life. In this regard, Fujisawa et al. looked at QoL by using the SF-36 questionnaire in 56 patients finding no statistically significant difference between patients reconstructed with neobladders or ileal conduits, although both groups scored lower in the physical functions and emotional self-perceptions than the general United States population (92). Depression was reported by 33% of the cases and persisted six months onward in 50%, although only 6% sought specialized help. Even more unexpected, when the different forms of urinary reconstruction was compared (incontinent urinary diversion versus continent or orthotopic urinary diversion) no clear superior outcome can be advised among the different options as they present different impacts on daily-living activities but with unchanged scores on perceptions of mental health (93-94). However, some studies continue to claim that urinary stomas are associated with worse psychosocial effects with up to 63%, 58%, and 42% of the patients referring that ileal conduit was respectively associated with lack of “completeness,” anxiety about stomal leakage or embarrassment due to the stoma existence (95).

Delayed cystectomy

As with many major operations, cystectomies may take additional time related to preoperative evaluation unpredictably affecting the chance to cure. Chang et al. (96) reported that at >90 days after endoscopic resection, sampling-confirmed muscle invasive bladder cancer was correlated with higher chances of having pT3 than those having cystectomies earlier (81% versus 52%, p=0.01) and similar observations was done regarding node positivity (97).

Quality of care for patients with bladder cancer

The minimum of care for bladder cancer from the main health agencies (AUA, NCCN, EAU) for the first two years is:

 cystoscopy and urinary cytology - every 3 months  upper tract imaging - once at least  instillation of perioperative mitomycin C and endoscopic resection  induction course of BCG

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It has long been recognized that 40% of bladder cancer patients had biannual cystoscopy and urinary cytology (98). In high-grade non-invasive bladder cancer cases, only 42% received complementary immune or chemotherapy after endoscopic resection, indicating a lack of minimal recognized measures to control the disease (99). By the same token, despite being largely reported that immunotherapy or chemotherapy significantly decreases the recurrence rates in stage Ta and T1 bladder cancers by 39%, only 0.3% of the cases received some immunotherapy instillation despite its published effectiveness in reducing recurrences (100, 101). As a complex disease, an incomplete form of verification for the best quality of care is yet to be determined although another way to measure for the quality of care can be done by measuring the number of cases where the reconstruction was attained with orthotopic neobladder.

Should we have specialized centers for cystectomies? Evidences from the literature

It is surprising to determine that a lower than expected rate of cystectomies is accomplished in cases where it seems to be the gold-standard of care. A population-based study from the SEER database found that only 21% of stage II bladder cancer patients underwent cystectomies which called for attention on the reasons behind this (103). A broad Dutch study also showed an underuse of cystectomy in Stage II (42%) and III (44%) for bladder cancer cases, noting an important weight of age (< or >75 years old) on the decision-making to adopt either operation or other forms of treatment. Moreover, the decision to go to cystectomy was significantly lower if diagnosed in low-volume hospitals when compared to high-volume ones (34% vs. 42%, respectively, (p<0.05) (57). Amazingly, distance to an available urologist able to perform cystectomy decreased the odds of receiving cystectomy (0–4 miles (odds ratio, OR=1), 5-19 miles (OR=0.9), 20-49 miles (OR=0.73) and >50 (OR=0.60) even though the overall survival was better for those who underwent cystectomy when compared to those having chemotherapy and/or radiation (OR=1.5) (102). Surprisingly, costs may vary from USD $14,007 to USD $110,358/case representing a 7.8-fold difference in the mean costs of the least and the costliest deciles. As already pointed out, high-volume surgeons seem to decrease the grade of reintervention and complications but the interference of the high- volume hospital personnel in the postoperative care on the outcome must not be neglected with low-volume hospitals showing 90-day mortality of 8.5% and high-volume hospitals showing 5.6% (>30 cystectomies/year) (103-104). Surprisingly, after statistical adjustments, hospital volume seems to interfere in mortality more markedly than surgeon volume (105).

Preservation of the bladder

“Diseased-field theory” claims that bladder tumors spawn from multiple origins, hampering one to treat it by partial resection due to its lack of effectiveness. For those patients who received carboplatin-gemcitabine-based chemotherapy where a regression to cT0 was observed, they should undergo surveillance with regular cystoscopy in order to preserve the bladder. By the same reason, curative treatment might be achieved endoscopically in 5 to Complimentary Contributor Copy Bladder cancer 355

20% of the cases (106). Bladder-preserving protocols in bladder cancer in prospective trials revealed 5-year survival rate of 45 to 60% and that 3/4 of the cases maintain their organ although long-life follow-up is required (107). One of the rare studies looking to this issue by randomizing patients to radiotherapy or radical cystectomy after neo-adjuvant chemotherapy showed better cancer-specific survival, time to loco-regional recurrence or metastatic disease free-survival in favor of the surgery, but involved a high-selected and initially randomized group of selected cases of 145 patients filtered from 729 bladder cancer cases (108). The treatment consists of a thorough Transurethral Resection of a Bladder Tumor (TURBT) followed by irradiation of 64–65 Gy with concurrent sensitizing chemotherapy. Patients with a complete response are followed with surveillance cystoscopy, with cystectomy reserved for patients with recurrent disease and promptly redirected to cystectomy (109). Up to 30% of the patients entering a potential bladder preserving protocol with trimodality therapy (initial TURBT followed by concurrent chemoradiation) will ultimately require a salvage radical cystectomy. In the RTOG 89-03 trial, 123 eligible patients with tumor, node, metastasis system clinical stage T2 to T4aNxM0 bladder cancer were randomly assigned to receive (n=61) two cycles of cisplatin, methotrexate, and vinblastine (CMV) before 39.6-Gy pelvic irradiation with concurrent cisplatin 100 mg/m2 while arm 2 (n=62) did not receive CMV before concurrent cisplatin and radiation therapy. The patients with complete response (CR) at cystoscopy were treated with an additional 25.2 Gy summing up to 64.8 Gy, and one additional dose of cisplatin. Those with less than a CR underwent cystectomy. Two cycles of MCV neoadjuvant chemotherapy were not beneficial to CR, overall survival, or rate of distant metastases. (110). The RTOG 9906 phase I/II trial enrolled 81 patients from 1999 to 2002 at 26 institutions. After TURBT in patients with Stage T2-T4a bladder cancer, patients underwent induction accelerated RT twice-daily for over 13 days, including 1.6 Gy to the pelvis in the morning, and 1.5 Gy to the bladder for the first 5 days (7.5 Gy) and then 1.5 Gy to the tumor site for the next 8 days (12.0 Gy) in the afternoons (total dose, 20.8 Gy to pelvis, 28.3 Gy to whole bladder, and 40.3 Gy to bladder tumor) with concurrent weekly cisplatin (20 mg/m2 2 days a week) and paclitaxel (50 mg/m2 per week). Patients with a CR on rebiopsy after 40.3 Gy of RT received 1.5 Gy twice-daily pelvic RT to a dose of 24 Gy (total dose 64.3 Gy to the bladder tumor and 44.8 Gy to the pelvis) with concurrent weekly cisplatin/paclitaxel. Patients then received four cycles of adjuvant cisplatin (70 mg/m2) and gemcitabine (1,000 mg/m2). The post-induction complete response rate was 81%. At a median follow-up of 49.4 months, overall and disease-specific survival rate were 56% and 71%, respectively. Chemoradiotherapy induction resulted in 26% developing grade 3-4 acute toxicity, mainly gastrointestinal (25%). During consolidation, transient grade 3-4 acute toxicities were reported in 8% (111). Targeting only the bladder with 2-cm margins did not adversely affect survival and might minimize side effects compared with a whole-pelvis volume (112). In the BC2001 trial, irradiating the bladder +1.5 cm (2 cm around the visible tumor) produced a nodal recurrence rate of only 5% (113). To date, the current radiation protocol for bladder preservation includes external-beam RT to the bladder (either once daily or twice daily) and limited pelvic lymph nodes to an initial dose of 40 Gy, with a boost to the whole bladder to 54 Gy and a further tumor boost (which incorporates all TUR and radiographic information) to a total dose of 64–65 Gy.

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For very old patients (> 80 years-old), programs to preserve the bladder is soaring as there was no difference between surgery and preserving management, albeit the conservative group showed 24 days of hospitalization and RC 50 days or 8.7% and 12.9% of the remaining life-time, respectively (114). Recently, Cahn et al. (115) studied 32,300 stage II or III bladder cases in a 10-year period identified by the National Cancer Data Base (NCDB) where 70.2% underwent radical cystectomy and 29.8% had bladder preservation therapies, 26.4% definitive radiotherapy (2,540 patients), and 15.5% chemo-radiotherapy (1,489 patients). In this study, temporal trend in favor of a more comprehensive use of radiotherapy in conjunction with chemotherapy was observed along the studied period but as patients were accrued to bladder preservation therapies, it was found that organ-preserving protocols showed worse overall survival in comparison to those who had radical cystectomy (115, 116).

Chemotherapy

The survival of patients with metastatic disease was approximately 6 months and this number increased to 15 months with the advent of new generations of chemotherapy (117). MVAC regimen is the choice for patients with good performance status and candidates for platinum therapy but the combination of cisplatin + gemcitabine studied in 405 randomized patients resulted in similar response rates (49 vs. 46%), time to progression (seven months in each arm), and identical results in terms of overall survival (14 vs. 15 m), and 5-year survival rate (13 vs. 15 percent) (117-118). The addition of Paclitaxel to the scheme resulted in an increase in the ORR (56 vs. 44 percent, p=0.003) and a trend towards longer OS (16 vs. 13 m). On cases where cisplatin contraindicated, Carboplatin may be an alternative platinum agent. A study conducted by the EORTC, in which 238 patients with impaired renal function and/or poor performance status were randomly assigned to treatment with carboplatin and gencitabine or methotrexate, carboplatin, and vinblastine (MCAVI). In this trial, the combination of Carboplatin + gemcitabine was superior in terms of response rate, but with no statistically significant difference. In view of these results, the association of Carboplatin + gemcitabine is an alternative for these patients with irreversible renal dysfunction (119). Immunotherapy with Anti-PD-1/PDL-1 is an alternative for patients who present with contraindications to chemotherapy in the first-line setting. In a phase II study, the atezoluzumab antibody was used in 119 patients with a response rate of 23%, with complete response rate of 9% and overall survival of 16 months (120).

CONCLUSION

The paper reviewed comprehensively the contemporary practices for bladder cancer with a special focus on the epidemiology of Latin America. It was noted that a scarce number of papers originated from the region and on its peculiar demands. Attention was drawn to the fact that even epidemiological studies on the region are very limited as the Health systems are heterogeneous, non-centralized in many countries and hard to access, thereby generating unreliable data that affects governmental policies.

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[105] Waingankar N, Mallin K, Smaldone M, EglestonBL, Higgins A, Winchester DP, et al. Assessing the relative influence of hospital and surgeon volume on short-term mortality after radical cystectomy. BJU Int 2017;120(2):239-45. [106] Tilki D, Svatek RS, Novara G, Seitz M, Godoy G, Karakiewicz PI, et al. Stage pT0 at radical cystectomy confers improved survival: an international study of 4,430 patients. J Urol 2010;184(3):888-94. [107] Rodel C, Weiss C, Sauer R. Trimodality treatment and selective organ preservation for bladder cancer. J Clin Oncol 2006;24(35):5536-44. [108] Huddart RA, Birtle A, Maynard L, Beresford M, Blazeby J, Donovan J. Clinical and patient-reported outcomes of SPARE – a randomised feasibility study of selective bladder preservation versus radical cystectomy. BJU Int 2017;120(5):639-50. [109] Mak RH, Hunt D, Shipley WU, Efstathiou JA, Tester WJ, Hagan MP, et al. Long-term outcomes in patients with muscle-invasive bladder cancer after selective bladder-preserving combined-modality therapy: a pooled analysis of Radiation Therapy Oncology Group protocols 8802, 8903, 9506, 9706, 9906, and 0233. J Clin Oncol 2014;32(34):3801-9. [110] Shipley WU, Winter KA, Kaufman DS, Lee WR, Heney NM, Tester WR, et al. Phase III trial of neoadjuvant chemotherapy in patients with invasive bladder cancer treated with selective bladder preservation by combined radiation therapy and chemotherapy: initial results of Radiation Therapy Oncology Group 89-03. J Clin Oncol 1998;16(11):3576-83. [111] Kaufman DS, Winter KA, Shipley WU, Heney NM, Wallace HJ 3rd, Toonkel LM, et al. Phase I-II RTOG study (99-06) of patients with muscle-invasive bladder cancer undergoing transurethral surgery, paclitaxel, cisplatin, and twice-daily radiotherapy followed by selective bladder preservation or radical cystectomy and adjuvant chemotherapy. Urology 2009;73(4):833-7. [112] Tunio MA, Hashmi A, Qayyum A, Mohsin R, Zaeem A. Whole-pelvis or bladder-only chemoradiation for lymph node-negative invasive bladder cancer: single-institution experience. Int J Radiat Oncol Biol Phys 2012;82(3):457-62. [113] James ND, Hussain SA, Hall E, Jenkins P, Tremlett J, Rawlings C, et al. Radiotherapy with or without chemotherapy in muscle-invasive bladder cancer. N Engl J Med 2012;366(16):1477-88. [114] Martini T, Mayr R, Wehrberger C, Dechet C, Lodde M, Palermo S, et al. Comparison of radical cystectomy with conservative treatment in geriatric (≥ 80) patients with muscle invasive bladder cancer. Int Braz J Urol 2013;39(5):622-30. [115] Cahn DB, Handorf EA, Ghiraldi EM, Ristau BT, Geynisman DM, Churilla TM, et al. Contemporary use trends and survival outcomes in patients undergoing radical cystectomy or bladder-preservation therapy for muscle-invasive bladder cancer. Cancer 2017;123(22):4337-45. [116] Chamie K, Hu B, Devere White RW, Ellison LM: Cystectomy in the elderly: does the survival benefit in younger patients translate to the octogenarians? BJU Int 2008;102(3):284-90. [117] von der Maase H, Sengelov L, Roberts JT, Ricci S, Dogliotti L, Oliver T, et al. Long-term survival results of a randomized trial comparing gemcitabine plus cisplatin, with methotrexate, vinblastine, doxorubicin, plus cisplatin in patients with bladder cancer. J Clin Oncol 2005;23(21):4602-8. [118] Sternberg CN, de Mulder PH, Schornagel JH, Theodore C, Fossa SD, van Oosterom AT, et al. Randomized phase III trial of high-dose-intensity methotrexate, vinblastine, doxorubicin, and cisplatin (MVAC) chemotherapy and recombinant human granulocyte colony-stimulating factor versus classic MVAC in advanced urothelial tract tumors: European Organization for Research and Treatment of Cancer Protocol no. 30924. J Clin Oncol 2001;19(10):2638-46. [119] De Santis M, Bellmunt J, Mead G, Kerst JM, Leahy M, Maroto P, et al. Randomized phase II/III trial assessing gemcitabine/carboplatin and methotrexate/carboplatin/vinblastine in patients with advanced urothelial cancer who are unfit for cisplatin-based chemotherapy: EORTC study 30986. J Clin Oncol 2012;30(2):191-9. [120] Balar AV, Galsky MD, Rosenberg JE, Powles T, Petrylak DP, Bellmunt J, et al. Atezolizumab as first-line treatment in cisplatin-ineligible patients with locally advanced and metastatic urothelial carcinoma: a single-arm, multicentre, phase 2 trial. Lancet 2017;389(10064):67-76.

Chapter 24

MANAGEMENT OF RENAL CANCER IN LATIN AMERICA

Rafael Corrêa Coelho1,2,, MD MSc, Cleber Brenner3, MD, João Paulo Fogacci de Farias4, MD, Fiona Lim5, MBBS, Bo Angela Wan6, MD(C) and Maurício F Silva7,8,9, MD, PhD 1Department of Clinical Oncology and Hematology, Hospital Universitário de Santa Maria, Santa Maria, Brazil 2Medical Sciences Post Graduation Program, Universidade Federal do Rio Grande do Sul, Porto Alegre, Brazil 3Department of Urology, Hospital Universitário de Santa Maria, Santa Maria, Brazil 4Department of Clinical Oncology, Hospital Federal de Bonsucesso, Rio de Janeiro, Brazil 5Department of Oncology, Princess Margaret Hospital, Hong Kong, PR China 6Odette Cancer Centre, Sunnybrook Health Sciences Centre, Toronto, Ontario, Canada 7Radiation Oncology Unit, Santa Maria Federal University, Santa Maria, Brazil 8Radiation Oncology Unit, Hospital de Caridade Astrogildo de Azevedo, Santa Maria, Brazil 9Latin America Cooperative Oncology Group, Porto Alegre, Brazil

ABSTRACT

Renal cell carcinoma is increasing in incidence and represents a major health concern. Global actions for improving public health and reducing treatment costs to widen access are needed. This chapter aims to outline the treatment of RCC and discuss some alternatives for treatment in Latin America.

 Corresponding Author’s Email: [email protected]. Complimentary Contributor Copy 364 Rafael Corrêa Coelho, Cleber Brenner, João Paulo Fogacci de Farias et al.

INTRODUCTION

Renal cell carcinoma (RCC) represents a major health concern, being the ninth most common cancer in men and 14th most common cancer in women. In 2012, there were an estimated 143,000 deaths by RCC, making it the 16th most common cause of cancer death globally (1). In Latin America, the highest mortality rates are in Uruguay (5.97/100,000 in men and 2.32/100,000 in women) and the lowest in Ecuador (1.17/100,000 in men and 0.76/100,000 in women) (2). Epidemiologic data shows an increasing incidence of RCC, demanding global actions for improving public health policies aimed at promoting early diagnosis, creating comprehensive national registries and implementing earlier treatment plans (3). There are differences in RCC management among Latin America countries due to access and budget available for treating patients. This review article aims to discuss the best alternatives for treating RCC in Latin America.

OUR SEARCH

The search emphasized studies representing high levels of evidence (i.e., systematic reviews [SRs] with meta-analysis [MA], randomized controlled trials [RCTs], and prospective nonrandomised comparative studies only) and published in the English language. Data from retrospective studies and case reports were used only if no prospective studies were available about relevant subjects. The search was restricted to articles published between January 1st 1985 and February 28th 2019. Databases covered included PubMed, EMBASE and Cochrane Library. After removal of duplicates, a total of 2,657 unique records were identified, retrieved and screened for relevance. We also added data regarding renal cell cancer treatment from important abstracts presented in 2018 and 2019, but not yet published.

LOCALIZED RENAL CELL CARCINOMA MANAGEMENT

Surgical treatment includes partial and radical nephrectomy made by open, laparoscopic or robotic interventions (4, 5). Minimally invasive approaches characterized by laparoscopic and robotic surgery are associated with shorter hospital stay, fewer analgesic requirement and shorter convalescence time (4, 5). As that there are no differences in oncologic outcomes among these approaches; the preferred technique depends on the available technology, budget, and surgeon experience (4-9). Partial nephrectomy (PN) and radical nephrectomy (RN) have comparable cancer specific survival in patients with organ-confined RCC of limited size. Nevertheless, PN better preserves kidney function, lowering the risk of metabolic or cardiovascular disorders (10-12). It has been suggested that the more pronounced deterioration of renal function after RN negatively affects patients’ survival (13, 14). Positive surgical margins (PSM) can be found in until 8% of PN. Nevertheless, long-term oncologic outcomes remain to be determined in these situations and PSM not necessarily are

Complimentary Contributor Copy Management of renal cancer in Latin America 365 translated into worse outcomes. Therefore, RN or resection of margins may be an overtreatment in many cases (15-17). Some patients with early renal cell cancer can be unsuitable to PN if the volume of remaining parenchyma is insufficient to maintain proper organ function, presence of renal vein thrombosis, unfavorable tumor location and/or use of anticoagulants. In these situations, the curative therapy is RN including removal of the tumor-bearing kidney (18). Adrenalectomy is commonly justified using criteria based on radiographic and intraoperative findings. However, no difference in overall survival (OS) at five or ten years has been seen with or without adrenal surgical approach. Upper pole location has not been predictive of adrenal involvement, but tumor size is (19, 20). The indication for lymph node dissection (LND) during PN or RN is still controversial. Less than 20% of suspected metastatic nodes are positive for metastatic disease at histopathological analysis. Both CT and MRI fails in detecting malignant disease in nodes of normal shape and size. However, if suspicious lymphadenopathies are identified on imaging or during surgical approach, LND should be performed for staging and prognosis purposes. LND need not be performed routinely in patients with localized kidney cancer and clinically negative nodes (21-24). Tumour thrombus formation in the inferior vena cava is a significant adverse prognostic factor. Traditionally, patients with venous tumor thrombus undergo surgery to remove the kidney and tumor thrombus. Aggressive surgical resection is widely accepted as the standard management option for patients with venous tumor thrombus (25). In patients with non-resectable disease or unfit for surgery, embolization can control symptoms, including hematuria and/or flank pain (26). Active surveillance (AS) is defined as the initial monitoring of tumor size by serial abdominal imaging with delayed intervention reserved to tumors showing clinical progression during follow-up. A growing body of literature exists supporting AS for patients with clinically localized small renal masses (cT1a, ≤4 cm) (27, 28). The use of neoadjuvant targeted therapies to downsize tumors is experimental and cannot be recommended outside clinical trials.

Ablative therapies

Cryoablation (CA) techniques have been developed in an effort to improve patient procedural tolerance and reduce PN complications. Candidates for CA procedures may be patients with advanced age and/or those with significant comorbidities who prefer a proactive approach but are not optimal candidates for conventional surgery. Local recurrence after previous nephron sparing surgery and multifocal lesions can be other indications for CA (29-31). Radiofrequency ablation (RFA) is another option with indications resembling CA. It is accepted that oncologic outcomes are similar for both approaches. CA and RFA have been performed through a variety of approaches, including open, laparoscopic, and percutaneous. Concerns regarding ablative approaches include the limited follow-up of patients, lack of pre and post treatment biopsy to define malignancy and efficacy, since there is an increased rate of local recurrences when compared to surgical excision (32, 33).

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Table 1. Adjuvant treatment in renal cell cancer

References Number of Treatment regimen Eligibility criteria Toxicities Disease Free Survival Overall Survival patients (DFS) (months) (OS) (months) Haas et al, Sunitinib Sunitinib - 50 mg Completely resected high-risk clear Sunitinib - 57% had grade 3 and 5% Sunitinib 5 year overall 2016,2017 647 per day orally cell or non-clear cell renal cell grade 4 adverse events. 70 months survival (34,35) throughout the first carcinoma within 12 weeks of Hypertension, fatigue, hand and foot (5.8 years, (ASSURE Sorafenib 4 weeks of each 6 removal of the primary tumor. syndrome and diarrhea were the most IQR 1.6-8.2) Sorafenib trial) 649 week cycle The high-risk designation included frequent 77.9% Phase III Sorafenib - 400 mg the following criteria in accordance Sorafenib (97.5% CI, trial Placebo twice per day orally with the American Joint Committee Sorafenib - 68% had grade 3 and 3% 73.4 months 74.1-81.9) 647 throughout each on Cancer (AJCC) Cancer Staging grade 4 adverse events.Hand and foot (6.1 years, IQR 1.7-NE) cycle Manual, 6th edition (2002) (36) and syndrome, hypertension and rash Sorafenib Placebo - the same Fuhrman nuclear grades : pT1b were the most frequent Placebo 80.5% (76.8-84.2) sunitinib or G3−4 N0 (or pNX where clinically 79.6 months sorafenib schedule N0) M0 to T(any) G(any) N + (fully Placebo - 22% had grade 3 and 4% (6.6 years, IQR 1.5-NE) Placebo 1 year treatment resected) M0 grade 4 adverse events No statistical difference 80.3% (76.7-84.0)

No statistical difference Ravaud et Sunitinib Sunitinib - 50 mg Locoregional completely resected Sunitinib - 48.4% had grade 3, 12,1% Sunitinib Not reached in al, 2016 309 per day orally renal-cell carcinoma (tumor stage 3 grade 4 adverse events. both groups (37) throughout the first or higher, regional lymph-node Hand and foot syndrome, 6.8 years (95% CI, 5.8 to (S-TRAC Placebo 4 weeks of each 6 metastasis, or both). hypertension, neutropenia, not reached) HR, 1.01 trial) 306 week cycle Other eligibility criteria included trombocytopenia, mucositis and HR, 0.76 (95% CI, 0.59 (95% CI, 0.72 to Phase III histologic confirmation of clear-cell fatigue were the most frequent to 0.98; P = 0.03) 1.44; P = 0.94) trial Placebo - the same renal-cell carcinoma, no previous sunitinib schedule systemic treatment, ECOG < 3 Placebo - 15.8 % had grade 3 and Placebo before nephrectomy and treatment 3.6% grade 4 adverse events 5.6 years 1 year treatment initiation within 3 to 12 weeks after (95% CI, 3.8 to 6.6) nephrectomy. The absence of macroscopic residual or metastatic disease after nephrectomy

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References Number of Treatment regimen Eligibility criteria Toxicities Disease Free Survival Overall Survival patients (DFS) (months) (OS) (months) Motzer Pazopanib Pazopanib - patients Resected non-metastatic Pazopanib 3 year DFS Pazopanib et al. 2017 800 mg received 800 mg or clear-cell or predominant clear-cell 60% had grade 3 or 4 adverse events. 600 mg (38) 198 600 mg daily RCC histology, fulfilling any of Hypertension, increase ALT, Pazopanib 600mg HR, 0.79 (95% (PROTECT the following combinations of diarrhea, increased AST the most 67% (95% CI, 62% to 71%) CI, 0.57 to 1.09) trial) Pazopanib Placebo - the same pathologic staging based on TNM common Pazopanib 800mg Pazopanib Phase III 600 mg pazopanib schedule classification Discontinuations because of AEs 66 % (95%CI, 58% to 72%) 800 mg trial 571 per the American Joint Committee were similar in both pazopanib No statistical difference HR, 0.89 (95% 1 year treatment on Cancer (2010 version)(39) and groups when compared to placebo CI, 0.54 to 1.46) Placebo Fuhrman nuclear grades: pT2 G3- No statistical 769 4N0, pT3-T4 GanyN0, or Placebo difference when pTanyGanyN1 21 % had grade 3 or 4 adverse events compared to placebo Gross- Axitinib Axitinib - 5 mg Resected non-metastatic Axitinib HR, 0.870 (95% CI, 0.660- Data are Goupil et al. 363 twice-daily RCC, ≥pT2 and/or N+, any 61% had grade 3 or 4 adverse events. 1.147; P = 0.3211). immature 2018 (40) Furhrman Grade, ECOG ≤1 The most common adverse events The trial was stopped due to (ATLAS Placebo Placebo - the same Previous antiangiogenic treatment or were hypertension, diarrhea, futility. HR, 1.026 trial) 361 axitinib schedule systemic treatment of RCC was not dysphonia, hand and foot syndrome, In a pre-specified subgroup (95% CI, 0.600- Phase III permitted. fatigue and hypothyroidism analyses, highest risk 1.756 P = 0.9246) trial Patients were 73 % of patients were Asiatic and patients (pT3 with FG ≥3 or treated for up to 3 25% white Placebo pT4 and/or N+, any T, years and for a any FG) HR, 0.641 minimum of 1 year 30% had grade 3 or 4 AEs (95% CI,0.468-0.879, P = 0.00510) HR - Hazard ratio FG - Fuhrman Grade AEs - Adverse Events.

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Adjuvant therapy

Adjuvant therapy in RCC is controversial and no clinical trial showed benefits in overall survival to our knowledge (see Table 1). Ongoing trials are evaluating other tyrosine kinase inhibitors (TKI) and/or immune checkpoint inhibitors. These trials are targeting high risk populations trying to select better the patients that would have more benefits from adjuvant treatment. It is also expected that adjuvant immunotherapy can impact favorably the outcomes with less adverse events than TKIs.

ADVANCED DISEASE MANAGEMENT

Since 2001, when two randomized phase 3 trials showed a survival advantage with nephrectomy plus interferon over interferon alone, nephrectomy became accepted as first step in management of metastatic RCC (41, 42). With the approval of drugs targeting angiogenesis, nephrectomy continued to be performed, extrapolating data from these trials. Nevertheless, concerns were raised that surgery, mainly in poor risk patients, could lead to harmful outcomes. The CARMENA (Cancer du Rein Metastatique Nephrectomie et Antiangiogéniques) trial evaluated the role of nephrectomy added to sunitinib in patients with metastatic clear-cell RCC (43). The standard arm underwent nephrectomy and then received sunitinib; the experimental arm received sunitinib alone. Randomization was stratified according to prognostic risk (intermediate or poor) in the Memorial Sloan Kettering Cancer Center (MSKCC) prognostic model (44). A total of 450 patients were enrolled and 43% had poor risk disease. The standard arm had a higher percentage of locally advanced tumors of stage T3 or T4 than the sunitinib group (70.1% vs. 51.0%) and details about surgery as lymph nodes status and invasion of adjacent structures are lacking. The study met its primary endpoint showing that sunitinib-alone group were noninferior to those in the nephrectomy- sunitinib group with regard to overall survival (stratified hazard ratio for death, 0.89; 95% confidence interval, 0.71 to 1.10; upper boundary of the 95% confidence interval for noninferiority, ≤1.20). The median overall survival was 18.4 months in the sunitinib-alone group and 13.9 months in the nephrectomy-sunitinib group (44). The CARMENA trial included only intermediate and poor risk patients by MSKCC criteria and did not include patients with non-clear cell RCC (43). It is reasonable to believe that well selected patients with favorable risk could still benefit from upfront nephrectomy. Higher risk patients could also benefit from surgery if they have a good response and well controlled disease; however, data are lacking to consolidate this approach as routine. The presence of factors including histologic findings of sarcomatoid disease on preoperative biopsy, a low serum albumin level, a clinical stage of T3 or T4, retroperitoneal or supradiaphragmatic adenopathy and symptoms emanating from metastatic sites should be considered before indicating nephrectomy since they are linked to worse prognosis and absence of surgical benefit (45).

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Local therapies

To our knowledge, there is no prospective trial showing overall survival benefit with local therapies in advanced RCC. However, retrospective data have been showing that well selected patients would benefit from metastasectomy, radiation therapy, embolisation or other locorregional therapies modalities (46-48).

CLEAR-CELL RENAL CARCINOMA

Chemotherapy has limited efficacy in metastatic clear-cell renal carcinoma (mCCRC) and is not recommended (18). Interferon-α and interleukin-2 (IL-2) were the first immunotherapies to show activity in mCCRC, with response rates ranging from 6-27% and potential survival benefits in a small subset of patients (49-52). Targeted therapies superseded interferon-α and IL-2 in mCCRC treatment due to greater efficacy and tolerability, becoming the first choice. Nowadays, the greatest challenge is to determine the best treatment sequencing for each patient (see Table 2).

Subsequent lines

Many targeted therapies have been incorporated in subsequent lines for metastatic clear-cell RCC treatment, improving significantly oncologic outcomes. In 2007, the TARGET trial, a phase 3 randomized trial with 903 patients studied the efficacy of sorafenib after failure of the first line systemic therapy, mostly cytokines, compared to best supportive care. Overall survival (OS) was the primary endpoint, and progression free survival (PFS) was a secondary endpoint. An interim analysis showed significantly higher PFS for sorafenib versus placebo: 5.5 months versus 2.8 months (HR 0.44; P = 0,000001). Cross-over was allowed and OS in the final analysis was similar across arms. Censoring the cross-over data, sorafenib had an overall advantage :17.8 months versus 14.3 months (HR 0.78, P = 0.0287). The most common adverse effects were fatigue, hypertension and hand-foot syndrome (67, 68). The phase 3 randomized trial RECORD-1 with 410 patients randomized 2:1 for the mTOR inhibitor everolimus or placebo after first line anti-vascular endothelial growth factor (VEGF) failure (sorafenib or sunitinib), respectively. The primary endpoint was PFS and it favored everolimus: 4.9 months versus 1.9 months, with the main adverse effects being stomatitis, rash and fatigue (69). The AXIS study, a phase 3 randomized trial evaluated the efficacy of axitinib. Most patients failed to sunitinib (54%) or cytokines (35%), and they were randomized 1:1 in second line setting to axitinib or sorafenib. The primary endpoint was PFS which favored axitinib: 6.7 months versus 4.7 months (HR 0.665; P < 0.0001), with a greater response-rate (19% versus 9%; P = 0.0001). When analyzed separately the subgroup that failed prior to cytokines, the difference was even higher: 12.1 months versus 6.5 months (HR 0.464; P <

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0.0001) (70). Blood pressure (BP) can be a potential clinical biomarker, predicting a median PFS around 20 months for those with BP equal or more than 140 x 90 mmHg (71). The FavorAx, a phase 2 multicentric study. addressed the question of axitinib’s efficacy in patients with a favorable risk who failed to an anti-VEGF on first line therapy. Twenty-one patients were treated after failing to pazopanib or sunitinib. The PFS in 10 months was 71.4%, with OS and PFS non-reached at the time of presentation (72). The phase 3 trial, Checkmate 025, evaluated 821 patients who had failed to first or second line therapy with at least one anti-VEGF therapy prior (73). The randomization was 1:1 between nivolumab or everolimus with the majority of patients receiving only one prior line of therapy (72%). The primary endpoint was OS and it was met with nivolumab median of 25 months versus 19.6 months with everolimus (HR 0.73; P = 0.0018). Updated data confirmed that the benefit in OS remained after 3 years with 25.8 months over 19.7 months (HR:0,74; P = 0.0005). The benefit was obtained across subgroups, regardless of status of PDL1. Response rate favored nivolumab group with 21,5% versus 3,9%. The tolerance was better in nivolumab group with adverse events grade 3 and 4 in 20% of patients, 17% lower than everolimus group (73, 74). The NIVOREN study, a French multicenter prospective study to evaluate safety and efficacy of nivolumab in a real world setting, had the results of the first 528 patients reported. This trial allowed the inclusion of patients with more than 2 lines therapy previously, ECOG PS2, asymptomatic brain metastasis, renal insufficiency, poor IMDC prognosis and who was exposed to mTOR inhibitors prior. Despite the wider inclusion criteria, the results were in line to Checkmate 025. OS, PFS and RR were 18.6 months, 4 months and 18.5%, respectively (75). A common mechanism of acquired resistance after failure anti-VEGF therapy is up regulation of MET-AXL axis. The co-inhibition of VEGF and MET-AXL in pre-clinic models showed that it could be possible to restore sensitivity of angiogenesis agent after failure (76-78). The METEOR trial evaluated cabozantinib, a VEGF-MET-AXL TKI inhibitor, against everolimus. Patients had to fail to anti-VEGF therapy in first or subsequent lines. Six hundred fifty eight patients were randomized 1:1 either to cabozantinib or everolimus. PFS was the primary endpoint and favored cabozantinib with 7.4 months versus 3.8 months in everolimus group (HR 0.58; P < 0.001). Grade 3-4 adverse events occurred in 68% of patients in cabozantinib arm, with dose reductions needed in 60% of patients and interruption in 9%. The most common side effects were the main reasons were diarrhea, hand-foot syndrome and fatigue. OS and RR also favored cabozantinib with the final analyses published in 2016 showing 21.4 versus 16.5 months and 17 % versus 3 %, respectively (76,78). In a subgroup analysis of bone related outcomes, it was showed a decrease of 6% in bone events favoring cabozantinib (78, 79).

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Table 2. First-line treatment for clear-cell renal carcinoma

References Number of Treatment regimen Eligibility criteria Toxicities Response Rates Progression Free Overall Survival patients (RR) Survival (PFS) (OS) (months) (months) Motzer et al. Sunitinib Sunitinib 50 mg per day Metastatic renal-cell Sunitinib - Grade 3 or 4 Sunitinib Primary Secondary 2007 and 2009 375 orally throughout the first carcinoma with a clear-cell diarrhea, vomiting, 47% endpoint endpoint (53,54) 4 weeks of each 6 week histologic component, no hypertension, hand-foot (95% CI, 42 Interferon-α cycle previous systemic therapy. syndrome, leukopenia, to 52%, Sunitinib Sunitinib Phase III trial 375 Patients were ineligible if neutropenia, and P < 0.001) 11 26.4 Interferon-α -9 MIU they had brain metastases, thrombocytopenia had a higher (95% CI, 10 to HR 0.818 subcutaneously three times uncontrolled hypertension, incidence than with interferon-α Interferon-α 12) (95% CI, 0.669 weekly or clinically significant 12% HR 0.42 (95% to 0.999; cardiovascular events or Interferon-α - grade 3 or 4 (95% CI, 9 CI, 0.32 to 0.54; P = 0.49) disease fatigue was significantly higher to 16%) P < 0.001) during the preceding 12 (12% vs. 7%, P < 0.05). Interferon-α months Pyrexia, Only 6.4% of Interferon- α 21.8 chills, myalgia, and influenza- patients 5 65% of patients like symptoms were all reported included in this (95% received more frequently trial had poor CI, 4 to 6) sunitinib or risk by MSKCC other TKI after criteria (44) discontinuation of the trial Hudes et al. Interferon-α Interferon-α starting dose At least three of the Grade 3 or 4 asthenia was Interferon-α Secondary Primary 2007 (55) 207 of 3 MIU subcutaneously following six predictors of reported in 11% of patients in 4.8% endpoint endpoint (Global ARCC three times per week for short survival were required: the temsirolimus group, in 26% (1.9-7.8) trial) Temsirolimus the first week. The dose a serum lactate of those in the interferon group Interferon-α Interferon-α 209 was raised to 9 million U dehydrogenase level of more (P < 0.001), and in 28% of Temsirolimus 3.1 7.3 Phase III trial three times per week for than 1.5 times the upper those in the combination 8.6% (2.2-3.8) (6.1-8.8) Interferon-α plus the second week limit of the normal range, a therapy (4.8-12.4) temsirolimus and to 18 million U three hemoglobin level below the group (P < 0.001) 210 times per week for week 3. lower limit of the normal Mild to moderate rash, Interferon plus Temsirolimus Temsirolimus Patients received the range; peripheral edema, stomatitis, Temsirolimus 5.5 10.9 highest tolerable dose a corrected serum calcium hyperglycemia, 8.1% (3.9-7.0) (8.6-12.7) level of more than 10 mg hypercholesterolemia, and (4.4-11.8) HR .73 (95% Temsirolimus 25 mg per deciliter (2.5 mmol per hyperlipidemia Interferon plus CI, 0.58 weekly liter), a time from initial were more common with Temsirolimus to 0.92; diagnosis of renal-cell temsirolimus 4.7 P = 0.008) (3.9-5.8)

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Table 2. (Continued)

References Number of Treatment regimen Eligibility criteria Toxicities Response Rates Progression Free Overall Survival patients (RR) Survival (PFS) (OS) (months) (months) Combination group - 15 carcinoma to Grade 3 or 4 adverse events 74 % of patients Interferon plus mg of temsirolimus randomization of less than 1 occurred in 67% of patients in were poor and Temsirolimus weekly plus interferon year, a Karnofsky the temsirolimus group, and 26% 8.4 (6.6-10.3) at a starting dose of 3 MIU performance score of 60 or 78% of patients in the interferon intermediate risk three times per week for 70, or metastases in multiple group (P = 0.02) and 87% of by MSKCC week 1 and 6 MIU organs patients in the combination- criteria (44) subcutaneously three times therapy group (P = 0.02) per week thereafter Escudier et al. Bevacizumab Bevacizumab 10mg/Kg Patients had to have In both groups the most Bevacizumab Secondary Primary 2007 and 2010 plus Interferon-α every 2 weeks predominantly commonly reported grade 3 or plus Interferon- endpoint endpoint (56,57) 327 Interferon-α 9 MIU clear-cell renal cell worse adverse events were α (AVOREN trial) subcutaneously three times carcinoma (>50%) and had established interferon-related 31% Bevacizumab Bevacizumab Phase III trial Interferon-α weekly undergone primary tumor toxicities as fatigue, (P = 0·0001) plus interferon-α plus interferon-α 322 surgery asthenia and neutropenia 10.2 23.3 Exclusion criteria included Combination arm – Placebo plus HR .63 (95% HR .86 (95% prior systemic treatment for The incidence of interferon- Inteferon-α CI, CI, 0.72 to 1.04; metastatic renal cell related toxicities was 10% 13% 0·52-0·75; p = P = .1291) carcinoma, recent major higher per patient-year in 0·0001) surgical procedures, this group evidence of brain Interferon-α Interferon-α metastases,ongoing full- 5.4 21.3 dose oral or parenteral (> 55%) in both anticoagulant or anti-platelet arms received at aggregation treatment, least one uncontrolled hypertension postprotocol on medication, clinically antineoplastic significant cardiovascular therapy disease, or chronic corticosteroid treatment

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References Number of Treatment regimen Eligibility criteria Toxicities Response Rates Progression Free Overall Survival patients (RR) Survival (PFS) (OS) (months) (months) Motzer et al. Pazopanib Pazopanib 800mg once Advanced or metastatic Pazopanib - changes in hair Pazopanib Primary Secondary 2013 (58) 557 daily; renal-cell carcinoma with a color, weight loss, and alopecia, 31% endpoint endpoint (COMPARZ clear-cell histologic increased levels of alanine (P = 0.03) Pazopanib trial) Sunitinib Sunitinib 50 mg per day component, and no systemic aminotransferase or bilirubin of 8.4 Pazopanib Phase III non- 553 orally throughout the first treatment previously. any grade and a higher risk of Sunitinib (95% CI, 8.3 to 28.4 inferiority trial 4 weeks of each 6 week Exclusion criteria were brain increased levels of alanine 25% 10.9) (95% CI, 26.2 to cycle metastases, poorly aminotransferase or aspartate Investigator- Sunitinib 35.6) controlled hypertension, and aminotransferase of grade 3 or 4 assessed ORR 9.5 HR 0.91 cardiac and vascular Sunitinib - hand-foot syndrome, were similar (95% CI, 8.3 (95% CI, 0.76 conditions within 6 months mucosal inflammation, between the two to 11.1) to 1.08; before screening stomatitis, hypothyroidism, groups (33% in dysgeusia, dyspepsia, epistaxis, the pazopanib HR 1.05 (95% Sunitinib fatigue and a higher risk of group and 29% CI, 0.90 to 29.3 hematologic laboratory in the sunitinib 1.22), (95% CI, 25.3 to abnormalities of any grade and group, The study met 32.5) of grades 3 and 4, including P = 0.12) the predefined leukopenia,thrombocytopenia, criterion for neutropenia, and anemia non-inferiority Choueiri et al. Cabozantinib Cabozantinib 60 mg once Advanced RCC or mRCC The incidence of grade 3 or 4 Cabozantinib Primary Secondary 2017 and 2018 79 daily (not amenable to curative adverse events was 67% with 20% endpoint endpoint (59,60) surgery or radiotherapy) cabozantinib and 68% with (95% CI, 12 to Cabozantinib Cabozantinib (CABOSUN Sunitinib Sunitinib 50 mg per day with a clear cell component. sunitinib. The most common 30.8%) 8.6 26.6 trial) 78 orally throughout the first Patients must have been grade 3 or 4 adverse events with (95% CI, 6.8 to (95% CI, Phase II trial 4 weeks of each 6 week classified as intermediate or cabozantinib were hypertension Sunitinib 14 months) 14.6 to not cycle poor risk by IMDC criteria (28%), diarrhea (10%), palmar- 9% HR 0.48 (95% estimable) (61) and must not have plantar erythrodysesthesia (8%), (95% CI, 3.7 to CI, 0.31 to 0.74; HR 0.80 received prior systemic and fatigue (6%); with 17.6%) P = 0.0008) (95% CI, 0.53 to treatment. sunitinib, hypertension (22%), 0.1.21) Patients with known brain fatigue (15%), diarrhea (11%), metastases who were and thrombocytopenia (11%) Only19% of Sunitinib Sunitinib adequately treated and stable were more common patients were 5.3 21.2 for 3 months were eligible classified as (95% CI, 3.0 to (95% CI, 16.3 to poor risk by 8.2 months) 27.4) IMDC criteria

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Table 2. (Continued)

References Number of Treatment regimen Eligibility criteria Toxicities Response Rates Progression Free Overall patients (RR) Survival (PFS) Survival (months) (OS) (months) Motzer et al. Without Atezolizumab 1200mg Untreated advanced renal- 40% of atezolizumab plus In the PD-L1positive Co-primary Co-primary 2018. (62) description in plus bevacizumab 15 cell carcinoma with clear bevacizumab treated group, confirmed endpoint endpoint (IMmotion 151) the abstract mg/kg every 3 weeks cell and/or sarcomatoid patients compared to 54% objective (PFS in PD-L1 Phase III trial histology regardless of of sunitinib response rates were positive patients) Data was (ABSTRACT) Sunitinib - 50 mg per day MSKCC risk group (44) treated patients had grade 43% and 35% for Combination immature at orally throughout the first 3-4 treatment-related atezolizumab plus 11.2 first interim 4 weeks of each 6 week adverse events bevacizumab versus HR .74 (95% CI, analysis cycle sunitinib, 0.57-0.96, respectively P = 0.02) Sunitinib 7.7 ITT population HR.83 (95% CI 0.70-0.97) Motzer RJ et al, Nivolumab plus Nivolumab Untreated advanced renal- Nivolumab plus Co-primary end point Co-primary end Co-primary 2018. ipilimumab 3 mg/Kg and ipilimumab1 cell carcinoma with a clear- ipilimumab - in intermediate and point in end point in (63) 550 mg/Kg, every 3 weeks for cell component. Key 46 % had grade 3 or 4 poor - risk patients intermediate and intermediate (CHECKMATE four doses (induction exclusion criteria events. The most common Combination group poor - risk patients and poor - risk 214) Sunitinib phase), followed were central nervous adverse events of any 42% Combination group patients Phase III trial 546 by nivolumab system metastases or grade were: fatigue (95% CI, 37 11.6 18-month OS monotherapy at a dose of 3 autoimmune disease and (37%), pruritus (28%), to 47) (95% CI, 8.7 to Combination mg/Kg every 2 weeks glucocorticoid or diarrhea (27%), rash (P < 0.001) 15.5) group (maintenance phase). immunosuppressant (22%), nausea (20%), 9% CR HR 0.82 (99.1% CI, 75% use. Patients were increased lipase level Sunitinib 0.64 to 1.05; (95% CI, 70 to Sunitinib 50 mg per day characterized according (16%) and 27% (95% CI, 22 to P = 0.03) 78) orally throughout the first to IMDC risk score (61) hypothyroidism (16%). 31) Sunitinib 8.4 HR 0.63 4 weeks of each 6 week 22% of patients 1% CR (95% CI, 7.0 to (99.8% CI, cycle discontinued treatment 16% of patients 10.8) 0.44 to 0.89; because toxicity. were poor risk, 61% (P < 0.001) P < 0.001) Sunitinib - 63% had grade intermediate and In first interim 3 or 4 events. 23% favorable analysis the Sunitinib Discontinuation due to combination grouo 60% (95% CI, toxicity occurred in 12% was outperformed 55 to 65) of patients by sunitinib

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References Number of Treatment regimen Eligibility criteria Toxicities Response Rates Progression Free Overall patients (RR) Survival (PFS) Survival (months) (OS) (months) Donskov F, et Pembrolizumab Pembrolizumab 200mg Patients with recurrent or 73.6% had a treatment- Primary endpoint The median 92.4% of al, 2018. every three weeks. advanced RCC with clear- related adverse event, Favorable risk progression-free patients were (64) cell histology most commonly fatigue, 27.5% survival was 6.9 alive at 6 (KEYNOTE pruritus, diarrhea, and Intermediate risk (95% CI, 5.1 to months 427 Cohort A) rash. 18.2% of patients 37.3% NE) Phase II trial experienced a grade 3-5 (ABSTRACT) treatment-related adverse 37.3%, 47.3%, event and 15.5% had IMDC risk categories of favorable, intermediate, and poor, respectively Motzer et al, Avelumab plus Avelumab 10mg/Kg Previously untreated Avelumab PD-L1-positive PD-L1-positive Data are 2019. axitinib every 2 weeks and advanced plus axitinib - 166 patients tumors tumors immature for (69) 442 axitinib 5 mg twice renal-cell carcinoma with (38.2%) had adverse Axitinib plus Primary endpoint calculating this (JAVELIN daily a clear-cell events that were avelumab endpoint Renal 101) Sunitinib component. Key exclusion categorized as immune- 55.2% (95% CI, Axitinib plus Phase III trial 444 Sunitinib 50 mg per day criteria were active central related. 71.2% had grade 3 49.0 to 61.2) avelumab orally throughout the nervous system or more adverse events 13.8 first 4 weeks of each 6 metastases, Sunitinib - 71.5 % had Sunitinib (95% CI, 11.1 to week cycle autoimmune disease, and grade 3 or more adverse 25.5% (95% CI, NE) current or previous events 20.6 to 30.9) HR .61 (95% CI, use of glucocorticoids or Adverse events were 0.47 to 0.79; other immunosuppressants typical to tyrosine kinase IMDC risk group P < 0.001) within 7 days before and immune checkpoint overall randomization inhibitors population: Sunitinib Favorable 21.44% 7.2 (95% CI, Intermediate 5.7 to 9.7) 61.74% Poor 16.14%

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Table 2. (Continued)

References Number of Treatment regimen Eligibility criteria Toxicities Response Rates Progression Free Overall patients (RR) Survival (PFS) Survival (months) (OS) (months) Rini et al, 2019. Pembrolizumab Pembrolizumab 200 mg Newly diagnosed or Adverse events Pembrolizumab Pembrolizumab OS at 12 (69) plus axitinib every 3 weeks plus recurrent stage IV were of grade 3 or higher plus axitinib plus axitinib months (KEYNOTE- 432 axitinib 5 mg twice clear-cell renal-cell in 75.8% of the patients in 59.3% 15.1 Pembrolizumab 426) daily. Pembrolizumab carcinoma, no previous the pembrolizumab- (95% CI, 54.5 to (95% CI, 12.6 plus axitinib Phase III trial Sunitinib was administered systemic therapy for axitinib group and 63.9) to 17.7) 429 for a maximum of 35 advanced disease; patients in 70.6% of the patients in (P < 0.001) HR .69 (95% CI, 89.9% cycles. Patients who had were excluded if they had the sunitinib group. In 5.8% CR 0.57 to 0.84, (95% CI, a confirmed complete symptomatic both groups, the most P < 0.001). 86.4 to 92.4 response could central nervous system common adverse events of Sunitinib HR .53; 95% discontinue metastases, active any cause and the most 35.7% Sunitinib CI, 0.38 to treatment autoimmune disease, or common adverse events (95% CI, 31.1 11.1 0.74; poorly controlled related to treatment were to 40.4) (95% CI, 8.7 P < 0.0001). Sunitinib 50 mg per day hypertension had had an diarrhea and hypertension to 12.5) orally throughout the ischemic cardiovascular The IMDC risk Sunitinib first 4 weeks of each 6 event or category was 78.3% (95% week cycle New York Heart favorable for CI, 73.8 to 82.1 Association class III or IV 31.2% of patients, congestive heart failure intermediate for In the sunitinib within 1 year before 56.2%, and poor group, 60.7% screening, or if they were for 12.5% received other receiving systemic 60.5% had a PD- anticancer immunosuppressive L1 positive score therapy (PD-1 treatment of 1% or more or PD-L1 inhibitor in 37.6%) ITT: intention to treat; HR: Hazard ratio; CR: Complete response; NE: Non-estimable.

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Lenvatinib was evaluated in a phase 2 randomized trial with 153 patients who had failed to anti-VEGF therapy. It was tested if the co-inhibition of VEGF and fibroblast growth factor (FGF) pathways with this drug in second line therapy could be tolerable and effective alone or in combination with everolimus. The three arms were lenvatinib, everolimus or combination of both. PFS was the primary endpoint and favored the use of lenvatinib plus everolimus over everolimus alone: 14.6 (95% CI, 5.9-20.1) months versus 5.5 (3.5-7.1) months (HR 0.40; 95% CI, 0.24-0.68; P = 0.0005). Levantinib alone was also superior to everolimus with a PFS of 7.4 months (HR 0·66; 95% CI, 0.39-1.10; P = 0.12). Other endpoints also favored the combination arm over lenvatinib or everolimus, being the response rate 43% versus 27% versus 6% and overall survival 25.5 months versus 18.4 versus 17.5 months, respectively. The combination was more toxic with 71 % of patients presenting grade 3 and 4 adverse events, being the most common diarrhea, fatigue and hypertension (80). The European Society for Medical Oncology (ESMO) and the National Comprehensive Cancer Network (NCCN) guidelines for metastatic kidney cancer put as a preferential modern second line systemic therapy nivolumab, cabozantinib, axitinib and lenvatinib associated with everolimus based on the trials discussed above. Sorafenib is also an option but is no longer considered the best choice as well everolimus alone (73-82).

Non clear-cell renal cancer subtypes

The three most common histologic RCC types are: clear-cell, papillary and chromophobe. Clear-cell corresponds to, approximately, 70 % of all cases. As other subtypes are less common, clinical trials are harder to be performed and evidences are weaker. Nonetheless, new data presented recently may help these patients since their treatment options are restricted (83,84). Sunitinib has been the preferred agent for treating the majority of non-clear-cell RCC (nccRCC) patients. The ASPEN trial, phase II, open-label, randomized study, assigned 108 patients with metastatic non-clear-cell renal cell carcinoma to receive oral treatment with either the mTOR inhibitor everolimus (n = 57) or the VEGF tyrosine kinase inhibitor sunitinib (n = 51) until disease progression or unacceptable toxic effects. Sunitinib significantly increased progression-free survival compared with everolimus 8.3 months (80% CI 5.8-11.4) vs 5.6 months (5.5-6.0) (HR 1.41; 80% CI 1.03-1.92; P = 0.16), although heterogeneity of the treatment effect was noted on the basis of histological subtypes and prognostic risk groups. The data showed in an exploratory, non-powered analyses, that sunitinib was more effective in prolonging progression-free survival in patients with favorable or intermediate risk according to MSKCC criteria and in patients with papillary or unclassified histologies; on the other hand, everolimus was more effective in prolonging PFS in patients with poor risk or with chromophobe histology (44,85). The ESPN trial also evaluated sunitib versus everolimus in nccRCC and demonstrated a slight difference of 2.1 months in PFS favoring the first drug without significance. There was no statistical difference in OS, however sunitinib outperformed everolimus in 1.3 months. In the subset of patients with no sarcomatoid features in their tumors, the median OS was 31.6 with sunitinib and 10.5 months with everolimus (P = 0.075). This study was stopped after a futility analysis for PFS and OS (86).

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Everolimus is also an alternative for treating these patients, and may be a better option than sunitinib for poor risk patients and those with chromophobe tumors. The RAPTOR trial confirmed the anti-tumor effect of this agent in patients with papillary metastatic RCC in first line setting and a phase II trial showed and overall response rate (ORR) of 10% in nccRCC refractory to sunitinib or sorafenib (87,88). Erlotinib was evaluated in a phase II trial in patients with advanced papillary RCC and had an ORR of 11% (89). Sorafenib has activity similar to sunitinib in nccRCC and could be an option in places without access to sunitinib. A study that included patients with papillary or chromophobe histologies, the ORR to sunitinib or sorafenib was 23%; median PFS was 10.6 months (90). Pazopanib activity was evaluated retrospectively in the PANORAMA study. Thirty - seven patients with nccRCC were treated with first-line pazopanib; 51% had papillary histology, 24% chromophobe, 22% unclassified, and 3% had Xp11.2 translocation. 81% achieved disease control, with 10 partial responses (27%) and 20 cases of stable disease (54%); 16% of patients had disease progression as best response. Median PFS and OS were 15.9 and 17.3 months, respectively (91). A phase II trial in Korea demonstrated an ORR of 28% in patients with advanced nccRCC excluding collecting duct or sarcomatoid histology (92). Axitinib showed activity after temsirolimus failure with a PFS of 7.4 months and ORR of 28%. An abstract presented at ESMO 2018 (AXIPAP trial), demonstrated efficacy of axitinib in papillary RCC. 26% of patients had a partial response, 64% had stable disease and 9.5% had progressive disease. Median PFS was 23.8 weeks for all patients and numerically similar for papillary type 1 and papillary type 2 (21.0 and 23.8 months). Median overall survival was 18.9 months for all patients and has not been reached for papillary type 1 patients (93, 94). A phase II trial evaluated the combination of everolimus and bevacizumab in first line setting for nccRCC. For the 34 patients includes, the median PFS, OS and ORR were 11 months, 18.5 months and 29% (95). Temsirolimus activity in nccRCC was evaluated retrospectively in the global ARCC trial. The OS was 11.6 months with temsirolimus and 4.3 months with IFN-α (96). Bevacizumab and erlotinib may be an alternative in patients with hereditary leiomyomatosis and papillary RCC (HLRCC) or with sporadic papillary RCC (SPRCC). The ORR was 60% for those with HLRCC compared to 29% with SPRCC. The median PFS was 24.2 months in HLRCC group and 7.4 months in SPRCC (97). Atezolizumab plus bevacizumab could be and alternative for sarcomatoid tumors; however, more data about this subgroup of patients in the study IMmotion 151 are needed (62). Other possible alternative could be pembrolizumab because patients with clear cell carcinomas and sarcomatoid differentiation did exceptionally well with this intervention, reaching RR of 64% and disease control rate of 73%. There was only 11 patients at KEYNOTE 427 Cohort A with this characteristic but data are intriguing (64). A retrospective study evaluating cabozantinib in 30 patients with nccRCC found clinical benefit with median PFS of 8.6 months and median OS of 25.4 months. The ORR was 14.3% in those with measurable disease. Nivolumab was evaluated in retrospective studies. Partial responses of 20% and stable disease in 29 % were reported, with a PFS of 3.5 months (99, 100). Chemotherapy could be an alternative in the absence of better alternatives. The most common chemotherapeutic agents used alone or in combination are: gemcitabine, Complimentary Contributor Copy Management of renal cancer in Latin America 379 doxorubicin, capecitabine and/or platinum compounds. Sarcomatoid histology, renal medullary carcinoma and collecting-duct carcinoma are subtypes frequently treated with these agents (101,102). New treatment strategies have been evaluated by clinical trials and some results have been presented as abstracts. The CALYPSO phase II trial evaluated the safety and efficacy of savolininib and durvalumab in metastatic papillary renal cancer. The majority of patients had IMDC favorable or intermediate risk. 85% of patients had prior nephrectomy and most patients were treatment naïve (68%). The objective response rate (primary endpoint) was 27% (11/41) with a median PFS of 5.3 months. Grade 3/4 toxicity occurred in 15 patients (61,105). The KEYNOTE-427 Cohort B evaluated pembrolizumab monotherapy for advanced nccRCC in first line setting. There were 165 patients with histologically confirmed non- ccRCC and no prior systemic therapy. The primary endpoint for this study was ORR and secondary end points included the duration of response, PFS, and OS. Histology was as follows: papillary 71% (n = 118), chromophobe 13% (n = 21), and unclassified 16% (n = 26). Most patients (68%) were intermediate/poor IMDC risk, and 62% were PD-L1 positive (61,106). At a median follow-up duration of 11.1 months (range 0.9-21.3), 56% of patients discontinued pembrolizumab due to progressive disease or clinical progression. The overall ORR was 24.8% (95%CI 18.5-32.2), which included 8 patients with a complete response and 33 with a partial response. The ORR by histologic type was 25.4% (95%CI 17.9-34.3) for papillary, 9.5% (95%CI 1.2-30.4) for chromophobe, and 34.6% (95%CI 17.2-55.7) for unclassified nccRCC. According to IMDC risk group, ORR was 28.3% (95%CI 16.8-42.3) for favorable and 23.2% (95%CI 15.8-32.1) for intermediate/poor risk. In tumors expressing PD-L1 ≥ 1% the ORR was 33.3% (95%CI 24.3-43.4) and 10.3% (95%CI 3.9-21.2) for those with PD-L1 expression <1%. The median PFS was 4.1 months (95% CI, 2.8-5.6 months). 72% of patients were alive at 12 months. These results indicates that pembrolizumab could also be an alternative for treating patients with nccRCC (105,106).

DISCUSSION

The best surgical approach depends on surgeon experience and available technology. The laparoscopic surgery is an interesting approach because it is less expensive than robotic intervention and the recovery is much faster than open techniques. An increased interest in expanding the use of robotic approaches exists; however, there is a lack of strong evidences showing superiority when compared to laparoscopic approach. One retrospective study evaluated outcomes of patients who had undergone robotic-assisted or laparoscopic radical nephrectomy for renal mass at 416 US hospitals between 2003 and 2015, and concluded that the use of robotic-assistance was associated with prolonged operating time and higher hospital costs compared with laparoscopic surgery. In Latin America scenario, it would be the advisable as standard approach the laparoscopic surgery, respecting differences in budget and accessibility (7-9). In a scenario with budget restrictions, it is difficult to advice in favor of adjuvant treatment outside a clinical trial because no phase III trial showed overall survival benefit and TKIs are toxic and expensive (34, 37, 38, 40).

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Surgery of primary tumor in metastatic setting should not be performed upfront in intermediate and high risk patients (43). However, patients with low risk and those who respond well to front line systemic therapy can be considered for surgical approach. Maybe, in a scenario with restrictions in access to new expensive drugs, surgery may play a more important role. The best sequencing for clear-cell RCC treatment is yet to be determined. Many trials have been published with outstanding results when compared to the old standard of care (62- 66). Table 2 describes with details the main points of each trial and may help to decide which treatment would fit better for the patient in a scenario without budget restrictions. However, real world is different, especially in developing countries, and probably tyrosine kinase inhibitors alone will remain as the most prescribed treatment. A retrospective study evaluated sunitinib efficacy at Brazilian National Cancer Institute in real world setting. The results were in line with literature and showed a low efficacy of this agent in poor MKCC risk group patients with only 11% of partial response, but higher number of partial responses in intermediate and favorable risks, 33.3% and 55.6%, respectively (44,107). PFS also differed among groups, reaching 8.9 months, 5.1 months and 2.6 months for favorable, intermediate and poor risk patients by MSKCC criteria (4,107). In poor risk patients by IMDC or MSKCC criteria, agents asnivolumab plus ipilimumab, axitinib plus pembrolizumab or axitinib plus avelumab, temsirolimus and cabozantinib should be preferred. Probably other alternatives will be available soon as bevacizumab plus atezolizumab; nonetheless, all new treatment strategies are expensive and the access to them is uncertain (44, 55, 59-66). Further lines will depend on the first line treatment and the level and duration of response. There are no standard recommendations and it should be evaluated in an individual basis. Data in non-clear-cell RCC are less robust and in general TKIs are used in first line setting. With the presentation of Calypso and Keynote-427Cohort B novel alternatives could be incorporated in a near future (85-106).

CONCLUSION

There is no standard of care in renal cell cancer treatment and the choice of treatment should be performed in an individual basis considering the surgeon expertise, budget, technology available, access to drugs and ablative therapies.

REFERENCES

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SECTION TWO: ACKNOWLEDGMENTS

Chapter 25

ABOUT THE EDITORS

Maurício F Silva, MD, PhD, is a clinical and academic specialist in radiation oncology, with a number of internationally recognised senior positions dedicated to clinical practice and research in this field. Head of Radiation Oncology, Assistant Professor of Radiation Oncology at Santa Maria Federal University, in South Brazil and the Head of Education for the Brazilian Society of Radiotherapy, with extensive international clinical research experience across academic centres of excellence, in Brazil, Spain (in 2007), Australia (in 2009) and Canada. Chair of the Radiation Oncology (advisory) arm at the Latin America Cooperative Oncology Group (LACOG), a contract research organization responsible for the development and oversight of all steps involved with clinical trials development. These unique work experiences, at the interface of clinical oncology, academia and contract research organisations, have resulted in extensive ongoing input to the design and implementation of large oncology clinical trials, and co-authorship of critical documents in the field of radiation oncology, such as the updated systematic review in hypofractionated radiotherapy in patients suffering from bone metastases, published in the Radiotherapy and Oncology Journal – the official journal of the European Society of Radiotherapy and Oncology. Currently the Chief Investigator (international PI) of a phase 3 multi-centre international randomised clinical trial (involving eight countries in five continents), evaluating the safety of radiation therapy on bone metastases, and its effects on patient reported clinical outcomes, such as pain control and quality of life. Main academic interests include: Exploring the potential interaction between radiotherapy and drug therapies (with focus on novel immunotherapies). It is likely that the net therapeutic effect is stronger than the sum of their parts, and this is a largely unexplored field of oncology. Currently investigating possible academic collaborations with industry and other partners to implement trials in this field. Understanding the effects of radiation therapy on patient reported outcomes (PROs)/clinical outcome assessments (COAs). Email: [email protected]

Gustavo Nader Marta, MD, PhD, is a clinical and academic specialist in radiation oncology working at the Hospital Sírio Libanês and University of Sao Paulo Medicine School - Sao Paulo State Cancer Institute in Brazil. Professor of Oncology (postgraduate level) and Head of research for the Brazilian Society of Radiotherapy. Vice-chair of the Radiation Oncology (advisory) arm at the Latin America Cooperative Oncology Group (LACOG). Member of the

Complimentary Contributor Copy 390 About the Editors

Board of Directors for International Education Committee – American Society for Radiation Oncology (ASTRO). Email: [email protected]

Luis CM Antunes, MD, MSc, PhD, is a clinical and academic specialist in oncology. He received his medical degree and completed his residence in oncology at the University of Santa Maria (UFSM), in South Brazil. He them obtained his PhD in Health Science from the UFRGS. He is head oncologist of multi-professional Team Care of Hematology-Oncology Service of the University Hospital of Santa Maria and Professor of Oncology at Franciscan University in Santa Maria, Brazil. He is a principal investigator in studies of immunotherapy drugs for cancer. Investigator at the Cancer and Neurobiology Laboratory, Experimental Research Center, Porto Alegre Clinical Hospital, in Porto Alegre, Brazil. His main areas of interest include signal pathways cancer, immunotherapy, gastrointestinal tumors and melanoma. He has served on the editorial board member of a number of journals. He is member of the American Society of Clinical Oncology (ASCO), Brazilian Gastrointestinal Tumors Group (GTG), Brazilian Group of Melanoma (GBM) and of the Brazilian Society of Clinical Oncology (SBOC). Email: [email protected]

Fiona Lim, MBBS(HKU) FRCR(UK) FHKCR FHKAM (Radiology) DipPallMed (Wales), graduated from The University of Hong Kong in 2006. She received residency training in clinical oncology in the Department of Oncology, Princess Margaret Hospital. She obtained the fellowship in the Royal College of Radiologist in Clinical Oncology and Diploma with Merit in Palliative Medicine (Cardiff University) in 2014. She is also the honorary clinical assistant professor at the Department of Oncology (The University of Hong Kong), Department of Medicine and Therapeutics (The Chinese University of Hong Kong), School of Pharmacy (The Chinese University of Hong Kong) and visiting lecturer for Department of Health Technology and Informatics (The Hong Kong Polytechnic University). She received further overseas training in stereotactic body radiotherapy and image-guided brachytherapy in Sunnybrook Health Sciences Center, Toronto and Mount Vernon Hospital, United Kingdom in 2016. Dr Lim also actively participated in various clinical researches and was appointed as panel member in Research Ethics Committee of Kowloon West Cluster. Her current interest is in lung cancer, gynecological cancer, stereotactic body radiotherapy and palliative medicine. Email: [email protected]

Bo Angela Wan, MD(C), is a third year medical student from Canada. Her interests are in oncology, hematology and palliative care. Email: [email protected]

Beatriz Amendola, MD, DABR, FACR, FASTRO, FACRO, completed her residency in Radiation Oncology at the Medical College of Virginia in Richmond, Virginia with Board Certification in Therapeutic Radiology by the American Board of Radiology in 1980. She has held several academic positions, including Acting Chairman of the Department of Radiation Oncology at the University of Michigan and Associate Professor and Director of Residency Training at the University of Miami, Department of Radiation Oncology. Founder and Director of Innovative Cancer Institute and the Brachytherapy Institute of South Florida presently. She has edited a textbook on radiation oncology and published more than 60 scientific articles in peer-reviewed medical journals of the specialty. She has been awarded Fellowship from the American Society of Radiation Oncology (ASTRO), from the American Complimentary Contributor Copy About the Editors 391

College of Radiation Oncology (ACRO) and from The American College of Radiology (ACR). Her main areas of interest include breast, lung, head/neck and prostate cancer as well as brain tumors. Extensive knowledge in the field of radiation therapy, with expertise in brachytherapy, as well as in radiosurgery using gamma knife and LINAC based radiosurgery. Delivered more than 500 scientific presentations, scientific exhibits, and lectures nationally and internationally. She has received multiple honors and awards including the Gold Medal from CRILA (Circulo de Radioterapeutas Ibero Latino Americano). In 2015 awarded Honorary Membership in the Spanish Society of Radiation Oncology (SEOR) because of her multiple contributions to the specialty of radiation oncology in Spain. She is a volunteer faculty member of eCancer since 2015 and Lacort Medical since 2018. Email: [email protected]

Joav Merrick, MD, MMedSci, DMSc, born and educated in Denmark is professor of pediatrics, Division of Pediatrics, Hadassah Hebrew University Medical Center, Mt Scopus Campus, Jerusalem, Israel and Kentucky Children’s Hospital, University of Kentucky, Lexington, Kentucky United States and professor of public health at the Center for Healthy Development, School of Public Health, Georgia State University, Atlanta, United States, the former medical director of the Health Services, Division for Intellectual and Developmental Disabilities, Ministry of Social Affairs and Social Services, Jerusalem, the founder and director of the National Institute of Child Health and Human Development in Israel. Numerous publications in the field of pediatrics, child health and human development, rehabilitation, intellectual disability, disability, health, welfare, abuse, advocacy, quality of life and prevention. Received the Peter Sabroe Child Award for outstanding work on behalf of Danish Children in 1985 and the International LEGO-Prize (“The Children’s Nobel Prize”) for an extraordinary contribution towards improvement in child welfare and well-being in 1987. In 2017 appointed a Kentucky Colonel by the Commonwealth of Kentucky, the highest honor the governor can bestow to a person. Email: [email protected]

Chapter 26

ABOUT THE RADIATION ONCOLOGY UNIT, SANTA MARIA UNIVERSITY HOSPITAL (UFSM), SANTA MARIA, BRAZIL

The Santa Maria Federal University in Brazil is a public university with almost 40.000 students under the auspices of the Ministry of Education. It is a Brazilian public university located in Santa Maria in the state of Rio Grande do Sul and funded by the federal government of Brazil. It was founded in 1960 by Professor José Mariano da Rocha Filho (1915-1998), a physician, educator and the first Dean. UFSM's presence in the municipality of Santa Maria is one of the reasons why the city is sometimes called "university city" or "culture city". It is located in western Rio Grande do Sul, approximately 290 km far from the capital city of the state, Porto Alegre, thus being set in the heart of the pampas of Brazil. As a public university, students do not pay tuition fees. It is the oldest federal university not located in a Brazilian state capital city and the largest in number of undergraduate courses offered in Rio Grande do Sul state. As for 2015, the university was ranked at position 15 at national ranking from MEC (Wikipedia). The university is divided into nine academic centers, which administer and organize the undergraduate and postgraduate courses offered. The Centro de Ciências da Saúde (CCS) or Centre of Health Sciences provides undergraduate courses at the Campus of Santa Maria in nursing, pharmacy and biochemistry, physical therapy, speech and language therapy, occupational therapy, medicine and dentistry, but with some classes offered in downtown Santa Maria. The Radiation Oncology Unit at Santa Maria University Hospital is a reference center for the South of Brazil, assisting about 500 new patients a year with excellence. The unit is involved in teaching activities in several under- and graduate courses, local and international research and collaborations.

Contact Maurício F Silva, MD, PhD Director, Radiation Oncology Unit Santa Maria Federal University Santa Maria, Brazil Email: [email protected] Complimentary Contributor Copy Complimentary Contributor Copy In: Cancer Management in Latin America I ISBN: 978-1-53616-733-7 Editors: Maurício F Silva, Gustavo Nader Marta et al. © 2020 Nova Science Publishers, Inc.

Chapter 27

ABOUT THE NATIONAL INSTITUTE OF CHILD HEALTH AND HUMAN DEVELOPMENT IN ISRAEL

The National Institute of Child Health and Human Development (NICHD) in Israel was established in 1998 as a virtual institute under the auspices of the Medical Director, Ministry of Social Affairs and Social Services in order to function as the research arm for the Office of the Medical Director. In 1998 the National Council for Child Health and Pediatrics, Ministry of Health and in 1999 the Director General and Deputy Director General of the Ministry of Health endorsed the establishment of the NICHD.

Mission

The mission of a National Institute for Child Health and Human Development in Israel is to provide an academic focal point for the scholarly interdisciplinary study of child life, health, public health, welfare, disability, rehabilitation, intellectual disability and related aspects of human development. This mission includes research, teaching, clinical work, information and public service activities in the field of child health and human development.

Service and academic activities

Over the years many activities became focused in the south of Israel due to collaboration with various professionals at the Faculty of Health Sciences (FOHS) at the Ben Gurion University of the Negev (BGU). Since 2000 an affiliation with the Zusman Child Development Center at the Pediatric Division of Soroka University Medical Center has resulted in collaboration around the establishment of the Down Syndrome Clinic at that center. In 2002 a full course on “Disability” was established at the Recanati School for Allied Professions in the Community, FOHS, BGU and in 2005 collaboration was started with the Primary Care Unit of the faculty and disability became part of the master of public health course on “Children and society”. In the academic year 2005-2006 a one semester course on “Aging with disability” was started as part of the master of science program in gerontology in our collaboration with the Center for Multidisciplinary Research in Aging. In 2010 collaborations

Complimentary Contributor Copy 396 About the National Institute of Child Health and Human Development in Israel with the Division of Pediatrics, Hadassah Hebrew University Medical Center, Jerusalem, Israel around the National Down Syndrome Center and teaching students and residents about intellectual and developmental disabilities as part of their training at this campus.

Research activities

The affiliated staff have over the years published work from projects and research activities in this national and international collaboration. In the year 2000 the International Journal of Adolescent Medicine and Health and in 2005 the International Journal on Disability and Human Development of De Gruyter Publishing House (Berlin and New York) were affiliated with the National Institute of Child Health and Human Development. From 2008 also the International Journal of Child Health and Human Development (Nova Science, New York), the International Journal of Child and Adolescent Health (Nova Science) and the Journal of Pain Management (Nova Science) affiliated and from 2009 the International Public Health Journal (Nova Science) and Journal of Alternative Medicine Research (Nova Science). All peer-reviewed international journals.

National collaborations

Nationally the NICHD works in collaboration with the Faculty of Health Sciences, Ben Gurion University of the Negev; Department of Physical Therapy, Sackler School of Medicine, Tel Aviv University; Autism Center, Assaf HaRofeh Medical Center; National Rett and PKU Centers at Chaim Sheba Medical Center, Tel HaShomer; Department of Physiotherapy, Haifa University; Department of Education, Bar Ilan University, Ramat Gan, Faculty of Social Sciences and Health Sciences; College of Judea and Samaria in Ariel and in 2011 affiliation with Center for Pediatric Chronic Diseases and National Center for Down Syndrome, Department of Pediatrics, Hadassah Hebrew University Medical Center, Mount Scopus Campus, Jerusalem.

International collaborations

Internationally with the Department of Disability and Human Development, College of Applied Health Sciences, University of Illinois at Chicago; Strong Center for Developmental Disabilities, Golisano Children's Hospital at Strong, University of Rochester School of Medicine and Dentistry, New York; Centre on Intellectual Disabilities, University of Albany, New York; Centre for Chronic Disease Prevention and Control, Health Canada, Ottawa; Chandler Medical Center and Children’s Hospital, Kentucky Children’s Hospital, Section of Adolescent Medicine, University of Kentucky, Lexington; Chronic Disease Prevention and Control Research Center, Baylor College of Medicine, Houston, Texas; Division of Neuroscience, Department of Psychiatry, Columbia University, New York; Institute for the Study of Disadvantage and Disability, Atlanta; Center for Autism and Related Disorders, Department Psychiatry, Children’s Hospital Boston, Boston; Department of Pediatric and Adolescent Medicine, Western Michigan University Homer Stryker MD School of Medicine, Complimentary Contributor Copy About the National Institute of Child Health and Human Development in Israel 397

Kalamazoo, Michigan, United States; Department of Paediatrics, Child Health and Adolescent Medicine, Children's Hospital at Westmead, Westmead, Australia; International Centre for the Study of Occupational and Mental Health, Düsseldorf, Germany; Centre for Advanced Studies in Nursing, Department of General Practice and Primary Care, University of Aberdeen, Aberdeen, United Kingdom; Quality of Life Research Center, Copenhagen, Denmark; Nordic School of Public Health, Gottenburg, Sweden, Scandinavian Institute of Quality of Working Life, Oslo, Norway; The Department of Applied Social Sciences (APSS) of The Hong Kong Polytechnic University Hong Kong.

Targets

Our focus is on research, international collaborations, clinical work, teaching and policy in health, disability and human development and to establish the NICHD as a permanent institute in Israel in order to conduct model research and policy.

Contact

Professor Joav Merrick, MD, MMedSci, DMSc Director, National Institute of Child Health and Human Development, Jerusalem, Israel. E-mail: [email protected]

Chapter 28

ABOUT THE BOOK SERIES “HEALTH AND HUMAN DEVELOPMENT”

Health and human development is a book series with publications from a multidisciplinary group of researchers, practitioners and clinicians for an international professional forum interested in the broad spectrum of health and human development.

 Merrick J, Omar HA, eds. Adolescent behavior research. International perspectives. New York: Nova Science, 2007.  Kratky KW. Complementary medicine systems: Comparison and integration. New York: Nova Science, 2008.  Schofield P, Merrick J, eds. Pain in children and youth. New York: Nova Science, 2009.  Greydanus DE, Patel DR, Pratt HD, Calles Jr JL, eds. Behavioral pediatrics, 3 ed. New York: Nova Science, 2009.  Ventegodt S, Merrick J, eds. Meaningful work: Research in quality of working life. New York: Nova Science, 2009.  Omar HA, Greydanus DE, Patel DR, Merrick J, eds. Obesity and adolescence. A public health concern. New York: Nova Science, 2009.  Lieberman A, Merrick J, eds. Poverty and children. A public health concern. New York: Nova Science, 2009.  Goodbread J. Living on the edge. The mythical, spiritual and philosophical roots of social marginality. New York: Nova Science, 2009.  Bennett DL, Towns S, Elliot E, Merrick J, eds. Challenges in adolescent health: An Australian perspective. New York: Nova Science, 2009.  Schofield P, Merrick J, eds. Children and pain. New York: Nova Science, 2009.  Sher L, Kandel I, Merrick J, eds. Alcohol-related cognitive disorders: Research and clinical perspectives. New York: Nova Science, 2009.  Anyanwu EC. Advances in environmental health effects of toxigenic mold and mycotoxins. New York: Nova Science, 2009.  Bell E, Merrick J, eds. Rural child health. International aspects. New York: Nova Science, 2009.

Complimentary Contributor Copy 400 About the book series “Health and human development”

 Dubowitz H, Merrick J, eds. International aspects of child abuse and neglect. New York: Nova Science, 2010.  Shahtahmasebi S, Berridge D. Conceptualizing behavior: A practical guide to data analysis. New York: Nova Science, 2010.  Wernik U. Chance action and therapy. The playful way of changing. New York: Nova Science, 2010.  Omar HA, Greydanus DE, Patel DR, Merrick J, eds. Adolescence and chronic illness. A public health concern. New York: Nova Science, 2010.  Patel DR, Greydanus DE, Omar HA, Merrick J, eds. Adolescence and sports. New York: Nova Science, 2010.  Shek DTL, Ma HK, Merrick J, eds. Positive youth development: Evaluation and future directions in a Chinese context. New York: Nova Science, 2010.  Shek DTL, Ma HK, Merrick J, eds. Positive youth development: Implementation of a youth program in a Chinese context. New York: Nova Science, 2010.  Omar HA, Greydanus DE, Tsitsika AK, Patel DR, Merrick J, eds. Pediatric and adolescent sexuality and gynecology: Principles for the primary care clinician. New York: Nova Science, 2010.  Chow E, Merrick J, eds. Advanced cancer. Pain and quality of life. New York: Nova Science, 2010.  Latzer Y, Merrick, J, Stein D, eds. Understanding eating disorders. Integrating culture, psychology and biology. New York: Nova Science, 2010.  Sahgal A, Chow E, Merrick J, eds. Bone and brain metastases: Advances in research and treatment. New York: Nova Science, 2010.  Postolache TT, Merrick J, eds. Environment, mood disorders and suicide. New York: Nova Science, 2010.  Maharajh HD, Merrick J, eds. Social and cultural psychiatry experience from the Caribbean Region. New York: Nova Science, 2010.  Mirsky J. Narratives and meanings of migration. New York: Nova Science, 2010.  Harvey PW. Self-management and the health care consumer. New York: Nova Science, 2011.  Ventegodt S, Merrick J. Sexology from a holistic point of view. New York: Nova Science, 2011.  Ventegodt S, Merrick J. Principles of holistic psychiatry: A textbook on holistic medicine for mental disorders. New York: Nova Science, 2011.  Greydanus DE, Calles Jr JL, Patel DR, Nazeer A, Merrick J, eds. Clinical aspects of psychopharmacology in childhood and adolescence. New York: Nova Science, 2011.  Bell E, Seidel BM, Merrick J, eds. Climate change and rural child health. New York: Nova Science, 2011.  Bell E, Zimitat C, Merrick J, eds. Rural medical education: Practical strategies. New York: Nova Science, 2011.  Latzer Y, Tzischinsky. The dance of sleeping and eating among adolescents: Normal and pathological perspectives. New York: Nova Science, 2011.  Deshmukh VD. The astonishing brain and holistic consciousness: Neuroscience and Vedanta perspectives. New York: Nova Science, 2011.

Complimentary Contributor Copy About the book series “Health and human development” 401

 Bell E, Westert GP, Merrick J, eds. Translational research for primary healthcare. New York: Nova Science, 2011.  Shek DTL, Sun RCF, Merrick J, eds. Drug abuse in Hong Kong: Development and evaluation of a prevention program. New York: Nova Science, 2011.  Ventegodt S, Hermansen TD, Merrick J. Human Development: Biology from a holistic point of view. New York: Nova Science, 2011.  Ventegodt S, Merrick J. Our search for meaning in life. New York: Nova Science, 2011.  Caron RM, Merrick J, eds. Building community capacity: Minority and immigrant populations. New York: Nova Science, 2012.  Klein H, Merrick J, eds. Human immunodeficiency virus (HIV) research: Social science aspects. New York: Nova Science, 2012.  Lutzker JR, Merrick J, eds. Applied public health: Examining multifaceted Social or ecological problems and child maltreatment. New York: Nova Science, 2012.  Chemtob D, Merrick J, eds. AIDS and tuberculosis: Public health aspects. New York: Nova Science, 2012.  Ventegodt S, Merrick J. Textbook on evidence-based holistic mind-body medicine: Basic principles of healing in traditional Hippocratic medicine. New York: Nova Science, 2012.  Ventegodt S, Merrick J. Textbook on evidence-based holistic mind-body medicine: Holistic practice of traditional Hippocratic medicine. New York: Nova Science, 2012.  Ventegodt S, Merrick J. Textbook on evidence-based holistic mind-body medicine: Healing the mind in traditional Hippocratic medicine. New York: Nova Science, 2012.  Ventegodt S, Merrick J. Textbook on evidence-based holistic mind-body medicine: Sexology and traditional Hippocratic medicine. New York: Nova Science, 2012.  Ventegodt S, Merrick J. Textbook on evidence-based holistic mind-body medicine: Research, philosophy, economy and politics of traditional Hippocratic medicine. New York: Nova Science, 2012.  Caron RM, Merrick J, eds. Building community capacity: Skills and principles. New York: Nova Science, 2012.  Lemal M, Merrick J, eds. Health risk communication. New York: Nova Science, 2012.  Ventegodt S, Merrick J. Textbook on evidence-based holistic mind-body medicine: Basic philosophy and ethics of traditional Hippocratic medicine. New York: Nova Science, 2013.  Caron RM, Merrick J, eds. Building community capacity: Case examples from around the world. New York: Nova Science, 2013.  Steele RE. Managed care in a public setting. New York: Nova Science, 2013.  Srabstein JC, Merrick J, eds. Bullying: A public health concern. New York: Nova Science, 2013.  Pulenzas N, Lechner B, Thavarajah N, Chow E, Merrick J, eds. Advanced cancer: Managing symptoms and quality of life. New York: Nova Science, 2013.

Complimentary Contributor Copy 402 About the book series “Health and human development”

 Stein D, Latzer Y, eds. Treatment and recovery of eating disorders. New York: Nova Science, 2013.  Sun J, Buys N, Merrick J. Health promotion: Community singing as a vehicle to promote health. New York: Nova Science, 2013.  Pulenzas N, Lechner B, Thavarajah N, Chow E, Merrick J, eds. Advanced cancer: Managing symptoms and quality of life. New York: Nova Science, 2013.  Sun J, Buys N, Merrick J. Health promotion: Strengthening positive health and preventing disease. New York: Nova Science, 2013.  Merrick J, Israeli S, eds. Food, nutrition and eating behavior. New York: Nova Science, 2013.  Shahtahmasebi S, Merrick J. Suicide from a public health perspective. New York: Nova Science, 2014.  Merrick J, Tenenbaum A, eds. Public health concern: Smoking, alcohol and substance use. New York: Nova Science, 2014.  Merrick J, Aspler S, Morad M, eds. Mental health from an international perspective. New York: Nova Science, 2014.  Merrick J, ed. India: Health and human development aspects. New York: Nova Science, 2014.  Caron R, Merrick J, eds. Public health: Improving health via inter-professional collaborations. New York: Nova Science, 2014.  Merrick J, ed. Pain Mangement Yearbook 2014. New York: Nova Science, 2015.  Merrick J, ed. Public Health Yearbook 2014. New York: Nova Science, 2015.  Sher L, Merrick J, eds. Forensic psychiatry: A public health perspective. New York: Nova Science, 2015.  Shek DTL, Wu FKY, Merrick J, eds. Leadership and service learning education: Holistic development for Chinese university students. New York: Nova Science, 2015.  Calles JL, Greydanus DE, Merrick J, eds. Mental and holistic health: Some international perspectives. New York: Nova Science, 2015.  Lechner B, Chow R, Pulenzas N, Popovic M, Zhang N, Zhang X, Chow E, Merrick J, eds. Cancer: Treatment, decision making and quality of life. New York: Nova Science, 2016.  Lechner B, Chow R, Pulenzas N, Popovic M, Zhang N, Zhang X, Chow E, Merrick J, eds. Cancer: Pain and symptom management. New York: Nova Science, 2016.  Lechner B, Chow R, Pulenzas N, Popovic M, Zhang N, Zhang X, Chow E, Merrick J, eds. Cancer: Bone metastases, CNS metastases and pathological fractures. New York: Nova Science, 2016.  Lechner B, Chow R, Pulenzas N, Popovic M, Zhang N, Zhang X, Chow E, Merrick J, eds. Cancer: Spinal cord, lung, breast, cervical, prostate, head and neck cancer. New York: Nova Science, 2016.  Lechner B, Chow R, Pulenzas N, Popovic M, Zhang N, Zhang X, Chow E, Merrick J, eds. Cancer: Survival, quality of life and ethical implications. New York: Nova Science, 2016.

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 Davidovitch N, Gross Z, Ribakov Y, Slobodianiuk A, eds. Quality, mobility and globalization in the higher education system: A comparative look at the challenges of academic teaching. New York: Nova Science, 2016.  Henry B, Agarwal A, Chow E, Omar HA, Merrick J, eds. Cannabis: Medical aspects. New York: Nova Science, 2017.  Henry B, Agarwal A, Chow E, Merrick J, eds. Palliative care: Psychosocial and ethical considerations. New York: Nova Science, 2017.  Furfari A, Charames GS, McDonald R, Rowbottom L, Azad A, Chan S, Wan BA, Chow R, DeAngelis C, Zaki P, Chow E, Merrick J, eds. Oncology: The promising future of biomarkers. New York: Nova Science, 2017.  O’Hearn S, Blake A, Wan BA, Chan S, Chow E, Merrick J, eds. Medical cannabis: Clinical practice. New York: Nova Science, 2017.  Lui LC, Wong K, Yeung R, Merrick J, eds. Palliative care: Oncology experience from Hong Kong. New York: Nova Science, 2017.  Shek DTL, Leung JTY, Lee T, Merrick J, eds. Psychosocial needs: Success in life and career planning. New York: Nova Science, 2017.  Kopytin A, Lebedev A. Clinical art psychotherapy with war veterans. New York: Nova Science, 2017.  Malek L, Lim F, Wan BA, Diaz PL, Chow E, Merrick J, eds. Cancer and exercise. New York: Nova Science, 2018.

Contact Professor Joav Merrick, MD, MMedSci, DMSc Director, National Institute of Child Health and Human Development, Jerusalem, Israel E-mail: [email protected]

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SECTION THREE: INDEX

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INDEX

alkaline phosphatase, 291, 323, 331 A alopecia, 373 alternative treatments, 292 abuse, viii, ix, 22, 391, 401 American Heart Association, 337 Accelerated Partial Breast Irradiation, 207 amine, 346, 357 accelerator, 56, 294 analytical framework, 89 access, 25, 36, 39, 43, 55, 56, 61, 62, 64, 65, 99, 120, anastomosis, 97, 99, 180, 288, 320 160, 181, 200, 356, 363, 364, 378, 380 anatomy, 212, 265, 266, 271, 308 accounting, 10, 104, 134, 166 androgen, 290, 292, 307, 308, 309, 311, 333, 335, adenocarcinoma, xiv, 8, 32, 59, 65, 66, 70, 71, 73, 336, 337, 338, 339, 346 74, 77, 78, 90, 91, 98, 100, 108, 110, 117, 121, angiogenesis, 60, 61, 62, 66, 121, 161, 277, 282, 123, 131, 149, 175, 176, 177, 226, 227, 234, 236, 368, 370 245, 247, 248, 249, 250, 252, 254, 278, 283, 309, annual rate, 32, 252 312, 313, 335 antagonism, 291 adenomyosis, 121 antibody, 17, 170, 198, 356 adenopathy, 304, 368 antigen, 17, 110, 312, 317, 332, 334, 335, 337, 339, adenosine triphosphate, 123 340 adjustment, 187, 221 antitumor, 88, 198 adrenal gland, 292, 381 antiviral drugs, 154 advancement, 194, 252 anus, 182, 185, 188, 192, 194, 196, 197, 198 adverse effects, 129, 170, 271, 272, 273, 302, 303, anxiety, 353 369 arms control, 288 adverse event, 12, 14, 60, 61, 195, 237, 243, 322, arsenic, 344, 346, 358 324, 366, 367, 368, 370, 372, 373, 374, 375, 376, artery, 15, 86, 96, 97, 112, 113, 124, 127, 145, 148, 377 160, 221, 225, 227, 239, 254, 259, 260, 264, 266, advocacy, 391 382 aerodigestive tract, 40, 49 asbestos, 106 age, 10, 11, 15, 32, 50, 57, 70, 75, 77, 82, 84, 94, ascites, 84, 94, 141 105, 121, 123, 138, 154, 164, 165, 168, 173, 201, Asia, 61, 71, 83, 115, 120, 134, 154 202, 206, 207, 208, 212, 214, 219, 224, 233, 234, aspiration pneumonia, 72 235, 236, 253, 254, 322, 348, 354, 358, 361, 365 assessment, 78, 88, 117, 131, 132, 177, 189, 193, agencies, 343, 353 197, 202, 220, 221, 223, 238, 239, 246, 280, 281, aggressiveness, 287 292, 358 aging population, 200 asymptomatic, 11, 81, 84, 110, 201, 253, 255, 323, alanine aminotransferase, 373 325, 327, 328, 330, 339, 370 alcohol abuse, 21, 22, 31, 32, 155 atherosclerosis, 272 alcohol consumption, 32, 44, 49, 70, 167 autoimmune disease, 374, 375, 376 alcoholic liver disease, 106, 107 Complimentary Contributor Copy 408 Index autosomal dominant, 166 brain tumor, 391 axilla, 200, 209, 214, 221, 223, 225, 227 Brazil, xv, 3, 4, 7, 21, 31, 32, 43, 44, 48, 49, 53, 54, 55, 56, 59, 61, 62, 63, 64, 69, 70, 78, 81, 82, 83, 89, 93, 103, 119, 133, 144, 153, 163, 164, 165, B 169, 172, 175, 182, 185, 199, 202, 213, 217, 233, 234, 251, 285, 315, 341, 343, 344, 345, 357, 363, barriers, 54, 56, 146 389, 390, 393 base, 8, 9, 13, 15, 22, 24, 25, 35, 60, 123, 256, 257, breast cancer, xiv, 199, 200, 201, 202, 203, 204, 205, 283, 294, 302, 321 206, 207, 208, 210, 211, 213, 214, 215, 217, 218, basic education, 54 219, 221, 225, 226, 227, 228, 229, 230, 231, 233, beneficial effect, 85, 128 234, 250, 347 benefits, 8, 15, 59, 87, 100, 103, 115, 136, 137, 146, breast cancer imaging screening, 201 168, 170, 187, 190, 191, 222, 224, 226, 238, 242, breast carcinoma, 215, 217, 218, 219, 229, 231 262, 276, 286, 299, 306, 322, 325, 368, 369, 381 benign, 71, 78, 94, 98, 110, 124, 128, 130, 317 bilateral, 9, 23, 24, 25, 34, 112, 138, 140, 202, 235, C 236, 237, 259 bile, 94, 95, 97, 99, 103, 104, 105, 106, 107, 108, calcium, 371 109, 110, 111, 124 campaigns, 164 bile duct, 94, 95, 97, 99, 103, 104, 105, 106, 107, cancer care, 353 108, 109, 110, 111, 124 cancer cells, 111 biliary obstruction, 99, 132 cancer death, 53, 81, 82, 134, 175, 176, 186, 200, biliary tract, 104, 105, 116, 117, 118, 130, 132, 165 207, 251, 252, 364 biomarkers, 89, 173, 202, 203, 358, 403 cancer progression, 171, 253 biopsy, 8, 14, 36, 61, 66, 81, 84, 86, 110, 157, 189, cancer screening, 84, 89, 213, 358 192, 193, 196, 201, 204, 208, 209, 214, 215, 220, candidates, 25, 35, 39, 54, 57, 75, 76, 95, 123, 134, 221, 236, 255, 259, 262, 276, 280, 286, 287, 289, 138, 143, 146, 161, 222, 238, 239, 240, 242, 349, 298, 305, 319, 322, 365, 368 356, 365 births, 253 capsule, 111, 227, 288 bladder cancer, 341, 342, 343, 344, 345, 346, 347, carbon, 16, 20, 114 348, 349, 351, 352, 353, 354, 355, 356, 357, 358, carcinoembryonic antigen, 111, 125, 141 359, 360, 361, 362 carcinoma, 8, 17, 28, 31, 32, 33, 40, 41, 42, 49, 50, bleeding, 60, 72, 82, 88, 142, 161, 234, 235, 243, 51, 59, 65, 71, 73, 74, 77, 79, 89, 90, 91, 108, 262, 272, 303 109, 116, 117, 118, 121, 123, 130, 131, 132, 150, blood, 61, 154, 156, 160, 165, 201, 267, 271, 278, 153, 154, 161, 162, 167, 182, 185, 186, 195, 196, 288, 292, 330 197, 198, 201, 202, 204, 208, 213, 220, 236, 237, blood flow, 267 245, 249, 254, 256, 278, 279, 280, 281, 282, 283, blood transfusion, 154 306, 313, 337, 348, 359, 361, 362, 363, 364, 366, blood urea nitrogen, 278 369, 371, 372, 373, 374, 375, 376, 379, 381, 382, blood vessels, 160, 271 383, 384, 385, 386 body composition, 308 cardiovascular disease, 372 body mass index, 122, 211 cardiovascular disorders, 364 bone, 8, 36, 56, 58, 65, 218, 256, 273, 276, 278, 287, Caribbean, viii, 11, 42, 211, 343, 357, 400 290, 291, 292, 308, 317, 318, 320, 323, 325, 327, cartilage, 46, 47 328, 330, 331, 333, 334, 338, 339, 340, 370, 384, castration, 290, 291, 292, 322, 323, 325, 326, 327, 389 328, 330, 331, 337, 338, 339, 340 bone scan, 292, 317, 318, 327, 328, 330 categorization, 172 bowel, 191, 270, 301, 350 central nervous system, 56, 165, 374, 375, 376 brachytherapy, 14, 19, 72, 118, 186, 190, 225, 239, certification, 344 240, 241, 246, 247, 248, 251, 252, 264, 265, 266, cervical cancer, xv, 64, 194, 213, 251, 252, 253, 254, 267, 268, 269, 270, 271, 273, 274, 275, 276, 280, 258, 259, 260, 262, 263, 264, 267, 268, 270, 271, 281, 299, 300, 304, 310, 312, 313, 322, 336, 390, 272, 274, 275, 279, 280, 281, 282 391 cervix, 254, 255, 256, 258, 259, 260, 261, 266, 269, brain, 218, 370, 371, 372, 373, 384, 391, 400 279, 280, 281, 282, 283 Complimentary Contributor Copy Index 409 challenges, 4, 36, 54, 55, 164, 403 compounds, 60, 291, 292, 379 chemical, 72, 106, 294 compression, 108, 291, 324, 331 chemotherapeutic agent, 114, 139, 160, 378 computed tomography, 8, 90, 111, 165, 180, 189, child maltreatment, 401 280, 308, 336 children, x, 8, 11, 399 computer, 317, 318 chlamydia, 253 congestive heart failure, 376 chlorination, 344 conization, 259 cholangiocarcinoma, xiv, 103, 104, 105, 106, 107, connective tissue, 124 108, 109, 110, 111, 113, 115, 116, 117, 118, 132 consciousness, 400 cholangiography, 125, 129 consensus, 14, 50, 89, 109, 111, 112, 116, 131, 137, cholangitis, 105, 107, 108, 116, 122, 131 138, 146, 147, 148, 162, 176, 214, 229, 235, 281, cholecystectomy, 119, 120, 123, 125, 126, 127, 128, 289, 305, 313, 328, 335 131 conservation, 51, 204, 214, 229 cholelithiasis, 119, 120, 121, 122, 128, 130 conserving, 197, 204, 207, 210, 211, 213, 214, 224, choline, 318, 319, 333, 334, 336 230 cigarette smoking, 32, 186 consolidation, 183, 355 cirrhosis, 94, 107, 109, 112, 138, 153, 154, 156, 159, consumption, 11, 32, 40, 70, 99, 155, 165, 272, 273, 162 344, 357 classification, 8, 9, 17, 31, 65, 79, 84, 85, 88, 89, 91, contamination, 127 94, 106, 107, 108, 109, 110, 115, 119, 144, 202, contour, 39, 321 236, 254, 256, 258, 259, 260, 261, 367, 385 control group, 144, 145, 227 clinical judgment, 237 controlled studies, 135, 188 clinical oncology, 214, 279, 389, 390 controlled trials, 50, 173, 213, 288, 308, 309, 328, clinical presentation, 110, 347 329, 364 clinical trials, 28, 39, 62, 128, 134, 144, 147, 234, controversial, 13, 26, 72, 76, 85, 86, 87, 88, 95, 99, 238, 244, 286, 288, 299, 301, 317, 338, 361, 365, 103, 106, 112, 126, 237, 262, 301, 319, 325, 365, 377, 379, 383, 389 368 closure, 36 controversies, 41, 45 coffee, 344, 357 cooperation, 151, 217 collaboration, 359, 395, 396 coronary heart disease, 352 colon, xiv, 64, 75, 77, 123, 149, 163, 164, 165, 166, correlation, 83, 116, 198, 223, 272, 273, 310, 346 167, 168, 170, 171, 172, 173, 180, 181, 278 corrosion, 79 colon cancer, 163, 164, 166, 167, 168, 170, 171, 172, cosmetic, 207 173, 278 cost, 8, 16, 24, 25, 35, 45, 48, 120, 155, 238, 252, colon polyps, 167 293, 306, 327, 347, 352 colonoscopy, 164, 165, 167, 171, 172 cryosurgery, 313 colorectal adenocarcinoma, 172 cryotherapy, 322 colorectal cancer, 133, 134, 136, 146, 147, 148, 149, crystals, 302 150, 164, 165, 167, 172, 173, 174, 181, 195, 234, culture, 393, 400 262 cure, 35, 37, 73, 111, 116, 145, 149, 158, 185, 186, colostomy, 176, 186, 187, 188, 189, 190, 192, 196 222, 306, 347, 351, 353 combination therapy, 177, 282, 371 cycles, 13, 46, 57, 60, 66, 87, 137, 168, 170, 179, common bile duct, 124 188, 189, 222, 242, 302, 355, 376 common symptoms, 71 cyclooxygenase, 277 community, 126, 191, 401 cystectomy, 349, 350, 351, 353, 354, 355, 356, 359, comorbidity, 32, 64, 77, 173, 287, 288, 305, 306, 361 360, 361 comparative analysis, 41, 334 cytokines, 121, 369, 383 complete blood count, 278 cytology, 95, 235, 237, 253, 254, 255, 348, 353, 354 complications, 15, 24, 45, 48, 50, 51, 71, 72, 75, 77, 95, 138, 139, 140, 141, 160, 181, 187, 194, 197, 227, 237, 262, 270, 271, 272, 273, 274, 289, 291, D 309, 310, 331, 336, 348, 352, 354, 358, 359, 361, dance, 400 365 danger, 138 Complimentary Contributor Copy 410 Index data analysis, 250, 344, 400 drainage, 24, 25, 36, 95, 112, 129, 132, 254, 301, database, 47, 49, 54, 113, 117, 136, 137, 173, 242, 304, 321, 352 332, 349, 354, 358 drinking water, 358 death rate, 82, 85 drug therapy, 78 deaths, 7, 10, 11, 15, 22, 32, 54, 69, 82, 94, 164, 186, drug toxicity, 331 200, 210, 251, 252, 253, 276, 345, 357, 364 drug treatment, 170 decision-making process, 209 drugs, 47, 59, 62, 63, 88, 113, 170, 171, 222, 251, deficiency, 171, 174, 291 267, 276, 277, 290, 291, 292, 326, 328, 345, 368, dehydration, 178, 302, 350 380, 390 demographic change, 200 duodenum, 95, 97, 99, 124, 126, 127 denaturation, 302 dyspepsia, 373 Denmark, 11, 32, 145, 391, 397 dysphagia, 15, 71, 72, 75, 79, 84 Department of Education, 396 dysplasia, 73, 120, 121, 123 deposits, 35, 134 deprivation, 290, 307, 308, 309, 311, 325, 335, 336, 337, 338, 339 E depth, 31, 34, 35, 36, 41, 46, 84, 85, 128, 194, 234, early breast cancer, xiv, 199, 200, 207, 213, 214, 235, 239, 254, 256, 257, 266, 302 227, 230, 231 derivatives, 291, 344, 346 eating disorders, 400, 402 destruction, 8, 46, 303 EBV infection, 11 detectable, 316, 327, 333, 335 E-cadherin, 84, 123 detection, 14, 17, 61, 64, 84, 90, 95, 105, 111, 120, economic development, 4 154, 155, 213, 218, 251, 253, 262, 292, 318, 319, economic evaluation, 313 332, 333, 334, 344, 347, 358 economic status, 49 developed countries, 4, 32, 49, 146, 164, 175, 176, edema, 218, 219, 221, 227, 255, 256, 258, 371 252, 343, 344, 346 edentulous patients, 36 diabetes, 98, 100, 107, 165, 262, 272, 345, 352 editors, xv, 4, 389 diabetic patients, 357 educated women, 253 diaphragm, 73, 75, 77 education, 278, 400, 402 diarrhea, 57, 60, 62, 98, 168, 178, 262, 272, 366, effusion, 8 367, 370, 371, 373, 374, 375, 376, 377 elderly population, 187 diet, 7, 18, 72, 165, 167, 344 electromagnetic, 160 differential diagnosis, 84 electromagnetic waves, 160 diffusion, 139, 334 electrons, 227 dilation, 72, 94, 107, 139 eligibility criteria, 366 diplopia, 8 emboli, 115, 139, 149, 160, 365, 383 disability, 391, 395, 397 embolization, 115, 139, 149, 160, 365, 383 disease progression, 58, 60, 61, 234, 243, 244, 289, emission, 95, 111, 317, 318 292, 322, 325, 330, 377, 378 employment, 123 diseases, 15, 54, 70, 82, 105, 200, 275, 341, 343, 347 endocrine, 94, 242, 243, 311, 325 disinfection, 357 endometrial biopsy, 239 distribution, 7, 11, 20, 28, 33, 55, 105, 120, 130, 211, endometrial carcinoma, 234, 235, 236, 239, 244, 270, 279, 358, 385 245, 246, 247, 248, 249, 250 divergence, 46 endometrial hyperplasia, 236, 245 diversity, 109, 116, 218 endoscopic retrograde cholangiopancreatography, DNA, 14, 19, 61, 62, 63, 121, 167, 171, 252, 277, 129 292 endoscopy, 14, 78, 81, 84, 85, 120, 348 DNA damage, 121 environment, 136, 267, 273 DNA sequencing, 61, 62, 63 environmental factors, 12 docetaxel, 47, 59, 63, 67, 88, 194, 197, 250, 276, enzyme, 123, 346 302, 317, 323, 326, 329, 330, 332, 337, 338, 340 epidemic, 40, 346 dosage, 187 epidemiologic, 42, 186 dose-response relationship, 243 Complimentary Contributor Copy Index 411 epidemiology, 17, 44, 78, 82, 83, 104, 115, 130, 211, 229, 341, 356, 358, 359, 361 G epigenetic alterations, 114 gallbladder, xiv, 97, 113, 117, 119, 120, 121, 122, epithelium, 8, 32, 104, 108, 134, 253, 254, 256, 257 124, 125, 126, 127, 128, 130, 131, 132 Epstein Barr, 83 gastrectomy, 84, 85, 86, 87, 89, 90, 91, 146 Epstein-Barr virus, 17, 89 gastric mucosa, 83 equipment, 299 gastroesophageal reflux, 83 esophageal cancer, xiii, 69, 70, 71, 72, 73, 74, 75, 76, gastrointestinal bleeding, 71 77, 78, 79 gastrointestinal tract, 186 esophagitis, 70, 71, 244 genetic predisposition, 202, 346 esophagus, 70, 71, 72, 73, 74, 75, 76, 77, 78, 79 genetic syndromes, 164 estrogen, 202, 203, 234, 243, 249, 278, 307 genetic testing, 61 ethanol, 158, 160 germline mutations, 89 ethical implications, 402 gerontology, 395 Europe, 22, 61, 70, 71, 134, 145, 238 gland, 207, 227, 302 eustachian tube, 8 globalization, 403 evidence, 4, 15, 23, 36, 38, 39, 44, 62, 65, 73, 75, 77, glutathione, 346, 358 83, 85, 86, 93, 100, 106, 110, 127, 128, 133, 134, gonadotropin-releasing hormone, 308 136, 137, 138, 140, 141, 142, 143, 144, 146, 159, gonorrhea, 253 166, 176, 185, 192, 200, 204, 207, 213, 214, 218, government policy, 346 219, 222, 223, 224, 226, 228, 243, 256, 273, 278, grades, 366, 367, 373 322, 324, 342, 357, 361, 364, 372, 401 gross domestic product, 343 excision, 123, 175, 176, 182, 183, 187, 205, 288, 365 growth, 16, 59, 60, 61, 62, 65, 66, 70, 106, 107, 108, exclusion, 206, 374, 375 109, 121, 123, 149, 156, 165, 170, 195, 198, 229, execution, 126, 160 277, 291 expenditures, 342, 344 growth factor, 16, 59, 61, 65, 66, 70, 121, 123, 195, expertise, 36, 39, 60, 61, 380, 391 198, 229, 277 exposure, 25, 32, 43, 106, 114, 160, 194, 278, 346, growth rate, 149 357, 358 guidelines, 38, 49, 50, 54, 57, 60, 64, 65, 90, 143, 148, 163, 165, 171, 172, 187, 194, 199, 204, 206, F 211, 244, 258, 280, 281, 302, 303, 307, 310, 321, 332, 333, 335, 357, 377, 381 facial pain, 8 facial palsy, 15 false negative, 35, 223 H families, 12, 84 hair, 373 family history, 164, 201, 202, 344 half-life, 268 fascia, 176, 181, 257, 259, 260, 320 head and neck cancer, 22, 28, 29, 40, 41, 42, 44, 50, federal government, 393 51, 70, 71, 402 fertility, 236, 245, 251, 258, 259, 262, 280, 343 headache, 8 fetus, 154 healing, 197, 401 F-FDG PET, 172 health, 3, 4, 23, 24, 34, 39, 43, 44, 45, 54, 55, 57, 61, fibroblast growth factor, 377 82, 163, 172, 202, 207, 268, 338, 343, 352, 353, fibrosis, 58, 106, 108, 221, 228, 259 358, 363, 364, 381, 391, 395, 397, 399, 400, 401, filtration, 352 402 financial, 28, 39, 48 health care, 3, 4, 163, 172, 202, 268, 358, 381, 400 fistulas, 48, 71, 141 health care costs, 381 fixation, 219, 255 health care system, 163, 202 fluid, 255, 344, 357 health insurance, 39, 54, 55 fluorescence, 222 Helicobacter pylori, 81, 83, 89 formation, 71, 74, 272, 331, 365 hematochezia, 255 freezing, 302 hematology, 390 functional changes, 220 Complimentary Contributor Copy 412 Index hematuria, 244, 255, 346, 347, 358, 365 improvements, 12, 63, 83, 84, 88, 114, 128, 138, hemoglobin, 255, 347, 371 143, 164, 172, 349 hemorrhage, 72, 141, 255, 262 in situ hybridization, 222 hepatitis, 106, 115, 138, 154, 162 in utero, 278 hepatocellular carcinoma, xiv, 104, 105, 106, 107, in vivo, 58 109, 112, 150, 153, 161, 162 incidence, 7, 8, 10, 11, 17, 22, 24, 28, 32, 44, 48, 49, heterogeneity, 4, 15, 44, 49, 71, 377 54, 55, 56, 65, 69, 70, 78, 82, 83, 89, 94, 103, high risk patients, 179, 265, 380 105, 106, 107, 110, 115, 120, 121, 134, 147, 153, high-risk populations, 202 154, 155, 164, 181, 186, 187, 200, 207, 228, 229, histological examination, 36 233, 234, 251, 252, 253, 254, 271, 272, 273, 274, histology, 17, 32, 57, 60, 65, 83, 89, 122, 165, 202, 278, 279,282, 285, 286, 287, 300, 304, 315, 332, 204, 234, 235, 238, 342, 367, 374, 375, 377, 378, 344, 345, 347, 357, 358, 359, 363, 364, 371, 372, 379, 385 373, 380 history, 19, 141, 147, 171, 187, 202, 203, 268, 272, income, 252, 253, 279, 343, 357 305, 330, 332, 337, 339, 344, 347 induction, 14, 16, 19, 26, 29, 42, 47, 66, 149, 188, holistic medicine, 400 189, 190, 191, 222, 353, 355, 374 hormone, 202, 219, 220, 221, 222, 243, 285, 286, induction chemotherapy, 14, 19, 26, 29, 42, 47, 188, 291, 292, 293, 297, 298, 299, 302, 303, 304, 307, 189, 190, 191, 222 308, 311, 315, 316, 317, 318, 320, 321, 322, 323, infection, 7, 11, 17, 21, 22, 32, 70, 83, 89, 106, 120, 324, 325, 326, 327, 328, 333, 335, 337, 338, 339, 122, 154, 186, 195, 252, 253, 254, 262, 278, 279 340 infectious mononucleosis, 11 hospitalization, 262, 288, 352, 356 inferior vena cava, 365 human development, xv, 391, 395, 397, 399, 402 inferiority, 183, 214, 247, 276, 277, 310, 324, 373 human leukocyte antigen, 12 inflammation, 83, 103, 105, 121, 122, 123, 219, 221, human papilloma virus, 21, 22, 27, 251, 252 373 hydronephrosis, 255, 256, 275 inflammatory bowel disease, 165 hypercholesterolemia, 371 inflammatory disease, 220, 272 hypertension, 159, 161, 352, 366, 367, 369, 371, inflammatory responses, 58 372, 373, 376, 377 informed consent, 128, 141 hypofractionated radiotherapy, 50, 204, 206, 213, inguinal, 188, 192, 194, 255 310, 389 inhibition, 139, 195, 198, 290, 370, 377 hypoglossal nerve, 35 inhibitor, 61, 66, 137, 277, 369, 370, 376, 377 hypothyroidism, 367, 373, 374 initiation, 58, 59, 95, 253, 366 hysterectomy, 235, 236, 237, 239, 240, 245, 259, injury, xii, 15, 121, 148, 226, 227 260, 261, 262, 272, 275, 280, 281 insertion, 72, 259, 269 institutions, 254, 350, 355 integration, 253, 399 I interference, 350, 354 interferon, 368, 369, 371, 372, 382, 383 ideal, 13, 46, 179, 269, 299 International Classification of Diseases, 344 identification, 7, 84, 107, 129, 139, 205, 223, 339 International Federation of Gynecology and idiosyncratic, 346 Obstetrics (FIGO), 255 ileostomy, 180 intervention, 128, 135, 143, 365, 378, 379, 382 ileum, 350 intestinal obstruction, 272, 273 image, 12, 111, 157, 267, 275, 280, 281, 293, 300, intestine, 267, 274 308, 390 intravesical chemotherapy, 361 imaging modalities, 131, 154, 157, 201 invasive cancer, 84, 253, 255 immigrants, 17 ipsilateral, 23, 24, 34, 139, 202, 204, 207, 218 immune response, 62, 63 irradiation, 13, 19, 72, 192, 199, 204, 205, 206, 207, immunodeficiency, 401 208, 209, 210, 211, 212, 214, 215, 224, 225, 227, immunohistochemistry, 62, 63, 200, 222, 224 228, 229, 230, 240, 245, 246, 247, 248, 249, 270, immunosuppression, 253 274, 280, 281, 298, 301, 304, 309, 311, 312, 313, immunotherapy, 53, 63, 67, 114, 171, 251, 339, 354, 321, 331, 355 368, 382, 390 Complimentary Contributor Copy Index 413

ligament, 112, 140, 259, 260 J ligand, 59, 186, 331, 334 light, 177 Japan, 16, 20, 78, 79, 82, 84, 90, 122, 157, 161, 226 liquids, 71 jaundice, 95, 99, 108, 110, 123, 129 liver, xiv, 58, 75, 77, 78, 84, 94, 95, 101, 103, 105, JCC, 96 106, 107, 109, 111, 112, 114, 116, 117, 118, 124, jejunum, 97 125, 126, 127, 133, 134, 135, 136, 137, 138, 139, joints, 188 140, 141, 142, 143, 144, 145, 146, 147, 148, 149, 150, 151, 153, 154, 155, 156, 157, 158, 159, 160, K 161, 162, 165, 166, 172, 173, 194, 195, 218, 220, 235, 256, 276, 291, 346, 358 keratin, 35 liver cancer, 147, 154, 161, 162, 165 kidney, 256, 358, 364, 365, 377, 381, 382, 384 liver cirrhosis, 106, 107 killer cells, 383 liver damage, 94, 107, 139, 155 kinetics, 226, 319, 334 liver disease, 78, 106, 109, 138, 141, 154, 155, 156, Korea, 82, 84, 120, 378 161 liver failure, 141, 160 liver function tests, 156 L liver metastases, 94, 95, 133, 134, 135, 136, 137, 140, 142, 143, 144, 145, 146, 147, 148, 149, 150, labeling, 139 151, 172, 173 laboratory tests, 110, 165 liver transplantation, 103, 140, 141, 143, 147, 149, lack of control, 46 158, 159, 162 laparoscopic cholecystectomy, 120 local anesthesia, 290 laparoscopic surgery, 86, 167, 237, 306, 379 localization, 159, 262, 293, 308, 334 laparoscopy, 81, 85, 90, 91, 94, 95, 112, 117, 142, low risk, 12, 26, 37, 141, 238, 264, 265, 286, 287, 147, 235, 237, 238, 245, 259, 262, 288, 290 296, 301, 303, 304, 305, 323, 380 laparotomy, 85, 131, 145, 167, 176, 181, 235, 245, lubricants, 278 258, 259, 272 lung cancer, xiii, 53, 54, 55, 64, 65, 66, 67, 68, 82, laryngeal cancer, xiii, 43, 44, 45, 46, 47, 48, 49, 50, 227, 390 51 luteinizing hormone, 291, 307 laryngectomy, 44, 45, 46, 47, 48, 50, 51 lymph node, 9, 12, 23, 24, 25, 28, 32, 33, 34, 35, 36, larynx, 44, 45, 46, 47, 50, 51 37, 38, 39, 40, 41, 42, 45, 58, 71, 74, 75, 77, 85, laser ablation, 24 86, 88, 90, 94, 95, 96, 98, 106, 108, 109, 110, Latin America, 1, ii, xi, xiii, xv, 3, 4, 11, 23, 34, 39, 112, 113, 115, 117, 119, 124, 125, 126, 127, 129, 42, 43, 44, 45, 46, 48, 49, 53, 54, 57, 59, 61, 64, 131, 166, 167, 172, 173, 177, 178, 192, 194, 199, 69, 81, 82, 83, 87, 88, 89, 90, 134, 136, 144, 146, 200, 201, 202, 204, 206, 207, 208, 209, 210, 211, 163, 164, 172, 175, 176, 199, 200, 211, 213, 263, 212, 214, 215, 217, 218, 219, 223, 224, 225, 230, 279, 286, 315, 341, 342, 343, 344, 356, 357, 363, 235, 237, 238, 239, 240, 246, 247, 256, 259, 260, 364, 379, 389 261, 262, 264, 266, 274, 280, 289, 306, 307, 313, lead, 13, 45, 47, 61, 62, 76, 154, 210, 271, 319, 347, 332, 336, 355, 360, 362, 365, 368, 381, 382 350, 368 lymphadenopathy, 13, 26 leakage, 75, 77, 302, 353 lymphatic system, 258 learning, 25, 37, 238, 402 lymphedema, 209, 221, 262 lesions, 21, 25, 32, 35, 45, 58, 71, 74, 76, 81, 83, 84, lymphoma, 8, 17, 32, 59, 62, 67, 84, 123, 277 85, 86, 89, 94, 95, 98, 108, 111, 112, 131, 134, 139, 142, 154, 155, 157, 164, 167, 170, 194, 204, 220, 254, 255, 256, 257, 262, 271, 279, 287, 292, M 322, 327, 345, 365 leukopenia, 371, 373 magnetic resonance, 8, 19, 81, 111, 124, 138, 139, leukoplakia, 32 180, 201, 281, 317, 334 life expectancy, 129, 204, 286, 287, 288, 304, 322, magnetic resonance imaging, 8, 19, 111, 124, 138, 323, 343 139, 180, 201, 317, 334 lifetime, 105, 155, 186, 201, 202, 203 magnitude, 58, 127, 204, 220, 345 Complimentary Contributor Copy 414 Index majority, 15, 63, 75, 82, 114, 121, 123, 153, 186, models, 139, 226, 370 205, 218, 243, 352, 370, 377, 379 modifications, 9, 260 malignancy, 94, 104, 117, 121, 124, 128, 130, 134, molecular biology, 62, 70, 76, 224 153, 154, 281, 365 monoclonal antibody, 16, 47, 60, 171, 331 malignant melanoma, 77 mood disorder, 400 malignant tumors, 8, 77 morbidity, 12, 15, 23, 24, 45, 71, 72, 75, 77, 86, 87, mammography, 201, 202, 213, 220, 221, 223, 228 93, 97, 98, 112, 126, 129, 136, 138, 139, 140, mandible, 35, 36, 41, 331 141, 143, 144, 146, 155, 159, 160, 179, 186, 191, manipulation, 348 193, 194, 196, 197, 248, 261, 262, 264, 271, 272, mapping, 215, 239, 307, 360 273, 280, 288, 290, 312, 336, 351, 361 mass, 8, 84, 89, 106, 107, 108, 109, 110, 111, 116, mortality, 17, 28, 38, 49, 69, 72, 78, 82, 83, 86, 87, 117, 124, 125, 156, 294, 379, 382 88, 89, 90, 93, 97, 112, 126, 129, 131, 134, 136, mastectomy, 200, 204, 205, 209, 212, 214, 215, 221, 139, 140, 141, 143, 144, 146, 155, 159, 164, 175, 223, 224, 226, 228, 229, 230 176, 181, 182, 186, 187, 207, 214, 215, 227, 229, matter, xii, 149, 307, 344, 348, 350 234, 248, 252, 253, 279, 282, 285, 286, 287, 289, maxillary sinus, 13, 35 294, 297, 304, 311, 315, 319, 320, 332, 333, 344, median, 48, 54, 59, 63, 72, 85, 99, 100, 114, 129, 346, 348, 349, 352, 354, 357, 358, 361, 362, 364, 134, 137, 138, 142, 143, 144, 146, 188, 189, 190, 380, 381 191, 192, 194, 226, 227, 234, 243, 254, 276, 277, mortality rate, 69, 82, 83, 181, 207, 227, 234, 287, 287, 296, 302, 321, 328, 348, 355, 368, 370, 375, 344, 348, 349, 352, 358, 364 377, 378, 379 mucin, 95, 108 medical, 4, 28, 53, 55, 56, 76, 82, 84, 173, 201, 217, mucosa, 15, 32, 33, 71, 119, 122, 124, 226, 241, 254, 218, 220, 235, 237, 242, 302, 303, 319, 331, 339, 256, 266, 269, 350 345, 358, 390, 391, 400 multidimensional, 343 medical history, 201, 220 multiple primary tumors, 40 medicine, 4, 53, 100, 158, 163, 207, 333, 361, 390, multivariate analysis, 113, 193 393, 399, 401 muscles, 9, 221, 258, 262, 320 melanoma, 32, 56, 123, 390 mutation, 59, 61, 62, 63, 65, 84, 130, 166, 170, 203, mellitus, 100, 107, 155, 161, 165, 345 278 membranes, 271, 302 mutations, 59, 60, 61, 62, 63, 66, 67, 89, 106, 115, meta-analysis, 13, 14, 18, 19, 22, 26, 28, 41, 47, 49, 122, 167, 170, 171, 174, 201, 253 50, 51, 54, 61, 64, 65, 66, 79, 90, 91, 100, 101, mycotoxins, 399 113, 118, 136, 148, 173, 183, 204, 209, 213, 214, 215, 223, 225, 227, 229, 230, 240, 241, 242, 243, 247, 274, 279, 281, 295, 307, 308, 309, 326, 333, N 334, 335, 337,338, 339, 359, 361, 364, 382 naming, 350 metabolic acidosis, 350 nasopharyngeal carcinoma, 8, 17, 18, 19, 20 metabolic syndrome, 107, 325 nasopharynx, 8, 9, 13, 17 metastasectomy, 133, 136, 146, 151, 369, 383 natural killer cell, 123 metastasis, 8, 9, 13, 14, 15, 24, 28, 32, 33, 34, 35, 36, nausea, 57, 59, 60, 84, 160, 244, 374 37, 39, 41, 47, 54, 74, 75, 94, 96, 101, 110, 111, necrosis, 15, 25, 74, 108, 160, 202, 221, 255, 267, 112, 117, 119, 123, 124, 125, 127, 134, 142, 148, 303 149, 150, 151, 161, 162, 166, 167, 177, 197, 210, negative outcomes, 295 214, 224, 225, 226, 228, 239, 240, 245, 246, 253, neglect, viii, 400 256, 262, 276, 278, 316, 318, 328, 333, 335, 339, neoangiogenesis, 70 355, 366, 370 neoplasm, 32, 94, 106, 108, 120, 166, 202 methodology, 178 nephrectomy, 364, 366, 368, 379, 381, 382, 383 methylation, 253, 347 nervous system, 67 microcirculation, 302 neurogenic bladder, 359 microscope, 24 neutropenia, 168, 243, 244, 366, 371, 372, 373 microspheres, 114, 118, 160 next generation, 45 Mitoxantrone, 329 Nobel Prize, 391 modelling, 306 Complimentary Contributor Copy Index 415 nodal involvement, 94, 96, 177, 258, 259, 289, 301, palliative, 53, 56, 65, 72, 79, 88, 95, 99, 101, 114, 303, 304, 317 115, 120, 129, 143, 146, 158, 234, 242, 244, 275, nodes, 9, 25, 36, 38, 45, 109, 112, 120, 124, 125, 276, 277, 287, 289, 303, 331, 382, 383, 390 126, 127, 167, 186, 188, 189, 190, 194, 208, 209, pancreas, 94, 96, 97, 98, 124, 165 210, 219, 221, 222, 223, 224, 225, 226, 235, 237, pancreatic cancer, xiv, 93, 94, 96, 100, 101, 113 238, 239, 240, 241, 254, 255, 258, 259, 260, 266, parallel, 195, 308, 349 267, 289, 301, 302, 304, 316, 351, 365 parasites, 106 nodules, 59, 109, 155, 159 parenchyma, 104, 138, 140, 149, 156, 365 non-smokers, 273 parotid gland, 9 nuclear magnetic resonance, 223 partition, 140, 145, 148, 149, 151 nuclei, 298, 303 pathogenesis, 11, 12, 82, 84, 89, 153, 164 nucleic acid, 115 pathology, 83, 90, 105, 116, 134, 147, 165, 202, 238, nulliparity, 234 239, 262, 264, 321, 349, 351 nutrition, 75, 278, 357, 402 pathophysiology, 186 pathway, 61, 67, 123, 195, 254, 277 pathways, 61, 62, 275, 377, 390 O pectoralis major, 36, 39, 48, 51 pediatrics, viii obesity, 70, 83, 107, 155, 164, 165, 167, 234, 262, pelvic floor, 181, 352 278 pelvic inflammatory disease, 272 obstruction, 8, 71, 82, 88, 99, 110, 120, 129, 149, pelvis, 81, 84, 94, 96, 165, 188, 190, 192, 193, 235, 167, 255, 258 242, 249, 256, 257, 260, 263, 265, 270, 276, 297, occlusion, 271 301, 304, 321, 322, 330, 355, 362 occult blood, 164 penis, 301 odynophagia, 71 peptic ulcer, 84 omentum, 86, 124 perforation, 71, 72, 167 omission, 206, 210 peripheral neuropathy, 57, 168, 243 oncogenes, 122, 253 peritoneal carcinomatosis, 85, 94 oophorectomy, 235, 236 peritoneum, 73, 84, 109, 110, 124, 143, 166 operations, 120, 350, 353 pharmacological treatment, 146 oral cavity, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, pharmacology, 67 42, 44, 49 Philadelphia, 28, 40, 78, 229, 230, 279, 281, 306, organ, 3, 4, 44, 46, 47, 48, 50, 51, 75, 77, 86, 124, 313, 333 134, 138, 140, 141, 146, 166, 205, 270, 293, 299, phosphate, 15, 19 311, 355, 356, 362, 364, 365 photons, 16, 298 osteomyelitis, 15 physical characteristics, 268 outcome relationship, 361 physical therapy, 393 ovarian cancer, 201, 203, 243 placebo, 57, 63, 66, 162, 174, 282, 320, 328, 329, oxidation, 267 330, 331, 339, 340, 367, 369, 382, 384 plaque, 32 P plasticity, 109 platelet aggregation, 372 p16INK4A, 29 platelet count, 220 paclitaxel, 59, 60, 66, 88, 194, 197, 198, 229, 242, platinum, 7, 26, 47, 48, 57, 59, 60, 63, 66, 67, 100, 243, 245, 247, 249, 250, 276, 277, 282, 355, 362 113, 197, 242, 243, 244, 250, 275, 276, 283, 349, pain, 72, 78, 84, 99, 110, 120, 123, 129, 142, 160, 356, 379, 386 234, 235, 237, 255, 272, 291, 303, 331, 340, 352, playing, 47, 70 365, 389, 399 pleura, 58, 73, 75, 77 pain management, 340 pleural effusion, 141, 258 palate, 24, 25, 32, 35, 36, 41 pneumonitis, 160 palliate, 120, 129 policy, 3, 4, 89, 202, 345, 357, 397 policy makers, 3, 4 politics, 401 Complimentary Contributor Copy 416 Index polycyclic aromatic hydrocarbon, 346 prostheses, 99 polymerase, 17 prosthesis, 48, 97, 228 polymorphism, 131 pruritus, 95, 374, 375 poor performance, 57, 65, 262, 356 PSA, 286, 287, 291, 292, 293, 294, 297, 298, 299, population, 4, 10, 12, 17, 18, 26, 43, 44, 45, 50, 54, 303, 304, 305, 306, 316, 317, 318, 319, 321, 322, 65, 78, 79, 84, 89, 105, 107, 115, 117, 118, 120, 323, 324, 325, 327, 328, 329, 330, 333, 334, 336, 121, 130, 134, 144, 147, 155, 163, 172, 182, 186, 337, 339 187, 200, 219, 229, 237, 243, 244, 295, 305, 306, psychiatry, 400, 402 317, 322, 332, 338, 341, 343, 344, 345, 347, 348, psychology, 400 350, 353, 354, 358, 359, 361, 374, 375 psychopharmacology, ix, 400 portal vein, 108, 124, 139, 140, 145, 148, 149, 151, psychotherapy, ii, 403 160 public health, 56, 61, 62, 120, 164, 165, 341, 363, positive axillary lymph nodes, 208, 210 364, 391, 395, 399, 400, 401, 402 positron, 8, 19, 111, 116, 125, 280, 317, 332, 334, public service, 395 336 pumps, 178 positron emission tomography, 8, 19, 116, 125, 280, pylorus, 96, 97, 98 332, 334, 336 pyrimidine, 99, 100 post-hoc analysis, 196 potential benefits, 57, 218, 277 prednisone, 292, 326, 329, 330, 337, 339 Q preservation, 45, 46, 47, 48, 50, 51, 77, 83, 86, 96, quality of life, 12, 13, 14, 17, 56, 58, 64, 73, 75, 99, 97, 98, 180, 181, 186, 205, 236, 251, 260, 262, 129, 132, 222, 227, 228, 248, 249, 260, 263, 276, 280, 349, 351, 355, 356, 359, 362 285, 287, 293, 322, 324, 331, 335, 353, 361, 389, primary biliary cirrhosis, 105 391, 400, 401, 402 primary tumor, 8, 12, 24, 25, 36, 40, 58, 73, 76, 110, questionnaire, 353 111, 134, 142, 146, 159, 165, 166, 170, 187, 190, 192, 202, 208, 217, 218, 221, 224, 225, 256, 322, 327, 366, 372, 380 R principles, 28, 40, 86, 126, 127, 281, 306, 333, 401 probability, 59, 85, 139, 157, 201, 218, 222, 225, race, 17, 32, 219, 385 226, 227, 267, 271, 272, 278, 305, 322, 326 radiation, 7, 12, 15, 16, 18, 20, 21, 22, 24, 25, 26, 27, proctitis, 272, 273, 300 28, 31, 35, 37, 38, 39, 40, 41, 45, 46, 49, 50, 51, professionals, 4, 28, 35, 310, 333, 384, 395 53, 55, 56, 72, 74, 77, 99, 110, 114, 119, 160, progenitor cells, 109 182, 188, 189, 190, 191, 192, 194, 195, 196, 197, progesterone, 202, 203, 222, 234, 243, 249, 291 199, 201, 204, 205, 207, 208, 210, 211, 213, 214, prognosis, 11, 13, 17, 21, 22, 35, 45, 46, 70, 82, 83, 215, 217, 218, 219, 221, 223, 226, 227, 228, 230, 88, 96, 104, 108, 112, 113, 115, 117, 119, 123, 231, 234, 235, 236, 237, 239, 240, 241, 242, 243, 124, 125, 126, 127, 138, 143, 146, 167, 170, 193, 245, 246, 247, 248, 249, 251, 259, 268, 269, 271, 200, 202, 214, 217, 218, 220, 221, 234, 242, 244, 272, 273, 274, 279, 280, 281, 285, 286, 293, 296, 255, 258, 262, 277, 278, 289, 316, 317, 318, 321, 299, 302, 303, 306, 308, 309, 311, 312, 315, 316, 332, 360, 365, 368, 370, 383 320, 331, 332, 333, 334, 335, 336, 339, 345, 351, proliferation, 61, 62, 121, 161, 222, 258, 271, 295 354, 355, 362, 369, 383, 389, 390 prophylactic, 77, 84, 301, 304 radiation cystitis, 271 prostate cancer, xv, 64, 285, 286, 287, 289, 290, 293, radiation therapy, 7, 12, 18, 20, 21, 22, 24, 25, 26, 294, 295, 296, 298, 299, 302, 303, 304, 305, 306, 27, 28, 31, 37, 38, 39, 45, 49, 51, 55, 77, 110, 307, 308, 309, 310, 311, 312, 313, 315, 316, 321, 114, 182, 196, 197, 201, 205, 211, 213, 218, 219, 322, 324, 325, 326, 327, 328, 330, 332, 333, 334, 223, 226, 230, 231, 234, 235, 236, 237, 239, 240, 335, 336, 337, 338, 339, 340, 345, 357, 360, 391 241, 243, 245, 246, 247, 248, 249, 272, 280, 285, prostate carcinoma, 307, 311, 313 286, 308, 309, 311, 312, 315, 316, 332, 334, 335, prostate specific antigen, 305, 332, 333, 336 336, 339, 355, 362, 369, 383, 389, 391 prostatectomy, 287, 288, 289, 302, 304, 305, 306, radiation treatment, 190, 191, 217, 221, 333 307, 312, 316, 317, 318, 319, 321, 322, 332, 333, radical cystectomy, 349, 351, 355, 356, 358, 359, 334, 335, 336, 337 360, 361, 362 Complimentary Contributor Copy Index 417 radical hysterectomy, 235, 259, 280, 282 122, 123, 130, 137, 153, 156, 164, 165, 197, 199, radical mastectomy, 205 208, 210, 211, 212, 213, 226, 228, 234, 236, 237, radicals, 104 240, 264, 272, 273, 316, 321, 322 radio, 35, 115, 293, 334, 336 risks, 21, 45, 49, 59, 63, 228, 238, 242, 262, 283, radioisotope, 268 286, 380 random assignment, 245 rural areas, 62, 64 randomized controlled clinical trials, 135 rash, 50, 62, 366, 369, 371, 374, 375 receptor, 16, 59, 61, 63, 65, 66, 67, 114, 123, 170, S 186, 195, 198, 203, 206, 209, 210, 219, 221, 222, sacrum, 259 229, 243, 277, 290, 291, 292 safety, 16, 66, 72, 160, 176, 183, 186, 214, 237, 245, recognition, 62, 341, 351 293, 301, 308, 310, 331, 351, 370, 379, 384, 385, recommendations, xii, 23, 34, 100, 172, 199, 200, 386, 389 205, 213, 214, 253, 254, 255, 260, 281, 307, 312, saliva, 11 333, 339, 340, 380 salivary gland, 32 reconstruction, 25, 36, 39, 97, 194, 197, 204, 228, Salmonella, 120, 122 262, 350, 353, 354 salpingo-oophorectomy, 235, 236, 237, 260 rectum, 64, 175, 176, 180, 181, 182, 183, 241, 255, sampling error, 110 256, 258, 260, 262, 267, 269, 270, 272, 273, 274, science, 252, 337, 395, 401 275, 281, 300, 301, 320 search terms, 44, 70, 135, 343 rectus abdominis, 194, 197 second degree relative, 165 regeneration, 139, 149 secretion, 291 registries, 341, 364 sedentary lifestyle, 165 regression, 97, 186, 190, 192, 279, 354 selective estrogen receptor modulator, 243 rehabilitation, 44, 48, 51, 391, 395 self-perceptions, 353 relevance, 47, 131, 173, 202, 364 seminal vesicle, 181, 288, 301, 320, 321 relief, 72, 75, 95, 99, 235 senility, 344 remission, 167, 187, 194, 229, 244, 386 sensation, 261 renal cell carcinoma, 364, 366, 372, 377, 380, 381, sensitivity, 61, 94, 95, 110, 125, 155, 226, 227, 229, 382, 383, 384, 385, 386 258, 259, 262, 318, 319, 347, 351, 370 renal dysfunction, 356 sequencing, 200, 222, 369, 380 renal medulla, 379 serology, 89, 106 repair, 121, 164, 174, 226 serum, 131, 156, 157, 287, 291, 307, 327, 333, 336, resection, 15, 35, 36, 39, 47, 48, 57, 58, 64, 71, 73, 339, 368, 371 76, 78, 81, 85, 86, 88, 90, 91, 96, 97, 99, 100, serum albumin, 368 101, 108, 110, 111, 112, 113, 116, 117, 119, 123, services, xii, 48 125, 126, 127, 128, 129, 131, 132, 133, 134, 135, showing, 25, 26, 32, 37, 97, 105, 111, 128, 130, 168, 136, 137, 138, 139, 140, 141, 142, 143, 144, 145, 194, 238, 243, 254, 264, 287, 288, 295, 298, 301, 146, 147, 148, 149, 150, 151, 158, 159, 161, 162, 321, 325, 334, 346, 348, 354, 365, 368, 369, 370, 165, 167, 170, 172, 175, 176, 180, 181, 183, 186, 379 195, 197, 202, 204, 207, 228, 242, 260, 261, 262, side effects, 24, 28, 39, 40, 62, 160, 161, 171, 187, 288, 342, 348, 353, 354, 359, 361, 365 188, 189, 191, 281, 290, 291, 300, 321, 322, 324, residual disease, 14, 57, 114, 126, 188, 348 325, 326, 327, 355, 370 response, 58, 59, 60, 61, 62, 63, 65, 88, 99, 113, 114, sigmoid colon, 360 129, 137, 138, 139, 141, 149, 155, 170, 171, 173, signaling pathway, 61, 139 176, 177, 178, 182, 185, 188, 189, 190, 191, 192, signs, 35, 94, 124, 255, 278, 325 193, 194, 195, 196, 198, 220, 221, 222, 223, 224, skin, 36, 39, 56, 191, 192, 194, 207, 212, 218, 219, 225, 243, 250, 269, 275, 276, 277, 278, 281, 308, 221, 226, 228 309, 325, 335, 339, 355, 356, 368, 369, 374, 376, skin cancer, 56 377, 378, 379, 380 smoking, 21, 22, 32, 44, 64, 70, 107, 164, 165, 167, restrictions, 270, 379, 380 211, 253, 278, 342, 344, 345, 346, 348, 357, 358 risk factors, 7, 11, 17, 22, 25, 26, 27, 31, 32, 37, 38, smoking cessation, 64, 278 39, 40, 43, 44, 70, 79, 103, 105, 106, 107, 115, social inequalities, 49 Complimentary Contributor Copy 418 Index social status, 54 304, 321, 325, 327, 329, 330, 365, 368, 371, 401, social workers, 303, 331 402 society, 279, 281, 352, 395 synchronous tumors, 35, 235 socioeconomic status, 54 syndrome, 70, 160, 165, 166, 234, 255, 366, 367, soft tissue sarcomas, 144 369, 370, 371, 373 solid tumors, 107, 277, 292 synergistic effect, 273 specialists, 53, 176, 200 speech, 35, 39, 393 sphincter, 48, 72, 176, 178, 180, 181, 183, 185, 186, T 197, 302 T cell, 59, 63 spinal accessory nerve, 36 T lymphocytes, 59, 63 spinal anesthesia, 303 tamoxifen, 206, 207, 214, 223, 234, 249, 250 spontaneous recovery, 261 target, 12, 13, 18, 59, 61, 63, 114, 191, 212, 214, squamous cell, 8, 16, 20, 23, 24, 27, 28, 29, 31, 32, 230, 265, 266, 268, 270, 301, 308, 335 34, 35, 40, 41, 42, 48, 49, 50, 70, 71, 73, 74, 77, Task Force, 253, 279 78, 79, 108, 194, 195, 196, 197, 198, 257, 278, taxane, 194, 229, 245 282 techniques, 15, 55, 71, 95, 97, 99, 113, 115, 129, squamous cell carcinoma, 8, 16, 20, 23, 24, 27, 28, 133, 134, 138, 139, 142, 146, 147, 159, 172, 180, 29, 31, 32, 34, 35, 40, 41, 42, 48, 49, 50, 70, 71, 188, 200, 211, 213, 227, 228, 251, 260, 262, 263, 73, 74, 77, 78, 79, 108, 194, 195, 196, 197, 198, 265, 274, 275, 288, 289, 293, 300, 302, 321, 350, 257, 282 365, 379 stability, 167, 308 technological advances, 16 staging systems, 154, 157, 161 technologies, 16, 164, 172, 213, 251 statistics, 28, 78, 88, 195, 213, 244, 304, 332 technology, 56, 146, 207, 211, 215, 227, 238, 252, steatorrhea, 98 364, 379, 380 stenosis, 95, 107, 272, 273, 303, 322 temperature, 70, 78, 142, 302, 303 stent, 72, 79, 129 testing, 62, 63, 66, 74, 115, 255, 279 sternocleidomastoid, 25, 36 testosterone, 290, 291, 292, 293, 307, 308, 325, 327 stimulation, 164, 234, 277 therapeutic approaches, 91 stoma, 350, 353 therapeutic effect, 227, 389 stomach, 74, 76, 77, 82, 83, 85, 91, 99, 124, 165 thiazolidinediones, 345 strictures, 71, 78 thrombocytopenia, 371, 373 suicide, 400 thrombosis, 160, 271, 365 superficial bladder cancer, 342, 348, 361 tirapazamine, 22 surgical intervention, 58 tissue, 9, 16, 35, 36, 48, 61, 71, 84, 94, 108, 114, surgical resection, 35, 47, 57, 58, 73, 76, 78, 97, 108, 121, 126, 138, 140, 150, 166, 190, 200, 206, 212, 110, 117, 131, 136, 141, 142, 146, 148, 158, 159, 221, 226, 228, 235, 239, 264, 265, 266, 269, 271, 175, 260, 342, 365 273, 288, 292, 294, 317, 327 surgical technique, 9, 128, 134, 137, 176, 180, 217, tobacco, 27, 28, 32, 40, 49, 79, 83, 155, 272, 273, 288 345, 346, 357 surgical techniques, 9, 134, 217, 288 tobacco smoking, 79 surveillance, 71, 131, 155, 156, 229, 239, 254, 279, toxic effect, 221, 222, 227, 377 285, 286, 287, 295, 303, 304, 305, 316, 317, 322, toxicity, 7, 12, 13, 14, 15, 17, 46, 50, 51, 59, 60, 62, 323, 348, 354, 358, 359, 361, 365, 382 168, 170, 171, 177, 179, 187, 188, 190, 191, 192, survival rate, 7, 27, 46, 47, 56, 57, 71, 86, 87, 94, 195, 196, 207, 211, 225, 227, 228, 238, 242, 243, 126, 154, 158, 160, 167, 169, 170, 193, 200, 205, 251, 263, 265, 267, 269, 271, 272, 273, 274, 275, 218, 235, 262, 273, 286, 287, 317, 322, 342, 349, 276, 277, 281, 287, 293, 295, 296, 298, 299, 300, 351, 355, 356 309, 310, 311, 313, 321, 322, 326, 328, 333, 335, susceptibility, 12, 105, 131, 346, 358 336, 355, 358, 374, 379 suture, 48, 181 toxicology, 274 symptomatic treatment, 287 tracheoesophageal fistula, 71, 77 symptoms, 8, 58, 64, 70, 78, 84, 88, 110, 120, 123, training, 56, 64, 390, 396 125, 157, 158, 160, 228, 234, 235, 255, 278, 291, transcatheter, 113, 383 Complimentary Contributor Copy Index 419 transcription, 62 transformation, 32, 109, 121, 123, 167, 254 V transforming growth factor, 123 vaccine, 251, 252 transitional cell carcinoma, 359 vagina, 181, 249, 256, 258, 259, 260, 261, 265, 266, translocation, 15, 62, 292, 378 267, 269, 274, 281, 283, 360 transplantation, 112, 115, 117, 134, 140, 143, 146, validation, 65, 161, 195, 307, 333, 337 147, 149, 150, 159, 160, 162 valve, 48 tuberculosis, 401 variables, 76, 106, 107, 109, 117, 176, 202, 239 tuition, 393 variations, 97, 105, 115, 307, 380 tumor, 8, 9, 11, 12, 14, 15, 16, 20, 22, 25, 26, 27, 32, vascular endothelial growth factor, 16, 60, 282, 369, 34, 35, 36, 37, 39, 40, 41, 45, 46, 48, 58, 59, 60, 383 61, 62, 63, 72, 74, 75, 76, 77, 94, 95, 96, 97, 98, vascularization, 156, 271 99, 103, 104, 105, 106, 107, 108, 109, 110, 111, vasculature, 156 112, 113, 114, 120, 123, 125, 126, 128, 131, 133, vegetables, 11, 79, 165 134, 136, 137, 138, 139, 140, 142, 143, 150, 151, vein, 25, 36, 73, 74, 139, 149, 221, 260, 365 154, 157, 159, 160, 161, 162, 165, 166, 170, 173, velocity, 328 176, 177, 180, 182, 186, 188, 190, 191, 192, 194, virus infection, 22, 83, 115 200, 202, 204, 205, 206, 207, 208, 212, 218, 219, vision, 139, 238, 288 220, 221, 222, 223, 224, 225, 226, 230, 234, 235, visualization, 165, 293 237, 239, 249, 255, 256, 257, 258, 259, 260, 262, vomiting, 57, 71, 84, 160, 244, 371 264, 267, 268, 273, 275, 280, 287, 293, 294, 295, vulva, 281 299, 303, 317, 323, 327, 346, 348, 351, 355, 358, 365, 366, 378, 382, 385 tumor cells, 58, 59, 60, 61, 62, 63, 74, 106, 108, 256, W 303 tumor depth, 39 war, 403 tumor invasion, 37, 72, 76, 77, 94 weakness, 23, 34 tumor necrosis factor, 123 weight loss, 71, 84, 110, 123, 161, 255, 373 tumor progression, 61, 131, 139, 140 welfare, 391, 395 tumours, 17, 35, 65, 67, 77, 81, 82, 85, 88, 125, 132, workforce, 64 245, 255, 280, 308, 339, 348, 359, 381, 385 working women, 253 tyrosine, 61, 62, 66, 67, 114, 143, 277, 368, 375, World Bank, 357 377, 380 World Health Organization (WHO), 8, 55 worldwide, 4, 7, 16, 17, 22, 28, 40, 44, 49, 78, 81, U 82, 83, 103, 115, 130, 146, 154, 200, 218, 252, 279, 304, 332, 342, 344 wound healing, 197 ulcerative colitis, 105, 165 wound infection, 75, 77 ultrasonography, 95, 111, 112, 153 ultrasound, 111, 116, 124, 201, 220, 223, 228, 258, 299, 302, 303, 312, 322 X uniform, 202, 205, 211 United States, 3, 69, 70, 105, 115, 118, 153, 186, xerostomia, 12, 13 189, 223, 234, 332, 353, 391, 397 urban, 343 urbanization, 343 Y ureter, 165, 259, 260, 261, 264, 266, 271 urinary bladder, 281, 345, 359 yield, 295, 317, 325 urinary bladder cancer, 345 young people, 82 urinary retention, 303, 322, 351, 352 young women, 245, 260, 278 urinary tract, 261, 271, 272, 280, 346, 350 uterine cancer, xv, 233, 234, 235, 245 uterus, 234, 235, 236, 237, 255, 256, 258, 259, 260, 266, 269, 351 Complimentary Contributor Copy Complimentary Contributor Copy

Complimentary Contributor Copy