2019, Vol. 15, Number 6, 281–342

Oncology in Clinical Practice 2019, Vol. 15, Number 6, 281–342

2019, Vol. 15, Number 6 ISSN 2450–1654

Jakub Żołnierek, Wojciech Poborski, Wojciech Rogowski, Bogumiła Arłukowicz-Czartoryska, Karolina Skalska, Małgorzata Gola, Jakub Kucharz, Piotr J Wysocki Retrospective analysis of the efficacy and safety of cabazitaxel treatment in castration-resistant prostate cancer after docetaxel failure

Katarzyna Stencel, Daria Świniuch, Rodryg Ramlau Molecular targeted therapy of patients with non-small-cell lung cancer

Wojciech P Olszewski, Andrzej Marszałek Pathomorphological assessment of tissue material after pre-operative systemic therapy (neoadjuvant therapy) in patients with breast cancer

Jakub Żołnierek Enzalutamide in systemic treatment of prostate cancer

Mateusz Spałek, Anna M Czarnecka The role of radiotherapy in melanoma

Marta Frąckowiak, Tomasz Lewandowski, Paweł Stelmasiak Molecular subtypes of colorectal cancer as a potential prognostic and predictive factor in the selection of the optimal treatment strategy

Kinga Krawiec, Sylwia Dębska-Szmich, Urszula Czernek, Rafał Czyżykowski, Piotr Potemski Short bowel syndrome and severe skin toxicity as a complication of FOLFOX chemotherapy with panitumumab in a patient with colorectal cancer — a case report

Wojciech Michalski, Grażyna M Poniatowska, Joanna G Jońska-Gmyrek, Karol E Nietupski, Anna Z Cencelewicz, Andrzej Mróz, Witold Gerke, Agnieszka Chreptowicz, Tomasz Demkow, Paweł J Wiechno hCG-secreting malignancies — diagnostic pitfalls

Aleksandra Piórek, Dariusz M Kowalski, Adam Płużański, Olga Stanowska, Maciej Krzakowski Adenoid cystic carcinoma of the lung — a case report

Magdalena Miedzińska EOTTD Meeting in Berlin, July 5–6, 2019

ONCOLOGY IN CLINICAL PRACTICE Official Journal of the Polish Society of Clinical Oncology https://journals.viamedica.pl/oncology_in_clinical_practice

Editor-in-Chief dr hab. med. Maria Litwiniuk prof. dr hab. med. Maciej Krzakowski dr med. Aleksandra Łacko prof. Ruggero De Maria (Rome, Italy) Deputy Editors dr Mario Mandala (Bergamo, Italy) prof. dr hab. med. Andrzej Kawecki dr hab. med. Radosław Mądry prof. dr hab. med. Piotr Potemski dr med. Janusz Meder prof. dr hab. med. Piotr Rutkowski dr hab. med. Sergiusz Nawrocki prof. dr hab. med. Krzysztof Składowski prof. dr hab. med. Włodzimierz Olszewski prof. dr hab. med. Piotr Wysocki prof. dr hab. med. Maria Podolak-Dawidziak dr hab. med. Barbara Radecka Scientific Board prof. dr hab. med. Tadeusz Robak dr Edita Baltruskeviciene (Vilnius, Lithuania) prof. dr hab. med. Kazimierz Roszkowski prof. Tomasz M. Beer (Portland, USA) prof. dr hab. med. Piotr Rutkowski dr hab. med. Ewa Sierko prof. Bartosz Chmielowski (Los Angeles, USA) dr Silvia Stacchiotti (Milan, Italy) dr med. Joanna Didkowska dr Ryszard Szydło (London, UK) dr hab. med. Renata Duchnowska prof. dr hab. med. Jerzy Walecki dr Rick Haas (Leiden, The Netherlands) prof. dr hab. med. Jan Walewski dr med. Beata Jagielska prof. dr hab. med. Krzysztof Warzocha dr med. Jerzy Jarosz prof. dr hab. med. Marek Wojtukiewicz prof. dr hab. med. Jacek Jassem dr Agnieszka Wozniak (Leuven, Belgium) prof. dr hab. med. Arkadiusz Jeziorski prof. Christoph Zielinski (Vienna, Austria) prof. dr hab. med. Jan Kornafel prof. dr hab. med. Jan Kulpa Managing Editor prof. dr hab. med. Radzisław Kordek Izabela Siemaszko

Opinions presented in the articles do not necessarily represent the opinions of the Editors

Oncology in Clinical Practice (ISSN 2450–1654) is published six times a year by VM Media sp. z o.o. VM Group sp.k. ul. Świętokrzyska 73, 80–180 Gdańsk, Poland Phone: (+48 58) 320 94 94, fax: (+48 58) 320 94 60 e-mail: [email protected], http://www.viamedica.pl, wap.viamedica.pl

Editorial Address Klinika Nowotworów Płuca i Klatki Piersiowej Narodowy Instytut Onkologii im. Marii Skłodowskiej-Curie — Państwowy Instytut Badawczy ul. Roentgena 5, 02–781 Warszawa, Poland Phone: (+48 22) 546 21 69 e-mail: [email protected]

Advertising For details on media opportunities within this journal please contact the advertising sales department, ul. Świętokrzyska 73, 80–180 Gdańsk, Poland, phone: (+48 58) 326 78 20; e-mail: [email protected]

The Editors accept no responsibility for the advertisement contents.

All rights reserved, including translation into foreign languages. No part of this periodical, either text or illustration, may be used in any form whatsoever. It is particularly forbidden for any part of this material to be copied or translated into a mechanical or electronic language and also to be recorded in whatever form, stored in any kind of retrieval system or transmitted, whether in an electronic or mechanical form or with the aid of photocopying, microfilm, recording, scanning or in any other form, without the prior written permission of the publisher. The rights of the publisher are protected by national copyright laws and by international conventions, and their violation will be punishable by penal sanctions. Legal note: http://czasopisma.viamedica.pl/owpk/about/legalNote

Indexed in Index Copernicus (ICV 2018 = 84.45), Ulrich's Periodicals Directory and CAS. According to the statement of the Polish Ministry of Science and Higher Education publication in the journal has been awarded with 20 points. Editorial policies and author guidelines are published on journal website: http://journals.viamedica.pl/oncology_in_clinical_practice

The journal “Oncology in Clinical Practice” is financed under Contract No. 790/P-DUNdem/2019 by the funds of the Minister of Science and Higher Education for the science promotion activities.

ONCOLOGY IN CLINICAL PRACTICE Official Journal of the Polish Society of Clinical Oncology https://journals.viamedica.pl/oncology_in_clinical_practice 2019, Vol. 15, Number 6

ORIGINAL ARTICLE Retrospective analysis of the efficacy and safety of cabazitaxel treatment in castration-resistant prostate cancer after docetaxel failure Jakub Żołnierek, Wojciech Poborski, Wojciech Rogowski, Bogumiła Arłukowicz-Czartoryska, Karolina Skalska, Małgorzata Gola, Jakub Kucharz, Piotr J Wysocki ...... 281

REVIEW ARTICLES Molecular targeted therapy of patients with non-small-cell lung cancer Katarzyna Stencel, Daria Świniuch, Rodryg Ramlau...... 289

Pathomorphological assessment of tissue material after pre-operative systemic therapy (neoadjuvant therapy) in patients with breast cancer Wojciech P Olszewski, Andrzej Marszałek...... 297

Enzalutamide in systemic treatment of prostate cancer Jakub Żołnierek...... 303

The role of radiotherapy in melanoma Mateusz Spałek, Anna M Czarnecka...... 310

Molecular subtypes of colorectal cancer as a potential prognostic and predictive factor in the selection of the optimal treatment strategy Marta Frąckowiak, Tomasz Lewandowski, Paweł Stelmasiak...... 320

CASE REPORTS Short bowel syndrome and severe skin toxicity as a complication of FOLFOX chemotherapy with panitumumab in a patient with colorectal cancer — a case report Kinga Krawiec, Sylwia Dębska-Szmich, Urszula Czernek, Rafał Czyżykowski, Piotr Potemski...... 326 hCG-secreting malignancies — diagnostic pitfalls Wojciech Michalski, Grażyna M Poniatowska, Joanna G Jońska-Gmyrek, Karol E Nietupski, Anna Z Cencelewicz, Andrzej Mróz, Witold Gerke, Agnieszka Chreptowicz, Tomasz Demkow, Paweł J Wiechno...... 331

Adenoid cystic carcinoma of the lung — a case report Aleksandra Piórek, Dariusz M Kowalski, Adam Płużański, Olga Stanowska, Maciej Krzakowski...... 336 report EOTTD Meeting in Berlin, July 5–6, 2019 Magdalena Miedzińska...... 339

REVIEW ARTICLE

Piotr Rutkowski, Maciej Krzakowski

The Maria Skłodowska-Curie National Research Institute of Oncology, Warsaw, Poland

National Cancer Strategy

National Cancer Strategy (NCS) is a very important and long-awaited document, which will be the keystone for activities in the field of oncology in Poland for the next 10 years. It was developed in record time in accordance with the Act of 26 May 2019 on the initiative of the President of the Republic of Poland. It was prepared by the Working Group of the Ministry of Health for National Cancer Strategy in cooperation with employees of the Ministry of Health and on 30 November 2019 it was forwarded to the Council of Ministers. The main tasks of the National Cancer Strategy, in accordance with the Act on the National Cancer Strategy, include: —— reducing the incidence of cancer through health education and promotion, including shaping health awareness and promoting a healthy lifestyle; —— improving cancer prevention, early detection, diagnosis, and treatment; —— development of the healthcare system in the field of oncology by concentrating activities around the patients and their needs, with particular emphasis on improving the quality of life of patients and their families; —— ensuring equal access to high-quality oncology healthcare services provided in accordance with current medical knowledge; —— development and implementation of organisational changes that will provide patients with equal access to coordinated and comprehensive healthcare in the field of oncology; —— development of training and education activities as well as training of medical staff in the field of oncology; —— development of scientific research aimed at improving and increasing the effectiveness and innovation of cancer treatment. These tasks are also in line with the published report of the National Audit Office on the healthcare system in Poland and the European guidelines for National Cancer Control Programme published by the European Part- nership for Action Against Cancer. To a large extent, the newly created National Research Institute of Oncology will be responsible for implementing the tasks of the NCS. The principal intention of the NCS is to reduce mortality in the most frequent cancers, where population interventions could bring about effects in a relatively short (10-year) time period. This strategy is a continuation of the already initiated reform of Polish oncology. The activities are to cover five areas that are key to achieving synergies (where the activities are the most important from the population and public health perspectives, as well as patient-oriented activities postulated for many years by patient advocacy groups, and in which there were the biggest shortcomings in Polish healthcare) and improving epidemiological indicators in Poland. The implementation of tasks is planned for 2020–2030, while the legislator sanctioned the need to create annual schedules for implementing the strategy.

Translation: dr n. med. Dariusz Stencel In view of the needs defined in this way, the NCS proposes to conduct activities in five areas: 1. Investments in human resources — improving the human resources situation and the quality of education in the field of oncology. The activities are aimed at increasing the number of oncologists and related specialists and including cancer prevention education in the undergraduate education program of physicians and nurses. It is also planned to organise courses on cancer prevention during the education of physicians of other specialties and nurses. 2. Investments in education, primary prevention, and lifestyle — limiting the incidence of cancer by reducing the risk through primary cancer prevention. The activities are aimed at implementing the recommendations of the European Code Against Cancer, with particular emphasis on tobacco control, as well as the involvement of doctors in primary prevention, including primary care and occupational medicine physicians. The novelty is the reimbursement of vaccination against human papillomavirus (HPV). 3. Investments in the patient, secondary prevention — improving secondary prevention effectiveness. The indicated actions increase the effectiveness of screening for colorectal, breast, cervical, and lung cancer. It is proposed that primary care and occupational medicine physicians be included in secondary prevention. 4. Investments in science and innovation — increasing the potential of scientific research and innovative projects in Po- land to make the most effective diagnostic and therapeutic solutions available for patients. The goal of the indicated actions is to increase the participation of oncological patients in clinical trials, to develop non-commercial clinical trials in the field of oncology, and to expand data analysis in medical registries. In addition, by 2030 a minimum of 90% of innovative oncological therapies reimbursed in European Union countries will also be reimbursed in Poland. 5. Investments in the oncological care system — improving the organisation of the oncological care system by providing patients with access to the highest quality diagnostic and therapeutic services as well as comprehensive care throughout the entire “patient path”. The proposed actions are aimed at alignment of the level of oncological care at the regional level, regardless of the patient’s place of residence. Within this area, it is proposed to introduce the National Oncological Network (NON) — competence centres for the treatment of lung cancer, colorectal cancer, gynaecological cancers, urological cancers, childhood cancers, and rare cancers, as well as to introduce diagnostic and therapeutic standards. The development of comprehensive oncological care is to include the development of rehabilitation, psychological, palliative, and hospice care. The important activity will be comprehensive data analysis and availability of information for patients and physicians on one integrated portal. In addition, investments in the oncological care system include activities to improve the quality of life of cancer patients during and after treatment. ORIGINAL ARTICLE

Jakub Żołnierek1, Wojciech Poborski2, Wojciech Rogowski3, Bogumiła Arłukowicz-Czartoryska4, Karolina Skalska5, Małgorzata Gola6, Jakub Kucharz7, Piotr J Wysocki8 1Cancer Centre — Maria Skłodowska-Curie Memorial, Warsaw, Poland 2Specialist Medical Practice, Wojciech Poborski, MD, PhD, Oncology and Internal Diseases, Katowice, Poland 3Individual Specialist Medical Practice Wojciech Rogowski, Oncologist, Olsztyn, Poland 4Białystok Oncology Centre — Maria Skłodowska-Curie Memorial, Poland 5Świętokrzyskie Centre of Oncology in Kielce, Poland 6Independent Public Health Care Institution, Voivodeship Specialist Hospital No. 4 in Bytom, Poland 7Clinic of Urinary System Cancer; Cancer Centre — Maria Skłodowska-Curie Memorial, Warsaw, Poland 8Department of Oncology, Jagiellonian University — Medical College, Cracow, Poland

Retrospective analysis of the efficacy and safety of cabazitaxel treatment in castration-resistant prostate cancer after docetaxel failure

Address for correspondence: ABSTRACT Prof. dr hab. n. med. Piotr J. Wysocki Introduction. Cabazitaxel has been approved by the FDA and EMEA for the treatment of metastatic castra- Oddział Kliniczny Onkologii tion-resistant prostate cancer (mCRPC) after failure of docetaxel-based chemotherapy. Between June 2011 and ul. Śniadeckich 10, 31–531 Kraków November 2013 cabazitaxel was reimbursed for Polish mCRPC patients as a non-standard chemotherapy. The Phone: 12 424 89 12 study objective was a retrospective analysis of the efficacy and safety data of mCRPC patients treated with e-mail: [email protected] cabazitaxel in this period.

Oncology in Clinical Practice Material and methods. Collection of retrospective data on 48 consecutive mCRPC patients treated with cabazitaxel 2019, Vol. 15, No. 6, 281–288 after docetaxel failure. Data on baseline characteristics, cancer history, and the efficacy and safety of cabazitaxel DOI: 10.5603/OCP.2019.0033 treatment were collected. Progression-free survival (PFS) (radiological/clinical/biochemical) and overall survival Copyright © 2019 Via Medica (OS) were estimated by the Kaplan-Meier method. Objective response rate and clinical benefit were also assessed. ISSN 2450–1654 Results. Forty-eight patients were included. Median PFS was 4.2 (95% CI 3.4–5.1) months, and median OS was 15.1 (95% CI 12.7–17.4) months. OS since docetaxel initiation in patients treated with cabazitaxel as second-line chemotherapy (n = 47) was 28.7 (95% CI 25,3–32,1) months. OS rates at 1, 2, and 3 years after first cabazitaxel cycle were 65%, 25%, and 15%, respectively. In total, 289 cycles of cabazitaxel were administered (mean six per patient). There were 41 patients evaluable for biochemical response, 19/41 (46%) of whom had a PSA decrease of at least 50% from baseline, including 3/41 who had an initial PSA flare followed by a decrease of at least 50% from baseline. Adverse events comprised predominantly haematological (26 patients) and gastrointestinal (14 patients) toxicities. Ten SAEs were reported, including one death due to acute renal failure. Conclusions. Treatment of mCRPC patients with cabazitaxel after docetaxel failure is an important therapeutic option with acceptable toxicity with respect to clinical stabilisation and possibly increased survival. Key words: castration-resistant prostate cancer, cabazitaxel, prostate-specific antigen, chemotherapy, cytotoxic agent, progression-free survival, overall survival, time to treatment failure

Oncol Clin Pract 2019; 15, 6: 281–288

281 Oncology in clinical practice 2019, Vol. 15, No. 6

Introduction a significant reduction in the relative risk of death by 30% (HR 0.70; 95% CI, 0.59–0.83). Median pro- Prostate cancer is the most commonly diagnosed gression-free survival (PFS), which was a composite cancer in men; it is the third most common cause of endpoint defined as time from randomisation to dis- cancer deaths in men after lung cancer and colorectal ease progression (biochemical, radiological, or clinical cancer in Europe [1]. progression) or death, was 2.8 months in the cabazitaxel Treatment of advanced/metastatic prostate cancer group vs. 1.4 months in the mitoxantrone group (HR is palliative, and the main form of systemic therapy is 0.74; 95% CI, 0.64–0.86). Biochemical and radiological endocrine therapy based on androgen ablation (surgical responses were also significantly more frequent with or pharmacological castration). Endocrine treatment in cabazitaxel compared to mitoxantrone. The updated advanced symptomatic prostate cancer patients allows TROPIC study data confirmed continuous improve- achievement of rapid clinical response (decrease in the ment of OS: the two-year survival rate was 15.9% in severity of bone pain, tumour burden reduction), and a bio- the cabazitaxel arm and 8.2% in the mitoxantrone arm chemical response (decreased level of prostate-specific [8]. Based on the TROPIC study, cabazitaxel has been antigen (PSA). However, at some point in time (median approved by the FDA and EMEA for the treatment 18–24 months), cancer becomes resistant to castration in all of mCRPC patients after failure of docetaxel-based patients (castration-resistant prostate cancer, CRPC) [2]. chemotherapy. It was subsequently shown in a phase Until 2010 chemotherapy with docetaxel II prospective, randomised trial that cabazitaxel retains (75 mg/m2 every 21 days IV) in combination with pred- its activity in patients who have progressed on novel nisone was the only therapy significantly improving androgen receptor-targeting agents [9]. overall survival (OS) in metastatic CRPC (mCRPC) In the period from June 2011 to November patients. Two prospective randomised phase III stud- 2013 cabazitaxel was reimbursed for Polish mCRPC ies (TAX327 and SWOG 9916), which enrolled ap- patients as a non-standard chemotherapy. The aim of proximately 2000 men [3–5], demonstrated a significant this multicentre, retrospective, observational study was superiority of docetaxel compared to mitoxantrone to analyse data on the efficacy and safety of treatment in mCRPC patients. Docetaxel in combination with with cabazitaxel in the population of Polish patients with prednisone given every 21 days reduced the relative mCRPC after docetaxel failure. risk of death by 24% compared with the combination of mitoxantrone plus prednisone (HR 0.76 [95% CI, 0.62–0.92]), while reducing the severity of pain and Material and methods positively affecting the patients’ quality of life. Cabazitaxel is a novel generation taxane, which was Data on the efficacy and safety of cabazitaxel was designed de novo to overcome resistance to docetaxel. collected for patients who received at least one course It has been shown that cabazitaxel is comparable to of chemotherapy (with cabazitaxel followed docetaxel) as docetaxel in terms of efficacy in tumour cells sensitive part of a non-standard chemotherapy reimbursement pro- to docetaxel, but in docetaxel-resistant cell lines and cedure in the period from 1 June 2011 to 31 August 2013. tumours it demonstrates 10-times higher anticancer Statistical analyses were descriptive [10, 11]. The pri- activity [6]. It was further shown that cabazitaxel, con- mary end-point was progression-free survival (defined trary to paclitaxel and docetaxel, crosses the blood-brain as time to PSA and/or radiological progression and/or barrier in vivo, and therefore may exhibit anticancer clinical progression and/or death). Secondary end-points activity in patients with brain or lepto-meningeal included PSA response rate (defined by a PSA decrease metastases. The efficacy of cabazitaxel in the treat- of at least 50% from baseline after three cycles), num- ment of mCRPC was demonstrated in a phase III ber of patients with PSA flare during the first 12 weeks study, TROPIC, which enrolled 755 men who had of therapy, clinical benefit as per physician judgment progressed during or after treatment with docetaxel. (based on performance status, pain, and analgesic con- Patients were randomly assigned in a 1:1 ratio to the sumption), OS, safety (incidence of adverse events and experimental arm (cabazitaxel 25 mg/m2 IV every three serious adverse events), and usage of G-CSF. weeks + prednisone 10 mg/day) or the control arm (mitoxantrone 12 mg/m2 IV every three weeks + pred- Sample size nisone 10 mg/day). In both arms, up to 10 courses of chemotherapy could be administered [7]. The study It was planned to collect data on approximately met its primary endpoint, achieving a significant im- 50 patients. This number was based on the estimated provement in overall survival in patients treated with number of patients treated with cabazitaxel in the pe- cabazitaxel compared to mitoxantrone (15.1 months riod 2011–2013 within the framework of non-standard vs. 12.7 months, respectively), which translated into chemotherapy reimbursement procedure in Poland.

282 Jakub Żołnierek et al., Cabazitaxel treatment in mCRPC

The study was approved by the Ethics Committee at Table 1. Disease history of patients included in the study the Cancer Centre — Maria Skłodowska-Curie Memo- rial in Warsaw. Number of patients (n = 48) Data collected Histopathological diagnosis Adenocarcinoma 45 The data were collected on the basis of a review N/A 3 of medical source records of mCRPC patients treated Histological grade in the Gleason scale (2–10) with cabazitaxel. The information covering at least < 7 13 12 months from the start of cabazitaxel treatment was 7 11 analysed for each patient included in the study. The 8 11 study design reflected the management of these patients 9 9 in a real-life setting. Collected retrospective data were N/A 4 related to the primary histopathological data on pros- Clinical stage at diagnosis tate cancer, information about prior curative treatment T2, M0 9 and palliative care (surgery, radiotherapy, hormone T3–T4, M0 6 therapy, chemotherapy), changes in the PSA levels in M1 16 the course of the disease, and the use of cabazitaxel in N/A 17 patients with castration-refractory prostate cancer — see Prior treatment with curative intent details below. Radical prostatectomy 9 The following data were collected at initiation of External beam radiation therapy 20 cabazitaxel therapy: age, the presence of metastases, Brachytherapy 1 their location (bone, lymph nodes, visceral), and disease burden (massive spread, defined as the presence of visceral metastases and/or ≥ 4 bone metastases, diagnosed with primarily metastatic disease with a high including at least one outside the pelvis and the spine); Gleason score (≥ 8). progression type (biochemical/clinical/radiological); In most cases, first-line endocrine therapy was phar- the presence of measurable disease (according to the macological castration — only one patient underwent standard criteria used at a given site or as defined by orchiectomy (2%). Half of the evaluated patients under- RECIST); the presence of symptoms; performance went secondary hormonal manipulations as part (mainly status (according to ECOG); changes in PSA value; with the use of maximum androgen blockade (flutamide, and other laboratory parameters. In the case of pain, bicalutamide); seven men (15% of the group) were information on the analgesics used was additionally col- treated with abiraterone acetate. In 47 of 48 patients lected (trade name of the drug, number of applications first-line chemotherapy was based on docetaxel; one paper day, and/or daily dose). tient received mitoxantrone as first-line chemotherapy. Moreover, for the period of cabazitaxel treatment, Less than half of the analysed patients (17 of 48; 35%) the following data were also collected: all adverse events received second-line chemotherapy (mostly docetaxel (AEs) and serious adverse events (SAEs), grade 3–4 ad- or mitoxantrone) before cabazitaxel initiation. verse events by WHO regarding hormone therapy and Treatment with cabazitaxel was preceded by a re-as- chemotherapy with cabazitaxel during follow-up; date sessment of disease severity, the number and location of last visit during follow-up; disease progression: yes of metastases, performance status, disease progression or no; type and date of progression; date of the last diagnosis method, PSA levels, and the use of analge- dose of the drug; and the patient’s condition during the sics. Cabazitaxel initiation was associated with clinical last visit in the follow-up period: survival, death (date), progression in 35% and radiological progression in 29%. cause of death. A significant percentage of patients (25 out of 48-men) met the criteria for diagnosis of massively advanced metastatic disease (the category “Many metastases”). Results ECOG performance status score was mainly 2 or higher (n = 30). Detailed data are provided in Table 2. In to- From the seven Polish cancer centres participating in tal, the study group reported 289 cycles of cabazitaxel the study, 48 patients with metastatic castration-resistant treatment (an average of six cycles of chemotherapy per prostate cancer treated with cabazitaxel after failure of patient), and 16 out of 48 men (33%) included in the docetaxel treatment were identified. analysis received the planned number of chemotherapy Disease history of patients enrolled in the registry cycles. In 230 cycles (80%) the typical dose of cabazi- is provided in Table 1. The majority of patients were taxel (25 mg/m2) was used, in 40 cycles (14%) the dose

283 Oncology in clinical practice 2019, Vol. 15, No. 6 was reduced to 20 mg/m2, and there was even a greater (worsening of performance status and an increase in pain reduction of cabazitaxel dose in a total of 19 cycles. The severity) — 6/48 (13%). Serious skeletal-related events dose reduction in eight patients was associated with (SRE) were reported in seven patients (15%). adverse events (a total of 19 cycles of chemotherapy, PSA response was evaluable in 41 patients as per representing 7% of the administered courses). Chemo- prostate cancer working group recommendations (i.e. therapy was delayed in 46 cycles of treatment, of which at least three cycles of cabazitaxel). Of these 41 patients, only 20 (7% of all) were delayed due to toxicity. Delays 19 (46%) had a PSA decrease of at least 50%, including for any other reason, including unavailability of the three who had an initial PSA flare followed by PSA drop drug, occurred in 26/289 (9%) cycles. Prednisone was below 50% of baseline. Median PFS was 4.2 months administered in 253/289 (88%) cycles. Table 3 shows (95% CI: 3.4–5.1), and median OS was 12.8 months the parameters related to cabazitaxel dosage. The (95% CI: 9.7–15.9). Detailed data on the primary end- most commonly used concomitant medications were point (progression-free survival) and OS are presented bisphosphonates (34/48) and denosumab (2/48) — 85% in Table 5. One-year survival rate in the study group was of patients had bone metastases. The G-CSF support 65%, and two-year and three-year survival rates were was used in 19/48 patients. Opioid analgesics were ad- 25% and 15%, respectively. A graphical representation ministered daily in 9/48 (19%), and non-opioid drugs in of PFS and OS analysis using the Kaplan-Meier method 6/48 (13%) of patients. is presented in Figure 1 and 2. The reasons for discontinuing cabazitaxel therapy are presented in Table 4. In most cases, chemotherapy was discontinued after administration of a pre-planned num- Table 3. Course of cabazitaxel therapy ber of cycles, or due to biochemical progression — 33% and 35% of cases, respectively. The next most common Number of cause of treatment cessation was performance status patients/number deterioration (21%). In two cases, the treatment was of cycles not completed due to the patient’s death. Finally, cancer Number of cycles administered 289 progression was seen in 41 of 48 (85%) men included in Mean (± SD); range 6.0 (3.4); 1–18 the analysis. The most common forms of progression were Median 5.0 biochemical progression (increase in PSA levels above the 1–6 31 defined value) — 17/48 (35%) and clinical progression 7–10 14 > 10 3 Number of patients who received the 25 Table 2. Patient characteristics at initiation of cabazitaxel planned number of cycles (4–13 cycles) therapy N patients (%) with dose reduction 8/48 (16.7%) n = 48 N cycles/total number of cycles with 19/289 (7%) a reduced dose Age, years — median (range) 65 (45–80) N cycles delayed/total number of cycles (%) 46/289 (16%) Metastases — location Due to toxicity 20 (7%) Bones 41 For other reasons (usually 26 (9%) Lymph nodes 15 unavailability of the drug) Visceral organs 7 Prednisone (number of cycles) 253/289 (88%) Numerous metastases 25 Missing data 4 Progression Table 4. Reasons for termination of cabazitaxel chemo- Biochemical 44 therapy1 Clinical 17 Number of Radiological 14 patients (n = 48) — in scintigraphy 12 Treatment completion, planned number 16 Opioid analgesics daily 9 of chemotherapy courses Non-opioid analgesics daily 6 Biochemical progression 17 ECOG Clinical progression 6 0–1 14 Radiological progression 1 2 24 Worsening of performance status 10 > 2 6 Toxicity (WHO grade 3–4 adverse events) 5 N/A 5 Other (e.g. death) 3 (2) PSA [ng/ml] (mean, median) 326; 186 1There could be more than one cause in a single patient

284 Jakub Żołnierek et al., Cabazitaxel treatment in mCRPC

Table 5. Cabazitaxel therapy efficacy assessment — progression-free survival (since cabazitaxel initiation until progression for whatever reason) and overall survival

Progression-free survival (PFS) and overall survival (OS) in months for cabazitaxel-treated patients PFS Number of patients Median 95% Cl Confirmed 44 4.2 3.4–5.1 Generalised1 48 4.1 3.3–5.1 OS Number of patients Median 95% Cl With known date 14 12.8 9.7–15.9 Confirmed2 19 10.5 7.9–13.1 Generalised1 48 15.1 12.7–17.4

1In both generalisations — the date of the last contact with the patient was used 2In case of the lack of the death date — the date of the last contact with the patient was used

Kaplan-Meier progression-free survival for 48 patients treated with cabazitaxel

1.0 Complete observations (progression) 0.9 Cut-off observations 0.8 0.7 0.6 0.5 0.4

Probability of survival 0.3 0.2 0.1 0.0 0 2.5 5 7.5 10 12.5 15 17.5 20 22.5 25 Months

Figure 1. Kaplan-Meier analysis of progression-free survival (PFS) in cabazitaxel-treated patients

Kaplan-Meier analysis of overall survival 48 patients treated with cabazitaxel

1.0 Complete observations (death) Cut-off observations 0.9 al

viv 0.8 sur of

0.7

0.6 Probability

0.5

0.4 0 5 10 15 20 25 30 35 40 45 50 55

Months

Figure 2. Kaplan-Meier analysis of overall survival in patients treated with cabazitaxel (n = 48)

285 Oncology in clinical practice 2019, Vol. 15, No. 6

1.0 Mean: 30.80 (95% CI: 26.37–32.23) 0.9

0.8 al

iv 0.7

surv 0.6 f o 0.5 ility

ab 0.4 ob

Pr 0.3

0.2 Median: 28.70 (95% CI: 25.30–32.10) 0.1

0.0 0 5 10 15 20 25 30 35 40 45 50 55 60 65 70 Months

Figure 3. Kaplan-Meier analysis of overall survival since docetaxel initiation in patients treated with cabazitaxel as second-line chemotherapy (n = 47)

The proportion of patients with a specic PSA value Percentage changes in PSA (relative to values in cycle 1) [ng/ml] in subsequent cycles of cabazitaxel use in 48 patients 700% 1400 Median 10th percentile 90th percentile 600% Percentage of patients with specific PSA value 1200

500% 1000

400% 800

300% 600

200% 400

100% 200

0% 0 1 2 3 4 5 6 7 8 9 Cycles

Figure 4. Percentage changes in PSA levels from baseline in the consecutive cycles of cabazitaxel therapy

The overall survival estimate since docetaxel discontinuation of abiraterone. No data on response to initiation is presented in Figure 3. The OS median was abiraterone was collected. 28.70 (95% CI: 25.30–32.10) months. Serum PSA level variations observed during cabazi- In order to reliably assess OS in cabazitaxel-treated taxel treatment, their range, and dynamics are presented patients, data on next-line systemic therapy was collected in Figure 4. (after the end of cabazitaxel therapy). Forty-seven pa- Clinical benefit from cabazitaxel, defined as objective tients (the date of docetaxel initiation in one patient was responses or disease stabilisation, was verified after each unavailable) were administered a treatment sequence of cycle of chemotherapy (Table 6). Furthermore, clinical docetaxel-cabazitaxel after failure of endocrine therapy. response (improvement in performance status and/or de- Nine patients (19%) in this study population received crease in the severity of pain and/or reduction of the need abiraterone acetate after progression on cabazitaxel. for analgesics) was seen after administration of 53 out of One of them received cabazitaxel rechallenge (six cycles 289 cycles of cabazitaxel treatment. Four of nine patients until biochemical progression; previously 10 cycles) after administered with narcotic analgesics and 4/6 patients

286 Jakub Żołnierek et al., Cabazitaxel treatment in mCRPC

Table 6. Clinical effects of cabazitaxel therapy Table 7. Safety assessment of cabazitaxel therapy — adverse events reported Number of cycles Adverse event Number 3˚ 4˚ (n = 289) of cases (n = 12) (n = 5) (n = 50)* Clinical benefit during cabazitaxel therapy — evaluation after each cycle Haematological Improvement in ECOG performance status1 21 Anaemia 10 3 – Neutropenia 8 2 2 Pain severity reduction 24 Thrombocytopenia 4 1 – Reduction of the need for analgesics2 53 Leucopaenia 2 1 1 Stable condition 174 (60%) Febrile neutropaenia 2 1 – No response 22 (7%) Gastrointestinal tract N/A 59 (20%) Diarrhoea 10 – – 1ECOG performance status improved in 4 patients with ECOG 3, in 5 patients Vomiting 2 – – with ECOG 2, and in 1 patient with ECOG 1 prior to cabazitaxel Abdominal pain 2 – – 24/9 and 4/6 patients, respectively, had their need for narcotic and non-narcotic daily analgesics at cabazitaxel initiation reduced Enteritis 1 1 – Urinary tract system taking non-narcotic analgesics at initiation of cabazitaxel Acute renal failure 1 – 1 therapy responded with reduction of the need for analgesics. Urinary incontinence 1 1 – In the analysis of investigator-reported adverse events Urinary tract infection 1 – – (AE) associated with cabazitaxel, there was a prevalence Cardiovascular system of haematological complications with anaemia (10 cases Myocardial infarction 1 – 1 [20.8%], including three cases [6.3%] in grade 3 of severity Unstable coronary 1 1 – according to the WHO), neutropaenia (nine cases, repre- artery disease senting 18.8% of the group, including two cases [4.2%] in Other grade 3, and two cases in grade 4), and thrombocytopaenia Paresthesia 2 1 – (10.4%), mainly in grade 1 and 2. Gastrointestinal adverse Dehydration 1 – – events (nine cases of diarrhoea [18.8%], and two cases Secondary neutropaenia 1 – – [4.2%] each of vomiting and abdominal pain) were the second most common AEs; however, their severity did not *44 adverse events occurred during cabazitaxel therapy exceed WHO grade 2. Symptoms of polyneuropathy (only sensory) was observed only in two patients (4.2%), and their severity did not exceed grade 2. The following cor- On the basis of the performed analyses, it was rective actions were taken: extending the interval between shown that in the vast majority of patients, cabazitaxel cycles (14 patients, 29 cycles), dose reduction (8 patients, was used in accordance with the Summary of Product 19 cycles), discontinuation of treatment (8 patients). Characteristics (in combination with prednisone), and Detailed data on adverse events are presented in Table 7. more than half of the patients received treatment with Ten serious adverse events (SAEs) related to the planned intensity. Dose reductions or delays in the cabazitaxel were reported, including one fatal event administration of the planned courses of chemotherapy due to acute renal failure eight months from the start were caused by both toxicity and problems with drug of cabazitaxel therapy (nine cycles). The others were: availability. The vast majority of patients did not re- anaemia (three times in the same patient), febrile neu- ceive primary prevention of febrile neutropaenia. In tropaenia (1), febrile neutropaenia with diarrhoea and the period covered by the retrospective analysis, the haematuria (1), secondary neutropaenia (1), diarrhoea majority of patients experienced disease progression. with abdominal pain and vomiting (1), myocardial in- Median overall survival and progression-free survival in farction (1), unstable coronary disease (1). the analysed population were characterised by similar values as in the pivotal study [12]. The use of cabazitaxel was associated with the oc- Discussion currence of adverse events of all grades; however, their frequency was comparable to the pivotal study, and the Data from seven national cancer centres, derived incidence of serious adverse events was relatively low from 48 patients with mCRPC receiving cabazitaxel, compared to the pivotal study. allowed a retrospective evaluation of the efficacy and Cabazitaxel, in addition to docetaxel, is one of two safety of this drug in routine clinical practice. cytotoxic drugs that significantly improve the prognosis in

287 Oncology in clinical practice 2019, Vol. 15, No. 6 patients with castration-resistant prostate cancer. This drug, JZ — scientific advisor, presenter, speaker (Jans- in addition to two hormonal drugs (abiraterone acetate and sen); travel grants (Janssen). enzalutamide), is a systemic treatment option for patients with mCRPC after failure of docetaxel therapy. It is an especially active drug in patients who have progressed during or Ethics after docetaxel [12, 13], and it retains its activity in patients progressing after novel AR-targeted agents [9]. Unlike The work described in this article has been carried cabazitaxel, both abiraterone acetate and enzalutamide can out in accordance with The Code of Ethics of the World be used, in accordance with their approved indications, in Medical Association (Declaration of Helsinki) for mCRPC patients who still do not require docetaxel. Thus, experiments involving humans; EU Directive 2010/63/ the value of cabazitaxel, as a drug with proven therapeutic /EU for animal experiments; Uniform Requirements for effect in patients after failure of docetaxel-based chemo- manuscripts submitted to Biomedical journals. therapy, who have already failed new-generation endocrine therapy. Is estimaeted important data were recently presented at the Congress of the American Society of Clinical References Oncology — ASCO 2016. A phase III study comparing two doses of cabazitaxel (25 mg/m2 and 20 mg/m2) in the 1. Ferlay J, Autier P, Boniol M, et al. Estimates of the cancer incidence and mortality in Europe in 2006. Ann Oncol. 2007; 18(3): 581–592, doi: treatment of mCRPC patients after failure of docetaxel 10.1093/annonc/mdl498, indexed in Pubmed: 17287242. therapy demonstrated comparable efficacy of the two doses, 2. de Wit R. Chemotherapy in hormone-refractory prostate cancer. BJU Int. 2008; 101 Suppl 2: 11–15, doi: 10.1111/j.1464-410X.2007.07485.x, with a clear reduction of toxicity in patients receiving the indexed in Pubmed: 18307687. lower dose. Also, taking into account the beneficial effect 3. Pond GR, Sonpavde G, de Wit R, et al. TAX 327 Investigators. Docetaxel plus prednisone or mitoxantrone plus prednisone for advanced prostate of cabazitaxel on the quality of life of mCRPC patients, cancer. N Engl J Med. 2004; 351(15): 1502–1512, doi: 10.1056/NEJ- which was shown, among others, in an expanded access Moa040720, indexed in Pubmed: 15470213. study conducted in the UK [14], this drug can certainly be 4. Petrylak DP, Tangen CM, Hussain MHA, et al. Docetaxel and estra- mustine compared with mitoxantrone and prednisone for advanced considered a valuable therapeutic option in clinical prac- refractory prostate cancer. N Engl J Med. 2004; 351(15): 1513–1520, tice. A randomised trial of cabazitaxel was also recently doi: 10.1056/NEJMoa041318, indexed in Pubmed: 15470214. 5. Berthold DR, Pond GR, Soban F, et al. Docetaxel plus prednisone or presented at the European Society of Medical Oncology mitoxantrone plus prednisone for advanced prostate cancer: updated (ESMO) Annual Meeting showed a significantly greater ac- survival in the TAX 327 study. J Clin Oncol. 2008; 26(2): 242–245, doi: 10.1200/JCO.2007.12.4008, indexed in Pubmed: 18182665. tivity than abiraterone or enzalutamide in mCRPC patients 6. Vrignaud P, Sémiond D, Lejeune P, et al. Preclinical antitumor activity of with high-risk features (liver metastases, time to castration cabazitaxel, a semisynthetic taxane active in taxane-resistant tumors. Clin less than one year with first androgen deprivation therapy, Cancer Res. 2013; 19(11): 2973–2983, doi: 10.1158/1078-0432.CCR- 12-3146, indexed in Pubmed: 23589177. high LDH — Kim Chi ESMO 2018) [15]. 7. de Bono JS, Oudard S, Ozguroglu M, et al. TROPIC Investiga- tors. Prednisone plus cabazitaxel or mitoxantrone for metastatic castration-resistant prostate cancer progressing after docetaxel treatment: a randomised open-label trial. Lancet. 2010; 376(9747): 1147–1154, Conclusions doi: 10.1016/S0140-6736(10)61389-X, indexed in Pubmed: 20888992. 8. Bahl A, Oudard S, Tombal B, et al. TROPIC Investigators. Impact of cabazitaxel on 2-year survival and palliation of tumour-related pain in In this cohort of patients cabazitaxel showed it can men with metastatic castration-resistant prostate cancer treated in the be an good therapeutic option for patients with meta- TROPIC trial. Ann Oncol. 2013; 24(9): 2402–2408, doi: 10.1093/annonc/mdt194, indexed in Pubmed: 23723295. static castration-resistant prostate cancer after docetaxel 9. Soest RV, Nieuweboer A, Morrée EDe, et al. 2564 The influence of prior failure and is an important therapeutic option with novel androgen receptor targeted therapy on the efficacy of cabazitaxel in men with metastatic castration-resistant prostate cancer. European Jo- acceptable toxicity with respect to clinical stabilisation urnal of Cancer. 2015; 51: S499, doi: 10.1016/s0959-8049(16)31383-1. and possibly increased survival. 10. ICH Harmonized Tripartite Guideline E2D: Post Approval Safety Data Management: Note for Guidance on Definitions and Standards for Expedited Reporting, 12 November 2003 (CPMP/ICH/3945/03)”. 11. International Society for Pharmocoepidemiology, April 2007, ‘Guidelines for Good Pharmacoepidemiology Practices’. Acknowledgments 12. Good Epidemiological Practice (GEP) proper conduct in epidemiology research – IEA European Federation (April 2007). The authors thank all patients who participated in 13. de Bono JS, Sartor O, Geffriaud-Ricouard C, Joulain F, Anders Widmark A, Cabazitaxel shows a consistently greater survival benefit compared this study. The study was sponsored by Sanofi. to mitoxantrone in patients with mCRPC. NOWOTWORY Journal of Oncology. 2014; 64(1): 1–6. 14. de Bono JS, Hardy-Bessard AC, Kim CS, et al. Phase III non-inferiority study of cabazitaxel (C) 20 mg/m2 (C20) versus 25 mg/m2 (C25) in pa- Conflict of interest tients (pts) with metastatic castration-resistant prostate cancer (mCRPC) previously treated with docetaxel (D). J Clin Oncol. 2016; 34(15_suppl): 5008, doi: 10.1200/jco.2016.34.15_suppl.5008. All authors received honoraria from Sanofi related 15. Bahl A, Masson S, Malik Z, et al. Final quality of life and safety data for to the study conduct. patients with metastatic castration-resistant prostate cancer treated with cabazitaxel in the UK Early Access Programme (EAP) (NCT01254279). PJW — scientific advisor, presenter, speaker (Astel- BJU Int. 2015; 116(6): 880–887, doi: 10.1111/bju.13069, indexed in las, Janssen); travel grants (Janssen). Pubmed: 25639506.

288 REVIEW ARTICLE

Katarzyna Stencel1, 2, Daria Świniuch1, 2, Rodryg Ramlau1, 2 1Chair and Department of Oncology, Karol Marcinkowski Poznan University of Medical Sciences, Poland 2Poznan University Hospital of Lord’s Transfiguration, Poland

Molecular targeted therapy of patients with non-small-cell lung cancer

Address for correspondence: ABSTRACT Dr n. med. Katarzyna Stencel Lung cancer is the most common cause of cancer-related death both in men and women in Poland and worldwide. Katedra i Klinika Onkologii Patients diagnosed with non-small-cell lung cancer (NSCLC) of non-squamous and not otherwise specified (NOS) Uniwersytet Medyczny histologies may benefit from targeted therapies, because these types of cancers most often harbor molecular im. Karola Marcinkowskiego w Poznaniu disturbances such as activating EGFR gene mutations, rearrangements of ALK, ROS1 or NTRK genes and BRAF e-mail: [email protected] gene mutation. These disorders are a positive predictors of the response to treatment with tyrosine kinase inhibitors. The necessity of molecular tests in patients with advanced NSCLC to be performed prior to qualification Oncology in Clinical Practice for systemic chemotherapy should be emphasized and — in the case of positive results — the use of targeted 2019, Vol. 15, No. 6, 289–296 therapy in the first line treatment. DOI: 10.5603/OCP.2019.0025 : non-small-cell lung cancer, EGFR, ALK, ROS1, BRAF, targeted therapy Translation: dr n. med. Dariusz Stencel Key words Copyright © 2019 Via Medica ISSN 2450–1654 Oncol Clin Pract 2019; 15, 6: 289–296

Introduction kinase inhibitors, which in this situation are more effective than classical chemotherapy, are associated with Lung cancer is the most common cause of can- improving the quality of life of patients, and also have cer-related death in men as well as in women in Poland a different toxicity profile. There is a need for molecular and worldwide. In Poland, there were 14,500 male tests in tissue or cytological material (when tissue is and 7700 female patients diagnosed with lung cannot available) in patients with advanced NSCLC prior cer in 2016. In the same year there were 16,200 and to qualification for systemic chemotherapy, and in the 7600 deaths from lung cancer among men and women, case of molecular abnormalities the molecular targeted respectively [1]. Recently, the incidence of adeno- therapy should be used in first-line treatment. carcinoma has increased, and currently it accounts This review presents the treatment options available for approximately 45% of all newly diagnosed lung in Poland for NSCLC patients with the presence of cancers. Patients diagnosed with non-small-cell lung EGFR gene mutations and ALK/ROS1 gene rearrange- cancer (NSCLC) of non-squamous histology (adeno- ments (Table 1, 2). carcinoma, large cell carcinoma, and mixed cancer, with the predominance of histological subtypes mentioned above), as well as with cancer of undetermined histo- EGFR tyrosine kinase inhibitors logical subtype (NOS, not-otherwise specified) may benefit from molecular targeted therapy, because this In the Caucasian population activating mutations type of cancer is characterized by the most frequent in EGFR gene occur in 10–15% of patients with ad- presence of molecular disturbances such as activating enocarcinoma or lung cancer with a predominance EGFR gene mutation, ALK, ROS1, or NTRK genes rear- of this histological type [2]. They are found more rangements, and BRAF gene mutation. The presence often in women, young people, and non-smokers. The of specific molecular disorders is a positive predictive most common EGFR gene mutations include exon marker of the effectiveness of treatment with tyrosine 19. deletion, representing approximately 45% of all

289 Oncology in clinical practice 2019, Vol. 15, No. 6

Table 1. Molecular-targeted therapies in non-small-cell lung cancer available within the Drug Program

TKI Study Therapeutic ARMS Results Comments EGFR TKIs Gefitinib IPASS Gefitinib vs. carboplatin *mPFS 9.5 vs. 6.3 months Asian race, non-smokers Phase 3 + paclitaxel HR 0.48 (95% CI 0.36–0.64) or light smokers p < 0.001 Without the need to confirm EGFR-positive status First-line treatment Gefitinib IFUM Gefitinib *mPFS 9.7 months Caucasian race Phase 4 ORR 69% EGFR+ Single-arm study Erlotinib EURTAC Erlotinib vs. *mPFS 10.4 vs. 5.1 months European study Phase 3 carboplatin/cisplatin HR 0.37 (95% CI 0.25–0.54) First-line treatment + docetaxel/gemcitabine p < 0.0001 Erlotinib OPTIMAL Erlotinib vs. *mPFS 13.1 vs. 4.6 months Asian race Phase 3 carboplatin + gemcitabine HR 0.16 (95% CI 0.10–0.26) First-line treatment p < 0.0001 Afatinib LUX-Lung 3 Afatinib vs. *mPFS 11.1 vs. 6.9 months Worldwide study Phase 3 cisplatin + pemetrexed HR 0.58 (96% CI 0.43–0.78) First-line treatment p = 0.001 COMMON MUTATIONS (del19. L858R ex21) *mPFS 13.6 vs. 6.9 months HR 0.47 (95% CI 0.34–0.65) p = 0.001 mOS del19 33.3 vs. 21.1 months HR 0.54 (95% CI 0.36–0.79) p = 0.0015 Afatinib LUX-Lung 6 Afatinib vs. *mPFS 11 vs. 5.6 months Asian race Phase 3 cisplatin + gemcitabine HR 0.28 (95% CI 0.20–0.39) First-line treatment p < 0.0001 mOS 31.4 vs. 18.4 months HR 0.64 (95% CI 0.44–0.94) p = 0.023 Osimertinib AURA 3 Osimertinib vs. *mPFS 10.1 vs. 4.4 months Second-line treatment Phase 3 cisplatin/carboplatin HR 0.30 (95% CI 0.23–0.41) after failure of first- and + pemetrexed p < 0.001 second-generation EGFR ORR 71% vs. 31% TKIs ALK TKIs Crizotinib PROFILE Crizotinib vs. *mPFS 7.7 vs. 3.0 months Further treatment lines 1007 pemetrexed/docetaxel HR 0.49 (95% CI 0.37–0.64) Phase 3 p < 0.001 Crizotinib PROFILE Crizotinib vs. *mPFS 10.9 vs. 7.0 months First-line treatment 1014 cisplatin/carboplatin HR 0.45 (95% CI 0.35–0.60) Phase 3 + pemetrexed p < 0.001 Alectinib ALEX Alectinib vs. crizotinib *mPFS 34.8 vs. 10.9 months First-line treatment Phase 3 HR 0.43 (95% CI 0.42–0.58) p < 0.001 Alectinib ALUR Alectinib *mPFS 9.6 vs. 1.4 months Further treatment lines Phase 3 vs. pemetrexed/docetaxel HR 0.15 (95% CI 0.08–0.29) p < 0.001

ROS1 TKI Crizotinib PROFILE Crizotinib *ORR 72% Single-arm study 1001 mPFS 19.2 months Phase 1 mPFS — medianprogression free survival; HR — hazard ratio; ORR — objectve response rate *The primary endpoint

290 Katarzyna Stencel et al., Molecular targeted therapy of patients with non-small-cell lung cancer

Table 2. Application and dosage regimen of TKIs in patients with EGFR+, ALK+, or ROS1+ non-small cell lung cancer

Drug Treatment line Dosage Dose reduction Basic criteria for inclusion in the drug program EGFR+ Gefitinib First-line treatment 1 × 250 mg Regardless No dose reduction Adenocarcinoma or large cell Second-line of the meal possible carcinoma (EGFR+ only) or non-small treatment cell cancer with a predominance of adenocarcinoma or large cell carcinoma Erlotinib First-line treatment 1 × 150 mg 1 hour before 150 mg → (EGFR+ only) or non-small cell lung Second-line or 2 hours 100 mg → cancer NOS (EGFR+ only) treatment after a meal 50 mg Absence of metastases in the Afatinib First-line treatment 1 × 40 mg 1 hour before 40 mg → central nervous system or features or 3 hours 30 mg → of progression of metastases in the after a meal 20 mg central nervous system in patients after Maximally 50 mg previous local treatment (surgery or radiotherapy) and absence of clinically Osimertinib Second-line 1 × 80 mg Regardless 80 mg → significant neurological symptoms treatment after of the meal 40 mg and the need to increase the dose of failure of first- and glucocorticoids in the last month before second-generation qualification to the program EGFR TKIs For alectinib, the absence of ALK+ Crizotinib 1st, 2nd, 3rd line 2 × 250 mg Regardless 2 × 250 mg → symptomatic metastases in central nervous system or features of ROS1+ treatment of the meal 2 × 200 mg → progression of metastases in central 1 × 250 mg nervous system in patients after ALK+ Alectinib 1st, 2nd, 3rd line 2 × 600 mg together with 2 × 600 mg → previous local treatment (surgery or radiotherapy) and the absence treatment meal 2 × 450 mg → of clinically significant symptoms 2 × 300 mg and absence of clinically significant neurological symptoms and the need to increase glucocorticosteroids dose during the last month before enrollment

detected mutations, and exon 21. point mutation, third generation (osimertinib), available in Poland for consisting of substitution of leucine with arginine in patients with secondary T790M resistance mutation in codon 858 (L858R), constituting 40–45% of all muta- exon 20. of EGFR gene). tions in EGFR gene. Other EGFR gene mutations are much less common and include, but are not limited to, Gefitinib exon 18. substitution or exon 20. insertion. All patients treated with EGFR tyrosine kinase inhibitors (EGFR Gefitinib is a first-generation EGFR TKI, which re- TKI) will eventually experience disease progression. versibly inhibits EGFR receptor (HER1), used once daily The most frequent mechanism of resistance to EGFR in a total daily dose of 250 mg regardless of the food intake TKI is the development of secondary mutations, in- [4]. In the phase 3 IPASS study, which included patients cluding T790M mutation in exon 20. of EGFR gene, with stage IIIB/IV NSCLC from the Asiatic population, which is found in more than 50% of patients with the efficacy of the first-line treatment with gefitinib was confirmed disease progression during treatment with compared with carboplatin/paclitaxel chemotherapy regi- first- or second-generation EGFR TKI [3]. Treatment men. Gefitinib was shown to be superior according to the with a small-molecule EGFR TKIs is the treatment primary endpoint, which was progression-free survival of choice for patients with metastatic NSCLC with an (PFS) in the entire study population, and in the subgroup activating EGFR gene mutation and should be first-line of patients with EGFR-activating mutation (reduction in systemic treatment; however, in patients receiving clas- the risk of disease progression by 52% in favor of gefitinib, sical chemotherapy as a front-line treatment EGFR mPFS 9.5 vs. 6.3 months, 95% CI 0.36–00.64, p < 0.001). TKIs should be used in a second line after the disease The most common adverse events in the gefitinib arm progression. EGFR TKIs are oral drugs and are di- were acne-like rash, dry skin, itching of the skin, stoma- vided into three generations: first generation (gefitinib titis, paronychia, and diarrhea, while the most common and erlotinib), available within the Therapeutic Drug side effects of chemotherapy included nausea, vomiting, Program in first- or second-line treatment; second gen- constipation, alopecia, peripheral neuropathy, neutrope- eration (afatinib and dacomitinib), of which in Poland nia, and anemia [5]. In Caucasian NSCLC patients with only afatinib in first-line treatment is available); and EGFR-activating mutation included in the single-arm

291 Oncology in clinical practice 2019, Vol. 15, No. 6 phase IV study IFUM a median PFS after first-line treat- afatinib and chemotherapy, respectively) [13]. Afatinib ment with gefitinib was similar [6]. is also effective in patients with metastatic lesions in the central nervous system (CNS) existing since the Erlotinib beginning of treatment, extending the median PFS by nearly 3 months compared to chemotherapy [14]. The Erlotinib is another first-generation EGFR TKI that combined analysis of the results LUX-Lung 2, 3, and can be used in both first- and second-line treatment, 6 studies also showed the effectiveness of afatinib in after systemic chemotherapy. Erlotinib is used in a single terms of PFS prolongation in patients with uncommon daily dose of 150 mg and should be taken at least one EGFR gene mutations, such as G719X, L861Q, and hour before or two hours after a meal [7]. A multicenter, S768I [15]. Afatinib has also been registered by the open, randomized, phase 3 OPTIMAL study included American Food and Drug Administration (FDA) in 185 adult EGFR-positive, locally advanced or metastatic this indication [16]. NSCLC patients, randomly assigned to the arm receiving Another second-generation inhibitor is dacomitinib, erlotinib or chemotherapy (carboplatin + gemcitabine). which is not yet reimbursed in Poland within the Drug The study demonstrated the superiority of erlotinib over Program. In the ARCHER1050 study dacomitinib was platinum-based chemotherapy regarding PFS (mPFS, shown to be superior to gefitinib in term of PFS (me- 13.1 vs. 4.6 months, respectively) with a reduction in the dian PFS 14.7 months for dacomitinib and 9.2 months risk of disease progression of 84% in the erlotinib arm for gefitinib) [17], and OS (median OS 34.1 months [8]. In the EURTAC study, which included Caucasian vs. 26.8 months, respectively); however, at the expense patients diagnosed with stage IIIB/IV NSCLC with of much higher toxicity [18]. EGFR activating mutation, the efficacy of erlotinib Not without significance is the fact that EGFR TKI and standard platinum-based chemotherapy was com- treatment, in addition to the effectiveness in terms of pared. Again, in the Caucasian population erlotinib prolonging the disease progression-free time or overall was more effective regarding PFS, with a median of survival, also improves patients’ quality of life (QoL). In 10.4 vs. 5.1 months in the erlotinib and chemotherapy the LUX-Lung 3 and 6 studies it was shown that afatinib arm, respectively [9]. treatment was associated with a prolongation (in rela- tion to classic chemotherapy) of time to deterioration Afatinib of three basic lung cancer symptoms: cough, dyspnea, and pain [14]. It should be underlined that EGFR TKIs Afatinib is an irreversible pan-HER inhibitor of have a different toxicity profile, so the basic side effects the second generation, which covalently binds to the of chemotherapy, such as nausea, vomiting, hair loss, receptor and inhibits the formation of all homo- and or myelotoxicity, occur very rarely during treatment heterodimers of the HER family receptors. Afatinib is with inhibitors. The most common adverse events of administered in a single daily dose of 40 mg, at least one EGFR TKIs include diarrhea, acne-like rash, which is hour before or three hours after a meal, until disease localized mainly in the skin of the face, chest, or hairy progression or unacceptable toxicity [10]. The efficacy skin of the head, as well as paronychia or increase in and safety of afatinib were evaluated in two multicenter transaminase levels [8, 9, 19, 20]. In addition, there are clinical trials, LUX-Lung 3 being a global study and also differences in the toxicity profile between indi- LUX-Lung 6, which included only Asian patients. In vidual inhibitors — afatinib causes diarrhea and rash both studies, afatinib demonstrated superiority over more often, whereas an increase in aminotransferases chemotherapy (cisplatin/pemetrexed in the LUX-Lung is observed more often after gefitinib. Side effects are 3 study and cisplatin/gemcitabine in the LUX-Lung usually mild or moderate, are reversible, and are easily 6 study) regarding PFS. The median PFS in patients manageable with symptomatic treatment. In the case of treated with afatinib in an intention-to-treat popula- CTCAE (Common Terminology Criteria for Adverse tion (ITT) was 11.1 and 11 months in LUX-Lung 3 and Events) grade 3 toxicity or intolerable or not resolving 6 studies, respectively, while the median PFS in patients after symptomatic treatment grade 2 toxicity (diarrhea treated with chemotherapy was 6.9 and 5.6 months, re- lasting over 48 hours or rash not resolving during more spectively [11, 12]. In patients with common mutations, than seven days), treatment with an inhibitor should be i.e. deletion in exon 19. and substitution of L858R in interrupted until the side effect is resolved or its severity exon 21., there was an even greater benefit from afatinib reduced to grade 1. At the resumption of treatment, the use (13.6 vs. 6.9 months in the arm with chemotherapy). reduced dosage is mandatory; however, this reduction is In addition, patients with exon 19. deletion who had been possible only with erlotinib (150 mg – 100 mg – 50 mg) treated with afatinib showed an increase in overall sur- and afatinib (40 mg – 30 mg – 20 mg). In the case of vival (OS). As demonstrated in the LUX-Lung 3 study, afatinib, if the treatment is well tolerated during the afatinib reduces the risk of death by 46% compared first three weeks of therapy, there is a possibility of dose to chemotherapy (median OS 33.3 vs. 21.1 months for escalation to 50 mg daily.

292 Katarzyna Stencel et al., Molecular targeted therapy of patients with non-small-cell lung cancer

Osimertinib ALK tyrosine kinase inhibitors

During EGFR TKI therapy patients with primary The proportion of patients with NSCLC with ALK response can develop a secondary resistance to the treat- gene rearrangement is between 3% and 7%. This moment leading to disease progression. In 50–60% of cases lecular disorder is almost exclusively observed in patients the secondary T790M mutation in exon 20. of the EGFR with lung adenocarcinoma, more often with the signet gene is responsible for secondary resistance to treatment ring subtype, and more often in non-smokers. The pres- [21]. If the disease progresses during administration of ence of rearrangement virtually excludes the presence first- or second-generation EGFR TKI, the biological of mutations in EGFR, KRAS, and BRAF genes or rear- material should be re-sampled for histopathology to look rangements in ROS1 and NTRK genes. The rearrange- for T790M mutation. If the sampling is not possible or the ment leads to the formation of an oncogenic EML4-ALK patient does not consent to this procedure, the molecular fusion gene, which has constitutive tyrosine kinase activ- test may be carried out from peripheral blood. After ity, which results in a stimulation of intracellular signal- confirmation of the presence of the T790M mutation, ing pathways as well as neoplastic transformation and it is possible to use the third-generation tyrosine kinase tumor progression. Patients with ALK-positive NSCLC inhibitor osimertinib. Osimertinib binds to EGFR cova- are often clinically characterized by the presence of lently and irreversibly, demonstrating activity both in the metastases in supraclavicular/cervical lymph nodes, the presence of activating mutations in EGFR gene and in presence of pleural effusion, and a high rate of primary the presence of T790M resistance mutation. The efficacy central nervous system involvement. Rearrangement and safety of osimertinib in the second-line treatment was in the ALK gene is now routinely assessed in patients assessed in the international, multicenter AURA-3 study. with adenocarcinoma of the lung prior to initiation of Patients with T790M mutation were randomly assigned systemic therapy, and its presence determines the sensi- in a ratio of 2:1 to the arm receiving either osimertinib or tivity of tumor cells to small-molecule inhibitors of ALK standard chemotherapy (pemetrexed + cisplatin/carbo- tyrosine kinase. Similar to EGFR TKIs, ALK TKIs also platin). The study showed an increase in PFS in patients includes three generations: first generation (crizotinib), receiving osimertinib, with a 70% reduction in the risk second generation (alectinib, ceritinib, brigatinib) and of disease progression (median PFS 10.1 vs. 4.4 months, third generation (lorlatinib). HR 0.30, 95% CI 0.23–0.41, p < 0.001). The efficacy of Currently in Poland two ALK inhibitors are reim- osimertinib has also been confirmed in patients with bursed as part of the drug program: a first generation metastases in CNS. For these patients, the median PFS inhibitor — crizotinib in the first- and second- as well in the osimertinib arm was 8.5 months compared to as third-line treatment in patients with disease progres- 4.2 months in the chemotherapy arm (HR 0.32, 95% CI sion after or during treatment with platinum-based 0.21–0.49) [22]. Osimertinib is administered in a daily therapy, and (since July 1, 2019), second generation dose of 80 mg, at the same time, and regardless of the inhibitor — alectinib — available in the first-line and meal. If dose reduction is required, osimertinib should in subsequent treatment lines in case of ineffectiveness be used in a daily dose of 40 mg [23]. of or intolerance to crizotinib. Based on the results of the FLAURA trial, osimertinib has also been registered in the first-line treatment in Crizotinib patients with NSCLC with EGFR-activating mutation. In the FLAURA study patients were randomly assigned in The efficacy and safety of crizotinib in the treat- a ratio of 1:1 to the arm receiving either a first-generation ment of patients with advanced or metastatic NSCLC EGFR TKI (erlotinib or gefitinib) or osimertinib. The with ALK gene rearrangement after the failure of one median PFS in the osimertinib arm has been shown to in- prior line of platinum-based therapy was evaluated in crease in comparison to patients receiving chemotherapy. a multicenter, open-label, phase 3 PROFILE 1007 study. The median PFS was 18.9 and 10.2 months, respectively Patients were randomly assigned in the ratio 1:1 to (HR 0.46, p < 0.001) [24]. OS data are not mature yet. arm receiving either crizotinib 250 mg twice daily or At present, in Poland, within the framework of the standard second-line chemotherapy (pemetrexed Drug Program, erlotinib, gefitinib, and afatinib in the 500 mg/m2 intravenously every three weeks in patients first-line treatment and erlotinib and gefitinib in the with non-squamous NSCLC or docetaxel 75 mg/m2 in- second-line treatment in patients not previously receiv- travenously every three weeks). The primary endpoint ing EGFR TKI in the first line, as well as osimertinib of the study was PFS. A statistically and clinically sig- in the second line in patients with disease progression nificant benefit has been demonstrated for crizotinib while using first- or second-generation EGFR TKI, with compared to second-line chemotherapy. The median the presence of the T790M mutation in exon 20. of the PFS was 7.7 months and 3 months, respectively (HR EGFR gene, are reimbursed [25]. 0.49, 95% CI 0.37–0.64, p < 0.001), and the response

293 Oncology in clinical practice 2019, Vol. 15, No. 6 rate was 65% and 20%, respectively (p < 0.001). The allowing the majority of patients after disease progres- study showed no benefit in OS, probably due to the sion during or after chemotherapy to receive crizotinib possibility of using crizotinib in patients in the arm re- in the next treatment line (crossover). The median OS ceiving standard second-line chemotherapy after disease in the crizotinib arm was not reached, whereas in the progression (crossover). Investigators also pointed to chemotherapy arm it was 47.5 months (HR 0.76, 95% the fact that crizotinib had a beneficial effect on the CI 0.54–1.05, p = 0.09). After a median follow-up of patients’ quality of life. There has been a significant 46 months and after adjusting for the crossover effect reduction of intensity of symptoms like alopecia, cough, by means of appropriate statistical tools, OS benefit was dyspnea, fatigue, chest pain, shoulder or arm pain, and demonstrated in patients treated with crizotinib with a significant delay of deterioration of the three main a risk reduction of 66% (median OS 59.8 vs. 19.2 months, lung cancer symptoms: cough, dyspnea, and chest pain respectively; HR 0.34; 95% CI 0.081–0.718) [27]. Typi- (4.5 months in the crizotinib arm versus 1.4 months in cal side effects of ALK TKIs, which occur in patients the chemotherapy arm, HR 0.50, 95% CI 0.37–0.66, treated with chemotherapy much less frequently include: p < 0.001). The toxicity profile of crizotinib was differ- visual disturbances in the form of flares or light columns, ent from the chemotherapy toxicity profile. The most peripheral edema, diarrhea, constipation, vomiting, and common adverse reactions reported in at least 5% of elevation of aminotransferases. However, when using patients treated with crizotinib included visual impair- standard chemotherapy, patients are more likely to ment in the form of visual acuity loss or blurred vision, experience fatigue, anemia, neutropenia, thrombocy- diarrhea, nausea, vomiting, constipation, increased topenia, or oral mucositis [28]. In patients with disease liver enzymes, peripheral edema, dysgeusia, dizziness, progression during treatment with first-generation ALK or upper respiratory tract infections. The side effects inhibitor it is possible to use a second-generation inhibi- were mostly mild to moderate in severity, transient, and tor — brigatinib, ceritinib, or alectinib. responded well to symptomatic treatment. The most common side effects of chemotherapy were fatigue, Alectinib alopecia, dyspnea, and rash [26]. The efficacy and favorable safety profile of crizotinib Alectinib is second-generation ALK-TKI show- in second-line treatment in patients with ALK-positive ing high activity within the central nervous system, NSCLC became the basis for conducting a phase 3 clini- which is very important in ALK-positive lung cancer cal trial assessing the efficacy and safety of first-line patients. The efficacy and safety of this drug in previ- treatment with crizotinib. An open-label, multicenter ously untreated patients with advanced ALK-positive PROFILE 1014 study included 343 patients with NSCLC were evaluated in the ALEX study. This mul- ALK-positive advanced or metastatic non-squamous ticenter, open-label clinical trial involved 303 patients NSCLC, who had not received prior systemic treat- randomly assigned (1:1 ratio) to the arm receiving twice ment. Patients were randomly assigned in a ratio daily either alectinib 600 mg (n = 152) or crizotinib of 1:1 to the arm receiving either crizotinib 250 mg 250 mg (n = 151). The primary endpoint of the study twice daily until disease progression or unacceptable was investigator-assessed PFS, while the secondary end- toxicity (n = 172) or standard first-line chemotherapy points included IRC-assessed PFS, time to progression (pemetrexed 500 mg/m2 in combination with platinum in the CNS, ORR and OS. After median follow-up of derivative: cisplatin 75 mg/m2 or carboplatin AUC 5 or 17.6 months for crizotinib and 18.6 months for alectinib, 6 mg/mL/min up to a maximum of six cycles) (n = 171). disease progression or death occurred in 68% and 41% The primary endpoint of the study was PFS, and pa- of patients, respectively. At 12 months, the disease tients in the chemotherapy arm had the opportunity to progression was not detected in 68.4% of patients in change to the crizotinib arm after disease progression. the alectinib arm and 48.7% of patients in the crizotinib Similarly to the PROFILE 1007 study, in the PROFILE arm (HR 0.47, 95% CI 0.34–0.65, p < 0.001). It has been 1014 study the investigators also demonstrated the shown statistically and clinically significant prolongation superiority of crizotinib over chemotherapy in terms of of IRC-assessed PFS in patients treated with alectinib PFS (median 10.9 months vs. 7 months, respectively). by more than 15 months as compare to crizotinib. The It has been shown that the use of crizotinib in first-line median of PFS, as assessed by ICR, in alectinib arm was treatment reduces the risk of disease progression by as 25.7 months versus 10.4 months in crizotinib arm (HR much as 55% compared to chemotherapy (HR 0.45; 0.50; 95% CI 0.36–0.70; p < 0.0001) [30]. According to 95% CI 0.35–0.60; p < 0.001). In addition, there was the investigators, the median PFS was not achieved in a significantly higher response rate in patients receiving the alectinib arm: NE (17.7–NE). crizotinib (74% vs. 45%). Similarly to the PROFILE At the American Society of Clinical Oncology annual 1007 study, there were no statistically significant dif- meeting in 2018, updated PFS results were presented. ferences in OS, which results from the study design, Treatment with alectinib has been shown to reduce the

294 Katarzyna Stencel et al., Molecular targeted therapy of patients with non-small-cell lung cancer risk of disease progression or death by 57% compared to alectinib and 0% for chemotherapy (p < 0.001). The crizotinib and to prolong the progression-free survival by favorable safety profile of alectinib is also significant. almost 3 years (median PFS 34.8 months vs. 10.9 months The adverse events rate of any grade was comparable for alectinib and crizotinib, respectively; HR 0.43, 95% in both groups of patients [32]. CI 0.42–0.58) [31]. The study also highlighted high intracranial activity of alectinib. At enrollment, metastases in the CNS occurred in 42% of patients in the alectinib ROS1 tyrosine kinase inhibitors arm and 38% of patients in the crizotinib arm. It was shown that the time to progression of CNS metastases The percentage of patients with NSCLC harbouring was significantly longer in patients receiving alectinib. ROS1 gene rearrangement is between 1% and 2% and is The cumulative risk of progression or development of higher in the Asian population (2–3%). Rearrangement CNS metastases after 12 months of treatment with ALK in the ROS1 gene occurs more frequently in women TKI was 41.4% for crizotinib and 9.4% for alectinib, (60%), younger patients, non-smokers (75%), those therefore it is more than four times lower in patients diagnosed with adenocarcinoma, especially with solid receiving the second generation ALK inhibitor [30]. The subtype, and poorly differentiated NSCLC (G2–G3). median PFS for patients with metastatic CNS lesions was About 20% of patients have metastatic lesions in CNS. 27.7 months in the alectinib group and 7.4 months in the ROS1 gene rearrangements are most often mutually crizotinib group (HR 0.35) [31]. Data on OS are not yet exclusive with other leading molecular disorders. mature. The ALEX study protocol did not assume the The only drug available in Poland within the Drug possibility of crossover, however, some crizotinib-treated Program for ROS1-positive non-small-cell lung cancer patients received alectinib after disease progression as patients regardless of the treatment line is crizotinib. Its part of another clinical trial or expanded access program. effectiveness and safety in this indication has been demon- The adverse reactions rate was similar in both groups, strated in the multicenter, single-arm, phase 1 PROFILE however the investigators noted that toxicity profile 1001 study. This clinical trial included 50 patients, most of both inhibitors differed significantly. Side effects of whom previously received systemic treatment. The occurring more frequently in the alectinib group were primary endpoint was the response rate, which was 72%, anemia (20% vs. 5% in the crizotinib arm), myalgia (16% while mPFS was 19.2 months. The proportion of patients vs. 1%), blood bilirubin level increased (15% vs. 1%), who remained alive six and 12 months after starting treat- weight gain (10% vs. 1%), musculoskeletal pain (7% ment with crizotinib was 91% and 79%, respectively [33]. vs. 2%) and photosensitivity reactions (5% vs. 0%). However, adverse events that occurred more frequently in patients receiving crizotinib included nausea (48% Summary vs. 14% in the alectinib arm), diarrhea (45% vs. 12%), and vomiting (38% vs. 7%). Grade 3 to 5 adverse events The outcomes of systemic treatment of NSCLC pa- occurred more frequently in the crizotinib arm (41% for tients with standard chemotherapy is still unsatisfactory. alektynib and 50% for crizotinib, respectively), so that Molecular targeted therapy makes possible a significant alectinib appears to be a safer drug [30]. improvement of treatment results, with extension of The advantage of alectinib over chemotherapy in progression-free survival and overall survival. However, patients with resistance to crizotinib was confirmed this requires molecular assessment and insight into mo- in a multicenter, open-label phase III ALUR, study lecular abnormalities, which have predictive value for which included 107 patients. Patients were allowed to response to targeted therapy. Molecular targeted thera- use a single line of previous systemic chemotherapy. pies can be used in a small percentage of patients due to Patients were randomly assigned at a 2:1 ratio to the low incidence of molecular abnormalities. However, the arm receiving either alectinib 600 mg twice daily it is emphasized that it is necessary to search for them (n = 72) or investigator’s choice chemotherapy (pem- before starting standard systemic chemotherapy, which etrexed 500 mg/m2 or docetaxel 75 mg/m2 intravenously gives the possibility to offer the patients with molecular every three weeks) (n = 35). The primary endpoint changes more valuable therapy. It is also important that of the study was PFS, which was prolonged in the TKIs can improve patients’ quality of life and delay the alectinib arm compared to chemotherapy (median deterioration of lung cancer symptoms. In addition, the PFS 9.6 vs. 1.4 months, respectively; HR 0.15, 95% CI side effects are different from those of chemotherapy, 0.08–0.29, p < 0.001). The response rate was 37.5% usually mild or moderate, reversible, and easily man- in patients receiving alectinib, compared to 2.9% in ageable with symptomatic treatment. Therefore, TKI patients treated with chemotherapy. To note, alectinib treatment should be considered in the first place in pa- appeared to be very effective against central nervous tients with known molecular targets for which systemic system metastases. The ORR in CNS was 54.2% for therapies have been developed and registered.

295 Oncology in clinical practice 2019, Vol. 15, No. 6

References 16. www.fda.gov. 17. Wu YL, Cheng Y, Zhou X, et al. Dacomitinib versus gefitinib as first- line treatment for patients with EGFR-mutation-positive non-small-cell 1. http://onkologia.org.pl/raporty/. lung cancer (ARCHER 1050): a randomised, open-label, phase 3 trial. 2. Lindeman N, Cagle P, Aisner D, et al. Updated molecular testing The Lancet Oncology. 2017; 18(11): 1454–1466, doi: 10.1016/s1470- guideline for selection of lung cancer patients for EGFR and ALK 2045(17)30608-3. tyrosine kinase inhibitors: guideline from the College of American Pa- 18. Mok TS, Cheng Y, Zhou X, et al. Improvement in overall survival in a ran- thologists, the International Association for Study of Lung Cancer, and domized study that compared dacomitinib with gefitinib in patients with the Association for Molecular Pathology. Journal of Thoracic Oncology. advanced non-small-cell lung cancer and EGFR-activating mutations. J Clin Oncol. 2018; 36(22): 2244–2250, doi: 10.1200/JCO.2018.78.7994, 2018; 13: 323–358. indexed in Pubmed: 29864379. 3. Sharma S, Bell D, Settleman J, et al. Epidermal growth factor receptor 19. Maemondo M, Inoue A, Kobayashi K, et al. North-East Japan Study mutations in lung cancer. Nature Reviews Cancer. 2007; 7(3): 169–181, Group. Gefitinib or chemotherapy for non-small-cell lung cancer doi: 10.1038/nrc2088. with mutated EGFR. N Engl J Med. 2010; 362(25): 2380–2388, doi: 4. https://ec.europa.eu/health/documents/community-regi- 10.1056/NEJMoa0909530, indexed in Pubmed: 20573926. ster/2017/20170329137415/anx_137415_pl.pdf. 20. Sequist L, Martins R, Grunberg S, et al. First-line gefitinib in patients 5. Mok T, Wu YL, Thongprasert S, et al. Gefitinib or carboplatin–paclitaxel with advanced non-small-cell lung cancer harboring somatic EGFR in pulmonary adenocarcinoma. NEJM. 2009; 361(10): 947–957, doi: mutations. Journal of Clinical Oncology, 2008; 10; 26(20): 3472. 10.1056/nejmoa0810699. 21. Santarpia M, Liguori A, Karachaliou N, et al. Osimertinib in the treat- 6. Douillard JY, Ostoros G, Cobo M, et al. First-line gefitinib in cau- ment of non-small-cell lung cancer: design, development and place casian EGFR mutation-positive NSCLC patients: a phase-IV, in therapy. Lung Cancer: Targets and Therapy. 2017; 8: 109–125, doi: open-label, single-arm study. Br J Cancer. 2014; 110(1): 55–62, doi: 10.2147/lctt.s119644. 10.1038/bjc.2013.721, indexed in Pubmed: 24263064. 22. Wu YL, Ahn MJ, Garassino MC, et al. AURA3 Investigators. Osimertinib 7. https://ec.europa.eu/health/documents/community-regi- or platinum-pemetrexed in EGFRT 790M-positive lung cancer. N Engl J ster/2005/200509199999/anx_9999_pl.pdf. Med. 2017; 376(7): 629–640, doi: 10.1056/NEJMoa1612674, indexed 8. Zhou C, Wu YL, Chen G, et al. Erlotinib versus chemotherapy as in Pubmed: 27959700. first-line treatment for patients with advanced EGFR mutation-positive 23. https://ec.europa.eu/health/documents/community-regi- non-small-cell lung cancer (OPTIMAL, CTONG-0802): a multicentre, ster/2016/20160202133956/anx_133956_pl.pdf. open-label, randomised, phase 3 study. Lancet Oncol. 2011; 12(8): 24. Soria JC, Ohe Y, Vansteenkiste J, et al. FLAURA Investigators. Osim- 735–742, doi: 10.1016/S1470-2045(11)70184-X, indexed in Pubmed: ertinib in Untreated EGFR-Mutated Advanced Non-Small-Cell Lung 21783417. Cancer. N Engl J Med. 2018; 378(2): 113–125, doi: 10.1056/NEJ- 9. Rosell R, Carcereny E, Gervais R, et al. Spanish Lung Cancer Group Moa1713137, indexed in Pubmed: 29151359. in collaboration with Groupe Français de Pneumo-Cancérologie and 25. https://www.gov.pl/web/zdrowie/choroby-onkologiczne. Associazione Italiana Oncologia Toracica. Erlotinib versus standard 26. Shaw AT, Kim DW, Nakagawa K, et al. Crizotinib versus chemotherapy chemotherapy as first-line treatment for European patients with ad- in advanced ALK-positive lung cancer. N Engl J Med. 2013; 368(25): vanced EGFR mutation-positive non-small-cell lung cancer (EURTAC): 2385–2394, doi: 10.1056/NEJMoa1214886, indexed in Pubmed: a multicentre, open-label, randomised phase 3 trial. Lancet Oncol. 23724913. 2012; 13(3): 239–246, doi: 10.1016/S1470-2045(11)70393-X, indexed 27. Solomon BJ, Kim DW, Wu YL, et al. Final overall survival analysis in Pubmed: 22285168. from a study comparing first-line crizotinib versus chemotherapy 10. https://www.ema.europa.eu/documents/product-information/giotrif- in ALK-mutation-positive non-small-cell lung cancer. J Clin Oncol. -epar-product-information_pl.pdf. 2018; 36(22): 2251–2258, doi: 10.1200/JCO.2017.77.4794, indexed 11. Sequist LV, Yang JCH, Yamamoto N, et al. Phase III study of afatinib or in Pubmed: 29768118. cisplatin plus pemetrexed in patients with metastatic lung adenocarci- 28. Solomon B, Mok T, Kim DW, et al. First-line crizotinib versus chemo- noma with EGFR mutations. J Clin Oncol. 2013; 31(27): 3327–3334, therapy in ALK-positive lung cancer. New England Journal of Medicine. doi: 10.1200/JCO.2012.44.2806, indexed in Pubmed: 23816960. 2014; 371(23): 2167–2177, doi: 10.1056/nejmoa1408440. 12. Wu YL, Zhou C, Hu CP, et al. Afatinib versus cisplatin plus gemcitabine 29. Hanna N, Johnson D, Temin S, et al. First-Line Crizotinib versus Che- for first-line treatment of Asian patients with advanced non-small-cell lung cancer harbouring EGFR mutations (LUX-Lung 6): an open-label, motherapy in ALK-Positive Lung Cancer. J Clin Oncol. 2017; 35(30): randomised phase 3 trial. Lancet Oncol. 2014; 15(2): 213–222, doi: 3484–3515. 10.1016/S1470-2045(13)70604-1, indexed in Pubmed: 24439929. 30. Peters S, Camidge DR, Shaw AT, et al. ALEX Trial Investigators. Alectinib 13. Yang JH, Wu YL, Schuler M, et al. Afatinib versus cisplatin-based versus crizotinib in untreated ALK-positive non-small-cell lung cancer. chemotherapy for EGFR mutation-positive lung adenocarcinoma N Engl J Med. 2017; 377(9): 829–838, doi: 10.1056/NEJMoa1704795, (LUX-Lung 3 and LUX-Lung 6): analysis of overall survival data from indexed in Pubmed: 28586279. two randomised, phase 3 trials. The Lancet Oncology. 2015; 16(2): 31. Camidge D, Peters S, Mok T, et al. Updated efficacy and safety 141–151, doi: 10.1016/s1470-2045(14)71173-8. data from the global phase III ALEX study of alectinib (ALC) versus 14. Schuler M, Wu YL, Hirsh V, et al. First-Line afatinib versus chemotherapy crizotinib (CZ) in untreated advanced ALK+ NSCLC. ASCO 2018 in patients with non-small cell lung cancer and common epidermal Annual Meeting. growth factor receptor gene mutations and brain metastases. J Thorac 32. Novello S, Mazières J, Oh IJ, et al. Alectinib versus chemotherapy Oncol. 2016; 11(3): 380–390, doi: 10.1016/j.jtho.2015.11.014, indexed in crizotinib-pretreated anaplastic lymphoma kinase (ALK)-positive in Pubmed: 26823294. non-small-cell lung cancer: results from the phase III ALUR study. 15. Yang JCH, Sequist LV, Geater SL, et al. Clinical activity of afatinib in Ann Oncol. 2018; 29(6): 1409–1416, doi: 10.1093/annonc/mdy121, patients with advanced non-small-cell lung cancer harbouring uncom- indexed in Pubmed: 29668860. mon EGFR mutations: a combined post-hoc analysis of LUX-Lung 2, 33. Shaw AT, Ou SHI, Bang YJ, et al. Crizotinib in ROS1-rearranged non- LUX-Lung 3, and LUX-Lung 6. Lancet Oncol. 2015; 16(7): 830–838, -small-cell lung cancer. N Engl J Med. 2014; 371(21): 1963–1971, doi: doi: 10.1016/S1470-2045(15)00026-1, indexed in Pubmed: 26051236. 10.1056/NEJMoa1406766, indexed in Pubmed: 25264305.

296 REVIEW ARTICLE

Wojciech P Olszewski1, Andrzej Marszałek2 1Department of Pathology and Laboratory Diagnostics, The Maria Sklodowska-Curie Institute — Oncology Centre in Warsaw, Poland 2Department of Tumour Pathology and Prophylaxis, Poznan University of Medical Sciences and The Greater Poland Cancer Centre, Poznan, Poland

Pathomorphological assessment of tissue material after pre-operative systemic therapy (neoadjuvant therapy) in patients with breast cancer

Address for correspondence: ABSTRACT Dr n. med. Wojciech P. Olszewski Oncological management of patients with breast cancer, with the use of pre-operative systemic therapy in the last Zakład Patologii i Diagnostyki decade presented significant increase of effectiveness. The greater the number of cases with complete or major Laboratoryjnej pathomorphological response means that getting the right material for postoperative histopathological assessment Centrum Onkologii — Instytut is becoming more and more difficult. In addition, the demonstrated correlation between complete pathomorpho- im. Marii Skłodowskiej-Curie w Warszawie logical response (pCR) and long-term treatment effects (in HER2-positive and triple-negative subtypes of breast e-mail: [email protected] carcinoma) makes the standardisation of postoperative pathomorphological examination, both at the gross and Oncology in Clinical Practice microscopic level, a necessity. This article presents the recommended rules for the preparation of such material 2019, Vol. 15, No. 6, 297–302 and the method of its reporting, corresponding to the needs of contemporary oncology. DOI: 10.5603/OCP.2019.0022 Key words: pathology, gross pathology, neoadjuvant therapy, pathology report Translation: dr n. med. Dariusz Stencel Copyright © 2019 Via Medica Oncol Clin Pract 2019; 15, 6: 297–302 ISSN 2450–1654

Introduction ment (i.e. neoadjuvant therapy). It means that to describe the status in patients diagnosed with breast cancer, Due to the increasingly common introduction of who were then subjected to systemic treatment, and in neoadjuvant therapy, it has become necessary to modify whom the finally delivered postoperative material could the method of postoperative material evaluation. Recent not be found (pCR, pathologic complete response), publications have shown that the response rate to hor- the category ypT0N0 or ypTisN0 should be used. This mone treatment and/or chemotherapy before surgery is wording is currently dedicated to cancers in complete an important predictor of disease-free survival (DFS) [of remission after neoadjuvant therapy, and in whom no note, currently the US Food and Drug Administration invasive cancer can be revealed either in breast or in (FDA) prefers the term “event-free survival’ (EFS)] and lymph nodes. According to the current interpretation overall survival (OS). This was considered in the new, of this classification, the description of ypTX IS NOT currently applicable and generally available materials, ALLOWED to be used in the discussed case. such as material assessment paradigms according to the The need to develop a unified protocol for the as- College of American Pathologists (colloquially known sessment of postoperative material from breast cancer as CAP protocols [1]). In the latest materials published patients undergoing neoadjuvant treatment resulted in February this year, it was indicated that, due to the from many previous publications (meta-analysis [2]). systemic treatment used prior to breast resection, the In addition, new technologies are now being exploited pT0 and pTis categories (ductal carcinoma in situ, DCIS) (using information technology and statistical tools in the are reserved exclusively for the aforementioned treat- form of “machine learning”) to combine many variables

297 Oncology in clinical practice 2019, Vol. 15, No. 6 evaluated on baseline magnetic resonance images with —— tumour (cancer histology) with accompanying re- features of postoperative material — especially in pa- sidual lesions; tients with pCR [3]. Nevertheless, the most precise and —— tumour (cancer histology) without any changes consistent recommendations regarding the pathomor- after treatment. phological description in the case of pCR are presented This situation means that it is necessary for the in the publication by Bossuyt et al. [4]. pathologist collecting the material to have information about pre-treatment tumour characteristics (tumour size and location [e.g. quadrant]). The original tumour Principles of proceeding area is referred to as the tumour bed. Such information is available only in the case of close cooperation The source of material after systemic treatment between teams of radiologists, surgeons, pathomor- (after chemotherapy or hormonotherapy) is currently phologists, and clinical/medical oncologists. Without a tumourectomy (in form of so-called small or large proper documentation (marking) of tumour size before lumpectomy) or mastectomy with a sentinel node proce- treatment, it is not possible to determine the degree dure or lymphadenectomy. In the case of post-treatment of tumour response to treatment after completion of reduction of tumour size in imaging tests, and thus a de- neoadjuvant therapy and possible prognosis regarding crease of clinical stage (primary tumour and lymph nodes further course of the disease. Presence of the tumour shrinkage), surgery may be performed in accordance with has to be confirmed before treatment in tissue material the “new” clinical stage. Therefore, more and more often assessment (e.g. core needle biopsy) with a full panel organ-sparing surgery (tumourectomy and sentinel node of required factors (ER, PgR, HER2, Ki67), and in the procedure) can be used following the systemic treatment. presence of metastases in the lymph nodes it should Patients undergoing pre-operative treatment may be confirmed with fine needle biopsy. Therefore, it is harbour several groups of breast cancers: important to understand the assessment principles of —— infiltrating locally advanced breast cancers: all the above-mentioned specialists. • breast cancers with lymph node metastases, In the last decade, the results of clinical trials • inflammatory cancers, have been published showing that the pathomor- • cancers with breast skin infiltration; phological intensification of pre-operative systemic —— cancers belonging to subtypes of known aggressive treatment effects correlate with the long-term clinical clinical course: outcomes. Triple-negative and HER2-positive breast • triple-negative cancers, cancer patients with cPR have longer asymptomatic and • HER2-positive cancers (nonluminal), overall survival. The consequence of this situation is the • luminal B cancers (HER2-positive). recognition of cPR as a surrogate endpoint in clinical In these situations, chemotherapy and, if justified, trials. This means that when comparing a selected new targeted therapy is used. In recent years, hormone drug with an old one, according to the currently ap- therapy has also been used in selected cases of lumi- plied principles of the evaluation of the effectiveness nal carcinomas. of the therapy, it is not necessary to observe patients There are three reasons to use preoperative treatment. for many years in a clinical trial in order to determine The first is the proven benefit found in clinical trials in the superiority of the use of a new drug. Comparison of term of DFS and OS prolongation in locally advanced cPR rates can replace such long-term observation. The breast cancer and selected subtypes of breast cancer effects may include faster drug registration and lower regardless of clinical stage. The second reason is the pos- costs of clinical trials. sibility of using surgical treatment in initially inoperable A reliable assessment of response to systemic treat- cases. The third is the chance to use conservative treatment is currently one of the main criteria for its effec- ment in patients with the initial indication for mastectomy. tiveness in patients, including clinical trials. The effect of systemic treatment (including chemotherapy, targeted therapy, and hormone therapy) may be: —— complete pathologic response (cPR); Pathomorphological management —— partial pathologic response (pPR); of tissue material after systemic —— no pathologic response (nPR) or disease progression. treatment in patients with invasive The macroscopic picture after treatment can there- breast cancer fore be presented in the form: —— total tumour macroscopic regression, where it is Preparation and collection of tissue material impossible even to find the tumour site; —— absence of a tumour (cancer histology) with more Biopsy material or less visible residual lesions (e.g. fibrosis, necro- Preparation and collection of tissue material is not sis focuses); different from that used in other cases of core needle

298 Wojciech P Olszewski, Andrzej Marszałek, Pathomorphological assessment of tissue material after pre-operative systemic therapy or surgery biopsy. The microscopic evaluation should The varying degree of response to the treatment be carried out as described later in this paper. The makes the precise determination of the tumour bed collection of material from breast cancer during sys- difficult in some cases. In such situations: temic treatment is the method of assessing therapeutic —— one should reach the description or radiological im- response, providing the possibility to modify or change age (location of the lesion, its size before treatment, the treatment schedule in the absence of histopatho- number of tumours, their shape); logical features of response. This assessment allows the —— one should find a metal marker if it was implemented comparison of treatment responses in individual pa- during a diagnostic biopsy — it allows localisation tients. Indications for the use of a specific treatment do of the primary tumour site. not always translate into a reduction of tumour size and cellularity as well as a reduction in the mitotic index or Detailed recommendations for postoperative material proliferation index Ki67 in tumour cells. A comparison 1. Evaluation of the tumour bed size and collection of these clinical and pathomorphological indices enables of specimens from the tumourbed the identification of patients in whom a change in treat- After neoadjuvant treatment, the tumour bed is ment plan would be justified. a macroscopically indistinctly bounded, fibrous, often elastic area, instead of clear, solid tumour. A tumour Postoperative material bed can be more easily identified by the combined use General recommendations for postoperative material of visual assessment and palpation of tissue slices than 1. In invasive breast cancer it should be clearly indi- by visual inspection alone. Therefore, it is important that cated on referral that the material after systemic the pathologist conducts a careful macroscopic exami- treatment belongs to this group. nation of the tissues and correlates these results with 2. Fixation of the material and its initial preparation radiological images (or their descriptions) and the his- (cross-sectioning) follow a routine procedure. tory of the disease to find the primary tumour location. 3. After material fixation (24–72 h after the surgery) Macroscopically, the tumour bed should be meas- it is recommended to collect and describe the speci- ured and described in three dimensions. Any additional mens: lesions in the breast should also be measured and de- —— from the entire largest cross-section of the tumour scribed in three dimensions, with an estimated loca- bed (the tumour bed is the primary area occupied by tion and measurement of their distance from the main breast cancer prior to systemic treatment); tumour bed. The distance of each tumour bed from the —— from the tumour after treatment (if it is clearly vis- surgical margins should also be reported. ible macroscopically), typically it is recommended to It should be noted that the residual tumour bed may take at least one specimen for every centimetre of the have poorly visible borders, and rather recognise neigh- largest tumour dimension — at least two (up to five). bouring “satellite tumours” as part of the main tumour, The area of the tumour bed may or may not overlap unless they are distant from it by more than 0.5 cm or with the tumour area after treatment. The cancer form a distinctly separate tumour. Even then, however, tissue may reduce its diameter or dilute the cellu- the histopathological specimens should be taken from larity with preserved diameter, or an uneven tumour the tissues that separate the tumours, to exclude their disappearance can occur manifesting itself in pseu- connection to the main tumour. do-multifocality in postoperative image. Imaging examinations (e.g. mammography im- If lymph nodes are collected after systemic therapy, ages) or digital photographs of the material constitute the principle of taking all lymph nodes according to an important documentation of macroscopic results general rules is applied. This means that all lymph nodes and increase the accuracy of specimen collection for found during pathology processing are taken. They histopathological evaluation. They can be very help- are placed in separate baskets, after cutting them into ful for a pathologist if they are used as a “map” for 2–3-mm-thick slices (for lymph nodes). The exception a macroscopic description and indicate the place of are lymph nodes over 1 cm with macroscopically visible origin of each specimen prepared for histopathological macrometastases, which can be described macroscopi- examination. Moreover, the detailed mapping allows cally and taken only partially. This collection scheme more accurate examination of residual disease presence, applies to both sentinel lymph nodes (taken before measurement of tumour size, and residual tumour as- and after systemic treatment) as well as lymph nodes sessment, including the evaluation of tumour cellularity. after lymphadenectomy. In addition, attention should The postoperative material should be dissected as be paid to fibrosis focuses and the presence of resorp- thinly as possible into 3–5-mm-thick slices (material tion features in adipose tissue of the axillary cavity ac- from the breast). companying the lymph nodes and to collect specimens Note: In some international recommendations it from such sites. is indicated that dissected material should then be

299 Oncology in clinical practice 2019, Vol. 15, No. 6 subjected to a radiological examination (mammogra- are indicators, not real changes. Sometimes metal clips phy) with a radiographic evaluation of the images to migrate within the breast. In addition, the clips are determine the presence/extent of the residual disease. placed as focal indicators of a more extensive tumour. The pathologist should examine the sample visually and It is therefore important to carefully examine macro- palpatively to identify suspicious areas and proximity of scopically and radiographically surrounding tissues, the margins, and correlate these results with radiological rather than focusing only on the metal clips. Secondly, findings. The result of pathological and radiographic microcalcifications remain stable in the treated breast, examination should be discussed with the surgeon re- but can only represent the component of in situ tumour. garding the radicality of tissue removal and the possible Therefore, microcalcification is a helpful indicator of need for additional surgical resection. It is best to do this tumour location, but not necessarily the best indica- intraoperatively to facilitate a single operation. In the tor of its invasive component. Because HER2-positive local practice the organisation of such a scheme requires breast cancers may have extensive and distant in situ good cooperation between the surgeon and pathologist components, microcalcification should be taken, but it and radiologist and the full availability of radiological is not assumed that they represent the site and extent equipment for postoperative material assessment. of all residual invasive diseases. In the absence of a tumour, macroscopically de- monstrable residual cancer may still be present in the 2. Histopathological evaluation microscopic picture. To confirm that there is no residual Neoadjuvant systemic therapy can result in many infiltrating disease, specimens from the whole area of types of response — from non-identifiable to complete the tumour bed should be taken. absence of cancer. The tumour bed must be identified The residual tumour bed with fibrotic features in order to reliably determine the pCR, which is defined should be measured macroscopically in the three largest by exclusion, and therefore depends on the appropriate dimensions. It is recommended to prepare a map for the sampling of the correct area in the breast. pathologist and provide it with appropriate measure- Characteristic changes include oedematous fibrous ments and take into account the location of each tissue tissue with residual vascularity and dispersed mast cells sample collected for histopathological assessment. as well as lymphocytic infiltration, histiocytic cells with Specimens for histopathological examination should be degenerative vacuolisation, hyalinised vascular stroma, taken from suspicious areas and margins. It is best to fatty necrosis, macrophages with haemosiderin, and collect the samples taking into account the entire area lack of glandular tissue — all of which may indicate of the largest cross-section of the tumour bed and other a tumour bed. There is no doubt, however, that the exact suspect areas. The macroscopic description should clinical-pathological correlation during macroscopic include these specimens together with their orientation. examination and specimen collection remains the most The number of samples taken results from exact accurate method of identifying the tumour bed. material assessment, radiological characteristics, and Residual tumour cells may have an unusual, overall size of the surgical material. Some pathologists sometimes bizarre appearance or may contain subtle use cytological assessment of a freshly dissected tumour changes in the form of signet ring cells, plasmacytoid bed (touch imprint or gentle tissue scraping and smear cells, or have a histiocytoid appearance. Sometimes performing) to confirm the presence of cancer cells immunohistochemical staining may be required to de- during material collection, although this is optional. tect residual tumour cells in the tumour bed, surgical The largest cross-section of an alleged tumour bed margins, and/or lymph vessels in order to distinguish should be subjected to histological evaluation. It is ex- histiocytes (CD68 +) and epithelial cells (cytokeratin pected that in the case of a macroscopically complete AE1/AE3 + or cytokeratin 7+). response, at least 10–15 blocks will be needed to rule In the case of residual disease, routine histopathologi- out the microscopically residual disease. If the primary cal parameters such as type, size, vascular invasion, and tumour and/or resected material was large, it is recom- margin status should be recorded. A change of histologi- mended to take at least one block per 1 cm of tumour cal tumour grade occurs as a possible reaction to treat- size before treatment and additional specimens rep- ment, but it has not been confirmed as an independent resenting the margins of the material. If these blocks prognostic factor in residual disease. The assessment of do not contain a tumour, another series of material tumour grade in the material after neoadjuvant treat- collection should be made. If the residual tumour bed ment is currently recommended (College of American is small (< 3 cm) and there are no clear features of the Pathologists). Obviously, it cannot be done in the case of persistent cancer, it should be subjected to histopatho- complete or near-complete response to treatment (e.g. logical examination as a whole. If tumour bed is larger when only tumour embolism or cancer in situ or cancer than 3 cm, then at least 15 blocks should be taken. cells in the lymph nodes are preserved after treatment). To avoid the absence of residual invasive cancer, In order to correctly determine the pathologi- two issues need to be addressed. First of all, tags (clips) cal response, it is important to distinguish between

300 Wojciech P Olszewski, Andrzej Marszałek, Pathomorphological assessment of tissue material after pre-operative systemic therapy intra-lymphatic or endovascular cancer (without invasive sue are encountered after neoadjuvant treatment. Most features) from in situ cancer, and it should be considered commonly, with effective treatment, the area occupied as a residual invasive disease. by both components (in situ and infiltrating cancer) de- Changes in cellularity may lead to a false impression creases. However, even with low post-treatment cancer of multifocality. Immunohistochemistry can often show cellularity (e.g. 5%), based on recommended definition, altered cancer cells in fibrous tissue. If multifocality is the percentage of cancer in situ is 90%. suspected, it is recommended that samples be taken from the tissue between the focuses to find macroscopically Microscopic evaluation of the material after systemic hidden “branches” of the main tumour. In addition, rep- treatment resentative fragments of tissues adjacent to the tumour The microscopic evaluation of the material after bed are helpful in the search for residual invasive cancer systemic treatment is more complex and time-consuming and to ensure accurate measurement of tumour size. than the assessment in the absence of such treatment. The assessment of residual tumour size should be In addition to the routine elements of the pathomor- based entirely on histopathological examination of the tu- phological report, the response rate should be deter- mour after macroscopic and microscopic correlation, but mined according to the recommended scoring system: not on the size of the largest single lesion described macro- —— Pinder classification; scopically. Schematic mapping of cross-sections based on —— Residual Cancer Burden (RCB) score. macroscopic description is the most accurate method of From a practical point of view, the RCB is the measuring and assessing residual disease. Therefore, the preferred scoring system. The pathomorphologist can macroscopic dimensions (three) of the residual tumour use a convenient online calculator containing detailed bed can be changed up or down after histopathological instructions for evaluation of each individual parameter. evaluation of the appropriate tissue sections from the The results in the form of estimated RCB and RCB class tumour bed and representative surrounding tissues. also allow a more objective comparison of treatment effects in patients. It is also significant that this system 3. Evaluation of cellularity is more often used and analysed in the literature, espe- Cancer cellularity is the percentage of examined cially American, which in turn increases interest among tissue area (usually of tumour or tumour bed) that is Polish oncologists. occupied by malignant cells, i.e. breast cancer. Both systems include the response within the pri- It should be emphasised that, according to such mary tumour and metastases in lymph nodes. They also a definition, cellularity before treatment does not have take into account the presence of cancer in situ after to account for 100%, and in most cases is smaller. This systemic treatment. definition does not require knowledge about the cel- The evaluation of responses to systemic treatment lularity before treatment. Naturally, the reduction in in breast cancer according to Pinder classification is cellularity observed in the material after treatment is presented in Table 1. the result of therapy effectiveness. This parameter is The diagnosis description should include all in- required to correctly calculate the Residual Cancer formation regarding relevant points, as shown in the Burden (RCB). In practice, the calculation of cellularity microscope image. requires its evaluation in all specimens taken from the The RCB scoring is carried out using an online tumour bed and/or tumour and the calculation of the calculator (http://www3.mdanderson.org), which allows mathematical average from the obtained values. conversion of the required data using a complicated mathematical formula into the corresponding RCB 4. Evaluation of percentage of cancer in situ result and the RCB class assigned to the appropriate The assessment of in situ carcinoma in the material value ranges. after systemic treatment of breast cancer consists of The values required for calculating RCB are listed determining the percentage of in situ texture in rela- in Table 2. tion to the entire cancer histological structure (in situ It should be emphasised that the presence of in situ and infiltrating). texture in RCB scoring system does not exclude a com- The percentage of in situ cancer is one of the parame- plete pathomorphological response: ters required to calculate RCB. Theoretically, infiltrating —— additional parameters of histopathological evalua- cancer responds better to systemic treatment than cancer tion of the material after systemic treatment include in situ. A better blood supply of infiltrating cancer and assessment of Ki67 proliferative index after or during a higher mitotic index mean that the percentage of in situ treatment (material from core needle biopsy) and cancer increases with effective elimination of infiltrating comparison with pre-operative proliferative index; cancer. In practice, however, various combinations in the the use of this parameter requires an evaluation of proportions of cancer in situ and infiltrating tumour tis- at least 500 cells by immunohistochemical staining

301 Oncology in clinical practice 2019, Vol. 15, No. 6

Table 1. Pinder classification Table 3. Categories of Residual Cancer Burden (RCB) assessment system Evaluation of the response to systemic treatment in breast cancer according to Pinder classification Residual Cancer Residual Cancer Burden (RCB) Breast Burden class 1. pCR: (1) with no residual cancer or (2) with no residual RCB 0 With no cancer in the breast or lymph nodes infiltrating cancer, but with the presence of cancer in situ RCB 1 Partial response, minimal residual cancer 2. Partial response: RCB 2 Partial response, moderate residual cancer (1) minimal residual disease (< 10% of residual cancer) or RCB 3 Chemoresistance, extensive residual cancer (2) response from 10–50% of persistent cancer, or (3) > 50% of persistent cancer texture with the present features of injury after treatment can be used to calculate RCB, determine the Pinder 3. With no features of response to treatment classification, and give an indication of the degree of Lymph nodes pathomorphological response according to AJCC/UICC 1. With no metastases and no response to treatment (American Joint Committee on Cancer) (TNM, Tumour, 2. Metastases absent but visible features of response to Nodules, Metastases) and FDA, German Group. treatment The inclusion of the above data also allows the as- 3. Metastasis present, but with features of response to sessment of complete pathomorphological response treatment (pCR), regardless of its definition: 4. Metastases present, with no response to treatment —— pCR in the form of absent infiltrating cancer (in the breast and lymph nodes) — AJCC/UICC (TNM); —— pCR in the form of absent infiltrating cancer (in the breast and lymph nodes) and absent cancer in Table 2. Values required for calculating the Residual Cancer situ — FDA, German Group. Burden (RCB)

1. Primary tumour bed Values and their units Summary The area of the primary tumour bed [mm] × [mm] The introduction of neoadjuvant therapy imposes Total cancer cellularity (as a percentage of (%) the area) a change in the management of the surgical material. The proper principles at the pre-analytic stage, as well Percentage of cancer in situ (%) as modifications in the integrated pathomorphological 2. Lymph nodes diagnosis, are the main elements to properly establish The number of positive lymph nodes patient’s further prognosis. The principles presented in Diameter of the largest metastasis [mm] this report should be used in all cases of breast cancer The above values entered into appropriate patients subjected to systemic treatment before surgery. fields of the calculator allow calculation of the following: — Residual Cancer Burden (RCB) References — Residual Cancer Burden Class (Table 3) 1. CAP Protocols (Protocol for the examination of resection specimens from patients with invasive carcinoma of the breast. Version 4.2.0.0 posted February 2019). 2. Criscitiello C, Golshan M, Barry WT, et al. Impact of neoadjuvant for Ki67 index and determination of the index with chemotherapy and pathological complete response on eligibility for breast-conserving surgery in patients with early breast can- an approximation of at least 1%; cer: a meta-analysis. Eur J Cancer. 2018; 97: 1–6, doi: 10.1016/j. —— assessment of necrosis percentage — this parameter ejca.2018.03.023, indexed in Pubmed: 29734046. is less important than those mentioned above. 3. Tahmassebi A, Wengert GJ, Helbich TH, et al. Impact of Machine Learning With Multiparametric Magnetic Resonance Imaging of the The two additional parameters of histopathological Breast for Early Prediction of Response to Neoadjuvant Chemother- evaluation of the material after systemic treatment are apy and Survival Outcomes in Breast Cancer Patients. Invest Radiol. 2019; 54(2): 110–117, doi: 10.1097/RLI.0000000000000518, indexed now optional in routine diagnostics. They constitute an in Pubmed: 30358693. element of research, including clinical trials. However, 4. Bossuyt V. Processing and Reporting of Breast Specimens in the Neoadjuvant Setting. Surg Pathol Clin. 2018; 11(1): 213– their prognostic value is scientifically proven. –230, doi: 10.1016/j.path.2017.09.010, indexed in Pubmed: The elements of the pathomorphological report de- 29413658. 5. Symman WF, Peintinger F, Hatzis C, et al. Measurement of residual scribed in the points above allow the oncologist to obtain breast cancer burden to predict survival after neoadjuvant chemothe information about the response to treatment. This data rapy. J Clin Oncol. 2007; 25(28): 4414–4422.

302 REVIEW ARTICLE

Jakub Żołnierek Memorial Maria Sklodowska-Curie Oncology Institute, Warsaw, Poland Provincial Specialist Hospital in Biała Podlaska, Poland Magodent sp. z o.o, “Elbląska Hospital” Warsaw, Poland

Enzalutamide in systemic treatment of prostate cancer

Address for correspondence: ABSTRACT Dr n. med. Jakub Żołnierek Prostate cancer is one of the most common tumours in the human population and the most frequently diagnosed Centrum Onkologii — Instytut among genitourinary tumours. Despite relatively high efficacy of systemic treatment in prostate cancer, it is still one im. Marii Skłodowskiej-Curie w Warszawie of the most important causes of premature cancer mortality in men. There are several causes of this phenomenon. ul. Roentgena 5, 02–781 Warszawa One of the most important reasons for such are complications of disease spread and localisation of metastatic e-mail: [email protected] lesions. Others include complications related to implemented treatment, especially if chemotherapy is being administered. However, it is still the specific biological transformation and tumour evolution into state of resistance Oncology in Clinical Practice to castration (CRPC), which develops with time and under hormonal therapy, that is the major clinical challenge. 2019, Vol. 15, No. 6, 303–306 DOI: 10.5603/OCP.2019.0026 Progress in the field of molecular biology enabled identification of the crucial role of signal transduction pathway Copyright © 2019 Via Medica dependent on the androgen receptor (AR) in CRPC. Enzalutamide is the first anti-androgen that interferes with the ISSN 2450–1654 mechanism of progression related to AR gene amplification and/or AR over-expression. The results of the PREVAIL phase 3 trial in a population of men with metastatic CRPC not previously exposed to docetaxel were presented at ASCO GU 2014. These data prove a significant advantage of enzalutamide use over placebo in regard to all study end-points. Enzalutamide is a drug that prolongs progression-free survival and overall survival in different populations of men with CRPC. Key words: castration-resistant prostate cancer, androgen receptor, enzalutamide

Oncol Clin Pract 2019; 15, 6: 303–309

Introduction to castration-resistant status castration-resistant prostate cancer (CRPC). Prostate cancer is one of the most common diagnosed Resistance to castration is a biological stage of the cancers. In Poland it is the second most frequent cancer disease that is a consequence related to specific molecu- in men, which accounts for more than 13% of newly lar alterations that occur in tumour cells, and the cancer diagnosed cases. Its risk increases rapidly after age of progresses despite effective inhibition of androgen syn- 60 years and reaches its maximum at 75 years of age or thesis (serum concentration of testosterone < 50 ng/dL more (five-fold), and in 2013 it resulted in the diagno- or 1.7 nmol/L). These alteration are, among others, sis of 12,000 cases. At the same time, prostate cancer androgen receptor coding gene amplification and/or is one of the most important reasons for premature its over-expression on cancer cells, and structural al- men’s deaths. The incidence rates of prostate cancer terations of receptor protein that lead to its increased increase along with the ageing population and contem- activity (after stimuli caused also by physiological and porary life-style. Due to available effective treatment non-specific ligands). One of the most important fac- modalities, its mortality is not increasing. The serious tors here is the increased ability to convert adrenal clinical issue related to prostate cancer is its evolution androgens or production of de novo of testosterone and

303 Oncology in clinical practice 2019, Vol. 15, No. x its derivates in tumour tissue with secondary autocrine Clinical data stimulation [1]. Enzalutamide in the treatment of patients with castration-resistant prostate cancer Mechanism of action of enzalutamide in the context of CRPC molecular AFFIRM trial biology Chronologically the first conducted phase III clinical trial with enzalutamide was a study evaluating the Due to enormous progress in the field of molecu- efficacy of the drug in a population of patients with lar biology of prostate cancer the signal transduction metastatic CRPC (mCRPC) after failure of previous pathway related to androgen receptor (AR) has been treatment with docetaxel (AFFIRM) [4]. The primary identified to be of crucial importance in the development end-point of this placebo-controlled trial was the over- and progression of prostate cancer in sensitivity as well all survival (OS). Median OS for enzalutamide was as resistance to castration. 18.4 months (95% confidence interval [95% CI] 17.3–not Androgen receptor belongs to family of steroid reached), which was significantly better when compared receptors with transcription factor activity. While with the median in the control arm — 13.6 months inactive it is located in cytosol bound to heat shock (95% CI 11.3–15.8 months, hazard ratio [HR] 0.63; proteins (HSPs). Binding to the ligand initiates its 95% CI 0.53–0.75). The superiority of enzalutamide dissociation from complex of AR-HSPs, and then AR over placebo has been proven for secondary end-points dimerisation and translocation from cytosol to the cell such as: the proportion of patients with reduction in the nucleus. There the activation of androgen-dependent prostate-specific antigen (PSA) level by 50% or more genes occurs, which results in cells proliferation. It (54% vs. 2% in control arm); the soft-tissue response has been proven that castration resistance, as a very rate (29% vs. 4%); time to biochemical (PSA) progres- complex phenomenon by itself, is mainly the effect of sion (8.3 vs. 3.0 months); radiographic progression-free testosterone production in tumour tissue and para- and survival (rPFS) (8.3 vs. 2.9 months); and time to the first autocrine stimulation of prostate cancer cells and/or skeletal-related event (16.7 vs. 13.3 months). molecular changes in AR. These changes may be quan- titative and/or qualitative, such as: AR over-expression, The PREVAIL study prolongation of physiological AR/transcriptional During the American Society of Clinical Oncology complex with AR half-life time, mutations increas- — Genitourinary Annual Meeting 2014 (ASCO-GU) ing AR affinity to physiological ligands, mutations results of the international, randomised, multicentre, increasing AR affinity to ligands which normally do phase III, prospective PREVAIL trial were presented not activate the receptor, and finally — constitutive [5, 6]. The study evaluated the treatment effect of en- activating mutations of AR (which are independent zalutamide on OS and rPFS (co-primary end-points) in from ligand stimuli). a population of 1717 chemo-naïve men with mCRPC. Enzalutamide is the first and the most clini- Asymptomatic or mildly symptomatic patients were cally advanced novel drug of anti-androgen activity randomised (1:1 ratio) to receive a daily dose of 160 mg used in daily clinical practice. Its affinity to AR is of enzalutamide orally or matching placebo. Concomi- 5–8-fold higher when compared to bicalutamide [2] tant steroid use was allowed but not obligatory (finally and, unlike former generations of antiandrogens, about 4% patients received steroids in both arms). it lacks agonistic activity against its the molecular Patients were enrolled into the study during a two-year target molecule. It has been designed to effectively period — from September 2010 to September 2012. The inhibit AR activity and to allow the bypassing of the study population consisted mainly of white Caucasians mechanism of tumour progression resulting from (> 76% of patients in both arms), in very good perfor- the aforementioned molecular alterations of andro- mance status (Eastern Cooperative Oncology Group gen receptor in the phase of castration resistance. [ECOG] 0 in 67–69% of study population), with median The mechanism of action enzalutamide is based on age 71–72 years, and with diagnosis of high-grade adeno- inhibition of the full-length molecule of androgen carcinoma of the prostate — ≥ 8 according to Gleason receptor, inhibition of its translocation from cytosol score in 50.6% and 52.4% — for the enzalutamide and to cellular nuclei, and inhibition of its transcription the placebo arm, respectively. The mean baseline PSA activity by modulation of interaction between AR concentration was 54 ng/mL in the experimental arm and co-regulatory molecules in promoter regions of and 44 ng/mL in the comparator arm. Bone metastatic AR-dependent genes [3]. lesions were diagnosed at baseline in 85% of patients,

304 Jakub Żołnierek, Enzalutamide in systemic treatment of prostate cancer soft-tissue metastatic lesions in 59.3%, and visceral The aforementioned additional analysis confirmed involvement (liver and/or lungs) in 11.2% of patients the benefit of treatment with enzalutamide with respect treated with enzalutamide. Sites of metastatic lesions to rPFS and, what is most important, to OS. It should be were well balanced between the study arms. underlined that this effect has been documented despite The study was prematurely halted after the first the differences between study arms with respect to the interim analysis, due to a significant difference between type of subsequent anti-tumour treatment with their study arms in overall survival in favour of enzalutamide proven beneficial effect on OS. The subsequent treat- (reduction of risk of death by 30% [HR 0.70; 95% CI ment was administered to 81% patients from the control 0.59–0.83, p = 0.0001] and reduction of the risk of radio- arm and 52% patients from the enzalutamide arm. The graphic progression by 81% [HR 0.19; 95% CI 0.15–0.23, treatment with enzalutamide or abiraterone acetate was p = 0.0001]). At that time, after a mean follow-up time given to two-fold more men from the comparator arm of about 22 months, the estimated median OS was (64% vs. 30%, respectively). 32.4 months (95% CI, 31.5–not reached) in the enzalu- The secondary end-points in this study were: objec- tamide arm vs. 30.2 months (95% CI, 28–not reached) tive response rate (ORR), including complete response in patients receiving placebo. The subgroup analysis rate (CR) and partial response rate (PR), median time revealed significant benefit of enzalutamide with respect to PSA progression (TTP PSA), time to deterioration to median OS in each analysed subpopulation, except of quality of life (based on evaluation performed with patients from North America and patients with visceral FACT-P questionnaire — Functional Assessment of metastatic lesions (liver and/or lungs). Cancer Therapy — Prostate), and confirmed PSA At the same time, the median of rPFS for enzaluta- response rate with reduction of PSA concentration mide was not reached, but it was 3.9 months (95% CI by ≥ 50% and ≥ 90% compared to baseline results. 3.7–5.4) in the placebo arm. In the subgroup analysis Objective response rate (according to definitions highly significant benefits with respect to rPFS were of RECIST [Response Evaluation Criteria for Solid achieved in every subpopulation (HR < 0.5). The mean Tumours]) was 58.8% and 5.0% in the enzalutamide time of treatment duration (administered until disease arm and the placebo arm, respectively (p < 0.0001). progression, death, intolerable toxicity, or consent with- There were 19.7% vs. 1% and 39.1% vs. 3.9% rates of drawal) was three-fold longer in the enzalutamide arm complete and partial remission, respectively. Time to than in the control arm (16.6 vs. 4.6 months). PSA progression was 11.2 months for the experimental The results of analysis based on the data collected arm as compared to 2.8 months for the placebo arm (HR after a longer time of follow-up were published in 2016: 0.17, p < 0.0001), while the confirmed PSA response after an additional 20 months for rPFS, nine months for rate (decline of PSA ≥ 50% and ≥ 90% compared to OS and an additional four months for monitoring of baseline) was 78.0% and 46.8% in the enzalutamide arm adverse events related to the conducted treatment [7]. It and 3.5% and 1.2% in the placebo arm (p < 0.0001). was based on a modified population of patients in which These parameters prove the possibility to delay the deci- 325 men received enzalutamide [158 patients from the sion regarding systemic treatment with chemotherapy arm receiving enzalutamide from the beginning of the by 17 months. study and 68 men who were moved to the enzalutamide Based on these data enzalutamide was recognised therapeutic group after un-blinding of the study (26% as an effective agent with respect to activity and safety of experimental arm) and 167 patients who changed measures. Due to recognition of such large difference treatment group during cross-over]. between enzalutamide and placebo, the decision to Finally, 68% risk reduction for death or radiographic unblind the study was undertaken. As a result of this progression during enzalutamide treatment was docu- decision, 167 patients from the control arm crossed-over mented (HR 0.32, 95% CI 0.28–0.37, p < 0.0001) as to the group receiving active treatment. well as risk reduction for death by 23% (HR 0.77, 95% CI 0.67–0.88, p = 0.0002). The investigator assessed The TERRAIN trial median rPFS to be 20.0 months (95% CI 18.9–22.1) In 2016 the results of the TERRAIN study were for enzalutamide and 5.4 months (95% CI 4.1–5.6) for published [8], and its protocol was prepared more-less placebo. Median OS for enzalutamide was 35.3 months simultaneously with the protocols of the PREVAIL and (95% CI 32.2–not reached) and 31.3 months (95% CI PROSPER trials. In this trial, designed as a prospective, 28.8–34.2) for placebo. The most frequently reported blinded, randomised (assignment in 1:1 ratio), phase adverse events related to enzalutamide treatment II trial, the efficacy and safety of enzalutamide and were: fatigue, back pain, constipation, and arthralgia, bicalutamide treatment in a population of men with but these were assessed after exclusion of the popula- castration-resistant prostate cancer were compared. The tion of patients who received enzalutamide after study progression of the disease was defined as PSA progres- unblinding and cross-over. sion (according to the commonly accepted definition

305 Oncology in clinical practice 2019, Vol. 15, No. x for biochemical progression in CRPC), progression AR over-expression as the primary triggering factor of according to RECIST criteria, or progression of bone CRPC transformation. metastatic lesions according to PCWG2 (Prostate Can- cer Working Group) criteria. The PROSPER trial It included men with asymptomatic or mildly There was a hypothesis, based on previously col- symptomatic metastatic disease despite progres- lected data regarding the efficacy of enzalutamide in the sion on effective pharmacological castration (ADT, treatment of patients with castration-resistant prostate androgen-deprivation therapy) enrolled into the study. cancer, that the drug may also offer benefit to CRPC This status was defined as: BPI-SF (Brief Pain Inven- patients without clinically relevant metastatic lesions tory — Short Form) score as the answer to question no. and rapidly rising serum PSA as the only manifesta- 3 < 4, no need for use of opioids, performance status tion of disease progression (PSA DT [PSA doubling according to ECOG (Eastern Cooperative Oncology time] ≤ 10 months). This is the group of patients with Group) score system 0–1, and expected time of life at the highest risk of metastatic spread. To verify the least 12 months. Men with prostate cancer progress- aforementioned hypothesis, a prospective phase III trial ing on previously given anti-androgen treatment and has been conducted in this population, in which patients chemotherapy and with metastatic lesions in the central were randomly assigned (in a 2:1 ratio) to receive treat- nervous system were excluded. The experimental treatment with enzalutamide in a typically administered dose ment along with ADT was conducted in standard dose (160 mg daily) or placebo [9]. The primary end-point for both study drugs (160 mg daily for enzalutamide and was metastasis-free survival (MFS), which was defined 50 mg daily for bicalutamide) until disease progression. as the time from the beginning of the treatment until ra- Progression was defined as radiographic progression, diographic evidence for cancer progression or patient’s skeletal-related events (SRE) occurrence, or initiation death (even if it occurred before radiographic signs of of subsequent anti-cancer treatment. Stratification took metastatic spread). into consideration the method of castration (bilateral There were 1401 men with median PSA DT of orchiectomy or use of agonist/antagonist of luteinising 3.7 months enrolled and randomised to both therapeu- hormone-releasing hormone [LHRH]) before or after tic groups. At the time of data cut-off (June 2017), in the diagnosis of metastatic prostate cancer. The primary 219 out of 933 patients treated with enzalutamide (23%) end-point of the study was progression-free survival and in 228 out of 468 men receiving placebo (49%) (PFS) in the intention-to-treat population. Safety data metastatic disease was diagnosed or death occurred. was analysed in the entire population of patients who Median metastatic-free survival for enzalutamide and received at least one dose of anti-androgen. placebo was 36.6 and 14.7 months, respectively (HR Recruitment was performed between March for metastatic spread or death 0.29; 95% CI 0.24–0.35, 2011 and July 2013 and a total of 375 men were en- p < 0.001). There was significantly improved time rolled (184 and 191 men to receive enzalutamide to initiation of subsequent anti-cancer therapy after and bicalutamide, respectively). Median PFS was treatment with enzalutamide as compared to pla- significantly better in the enzalutamide arm as com- cebo — 39.6 vs. 17.7 months, respectively (HR 0.21, pared to the bicalutamide arm (15.7 months; 95% CI p < 0.001). Such treatment was initiated in 15% of 11.5–19.4 vs. 5.8 months; 95% CI 4.8–8.1 [HR 0.44; 95% patients from the active drug arm. In the control arm CI 0.34–0.57, p < 0.0001]). the rate was 48%. Median time to biochemical progres- The TERRAIN trial proved the significant ad- sion (progression from serum PSA) for enzalutamide vantage of enzalutamide over bicalutamide in respect was several times longer than for placebo and reached to radiographic progression-free survival, objective 37.2 months vs. 3.9 months, respectively (HR 0.07, response rate, time to biochemical progression (PSA p < 0.001). The disease progression was diagnosed in progression), and biochemical response, regardless 22% of men from the experimental arm and 69% of pa- of: patients age, performance status at baseline, PSA tients in the control arm receiving placebo. At the time of concentration at baseline, time of initiation of hormono- the first interim analysis, with evaluation of overall sur- therapy, or previous treatment with anti-androgen. The vival, death was ascertained in 11% and 13% of patients authors highlighted the unsupported use of bicalutamide from the enzalutamide and placebo arms, respectively, in patients diagnosed with CRPC in clinical practice. and these were rates of death in patients in whom no This practice is in conflict with the summary of product radiographic signs of progression had been detected. characteristics for bicalutamide, data indicating only It has been proven that these were sudden deaths not a short-lasting effect of such hormonal manipulation and related to the conducted anti-cancer treatment, except mechanism of action of this anti-androgen — namely two cases of men treated with enzalutamide. Analogi- the component of agonistic activity that creates the cally, clinically significant adverse events (of grade ≥ 3) risk for disease acceleration, especially in the case of were reported in 31% and 23% of patients. It should

306 Jakub Żołnierek, Enzalutamide in systemic treatment of prostate cancer be stressed that observations had been performed in of patients with SRE, as well as time to SRE in an a period of time four-times longer than typically set in intention-to-treat population. protocols of clinical trials for follow-up. The median time on treatment with enzalutamide In this way, it was proven that the treatment with was 16.6 months (interquartile range [IQR] 10.1–21.1) enzalutamide was safe and resulted in a 71% reduction and 4.6 months (range 2.8–9.7). The performed analysis of relative risk for radiographic progression or death in revealed significant differences in changes in assess- CRPC patients with no measurable metastatic lesions ments of quality of life (assessment performed at week but dynamic PSA progression. 61 compared to baseline) in favour of enzalutamide with respect to all end-points of the FACT-P questionnaire and analogue visual scale of EQ-5D. The median Safety issues. Toxicity profile and time to deterioration of quality of life as assessed with treatment effect on quality of life FACT-P questionnaire score was 11.3 months (95% CI 11.1–13.9) in the enzalutamide arm as compared After analysis of safety data from the clinical trials to 5.6 months (5.5–5.6) observed in the placebo group citated above, it should be stated that enzalutamide is (HR 0.62 [95% CI 0.54–0.72], p < 0.0001). There was well tolerated and safe. In the PREVAIL study (enzalu- a significantly higher rate of patients in the enzaluta- tamide in chemo-naive CRPC patients) adverse events mide arm as compared to the placebo group reporting occurred frequently (in 96.9% of patients receiving ac- significant improvement of quality of life based on tive drug and in 93,2% of patients in the control arm); FACT-P score (327 [40%] out of 826 vs. 181 [23%] out however, in 42.9% and 37.1% , then in 32% and 26.8%, of 790), EQ-5D index (224 [28%] out of 812 vs. 99 [16%] respectively, these were categorised as severe (G ≥ 3) out of 623), visual analogue scale (218 [27%] out of or serious. At the same time, the mean time to occur- 803 vs. 106 out of [18%] 603, p < 0.0001 for all as- rence of G ≥ 3 adverse events in the enzalutamide arm sessments). The median time to deterioration of pain was almost two-times longer as compared to placebo (the time of highest pain intensity based on BPI-SF (22.3 vs. 13.3 months). This indicates that most of the questionnaire) was 5.7 months (95% CI 5.6–5.7) in observed adverse events were caused by cancer rather the experimental arm and 5.6 months (5.4–5.6) in the than the toxic effect of the drug. It should be highlighted control arm (HR 0.62 [95% CI 0.53–0.74], p < 0.0001). that only in 5.6% and 6.0%, respectively, were adverse The events of deterioration of pain in week 13 were events the reason for treatment discontinuation and in less common in the enzalutamide arm compared to the 4.2% and 3.8% — the cause of death. placebo arm (220 [29%] out of 769 vs. 257 ]42%] out The most common adverse events related to the drug of 610, p < 0.0001); however, it was not observed for were: fatigue (35.6%), back pain (27%), constipation assessment performed in week 25 (225 [32%] out of (22.2%), arthralgia (20.3%), hypertension (13.4%), 705 vs. 135 [38%] out of 360, p = 0.068). At the time of and elevated serum alanine amino transferase activity data cut-off events of SRE were reported in 278 (32%) (0.9%). Side effects categorised as cardiologic were re- out of 872 patients receiving active drug and 309 (37%) ported in 10.1% of patients (7.8% in the placebo arm). out of 845 patients in the comparator group. The median It should be stressed that in the PREVAIL study there time to the first SRE was 31.1 months (95% CI 29.5–not were no previously reported (AFFIRM study) events of reached) and 31.3 months (95% CI 23.9–not reached) in seizures that had been raised as being a specific danger the enzalutamide arm and placebo group (HR 0.72 [95% related to the drug. The time to deterioration of qual- CI 0.61–0.84], p < 0.0001), respectively. ity of life (based on FACT-P questionnaire) was twice Based on the data discussed above, it was concluded as long in the experimental arm (11.3 vs. 5.6 months in that the drug offers significant clinical benefit with the control arm). respect to all anti-cancer activity parameters as well as In 2015 the results of analysis of the aforementioned quality of life parameters in patients treated with en- PREVAIL study regarding enzalutamide health-related zalutamide. quality of life (HRQoL), pain, and SRE were published [10]. In the TERRAIN trial, giving the possibility to HRQoL was assessed at baseline and during the compare enzalutamide and bicalutamide, there was course of treatment with FACT-P (Functional As- an observation regarding higher incidence in the en- sessment of Cancer Therapy-Prostate) questionnaires zalutamide arm of such side effects as: fatigue (28% and EQ-5D questionnaires, while pain assessment was vs. 20%), back pain (19% vs. 18%), and flushes (15% based on BPI-SF (Brief Pain Inventory Short Form) vs. 11%). However, such adverse events as nausea (17% questionnaire. The performed evaluation regarded vs. 14% in the enzalutamide arm) and arthralgia (in 16% changes of the parameter values as compared to base- vs. 10%, respectively) were more frequently related to line, the relative percentage improvement, and time to administration of bicalutamide. Clinically significant deterioration of HRQoL, pain intensity, percentage (grade ≥ 3) adverse events related to enzalutamide or

307 Oncology in clinical practice 2019, Vol. 15, No. x bicalutamide were quite rare. One out of 10 deaths Enzalutamide plays a similar role in common clinical observed in the trial was probably related to treatment practice because according to published results of pro- with enzalutamide (syndrome of generalised systemic spective clinical trials evaluating its efficacy and safety inflammatory reaction) as compared to one out of three in CRPC treatment after chemotherapy (AFFIRM deaths observed in the bicalutamide arm. trial) or before chemotherapy (PREVAIL, TERRAIN, In general, the toxicity profile of enzalutamide fa- PROSPER trials), the drug proved its advantage with vours its use over. respect to all classic and clinically important (from the perspective of clinicians and, what is more important, patients) endpoints. The indirect comparisons and Summary analyses [14] indicate the equipotency of novel agents in terms of their therapeutic effect on overall survival Although castration-resistant prostate cancer [HR 0.95 (95% CI 0.71–1.26)]. On the other hand, remains a lethal disease, recent years have brought comparative analyses based on meta-analysis of 19 clini- spectacular progress in its treatment. cal trials [15] suggest superiority of enzalutamide over Randomised clinical trials conducted so far indicate abiraterone acetate. According to the results presented several agents that, in a clinically and statistically signifi- in the aforementioned publication, enzalutamide offers cant manner, improve overall survival, progression-free the possibility to increase the median overall survival survival (biochemical and / or radiographic and/or clini- by 5.6 months over abiraterone acetate (p < 0.001, HR cal), as well as quality-of-life in treated patients. 0.81) and median PFS by 8.3 months (p < 0.001, HR Cytotoxic drugs from the taxanes group were ap- 0.47) if both drugs are administered before chemo- proved at first: docetaxel (based on results from the TAX therapy with docetaxel. The differences are even more 327 trial) [11] and cabazitaxel (TROPIC trial) [12]. For pronounced if the results are adjusted by tumour histo years it was docetaxel that dominated in clinical practice, logy grade according to Gleason score (to 19.5 months remaining the most effective treatment option in CRPC. and 14.6 months, respectively). However, the differences However, the important issue regarding chemotherapy, in median PPFS are rather small in the case of use of especially in the case of cabazitaxel, is its toxicity. these drugs after docetaxel chemotherapy [1.2 months Recent decades have been a time of intensive experi- in favour of enzalutamide (p = 0.02)] with no benefit mental efforts with use of anticancer vaccines and other achieved in terms of median OS. strategies to improve immune reactivity against cancer. To date, the results of only one prospective phase III clinical trial — the IMPACT trial with sipuleucel T in References 512 patients with asymptomatic or mildly symptomatic progressive mCRPC [13] — have been published. The 1. Attard G, Cooper CS, de Bono JS. Steroid hormone receptors in prostate cancer: a hard habit to break? Cancer Cell. 2009; 16(6): 458–462, drug significantly improves OS with a lack of effect with doi: 10.1016/j.ccr.2009.11.006, indexed in Pubmed: 19962664. respect to PFS. However, the use of Sipuleucel T was 2. Tran C, Ouk S, Clegg NJ, et al. Development of a second-generation antiandrogen for treatment of advanced prostate cancer. Science. restricted due to the complicated drug preparation pro- 2009; 324(5928): 787–790, doi: 10.1126/science.1168175, indexed cedure. Moreover, the agent lost its approval in CRPC. in Pubmed: 19359544. 3. Hu R, Denmeade SR, Luo J. Molecular processes leading to aberrant Despite this fact, it seems that use of immunotherapy androgen receptor signaling and castration resistance in prostate can- should be restricted to the treatment of patients with cer. Expert Rev Endocrinol Metab. 2010; 5(5): 753–764, doi: 10.1586/ (clinically) asymptomatic biochemical progression of eem.10.49, indexed in Pubmed: 21318111. 4. Scher HI, Fizazi K, Saad F, et al. AFFIRM Investigators. Increased su- prostate cancer and in cases where there is adequate rvival with enzalutamide in prostate cancer after chemotherapy. N Engl time to generate clonal response against the tumour. J Med. 2012; 367(13): 1187–1197, doi: 10.1056/NEJ- Moa1207506, indexed in Pubmed: 22894553. From a practical point of view, the most important 5. Beer TM. ASCO-GU 2014. Prezentacja ustna. Clinical Trials.gov iden- targeted drugs approved in CRPC are abiraterone ac- tifier: NCT01212991. 6. Armstrong AJ, Lin P, Higano CS, et al. PREVAIL Investigators. Enzalu- etate and enzalutamide. These drugs have different toxi tamide in metastatic prostate cancer before chemotherapy. N Engl J city profiles. Enzalutamide, as mentioned above, blocks Med. 2014; 371(5): 424–433, doi: 10.1056/NEJMoa1405095, indexed androgen receptor and inhibits binding to its ligands, in Pubmed: 24881730. 7. Beer TM, Armstrong AJ, Rathkopf D, et al. Enzalutamide in men while abiraterone acetate inhibits androgen synthesis with chemotherapy-naïve metastatic castration-resistant prostate in gonads, suprarenal glands, and within tumour tissue. cancer: extended analysis of the phase 3 PREVAIL study. Eur Urol. 2017; 71(2): 151–154, doi: 10.1016/j.eururo.2016.07.032, indexed in In the COU-AA-301 trial (given after chemotherapy Pubmed: 27477525. with docetaxel) and in the COU-AA-302 trial (chemo- 8. Hussain M, Fizazi K, Saad F, et al. Enzalutamide in men with non- -metastatic, castration-resistant prostate cancer. N Engl J Med. therapy-naive patients) abiraterone was characterised 2018; 378(26): 2465–2474, doi: 10.1056/NEJMoa1800536, indexed by significantly improved median progression-free sur- in Pubmed: 29949494. vival (biochemical, radiographic, and clinical) as well 9. Shore ND, Chowdhury S, Villers A, et al. Efficacy and safety of enzalutamide versus bicalutamide for patients with metastatic prostate cancer as overall survival. (TERRAIN): a randomised, double-blind, phase 2 study. Lancet Oncol.

308 Jakub Żołnierek, Enzalutamide in systemic treatment of prostate cancer

2016; 17(2): 153–163, doi: 10.1016/S1470-2045(15)00518-5, indexed 1147–1154, doi: 10.1016/S0140-6736(10)61389-X, indexed in Pub- in Pubmed: 26774508. med: 20888992. 10. Loriot Y, Miller K, Sternberg CN, et al. Effect of enzalutamide on health- 13. Crawford ED, Petrylak DP, Higano CS, et al. IMPACT Study Investi- -related quality of life, pain, and skeletal-related events in asympto- gators. Sipuleucel-T immunotherapy for castration-resistant prostate matic and minimally symptomatic, chemotherapy-naive patients with cancer. N Engl J Med. 2010; 363(5): 411–422, doi: 10.1056/NEJ- metastatic castration-resistant prostate cancer (PREVAIL): results from Moa1001294, indexed in Pubmed: 20818862. a randomised, phase 3 trial. Lancet Oncol. 2015; 16(5): 509–521, doi: 14. Li T, Thompson M, Todd M, et al. An indirect treatment comparison 10.1016/S1470-2045(15)70113-0, indexed in Pubmed: 25888263. (ITC) and cost-effectiveness analysis of abiraterone acetate and en- 11. Tannock I, Wit Rde, Berry W, et al. Docetaxel plus prednisone or mito- zalutamide for the treatment of metastatic castration-resistant prostate xantrone plus prednisone for advanced prostate cancer. N Engl J Med. cancer (mCRPC) post-chemotherapy. Journal of Clinical Oncology. 2004; 351(15): 1502–1512, doi: 10.1056/nejmoa040720. 2014; 32(4_suppl): 270–270, doi: 10.1200/jco.2014.32.4_suppl.270. 12. de Bono JS, Oudard S, Ozguroglu M, et al. TROPIC Investiga- 15. Fang M, Nakazawa M, Antonarakis ES, et al. Efficacy of Abiraterone and tors. Prednisone plus cabazitaxel or mitoxantrone for metastatic Enzalutamide in Pre- and Postdocetaxel Castration-Resistant Prostate castration-resistant prostate cancer progressing after docetaxel Cancer: A Trial-Level Meta-Analysis. Prostate Cancer. 2017; 2017: treatment: a randomised open-label trial. Lancet. 2010; 376(9747): 8560827, doi: 10.1155/2017/8560827, indexed in Pubmed: 29359049.

309 REVIEW ARTICLE

Mateusz Spałek, Anna M Czarnecka Department of Soft Tissue/Bone Sarcoma and Melanoma, Maria Skłodowska-Curie Institute — Oncology Centre, Warsaw, Poland

The role of radiotherapy in melanoma

Address for correspondence: ABSTRACT Lek. Mateusz Spałek The role of radiotherapy (RT) in the treatment of melanoma is constantly evolving. Although melanoma is consid- Klinika Nowotworów Tkanek Miękkich, ered a radioresistant tumour with great potential for repairing sub-lethal damage, RT is an important component Kości i Czerniaków of treatment. Indications for sole or adjuvant radiotherapy of the primary lesion are limited and include desmo- Centrum Onkologii — Instytut plastic melanoma, the presence of satellite lesions and/or in-transit metastases, the presence of melanoma cells im. Marii Skłodowskiej-Curie in blood or lymphatic vessels, infiltration of nerve trunks, recurrence after previous surgery, and locally advanced ul. Roentgena 5, 02–781 Warszawa melanomas of the head and neck region, especially inoperable. In the past, the most common indication for Phone: 22 546 24 55 radiotherapy in melanoma was adjuvant treatment after lymphadenectomy in patients with risk factors for nodal e-mail: [email protected] recurrence (large metastasis diameter, multiple nodes involved, extracapsular extension). Adjuvant radiotherapy after lymphadenectomy has been shown to almost double the local control of the disease, but it does not affect patient survival and may also lead to significant toxicity. Nevertheless, currently the recommended approach is systemic adjuvant treatment (anti-PD-1 immunotherapy with pembrolizumab or nivolumab and, in the presence of BRAF mutation, BRAF/MEK inhibitors), and RT should be reserved for situations in which there are contraindications to other adjuvant treatment. Stereotactic techniques, including radiosurgery of brain metastases, are becoming more widely used. RT could be a definitive treatment for a limited number of metastases or in cases of limited progression on systemic treatment. The effectiveness of RT can be increased by combining with hyperthermia. An increasing number of reports suggest great benefit from the combination of RT with immunotherapy. At present, there is no convincing evidence supporting the combination of RT with molecularly targeted treatment, and ac- Oncology in Clinical Practice cording to emerging data on the toxicity of such a combination it should be used with caution. 2019, Vol. 15, No. 6, 310–319 Key words: melanoma, radiotherapy adjuvant, immunotherapy, radiotherapy DOI: 10.5603/OCP.2019.0031 Translation: dr n. med. Dariusz Stencel Copyright © 2019 Via Medica Oncol Clin Pract 2019; 15, 6: 310–319 ISSN 2450–1654

Introduction especially over the past 20 years (Table 1). In 2004 it was calculated that, according to the current state of Radiotherapy (RT) is one of the three basic thera- knowledge and best clinical practice, RT should be used peutic modalities in oncology, and its role in the treat- in as much as 23% of patients with advanced melanoma ment of melanoma is constantly evolving. Historically, [1]. There are no such data in the literature for the last melanoma cells were considered to be radioresistant, 10 years; however, due to the prolonged survival of pa- hence the role of RT was mainly limited to the symp- tients and the beneficial effects of the combination of RT tomatic treatment of advanced disease. In the past, RT and immunotherapy, it can be assumed that nowadays was used in selected cases as an adjuvant treatment after this proportion should be even higher. surgery for primary lesion or lymph nodes, and as palliative treatment in patients with distant metastases. The rapid development of precise RT techniques, new im- Radiobiology of melanoma aging methods, and the introduction of new options of effective systemic treatments have caused the role of RT Studies on cell lines have shown that melanoma has in the treatment of melanoma to change significantly, a high ability to repair sub-lethal damage [2]. Hence, it

310 Mateusz Spałek, Anna M Czarnecka, The role of radiotherapy in melanoma

Table 1. Evolution of the role of radiotherapy in melanoma treatment

Radiotherapy type Past Present Adjuvant after lymphadenectomy +++ + Palliative +++ ++* Whole brain radiotherapy +++ + Adjuvant after primary tumour resection ++ +

Definitive + ++* Oligometastatic disease + ++*# Oligoprogression – +++*# “Boost” during immunotherapy – +++?*

*Including stereotactic techniques #Also treatment of brain metastases with radiosurgery was concluded that higher dose per fraction is needed clinical situation. For microscopic margins smaller than to achieve satisfactory local control (LC). The results 8 mm, adjuvant RT reduced the risk of local recurrence of retrospective analyses of large groups of patients by approximately 50% [7, 8]. carried out in the 1980s confirmed the hypothesis that In some clinical situations, RT may improve the LC a higher dose per fraction is an independent factor of the after surgical treatment. Adjuvant RT after primary effectiveness of RT. However, no significant differences tumour resection should be considered for high-risk were found between hypofractionated RT regimens [3]. local recurrence factors, which include the following [9]: Further studies questioned the benefit of hypofractiona- —— desmoplastic subtype with lesion thickness according tion over conventional RT regimens [4]. The results of to Breslow > 4 mm; a large international prospective randomised clinical —— extensive macroscopic ulceration; trial by the Radiation Therapy Oncology Group (RTOG —— presence of satellite lesions and/or in-transit me- 83-05) showed no significant difference in LC between tastases; 8 Gy per fraction administered four times over 21 days —— presence of melanoma cells in blood or lymphat- and 2.5 Gy per fraction administered five days a week ic vessels; for four weeks. In clinical practice, when calculating the —— infiltration of nerve trunks (regardless of subtype); biological effective dose or equivalent dose to a 2 Gy —— recurrence after surgery of the primary tumour; fraction dose, it should be assumed that the alpha/beta —— locally advanced melanomas of the head and ratio of melanoma is lower than 3 Gy [5]. neck area. The advantage of a specific fractionation regimen over the others was not demonstrated. One of the most Primary lesion treatment — skin commonly used is the administration of 30 Gy in five melanomas fractions of 6 Gy during 2.5 weeks [10]. Due to the growing evidence supporting the use of Wide local excision is the primary method of mela- neoadjuvant or adjuvant immunotherapy and molecu- noma treatment. Definitive RT is reserved only for larly targeted treatment in patients with locally advanced patients who cannot undergo surgery (e.g. locally ad- melanomas, definitive RT can also be a consolidation vanced disease, disability, comorbidities, lack of patient treatment after achieving a response to systemic therapy. consent). RT may be an alternative to surgical treatment Such management is not yet supported with scientific of lentigo maligna (extensive facial lesions) in selected evidence, and all decisions should be made individually groups of patients. The regimen consists of a total dose after discussing the clinical situation at a multidiscipli- of 50–52 Gy in 2 Gy fractions using superficial RT nary meeting. (kilovolt radiation). RT of lentigo maligna — definitive or adjuvant to non-radical surgery — provides LC of 83–97% [6]. Primary lesion treatment — mucosal Desmoplastic melanoma is a subtype of melanoma melanomas in which adjuvant RT is used. Because of the tropism to nerve cells (spreading along nerve trunks), wide local Mucosal melanomas account for about 1% of all excision may not be sufficient to achieve satisfactory LC. melanomas [11]. Most often they affect the head and Analysis of large groups of patients with neurotropic neck region, perianal area, rectum, and genitourinary melanomas supported the use of adjuvant RT in this tract. The treatment of choice is surgery. RT can be

311 Oncology in clinical practice 2019, Vol. 15, No. 6 a adjuvant treatment after non-radical surgery or did not differ significantly between the groups. Further- definitive therapy of inoperable lesions. Most reports more, RT often led to late toxicity. Low-grade toxicity, of the effectiveness of sole RT in the treatment of mu- such as chronic pain and fibrosis of skin and subcutane- cosal melanomas relate to the head and neck region, ous tissue, were common. In 22% of irradiated patients, in particular paranasal sinuses. Definitive RT allows serious toxicity (CTCAE grade 3 and 4) occurred, mainly a three-year LC of 50–85%. Due to the increasing role affecting the skin (10%) and subcutaneous tissue (7%). of systemic therapy in locally advanced melanomas and Five years after treatment completion a significantly the potential immunosensitization by RT, concomitant larger lower limb volume was observed in the irradiated definitive radioimmunotherapy might be considered. group than in patients undergoing surgery alone. The risk Such treatment should be carried out within clinical of lymphoedema was highest for groin irradiation, medi- trials or in tertiary centres with experience in the treat- um for axillary irradiation, and relatively low for irradia- ment of melanomas. tion of lymph nodes of the head and neck region (Fig. 1). Postoperative RT of mucosal melanomas improves On the other hand, nodal relapses may be associated with LC but has no effect on patient survival [12, 13]. In symptoms worsening the patient’s quality of life, such as some centres, adjuvant RT of mucosal melanomas ulceration, bleeding, pain, and lymphoedema. In turn, is used routinely because recurrence in these sites is RT for large lymphatic area is also associated with the usually unresectable and is associated with a dramatic risk of significant toxicity in the form of persistent lym- deterioration of patients’ quality of life. Due to the phoedema, fistulas, fibrosis, ulceration, and symptoms lack of recommendations, the management should be associated with particular anatomical regions. Hence, individual and include evaluation of: the decision to use RT after lymphadenectomy should —— performance status; be made taking into account the risk-benefit balance and —— risk factors for recurrence; availability of alternative treatments. The preferred RT —— potential RT toxicity and proximity of organs at risk; regimen is 48 Gy in 20 fractions of 2.4 Gy. —— the possibility of other adjuvant treatment (sys- Risk factors for nodal recurrence after lymphad- temic therapy). enectomy that may be indications for adjuvant radio- In some locations, the use of proton therapy may therapy include: benefit, allowing greater protection for radiosensitive —— extracapsular extension of nodal melanoma me- organs at risk such as central nervous system (CNS) tastases; structures and sense organs. In Poland in 2019, proton —— metastases to multiple lymph nodes (any number of therapy is reimbursed in cases of inoperable melanoma parotid nodes, two or more cervical or axillary nodes, of paranasal sinuses or as a adjuvant treatment after its three or more inguinal nodes); non-radical resection.

Adjuvant RT after lymphadenectomy Cervical 100 In the past the most common indication for RT in melanoma patients was macroscopic lymph node Axillary metastasis. The role of RT in this setting significantly 80 decreased after the introduction of effective systemic Groin therapies such as immunotherapy or molecularly 60 targeted treatment (BRAF and MEK inhibitors). At (%) present, US NCCN recommendations give adjuvant RT 5-year edema-free category 2B, while adjuvant systemic treatment has the ercent P 40 survival highest level of recommendation (category 1). Adjuvant RT after lymphadenectomy almost doubles LC but has Cervical = 90% no effect on patient survival [14, 15]. In the ANZMTG Axillary = 80% 20 Groin = 73% 01.02/TROG 02.01 randomised clinical trial, 250 pa- p < 0,001 tients with stage III melanoma were randomly assigned for adjuvant RT (48 Gy in 20 fractions) or observation 0 after lymphadenectomy. 0 5 10 Patients in the RT arm had a significantly lower Years from radiation percentage of nodal recurrences compared to non-irradiated patients (21 vs. 36%, hazard ratio 0.52, 95% CI Figure 1. The risk of lymphoedema following surgery and 0.31–0.88), but relapse-free survival and overall survival radiotherapy of large nodal areas [42]

312 Mateusz Spałek, Anna M Czarnecka, The role of radiotherapy in melanoma

—— large metastasis diameter (three or more centimetres rence after adjuvant treatment. An alternative approach for cervical lymph nodes, four or more centimetres is frequent follow-up and treatment (surgery ± RT ± sys- for axillary and inguinal nodes); temic treatment) in the case of locoregional recurrence. —— non-radical resection; The algorithm presented in Figure 2. —— recurrence after previous lymphadenectomy. Patients with skin melanoma of the head and neck Nevertheless, the recommended approach is to qual- region with lymph node metastases constitute a par- ify the patient for systemic adjuvant treatment (currently ticular group. Cervical lymphadenectomy with adjuvant available options include anti-PD-1 immunotherapy therapy (RT, immunotherapy, and BRAF and MEK with pembrolizumab or nivolumab and additionally, in inhibitors) is the preferred management; however, sole the case of BRAF mutations, BRAF/MEK inhibitors: radiotherapy can be an alternative to surgery. In an dabrafenib with trametinib), preferably within controlled American study, a small group of patients (n = 36) with clinical trials if available. RT should be considered in skin melanoma of the head and neck region underwent clinical situations in which neither immunotherapy (e.g. dissection of macroscopically suspicious lymph nodes active severe autoimmune disease) nor molecularly tar- followed by RT of lymphatics using 6 Gy twice a week for geted therapy (lack of BRAF mutation) can be used, or as a total dose of 30 Gy [16]. Five-year LC was higher than a rescue treatment after resection of locoregional recur- 90%, and the rate of late toxicities did not exceed 10%.

Lymph nodes with macroscopic metastases of melanoma after resection

Participation in Systemic treatment randomised (BRAF/MEK inhibitors, controlled immunotherapy) trials

Treatment not available or contraindications — risk factors of nodal relapse should be assessed

Cervical lymph nodes Axillary lymph nodes Inguino-iliac/obturator Inguino-iliac/obturator — one of the following: — one of the following: lymph nodes with BMI < 25 lymph nodes with BMI ≥ 25 — ECE (+) — ECE (+) — one of the following: — ECE (+) and one of the — diameter ≥ 2 cm — diameter ≥ 3 cm — ECE (+) following: — metastases in 2 lymph — ≥ metastases in ≥ 4 lymph — diameter ≥ 3 cm — diameter ≥ 3 cm nodes nodes — metastases in ≥ 4 lymph — metastases in 4 lymph — recurrence ≥ — recurrence nodes nodes — recurrence — recurrence

YES NO

Frequent follow-up Radiotherapy 48 Gy and treatment in 20 fractions upon progression

Figure 2. Algorithm of management after lymphadenectomy due to macroscopic melanoma metastases to lymph nodes

313 Oncology in clinical practice 2019, Vol. 15, No. 6

Stereotactic RT and radiosurgery mia 46%) [18]. Hyperthermia was very well tolerated. However, the results of the study should be interpreted Stereotactic body radiotherapy (SBRT) is a RT with caution due to the low percentage of patients who method that involves delivering a high fraction dose completed the treatment according to the protocol to a small volume of a macroscopically visible tumour, (14%). Most reports on the role of hyperthermia in sparing surrounding healthy tissues (without elective melanoma are from the 1980s and 1990s, and hence volume). Its particular type is stereotactic radiosurgery do not take into account the contemporary systemic (SRS), in which the prescribed dose is delivered in one treatments that might be combined with RT. The use of fraction. It is mainly used in irradiation of tumours of the hyperthermia during RT may allow for a better response CNS. SBRT and SRS are increasingly used in the treat- by increasing tumour perfusion and oxygenation, inhibit- ment of melanoma patients. Indications may include: ing DNA repair mechanisms, cell death, and extensive —— inoperable primary lesions, e.g. limited-volume immune modulation, including increased expression of mucosal melanomas; immunogenic surface receptors such as MHC-1 and heat —— inoperable recurrent melanoma with limited volume; shock protein secretion, which activate NK cells and —— brain metastases; antigen-presenting cells, thereby intensifying immune —— oligoprogression during systemic treatment; responses mediated by CD8+ cells [19]. —— oligometastatic disease; It seems necessary to conduct prospective clinical —— single spinal or other bones metastases. trials. The data available so far allow the routine use Fractionation regmens should be appropriate to the of hyperthermia in combination with RT in the treat- anatomical site, taking into account the tolerance of ment of advanced melanomas; however, in the case of organs at risk. It should be noted that there are currently concomitant use of immunotherapy or targeted therapy, no recommendations as to optimal fraction and total qualification should be careful. doses for SBRT and SRS in melanoma patients. In order to apply optimal RT regimen and dose constraints for organs at risk, protocols of ongoing clinical trials in oli- Palliative RT gometastatic disease such as NRG-BR001 can be used. RT can be an effective symptomatic treatment of melanoma metastases to the bone, brain, soft tissues, RT as a treatment of limited and lungs and a emergency therapy in case of devel- progression oping spinal cord compression or superior vena cava syndrome. Additionally, RT is also one of the options RT may play a role in local definitive treatment for achieving LC in patients with numerous unresectable of metastases that has progressed during a currently in-transit metastases of melanoma. Doses higher than effective systemic treatment. Oligoprogression occurs 4 Gy per fraction are preferred because of the higher when, in a single or several metastatic lesions, molecular probability of achieving a response (82% at doses > 4 Gy changes develop that determine resistance to treatment. vs. 44% at ≤ 4 Gy) [20]. The RT regimen should be An effective method of local treatment extends the time adapted to the patient’s performance status, cancer of use of systemic therapy, which provides benefit to stage, and possibilities of systemic treatment. patients [17]. SBRT seems to play a special role because The management of brain metastases is a separate it provides very good LC with minimal toxicity. In some issue. The role of whole brain RT decreased in the last cases, the combination of RT and immunotherapy may years due to low efficacy of such treatment and its severe enhance effectiveness of systemic treatment, which is toxicity. If possible, the treatment of choice should be described later in this article. surgery or SRS. The issue is discussed in detail in the Polish guidelines for the management of brain melanoma metastases [21]. RT in combination with hyperthermia A particularly challenging clinical situation is the presence of melanoma metastases to the spine (bones or Hyperthermia is a method of temporarily increasing soft tissues), due to the risk of fracture or the spinal cord the temperature within a tumour to increase the effect compression with neurological deficits and severe pain. of RT or chemotherapy. The mechanism of heat efficacy The combination of immunotherapy with RT and local in the treatment of cancer has not been fully explained, neurosurgical interventions often gives satisfactory LC but the effectiveness of such a combination of methods in this group of patients. The best results were obtained has been demonstrated in a randomised clinical trial: when SRS or SBRT was applied to residual tumour vol- combining local hyperthermia with RT in patients with ume after surgical spinal cord decompression, where the advanced melanomas led to a significantly increased LC one-year local recurrence rate did not exceed 10% [22, (sole radiotherapy 28%, radiotherapy with hyperther- 23]. The alternative may be a sole SRS/SBRT — some

314 Mateusz Spałek, Anna M Czarnecka, The role of radiotherapy in melanoma studies indicate that the LC rate of such treatment is SRS alone [27]. RN usually develops seven to 12 months higher than 90% [24]. At present, there are no data on after therapy and may be associated with the onset of the effectiveness of combining immunotherapy with neurological disorders, including convulsions, speech SRS/SBRT in the treatment of melanoma metastases disorders, psychomotor retardation, and sensory-motor to the spine. deficiency [28]. Final analysis and publication of the results of NCT01721603 study is awaited. Increasing number of publications raise the issue of RT in combination with molecularly potential enhancement of side effects. There are many targeted therapy case reports in the literature regarding increased skin toxicity when BRAF inhibitors are used concomitantly Data regarding the sense of combining BRAF in- with RT. RT while receiving BRAF inhibitors increases hibitors with simultaneous RT are contradictory, and the risk of RTOG grade 2 and 3 dermatitis and other the use of such a combination requires caution. Some rare skin complications (e.g. cutis verticis gyrata when reports suggest an advantage of using the described combined with whole brain RT). This effect is prob- combination in sensitising melanoma cells to RT after ably dose-dependent; therefore, doses ≥ 4 Gy are not the administration of BRAF inhibitors [25]. recommended for conventional radiotherapy in patients Targeted therapy can reduce the size and number taking BRAF inhibitors. No similar side effects have of metastases in CNS and thus in some cases allow the been reported in the literature for MEK inhibitors. The use of SRS instead of whole brain RT. However, there guidelines of the Eastern Cooperative Oncology Group is no clear biological explanation for the potential recommend discontinuation of BRAF and MEK inhibi- synergy of RT and BRAF/MEK inhibitors, as in the tors at least three days before the start of RT and the case of immunotherapy, except for the immunological re-use of these drugs at the earliest three days after its impact of BRAF-targeted therapy. However, recent completion or one day before and one day after CNS studies indicated that the combination of targeted SRS. However, it should be emphasised that these therapy with SRS, similarly to immunotherapy, seems recommendations are not based on strong scientific to improve overall survival [26]. An ongoing, prospec- evidence. The decision to temporarily withdraw targeted tive, open-label, phase II study (NCT01721603) will therapy during RT should be individualised after com- assess the effect of dabrafenib in combination with prehensive analysis of the patient’s clinical situation by SRS on the six-month brain metastasis-free survival a clinical oncologist and a radiation oncologist, because rate compared to historical control (SRS alone). In discontinuation of targeted therapy may lead to rapid this study, all patients will receive dabrafenib 150 mg disease progression [29]. twice daily (continuous dosing) and trametinib at an initial dose of 2 mg once daily, starting from cycle 3 on day 1. Treatment continues until disease progression, RT in combination with immunotherapy consent withdrawal, or development of intolerable treatment-related toxicity. MRI is performed after Available data suggest a beneficial effect of com- 28 days of dabrafenib treatment. Patients with complete bining RT with immunotherapy. This is confirmed by response (regression of all brain lesions) will continue to increased frequency of an extremely rare phenomenon receive dabrafenib and trametinib during the study but known as the abscopal effect (response of untreated will not be qualified for SRS. For patients with disease lesions as consequence of local treatment of another le- stabilisation or partial response to treatment, SRS will be sion) with simultaneous use of RT with immunotherapy performed in cycle 2 (± 3 days, 28-day cycle). The first [30]. The benefits of combining the described methods data from interim analysis showed that one-year overall may result from the so-called antigenic effect, when survival (64.3 vs. 40.4%, p = 0.205), local progression RT breaks down affected melanoma cells and releases rate (3.3 vs. 9.6%, p = 0.423), and distant intracranial antigens into the blood, which stimulates dendritic cells progression rate (63.9 vs. 65.1%, p = 0.450) were not and lymphocytes, and thus enhances the effect of im- statistically different between the SRS + BRAF inhibi- munotherapy (Fig. 3, Fig. 4). tors and SRS alone groups. Patients in the group receiv- Preclinical studies have shown that the combination ing both SRS and BRAF inhibitors had higher rates of of RT and anti-PD-1/PD-L1 immunotherapy activates radiation necrosis (RN) (22.2 vs. 11.0% after one year, cytotoxic T cells, reduces levels of bone marrow suppres- p < 0.001) and symptomatic radiation necrosis (SRN) sor cells, and induces a response of non-irradiated lesion (28.2 vs. 11.1% after one year, p < 0.001) than patients to RT of another lesion [31]. RT results in increased who received only BRAF inhibitors. Multivariate analy- antigen presentation and CD8+ T-cell infiltration, sis showed that treatment with BRAF inhibitors implies stimulation of tumour-specific cytotoxic T lymphocytes an increased risk of both RN and SRN compared to in many metastatic lesions, which can lead to abscopal

315 Oncology in clinical practice 2019, Vol. 15, No. 6

What determines clinical response to RT?

¯checkpoint function −checkpoint function

Apoptotic Necrotic Necro(pto)tic Senescent cell cell cell cell

Recruitment of Recruitment of neurophils, macrophages monocytes, macrophages Recruitment of and NK cells and dendritic cells monocytes, macrophages and dendritic cells

Production of anti- ? inflammatory cytokines Production of pro- inflammatory cytokines and enhanced cross presentation Tolerance induction ? Stimulation of adaptive anti-tumour immunity

Figure 3. Immunological factors determing response to radiotherapy [43]

Radiation

Apoptosis and death of some tumour cells

Primary tumour Vascular normalization

Mild immune response induced Peptide modulation MHC I elevation Cytokine and chemokine Immunotherapy APC infiltration Distant More CD8+ T-cells tumour MDSC reduction

Systemic immune response

Tumour-specific Tumor-specific T-cell T-cell infiltration infiltration

Tumour regression

Figure 4. Mechanism of radiotherapy and immunotherapy synergy [44]

316 Mateusz Spałek, Anna M Czarnecka, The role of radiotherapy in melanoma effect during immunotherapy. An example of this effect [38]. Median overall survival, objective response rate, was described in NEJM in 2013 [32]. In a melanoma overall response rate, and median progression-free sur- patient during treatment with ipilimumab, the progres- vival significantly improved in the ipilimumab and RT sion occurred in a form of constantly-growing metastatic group. In addition, no increase in toxicity was seen in the lesions within the pleura and new spleen lesions. She re- group receiving combination treatments compared to ceived palliative RT for the paravertebral conglomerate ipilimumab alone. We are currently awaiting the results metastases using 28.5 Gy in three fractions. Response of the phase II clinical trial NCT01970527 RADVAX, in was seen in lesions that were outside target volume. which the effects of combining SBRT with ipilimumab In one prospective clinical trial, 22 patients under- will be assessed. The results of the phase I clinical went RT for a single lesion five days after receiving trial NCT01996202 have not yet been published; in this the first dose of ipilimumab [33]. Six patients achieved study a combination of ipilimumab and RT was used as objective responses, including three partial regressions neoadjuvant or adjuvant therapy in melanoma patients and three complete responses. Similarly, another study with poor prognosis. This group included patients with showed that adding ipilimumab to RT significantly mucosal melanomas, desmoplastic melanomas, melano- prolongs the survival of patients with brain melanoma mas of the head and neck region, and melanomas from metastases compared to RT alone (median overall outside this area, but with macroscopic lymph node survival: 18.3 months vs. 5.3 months) [34]. Oncologists involvement and the presence of previously described from Penn University analysed a group of 22 patients risk factors being the indications for RT. with stage IV melanoma in a phase I study receiving In the study with RT combined with anti-PD-1 im- SBRT (2–3 fractions of 6–8 Gy), and after five days munotherapy the response rate of non-irradiated lesions four cycles of ipilimumab [35]. In the study, 8/22 (36%) was 46% [39]. Interesting observations also come from patients achieved complete or partial response to the analyses of effects of combining immunotherapy with treatment. At the same time, using the mouse model, RT in melanoma patients with brain metastases. The they described a number of molecular relationships, results of the retrospective analysis from 2016 confirm including the observation that RT increased the presen- the effectiveness of this combination with good toxicity tation of tumour cell antigens for T cells, administration profile. A group of 26 melanoma patients with brain of anti-CTLA-4 treatment promotes T-cell expansion, metastases who received nivolumab in the last six and anti-PD1 drugs reverse T-cell depletion. A team months before, during, or after RT underwent SRS of from the Dana-Farber Institute described a group of metastatic CNS lesions [26]. LC after six and 12 months 47 patients with stage IV melanoma, who received RT was 91% and 85%, respectively. Similar results were after ipilimumab treatment [36]. In this group, 53% obtained using pembrolizumab with RT. The results of patients were irradiated within three months of of a retrospective study assessing the effectiveness of ipilimumab treatment. The most frequent types of RT SRS and pembrolizumab in patients with diagnosed were: 34% = brain SRS, 19% = whole brain RT, and brain melanoma metastases support the hypothesis 17% = RT for soft tissue metastases. In total 11% of of the benefits of combining these methods. SRS with lesions responded after treatment with ipilimumab alone concurrent administration of pembrolizumab results in as compared to 25% of responses after adding ipilimum- significantly better responses (8/23 complete responses, ab to RT. RT was also associated with faster response. 8/23 partial responses, 16/23 in total) than SRS without BRAF mutation status, total dose and target volume concurrent immunotherapy (5/23). On the other hand, localisation, and time of ipilimumab administration did it should be remembered that not only BRAF inhibitors not affect response to treatment. Lower fraction doses increase the toxicity of RT, but also immunotherapy can (≤ 3 Gy) were the only factor that positively correlated be a factor associated with the development of RN [27]. with an increased response rate. The study from the Other observations, including data from the MD Ander- University of Cologne included 127 patients with stage son Cancer Centre, do not support this hypothesis [40]. IV melanoma, 82 of which received ipilimumab alone The optimal timing to start RT remains an open and 45 received local treatment, and 40 patients received question. Available data suggest that RT is most benefi- both ipilimumab and RT [37]. 17/45 (38%) obtained cial when used concurrently with immunotherapy [39]. objective responses in the group of patients treated with The optimal RT dose regimen during immunotherapy is ipilimumab and RT compared to 12/82 (15%) of those unknown. At present, many clinical studies are ongoing receiving only ipilimumab. The median overall survival with the combination of RT and immunotherapy in the was 93 weeks in the RT and immunotherapy group treatment of advanced melanomas, and their results will vs. 42 weeks in the group receiving radiotherapy alone; provide valuable data on the optimal combination of the difference was statistically significant (p = 0.003). RT with immune checkpoint inhibitors [41]. Particularly Koller et al. evaluated a cohort of patients with advanced interesting will be the results of the NCT03850691 study. melanoma treated with ipilimumab with or without RT This is a phase II clinical trial that aims to evaluate the

317 Oncology in clinical practice 2019, Vol. 15, No. 6 combination of nivolumab immunotherapy and aldesleu- 11. Chang AE, Karnell LH, Menck HR. The National Cancer Data Base report on cutaneous and noncutaneous melanoma: a summary kin (IL-2) therapy after receiving standard palliative RT of 84,836 cases from the past decade. The American College for the treatment of inoperable metastatic melanoma. of Surgeons Commission on Cancer and the American Cancer Society. Cancer. 1998; 83(8): 1664–1678, doi: 10.1002/(sici)1097- Patients with a diagnosis of cutaneous melanoma who 0142(19981015)83:8<1664::aid-cncr23>3.0.co;2-g, indexed in have at least three (preferably > 5) measurable > 1.5 cm Pubmed: 9781962. lesions and have already received systemic treatment in 12. Benlyazid A, Thariat J, Temam S, et al. Postoperative radiotherapy in head and neck mucosal melanoma: a GETTEC study. Arch Otolar- the form of immunotherapy, BRAF/MEK inhibitors, yngol Head Neck Surg. 2010; 136(12): 1219–1225, doi: 10.1001/ar- and/or chemotherapy are eligible for the study. choto.2010.217, indexed in Pubmed: 21173371. 13. Kirschner AN, Kidd EA, Dewees T, et al. Treatment approach and outcomes of vaginal melanoma. Int J Gynecol Cancer. 2013; 23(8): 1484–1489, doi: 10.1097/IGC.0b013e3182a1ced8, indexed in Pubmed: 23945202. Conclusions 14. Burmeister BH, Henderson MA, Ainslie J, et al. Adjuvant radiotherapy versus observation alone for patients at risk of lymph-node field relapse RT has an important role in the treatment of patients after therapeutic lymphadenectomy for melanoma: a randomised trial. Lancet Oncol. 2012; 13(6): 589–597, doi: 10.1016/S1470- with melanoma; however, the indications for RT in 2045(12)70138-9, indexed in Pubmed: 22575589. melanoma have changed significantly over the past few 15. Henderson MA, Burmeister BH, Ainslie J, et al. Adjuvant lymph-node field radiotherapy versus observation only in patients with melanoma years. Indications for palliative RT remain unchanged. at high risk of further lymph-node field relapse after lymphadenec- Adjuvant RT after lymphadenectomy is not recommended tomy (ANZMTG 01.02/TROG 02.01): 6-year follow-up of a phase 3, randomised controlled trial. Lancet Oncol. 2015; 16(9): 1049–1060, because more effective adjuvant treatments are available. doi: 10.1016/S1470-2045(15)00187-4, indexed in Pubmed: 26206146. RT is increasingly used to enhance the effectiveness of 16. Ballo MT, Garden AS, Myers JN, et al. Melanoma metastatic to cervical immunotherapy and targeted therapy, as well as to delay lymph nodes: Can radiotherapy replace formal dissection after local excision of nodal disease? Head Neck. 2005; 27(8): 718–721, doi: the withdrawal of effective systemic therapy in the case 10.1002/hed.20233, indexed in Pubmed: 15952196. of oligoprogression. This topic requires new prospective 17. Cheung P. Stereotactic body radiotherapy for oligoprogressive cancer. Br J Radiol. 2016; 89(1066): 20160251, doi: 10.1259/bjr.20160251, clinical trials; however, emerging data justify the use of indexed in Pubmed: 27556349. RT in the described clinical situations. Since the response 18. Overgaard J, Gonzalez Gonzalez D, Hulshof MC, et al. Randomised trial of hyperthermia as adjuvant to radiotherapy for recurrent or to RT is partly dependent on CD8+ T-cells, developing metastatic malignant melanoma. European Society for Hyperthermic future strategies to increase T-cell infiltration may improve Oncology. Lancet. 1995; 345(8949): 540–543, doi: 10.1016/s0140- the effectiveness of RT in melanoma patients. 6736(95)90463-8, indexed in Pubmed: 7776772. 19. Rogers SJ, Puric E, Eberle B, et al. Radiotherapy for Melanoma: More than DNA Damage. Dermatol Res Pract. 2019: 9435389, doi: 10.1155/2019/9435389, indexed in Pubmed: 31073304. 20. Seegenschmiedt MH, Keilholz L, Altendorf-Hofmann A, et al. Palliative References radiotherapy for recurrent and metastatic malignant melanoma: prognostic factors for tumor response and long-term outcome: a 20-year 1. Delaney G, Barton M, Jacob S. Estimation of an optimal radiotherapy utili- experience. Int J Radiat Oncol Biol Phys. 1999; 44(3): 607–618, doi: zation rate for melanoma: a review of the evidence. Cancer. 2004; 100(6): 10.1016/s0360-3016(99)00066-8, indexed in Pubmed: 10348291. 1293–1301, doi: 10.1002/cncr.20092, indexed in Pubmed: 15022299. 21. Rutkowski P, Kiprian D, Dudzisz-Śledź M, et al. Postępowanie w prze- 2. Radiation biology of malignant melanoma. PubMed — NCBI [Inter- rzutach czerniaka do mózgowia. Onkol Prakt Klin Edu. 2019; 5: 54–65. net]. [cited 2019 Sep 9]. Available from: https://www.ncbi.nlm.nih. 22. Laufer I, Iorgulescu JB, Chapman T, et al. Local disease control for gov/pubmed/3010642. spinal metastases following “separation surgery” and adjuvant hy- 3. Bentzen SM, Overgaard J, Thames HD, et al. Clinical radiobiology of pofractionated or high-dose single-fraction stereotactic radiosurgery: malignant melanoma. Radiother Oncol. 1989; 16(3): 169–182, doi: outcome analysis in 186 patients. J Neurosurg Spine. 2013; 18(3): 10.1016/0167-8140(89)90017-0, indexed in Pubmed: 2587808. 207–214, doi: 10.3171/2012.11.SPINE12111, indexed in Pubmed: 4. Chang DT, Amdur RJ, Morris CG, et al. Adjuvant radiotherapy for 23339593. cutaneous melanoma: comparing hypofractionation to conventional 23. Laufer I, Rubin DG, Lis E, et al. The NOMS framework: approach to fractionation. Int J Radiat Oncol Biol Phys. 2006; 66(4): 1051–1055, doi: the treatment of spinal metastatic tumors. Oncologist. 2013; 18(6): 10.1016/j.ijrobp.2006.05.056, indexed in Pubmed: 16973303. 744–751, doi: 10.1634/theoncologist.2012-0293, indexed in Pubmed: 5. van Leeuwen CM, Oei AL, Crezee J, et al. The alfa and beta of tumours: 23709750. a review of parameters of the linear-quadratic model, derived from clinical 24. Stereotactic radiosurgery: A new paradigm for melanoma and re- radiotherapy studies. Radiat Oncol. 2018; 13(1): 96, doi: 10.1186/s13014- nal cell carcinoma spine metastases. Journal of Clinical Oncology 018-1040-z, indexed in Pubmed: 29769103. [Internet]. [cited 2019 Sep 9]. Available from: https://ascopubs. 6. Hedblad MA, Mallbris L. Grenz ray treatment of lentigo maligna and early org/doi/abs/10.1200/jco.2010.28.15_suppl.2030. lentigo maligna melanoma. J Am Acad Dermatol. 2012; 67(1): 60–68, doi: 25. Ugurel S, Thirumaran RK, Bloethner S, et al. B-RAF and N-RAS 10.1016/j.jaad.2011.06.029, indexed in Pubmed: 22030019. mutations are preserved during short time in vitro propagation and 7. Varey AHR, Goumas C, Hong AM, et al. Neurotropic melanoma: differentially impact prognosis. PLoS One. 2007; 2(2): e236, doi: an analysis of the clinicopathological features, management strategies 10.1371/journal.pone.0000236, indexed in Pubmed: 17311103. and survival outcomes for 671 patients treated at a tertiary referral center. 26. Ahmed KA, Abuodeh YA, Echevarria MI, et al. Clinical outcomes of Mod Pathol. 2017; 30(11): 1538–1550, doi: 10.1038/modpathol.2017.76, melanoma brain metastases treated with stereotactic radiosurgery and indexed in Pubmed: 28731051. anti-PD-1 therapy, anti-CTLA-4 therapy, BRAF/MEK inhibitors, BRAF in- 8. Radiotherapy influences local control in patients with desmoplastic hibitor, or conventional chemotherapy. Ann Oncol. 2016; 27(12): 2288– melanoma. PubMed — NCBI [Internet]. [cited 2019 Sep 9]. Available –2294, doi: 10.1093/annonc/mdw417, indexed in Pubmed: 27637745. from: https://www.ncbi.nlm.nih.gov/pubmed/24142775. 27. Patel KR, Chowdhary M, Switchenko JM, et al. BRAF inhibitor and 9. Radiotherapy for cutaneous malignant melanoma: rationale and stereotactic radiosurgery is associated with an increased risk of indications. PubMed — NCBI [Internet]. [cited 2019 Sep 9]. Available radiation necrosis. Melanoma Res. 2016; 26(4): 387–394, doi: from: https://www.ncbi.nlm.nih.gov/pubmed/14768409. 10.1097/CMR.0000000000000268, indexed in Pubmed: 27223498. 10. Guadagnolo BA, Prieto V, Weber R, et al. The role of adjuvant ra- 28. Minniti G, Scaringi C, Paolini S, et al. Single-Fraction Versus Multifrac- diotherapy in the local management of desmoplastic melanoma. tion (3 × 9 Gy) Stereotactic Radiosurgery for Large (>2 cm) Brain Cancer. 2014; 120(9): 1361–1368, doi: 10.1002/cncr.28415, indexed Metastases: A Comparative Analysis of Local Control and Risk of in Pubmed: 24142803. Radiation-Induced Brain Necrosis. Int J Radiat Oncol Biol Phys. 2016;

318 Mateusz Spałek, Anna M Czarnecka, The role of radiotherapy in melanoma

95(4): 1142–1148, doi: 10.1016/j.ijrobp.2016.03.013, indexed in 37. Local Tumor Treatment in Combination with Systemic Ipilimumab Pubmed: 27209508. Immunotherapy Prolongs Overall Survival in Patients with Advanced 29. Cagney DN, Alexander BM, Hodi FS, et al. Rapid progression of Malignant Melanoma | Cancer Immunology Research [Internet]. [cited intracranial melanoma metastases controlled with combined BRAF/ 2019 Sep 9]. Available from: https://cancerimmunolres.aacrjournals. /MEK inhibition after discontinuation of therapy: a clinical challenge. org/content/early/2016/07/22/2326-6066.CIR-15-0156. J Neurooncol. 2016; 129(3): 389–393, doi: 10.1007/s11060-016-2196- 38. Koller KM, Mackley HB, Liu J, et al. Improved survival and complete 8, indexed in Pubmed: 27401151. response rates in patients with advanced melanoma treated with con- 30. Park SS, Dong H, Liu X, et al. PD-1 restrains radiotherapy-induced current ipilimumab and radiotherapy versus ipilimumab alone. Cancer abscopal effect. Cancer Immunol Res. 2015; 3(6): 610–619, doi: Biol Ther. 2017; 18(1): 36–42, doi: 10.1080/15384047.2016.1264543, 10.1158/2326-6066.CIR-14-0138, indexed in Pubmed: 25701325. indexed in Pubmed: 27905824. 31. Asna N, Livoff A, Batash R, et al. Radiation therapy and immunotherapy 39. Liniker E, Menzies AM, Kong BY, et al. Activity and safety of — a potential combination in cancer treatment. Curr Oncol. 2018; 25(5): radiotherapy with anti-PD-1 drug therapy in patients with meta- e454–e460, doi: 10.3747/co.25.4002, indexed in Pubmed: 30464697. static melanoma. Oncoimmunology. 2016; 5(9): e1214788, doi: 32. Postow MA, Callahan MK, Barker CA, et al. Immunologic correlates 10.1080/2162402X.2016.1214788, indexed in Pubmed: 27757312. of the abscopal effect in a patient with melanoma. N Engl J Med. 40. Fang P, Jiang W, Allen P, et al. Radiation necrosis with stereotactic 2012; 366(10): 925–931, doi: 10.1056/NEJMoa1112824, indexed in radiosurgery combined with CTLA-4 blockade and PD-1 inhibition for Pubmed: 22397654. treatment of intracranial disease in metastatic melanoma. J Neuroon- 33. Hiniker SM, Reddy SA, Maecker HT, et al. A Prospective Clinical Trial col. 2017; 133(3): 595–602, doi: 10.1007/s11060-017-2470-4, indexed Combining Radiation Therapy With Systemic Immunotherapy in Met- in Pubmed: 28500560. astatic Melanoma. Int J Radiat Oncol Biol Phys. 2016; 96(3): 578–588, 41. Crittenden M, Kohrt H, Levy R, et al. Current clinical trials testing doi: 10.1016/j.ijrobp.2016.07.005, indexed in Pubmed: 27681753. combinations of immunotherapy and radiation. Semin Radiat Oncol. 34. Silk AW, Bassetti MF, West BT, et al. Ipilimumab and radiation therapy 2015; 25(1): 54–64, doi: 10.1016/j.semradonc.2014.07.003, indexed for melanoma brain metastases. Cancer Med. 2013; 2(6): 899–906, in Pubmed: 25481267. doi: 10.1002/cam4.140, indexed in Pubmed: 24403263. 42. Ballo M, Ross M, Cormier J, et al. Combined-modality therapy for pa- 35. Twyman-Saint Victor C, Rech AJ, Maity A, et al. Radiation and dual tients with regional nodal metastases from melanoma. Int J Radiat On- checkpoint blockade activate non-redundant immune mechanisms in col Biol Phys. 2006; 64(1): 106–113, doi: 10.1016/j.ijrobp.2005.06.030. cancer. Nature. 2015; 520(7547): 373–377, doi: 10.1038/nature14292, 43. Lauber K, Ernst A, Orth M, et al. Dying cell clearance and its impact indexed in Pubmed: 25754329. on the outcome of tumor radiotherapy. Front Oncol. 2012; 2: 116, doi: 36. Chandra RA, Wilhite TJ, Balboni TA, et al. A systematic evaluation 10.3389/fonc.2012.00116, indexed in Pubmed: 22973558. of abscopal responses following radiotherapy in patients with met- 44. Meng X, Feng R, Yang L, et al. The role of radiation oncology astatic melanoma treated with ipilimumab. Oncoimmunology. 2015; in immuno-oncology. Oncologist. 2019; 24(Suppl 1): S42–S52, 4(11): e1046028, doi: 10.1080/2162402X.2015.1046028, indexed in doi: 10.1634/theoncologist.2019-IO-S1-s04, indexed in Pubmed: Pubmed: 26451318. 30819830.

319 REVIEW ARTICLE

Marta Frąckowiak1, Tomasz Lewandowski1, 2, Paweł Stelmasiak1 1Radom Oncology Center, Poland 2Centre of Postgraduate Medical Education, Warsaw, Poland

Molecular subtypes of colorectal cancer as a potential prognostic and predictive factor in the selection of the optimal treatment strategy

Address for correspondence: ABSTRACT Lek. Marta Frąckowiak Colorectal cancer is one of the most common cancers and is the third cause of death from malignant tumours. In Radomskie Centrum Onkologii recent years, a consensus has been developed that distinguishes four subtypes of colon cancer (CMS, consensus ul. Uniwersytecka 6, 26–600 Radom molecular subtypes): CMS1 — immunological, CMS2 — canonical, CMS3 — metabolic, and CMS4 — mesenchy- e-mail: [email protected] mal. They differ in terms of clinical course and response to chemotherapy and biological treatment. The practical application of molecular classification can be helpful as a prognostic and predictive factor in the selection of an Oncology in Clinical Practice 2019, Vol. 15, No. 6, 320–325 optimal and individualised strategy for the treatment of individual patients. DOI: 10.5603/OCP.2019.0036 Key words: colon cancer, CMS, chemotherapy, molecular-targeted treatment Translation: lek. Elżbieta Stelmaszczyk Copyright © 2019 Via Medica Oncol Clin Pract 2019; 15, 6: 320–325 ISSN 2450–1654

Colorectal cancer molecular lar features of colorectal cancer, resulted in the emer- classification gence and systemisation of new molecular subtypes [4]. Perez-Villamil et al. suggested a gene signa- According to GLOBCAN 2018, colorectal cancer is ture-based classification favouring four types of colo- classified as the fifth most common cancer in the world rectal cancer. The low-stroma-like type, which is the (1.8 million cases per year) and the third as a cause of most distinct and gives the best prognosis, also shows fatalities when considering malignant tumours (881 thou- gene expression that is least related to stroma, on the sand cases per year) [1]. In the EUROCARE-5 survey contrary to the high-stroma-like type. We also differenti- the five-year survival rate (conducted between 1999 and ate mucinous-like type, which is characterised by more 2007) was reported as 47% in Poland and 57% in the common BRAF gene detection and MSI presence, and whole of Europe [2]. The observed clinical improvement finally immunoglobulin-related type, which has greater is likely to be connected with screening tests and more immunoglobulin expression [5]. effective therapeutic procedures both in local cancer and Sadanandam et al. submitted six subtypes of colo- generalised disease. For many years, histopathological rectal cancer: stem-like subtype, which is the least dif- examination and staging alongside clinical assessment ferentiated with stem cell presence (high expression of were the only factors that contributed to making thera- Wnt/b-catenin trail) (I); inflammatory subtype with the peutic decisions. Identification of risk factors such as the highest expression of cytokine and interferon encoding presence of RAS and BRAF oncogenes or microsatellite genes (II); enterocyte subtype (specific for enterocytes) instability (MSI) were the foundation for the new defini- (III); goblet cell subtype with higher expression of tre- tion of colorectal cancer, seen as a heterogenic disease foil factor (TFF3) and MUC2 (IV); and two subtypes with varied molecular background with diverse course with features of TA-transit amplifying cells (different and prognosis [3]. Phenotype variety, reflecting molecu- cetuximab responsiveness) (V, VI) [6].

320 Marta Frąckowiak et al., CMS as a potential help in choosing the optimal therapy

As a result of the research of De Sous E Melo, CMS2 (canonical) three molecular subtypes were suggested. CCS1-CIN associated with chromosomal instability, CCS-MSI CMS2 canonical subtype is diagnosed most com- related to microsatellite instability, and CCS3-serrated monly (37% of cases). It is characterised by CIN. Typical characterised by a gene profile that is similar to sessile molecular features of this subtype are high expression serrated lesions (SSL) [7]. of Wnt/b-catenin trail and MYC transcription factor, In 2014, as a result of a summary analysis of all responsible for cell proliferation and diversion. CMS2 is research groups led by Sadanandam and De Sousa E not associated with hypermutation, and in comparison Melo, a conclusion was arrived at. Gene profiles and with CMS1 chromosomal rearrangements and ane- phenotype features of subtype CCS1-CIN (due to the uploidy are more frequently observed. Epithelial pheno- classification) correspond to TA and enterocyte type in type with accompanying loss of APC suppressor gene is Sadanandam order. Subtype CCS1-MSI corresponds to typical, the same as KRAS gene mutation and TP53 gene inflammatory and goblet cell subtypes, and stem-like inactivation. The most common location of CMS2 sub- subtype is close to CCS3-serrated type [6]. Further re- type cancer is the distal part of the large intestine (59% search led to establishing an international expert consor- of cases). It has better prognosis, and the five-year sur- tium and unifying six independently existing molecular vival rate is the highest out of all types. Longer survival, classifications. Thus, a final point was reached, and four reaching 35 months, is also observed in recurrence [10]. molecular subtypes of colorectal cancer were distinguished: CMS1 — immunological, CMS2 — canonical, CMS3 (metabolic subtype) CMS3 — metabolic, and CMS4 — mesenchymal [6]. CMS classification comprised around 87% of examined This occurs in 13% of patients with colorectal malignant colorectal cancer cases, and the rest (13%) cancer. It barely holds cases of CIN (chromosomal were characterised by a mix of all subtypes. CMS groups instability) and represents the highest occurrence of are differentiated in terms of gene signature, molecular KRAS gene mutations (68% of cases). In 3–5% of the changes, and clinical presentation. Recent data support cases HER2 gene amplification is stated [11]. Metabolic the theory claiming that particular subtypes of colorectal subtype appears with similar prevalence in different cancer are connected with the primary location, sex, parts of large intestine [8]. It has a relatively favourable histopathological results, and staging at the moment prognosis, at all stages a total of around 75% of patients of diagnosis [8]. live longer than five years [10].

CMS1 (immunological, MSI) CMS4 (mesenchymal subtype)

Subtype CMS1 is relatively rare (barely 14% of all This subtype is second in terms of colorectal cancer colorectal cancer cases), but its biology is very different occurrence (23% of cases). A crucial molecular feature from other groups [6]. It is characterised by high im- is compliance when speaking about gene signatures of munogenicity and MSI presence, created in the process activated stroma. Marked angiogenesis, transforming of mutator genes (MLH1, MSH1, PMS2, and MSH6) growth factor b (TGFb) trail activation, and proteins inactivation. MSI is a favourable prognostic factor, connected with microinflammation are common [12]. which might be connected to gross lymphocytic infiltra- Occurrence is higher in men (55% of cases), mainly tion around the tumour and immunological response in a distal part of the intestine. CMS4 subtype cancer is activation [9]. In the CMS1 subtype hypermutation related to poor prognosis, frequent relapse, and overall might be observed. V600E BRAF, PTEN, and ATM five-year survival and five-year survival free from relapse mutations occur frequently. CpG island methylator is 62% and 60%, respectively [8]. phenotype (CIMP), causing inactivation of suppressor genes, is also highly characteristic; it is one of the first processes when speaking about molecular processes Clinical significance in carcinogenesis. On clinical presentation CMS1 is seen as a mucinous cancer, which is usually located in Hand in hand with the development of molecular the proximal part of the intestines and occurs more classification, an attempt was made to implement it in frequently in women. It is less likely to recur and con- clinical practice. The work of Sadanandam et al. re- stitutes better prognosis, especially when diagnosed at vealed a connection between cancer molecular subtypes an early stage. Unfortunately, recurrence is related to and possible response to administered treatment [13]. the aggressive nature of a cancer and short life expec- In patients with generalised disease the first-line tancy. Precursor changes of this subtype are typically chemotherapy (due to FOLFIRI [folinic acid, fluo- serrated polyps [8]. rouracil, irinotecan] model) response percentage was

321 Oncology in clinical practice 2019, Vol. 15, No. 6

Table 1. Colorectal cancer molecular subtypes based on consensus molecular subtypes (CMS) (based on [8])

Subtype CMS1 CMS2 CMS3 CMS4 Additional name MSI, inflammatory Canonical Metabolic Stromal, mesenchymal Basic molecular Hypermutations, MSI, Epithelial, activation of Epithelial, metabolic High TGFb expression; features strong immunogenic WNT and MYC trails regulation disturbed epithelial invasion and activation angiogenesis ± WNT Incidence 14% 37% 13% 23% Gene signature MSI, high number of CIN, low-moderate CIN, moderate no. of CIN, low no. of mutations, mutations, low number mutation and copy index mutations, and low no. of and high no. of copies of copies copies Epigenome High methylation Low methylation Indirect methylation Low methylation features Molecular trails Inflammatory activation, WNR trail, MYC, EGFR, SRC, DNA repairing, Stroma activation, JAK-STAT, caspases VEFG/VEGRF activation; glutaminolysis, lipogenesis immunosuppression, integrins, TGFb, IGF, IRS2, integrins HNF4a and HER2, and cyclin activation Microenvironment Low no. of fibroblasts Really low number of CAF; Low CAF, highly High no. of CAF, connected to cancer (CAF), poorly immunogenic; immunogenic; acquired inflammatory, acquired highly immunogenic, congenital immunological immunological response immunological response, immunological infiltrations, response EMT acquired immunological response Related MSH6, RNF43, ATM, APC, KRAS, TP53, PIK3CA APC, KRAS, TP53, PIK3CA APC, KRAS, TP53, PIKC3CA, mutations TGFbR2, BRAF, PTEN TOP1, CES2 Age 69 66 67 64 Location Proximal Distal Mixed Distal

MSI — microsatellite instability; TGFb — transforming growth factor b; CIN — chromosomal instability; EFGR — epidermal growth factor receptor; SRC — sarcoma; VEGF — vascular endothelial growth factor; VEGFR — VEGFR receptor; IGF — insulin-like growth factor; HNF4a — hepatocyte nuclear factor 4a; CAF — carcinoma-associated fibroblasts; EMT — epithelial-mesenchymal transition

barely 71% in a stem-like subtype group and just 22% Results of research by Okita et al. also point out the in other subtypes. Specific gene signatures related to connection between colorectal cancer molecular subtype response to the FOLFIRI scheme were observed in and efficiency of systemic therapy. Over 193 patients all patients with stem-like subtype (100%, N = 74), in presenting generalised disease underwent retrospec- the majority of cases with inflammatory subtype (75%, tive analysis and were divided corresponding to types: N = 53), and only in 14% of TA-transit amplifying CMS1 (N = 21), CMS2 (N = 53), CMS3 (N = 69), subtype. Enterocyte and goblet cell subtypes comprise and CMS4 (N = 50). Then, chemotherapy efficiency 39% and 38%, respectively. Response for cetuximab was analysed based on irinotecan and oxaliplatin and therapy was assessed in a group of 80 patients based on anti-EGFR therapy in particular molecular subtypes. In molecular subtype. Clinical benefit (defined as overall the analysed group, longer progression-free survival response, partial response, and remission) during the (PFS) and overall survival (OS) were noted in patients cetuximab course was observed in 54% of the transient treated with irinotecan as first-line chemotherapy (com- amplifying patient (TA) group. Thus, two groups were pared to oxaliplatin therapy). Numbers presented are derived: cetuximab sensitive (CS-TA) and cetuximab 12.8 vs. 10.7 months (HR = 0.64; 95% CI 0.49–0.89, resistant (CR-TA). Response in patients with goblet p < 0.01) and 46.3 vs. 35.5 months (HR = 0.67; 95% cell subtype and stem-like subtype was observed only CI 0.44–1.0, p = 0.06). The biggest result was noted in in 22% of the cases. According to the authors, patients the CMS4 subtype mainly considering time free from with CR-TA, CS-TA, and goblet-cell subtypes do not progression (HR = 0.31; 95% CI 0.13–0.64), but less benefit from chemotherapy and might be considered considering OS rate (HR = 0.45; 95% CI 0.19–0.99). as candidates for molecular-targeted therapy, e.g. using Therefore, the percentage of objective responses anti-epidermal growth factor receptor (EGFR) globulin was higher in the group treated with irinotecan (for or central mucoepidermoid tumor of the jaws (cMET) CMS4 subtype it was 80%). The lowest percentage of inhibitor [13]. positive response was noted in CMS1 subtype. Irinote-

322 Marta Frąckowiak et al., CMS as a potential help in choosing the optimal therapy can, topoisomerase 1 inhibitor, is metabolised to an able for right-side location of primary tumour (OS active form using carboxylesterase (CES). Mutations median: left-side vs. right-side, 12.0 vs. 23.7 months, in TOP1 and CES2 genes constitute characteristic gene p = 0.035). Of the left-side tumour cases, the majority signature of CMS4 subtype and might be responsible for were CMS2 and CMS4 subtypes, and of the right-side results of the irinotecan treatment [14]. These observa- tumour cases, CMS1 and CMS3 [18]. tions are proven by other analysis [15]. Genes gathered In research by Sagawa et al. results obtained in in the RAS and RAF group were also examined in terms a group of patients treated with cetuximab, in terms of mutation presence. The biggest percentage of RAS of survival time free from progression and total sur- mutations was present in CMS3 subtype and BRAF mu- vival time, were significantly better for patients with tation in CMS1 subtype. Hypermethylation was noted in left-sided tumour (PFS: left vs. right, 18.3 vs. 6.8 months, the majority of the CMS1 group. Patients, who did not p = 0.0415; OS: 50.6 vs. 10.5 months, p = 0.0004). PFS carry the RAS mutation (wild type, RAS-wt) and went and OS were also significantly longer in right-sided through anti-EGFR therapy were also examined. The colon patients treated with bevacizumab: left vs. right, worst results were observed in the CMS1 subtype with 11.6 vs. 7.3 months (p = 0.1904) and 25.7 vs. 16.2 months a PFS median of 2.4 months (hazard ratio [HR] = 2.50; (p = 0.0389). Administering cetuximab in a primar- 95% CI 1.31–4.39, p < 0.01) and overall survival (OS) ily right-sided disease was connected with longer sur- median of 5.7 month (HR = 4.23; 95% CI 1.83–9.04, vival rate compared to bevacizumab (PFS: cetuximab p < 0.01). The best results were noted in the CMS2 sub- vs. bevacizumab, 18.0 vs. 11.6 months, p = 0.1088; OS: type with a PFS median of 8.0 months (HR = 0.67; 95% 50.6 vs. 25.7 months, p = 0.0354). There were no changes CI 0.44–1.01, p = 0.05) and OS median of 26.6 months observed in patients with primary tumour located on the (HR = 0.49; 95% CI 0.27–0.87, p = 0.02). On multi- right side of the colon [19]. causal analysis, status of DNA methylation turned out In additional analysis, conducted in the FIRE-3 (AIO to be the only predictive factor both for PFS and OS, KRK-0306) project, which compared the accuracy of whereas location of the primary tumour (on the left cetuximab and bevacizumab combined with first-line side of the colon) was predictive for PFS. According to chemotherapy, according to the FOLFIRI scheme, the authors, both identification of CMS1 subtype as well as CMS subtype was a relevant prognostic factor in terms methylation status might be helpful when considering of PFS (p < 0.001), OS (p < 0.001), and percentage of anti-EGFR treatment [14]. objective response (p = 0.023). The connection between Our conclusions correspond with the results pre- overall survival rate and subtype and type of adminis- sented by Fontan and Sandandam during the ASCO GI tered treatment was noted. In the CMS4 group this con- conference (2018). In the RAS-wt colon cancer group, nection was statistically relevant, and the OS median for objective response for anti-EGFR therapy was vastly cetuximab vs. bevacizumab was 41.3 vs. 22.3 months (HR differentiated depending on subtype: CMS1 — 20%, 0.53, p = 0.016). Details are presented in Table 2 [20]. CMS2 — 76%, CMS3 — 23%, and CMS4 — 88% [16]. The presence of molecular aims used currently in It seems that the connection between molecular other types of cancer might be a premise for targeted subtypes and location of primary tumour and prognosis therapy in particular subtypes of large intestine can- is of relevance. During the FIRE-3, CRYSTAL post-hoc cer. Approximately 3% of CMS3 cancer and 5% of research it was proven that the location of the primary CMS4 cancer have high protein expression of HER2 re- tumour in the proximal part of the colon is an adverse ceptor. In these cases, anti-HER2 antibodies or tyrosine prognostic factor for PFS and OS [17]. kinase inhibitors (TKI), related to the ERBB group, e.g. Retrospective data analysis of 728 patients partici- lapatinib and neratinib, might be active. Attempts to pating in the CALGB/SWOG 80405 trial (comparing use immunotherapy with checkpoint inhibitors (inter bevacizumab and cetuximab combined with first-line alia pembrolizumab and nivolumab) might be most ef- chemotherapy in metastatic colon cancer) showed that fective in CMS1, considering the immunogenetics [22]. patients with primary tumour on the left side of the colon have a significantly longer survival rate rather than those with primary tumour on the right side of the colon. OS Conclusions median for left-side location was 32.9 months in comparison with 19.6 months for right side (p < 0.0001). In Consensus molecular subtypes might be a helpful patients with KRAS/BRAF-wt, treated with cetuximab, classification enabling better understanding of colon the overall survival rate was far more different, in favour cancer’s biology. Subtypes: CMS1, CMS2, CMS3, and of primary tumour located on the left side of the colon CMS4 may have a significant prognostic and predic- (OS median: left-side vs. right-side, 40.3 vs. 18.4 months, tive quality and might influence the choice of optimal p = 0.003). In turn, in a group with BRAF mutation, treatment for particular patients (both in local and treated with bevacizumab, results were more favour- generalised disease). Most of the accessible research

323 Oncology in clinical practice 2019, Vol. 15, No. 6

Table 2. Results of chemotherapy with cetuximab or bevacizumab due to consensus molecular subtypes (CMS) (based on [20])

PFS median [months] OS median [months] FOLFIRI FOLFIRI (p*) FOLFIRI FOLFIRI (p*) Cetuximab Bevacizumab HR Cetuximab Bevacizumab HR CMS1 33/35 5.1 6.7 (0.83) 32/35 20.3 11.0 (0.28) (0.2–10.1) (3.9–9.4) 1.08 (8.4–32.3) (5.1–16.8) 0.68 CMS2 93/117 12.02 12.4 (0.54) 64/117 38.3 30.8 (0.40) (9.5–14.9) (10.9–13.8) 1.14 (27.5–49.2) (26.7–34.8) 0.80 CMS3 27/30 7.3 10.0 (0.76) 20/30 16.6 18.7 (0.60) (6.2–8.4) (4.2–15.7) 0.90 (NE–41.2) (12.7–25.6) 0.77 CMS4 81/93 10.5 9.7 (0.07) 56/93 41.3 22.3 (0.016) (6.9–14.1) (8.8–10.6) 0.67 (19.2–63.4) (15.9–28.8) 0.53

*p — log-rank test; PFS — progression-free survival; OS — overall survival; FOLFIRI folinic acid, fluorouracil, irinotecan; HR — hazard ratio; NE — not examinated

results concern oxaliplatin, irinotecan, bevacizumab, and Currently the main limitation of molecular testing, cetuximab. An advantage of bevacizumab in CMS3 and allowing to asses CMS, is its price, which is between cetuximab in CMS4, and CMS2 was noted [17, 23]. It 500 and 1500 euros. might be connected to proangiogenic factors produced e.g. by tumour macrophages [24]. The influence of complimentary treatment with oxaliplatin at the third References stage of disease was noted mainly in CMS1 type, whilst in CMS3 it was almost non-existent [25]. Benefits of 1. https://www.uicc.org/new-global-cancer-data-globocan-2018. 2. Holleczek B, Rossi S, Domenic A, et al. EUROCARE-5 Working irinotecan therapy were mainly related to CMS3 and Group:. On-going improvement and persistent differences in the CMS4 presence (with CMS2 less effective) [13]. Moreo- survival for patients with colon and rectum cancer across Europe 1999–2007 — results from the EUROCARE-5 study. Eur J Cancer. ver, biologic treatment and chemotherapy might mutu- 2015; 51(15): 2158–2168, doi: 10.1016/j.ejca.2015.07.024, indexed ally modify each other, e.g. combining oxaliplatin with in Pubmed: 26421819. 3. Van Cutsem E, Cervantes A, Adam R, et al. ESMO consensus guide- cetuximab in an environment rich in fibroblasts such lines for the management of patients with metastatic colorectal cancer. as CMS1 and CMS4 might be antagonistic [26]. The Ann Oncol. 2016; 27(8): 1386–1422, doi: 10.1093/annonc/mdw235, above-mentioned differences are eager to be respon- indexed in Pubmed: 27380959. 4. Rodriguez-Salas N, Dominguez G, Barderas R, et al. Clinical relevance sible for fluctuating prognosis and therapy observed of colorectal cancer molecular subtypes. Crit Rev Oncol Hematol. (depending on primary tumour location). According 2017; 109: 9–19, doi: 10.1016/j.critrevonc.2016.11.007, indexed in Pubmed: 28010901. to research presented by Lenz in 2017, tumours located 5. Perez-Villamil B, Romera-Lopez A, Hernandez-Prieto S, et al. Colon primarily on the left side were characterised by a signifi- cancer molecular subtypes identified by expression profiling and cant percentage of right-sided CMS2 occurrence rather associated to stroma, mucinous type and different clinical behavior. BMC Cancer. 2012; 12: 260, doi: 10.1186/1471-2407-12-260, indexed than left-sided — 48% vs. 23%, respectively, and lower in Pubmed: 22712570. CMS1 — 9% vs. 37%, respectively [27]. 6. Sadanandam A, Wang X, de Sousa E Melo F, et al. Reconciliation of classification systems defining molecular subtypes of colorectal Based on previous research, it transpires that cancer: interrelationships and clinical implications. Cell Cycle. 2014; CMS1 (immunological type) might be treated opti- 13(3): 353–357, doi: 10.4161/cc.27769, indexed in Pubmed: 24406433. mally by oxaliplatin, bevacizumab combined therapy, 7. De Sousa E Melo F, Wang X, Jansen M, et al. Poor-prognosis colon cancer is defined by a molecularly distinct subtype and develops CMS2 (canonical type) — cetuximab combined with ox- from serrated precursor lesions. Nat Med. 2013; 19(5): 614–618, doi: aliplatin or irinotecan chemotherapy, CMS3 (metabolic 10.1038/nm.3174, indexed in Pubmed: 23584090. 8. Thanki K, Nicholls ME, Gajjar A, et al. Consensus molecular subtypes type) — oxaliplatin with cetuximab and CMS4 (mesen- of colorectal cancer and their clinical implications. Int Biol Biomed J. chymal) combined irinotecan chemotherapy with cetuxi- 2017; 3(3): 105–111, indexed in Pubmed: 28825047. mab [27]. There is less information available in terms 9. Kumar S, Chang EY, Frankhouse J, et al. Combination of microsatellite instability and lymphocytic infiltrate as a prognostic indicator for of panitumumab therapy rather than cetuximab, but it adjuvant therapy in colon cancer. Arch Surg. 2009; 144(9): 835–840, cannot be excluded that the points previously stated doi: 10.1001/ archsurg.2009.162, indexed in Pubmed: 19797108. 10. Guinney J, Dienstmann R, Wang X, et al. The consensus molecular might apply to the entire anti-EGFR group. Improving subtypes of colorectal cancer. Nat Med. 2015; 21(11): 1350–1356, doi: access to molecular research methods may popularise 10.1038/nm.3967, indexed in Pubmed: 26457759. colorectal cancer classification and make it an efficient 11. Kavuri SM, Jain N, Galimi F, et al. HER2 activating mutations are targets for colorectal cancer treatment. Cancer Discov. 2015; 5(8): 832–841, and crucial tool for therapeutic decisions. doi: 10.1158/2159-8290.CD-14-1211, indexed in Pubmed: 26243863.

324 Marta Frąckowiak et al., CMS as a potential help in choosing the optimal therapy

12. Fessler E, Drost J, van Hooff SR, et al. TGFb signaling directs serrated 20. Stintzing S, Wirapati P, Lenz HJ, et al. Consensus molecular subgroups adenomas to the mesenchymal colorectal cancer subtype. EMBO Mol (CMS) of colorectal cancer (CRC) and first-line efficacy of FOLFIRI plus Med. 2016; 8(7): 745–760, doi: 10.15252/emmm.201606184, indexed cetuximab or bevacizumab in the FIRE3 (AIO KRK-0306) trial. J Clin in Pubmed: 27221051. Oncol. 2017; 35(15 Suppl): 3510–3510, doi: 10.1200/jco.2017.35.15_ 13. Sadanandam A, Lyssiotis CA, Homicsko K, et al. A colorectal cancer suppl.3510. classification system that associates cellular phenotype and responses 21. Siena S, Sartore-Bianchi A, Marsoni S, et al. Targeting the human epi- to therapy. Nat Med. 2013; 19(5): 619–625, doi: 10.1038/nm.3175, dermal growth factor receptor 2 (HER2) oncogene in colorectal cancer. indexed in Pubmed: 23584089. Ann Oncol. 2018; 29(5): 1108–1119, doi: 10.1093/annonc/mdy100, 14. Okita A, Takahashi S, Ouchi K, et al. Consensus molecular subtypes indexed in Pubmed: 29659677. classification of colorectal cancer as a predictive factor for chemo- 22. Boland PM, Ma WW. Immunotherapy for colorectal cancer. Cancers therapeutic efficacy against metastatic colorectal cancer. Oncotarget. (Basel). 2017; 9(5), doi: 10.3390/cancers9050050, indexed in Pubmed: 2018; 9(27): 18698–18711, doi: 10.18632/oncotarget.24617, indexed 28492495. in Pubmed: 29721154. 23. Colangelo T, Polcaro G, Muccillo L, et al. Friend or foe? The tumour 15. Del Rio M, Mollevi C, Bibeau F, et al. Molecular subtypes of metastatic microenvironment dilemma in colorectal cancer. Biochim Biophys Acta colorectal cancer are associated with patient response to irinotec- Rev Cancer. 2017; 1867(1): 1–18, doi: 10.1016/j.bbcan.2016.11.001, an-based therapies. Eur J Cancer. 2017; 76: 68–75, doi: 10.1016/j. indexed in Pubmed: 27864070. ejca.2017.02.003, indexed in Pubmed: 28284171. 24. Riabov V, Gudima A, Wang N, et al. Role of tumor associated macro- 16. Fontana E, Nyamundanda G, Cunningham D, et al. Molecular subtype phages in tumor angiogenesis and lymphangiogenesis. Front Physiol. assay to reveal anti-EGFR response sub-clones in colorectal cancer 2014; 5: 75, doi: 10.3389/fphys.2014.00075, indexed in Pubmed: (CRC). J Clin Oncol. 2018; 36(4 Suppl): 658–658, doi: 10.1200/ 24634660. jco.2018.36.4_suppl.658. 25. Song N, Pogue-Geile KL, Gavin PG, et al. Clinical Outcome From 17. Tejpar S, Stintzing S, Ciardiello F, et al. Prognostic and predictive Oxaliplatin Treatment in Stage II/III Colon Cancer According to Intrin- relevance of primary tumor location in patients with RAS wild-type sic Subtypes: Secondary Analysis of NSABP C-07/NRG Oncology metastatic colorectal cancer: retrospective analyses of the CRYSTAL Randomized Clinical Trial. JAMA Oncol. 2016; 2(9): 1162–1169, doi: and FIRE-3 trials. JAMA Oncol. 2017; 3(2): 194–201, doi: 10.1001/ja- 10.1001/jamaoncol.2016.2314, indexed in Pubmed: 27270348. maoncol.2016.3797, indexed in Pubmed: 27722750. 26. Zidar DA. Fibroblasts in colon cancer: turned traitor by chemotherapy. 18. Venook A, Ou FS, Lenz HJ, et al. Primary (1°) tumor location as Science Translational Medicine. 2014; 6(217): 217ec3–217ec3, doi: an independent prognostic marker from molecular features for overall 10.1126/scitranslmed.3008240. survival (OS) in patients (pts) with metastatic colorectal cancer (mCRC): 27. Lenz HJ, Ou FS, Venook A, et al. Impact of consensus molecular Analysis of CALGB / SWOG 80405 (Alliance). J Clin Oncol. 2017; subtyping (CMS) on overall survival (OS) and progression free 35(15 Suppl): 3503–3503, doi: 10.1200/jco.2017.35.15_suppl.3503. survival (PFS) in patients (pts) with metastatic colorectal cancer 19. Sagawa T, Hamaguchi K, Sakurada A, et al. Primary tumor location (mCRC): Analysis of CALGB/ SWOG 80405 (Alliance). J Clin Oncol. as a prognostic and predictive factor in metastatic colorectal cancer 2017; 35(15_suppl): 3511–3511, doi: 10.1200/jco.2017.35.15_ (mCRC) treated with chemotherapy plus cetuximab: A retrospective suppl.3511. analysis. J Clin Oncol. 2017; 35(4 Suppl): 711–711, doi: 10.1200/ 28. Aderka D. Explaining the “unexplainable”: CALGB and FIRE-3 “dis- jco.2017.35.4_suppl.711. crepant” data. ESMO WCGC, 2018.

325 CASE REPORT

Kinga Krawiec1, Sylwia Dębska-Szmich2, Urszula Czernek2, Rafał Czyżykowski2, Piotr Potemski2 1Medical University of Lodz, Poland 2The Department of Chemotherapy, Copernicus Memorial Multidisciplinary Centre for Oncology and Traumatology, Lodz; Chemotherapy Clinic, Medical University of Lodz, Poland

Short bowel syndrome and severe skin toxicity as a complication of FOLFOX chemotherapy with panitumumab in a patient with colorectal cancer — a case report

Address for correspondence: ABSTRACT Kinga Krawiec The combination of monoclonal antibodies targeting epidermal growth factor receptor (EGFR) with chemotherapy Klinika Chemioterapii Nowotworów is the standard treatment in advanced colorectal cancer without mutations in the RAS and BRAF genes. We pre- Uniwersytet Medyczny w Łodzi sent a case of a 55-year-old female patient with unacceptable skin toxicity and short bowel syndrome caused by WWCOiT im. M. Kopernika w Łodzi palliative FOLFOX chemotherapy combined with panitumumab. In 2012, after the emergence of an artificial anus ul. Pabianicka 62, 93–513 Łódź due to gastrointestinal obstruction in the course of rectal cancer, the patient underwent inductive chemotherapy, Phone: 42 689 54 31 preoperative chemoradiotherapy, and radical surgery. Tubular adenocarcinoma G2, ypT2N0 was diagnosed. In Fax: 42 689 54 32 2013 and 2015 she underwent two additional surgeries including intestinal resection due to obstruction of the e-mail: [email protected] gastrointestinal tract and enterovaginal fistula. In February 2018 she was qualified for palliative chemotherapy because of inoperable relapse. Due to very good performance status (PS0) and absence of mutations of RAS Oncology in Clinical Practice 2019, Vol. 15, No. 6, 326–330 and BRAF genes, regardless of being underweight and suffering from loose stools persisting from the time of DOI: 10.5603/OCP.2019.0039 surgery, FOLFOX chemotherapy with panitumumab was introduced. After the second administration of drugs an Translation: dr n. med. Dariusz Stencel acne-like rash, hand-foot syndrome, and diarrhoea appeared. Intensification of symptoms and manifestations of Copyright © 2019 Via Medica short bowel syndrome were observed afterwards. Topical treatment of skin lesions, doxycycline, and anti-diarrhoeal ISSN 2450–1654 therapy were introduced, with a mediocre therapeutic effect. Imaging confirmed disease stabilisation, but due to the deterioration of both performance status and life quality, anti-cancer treatment was discontinued. This case draws attention to the necessity of caution while qualifying for potentially toxic combination chemotherapy. Key words: panitumumab, monoclonal antibodies, colorectal cancer, epidermal growth factor receptor, skin rash, short bowel syndrome, nutritional intervention

Oncol Clin Pract 2019; 15, 6: 326–330

Introduction The main treatment method for disseminated CRC is chemotherapy and targeted therapy. The percentage The occurrence of colorectal cancer (CRC) is steadily of five-year overall survival (OS) in this group of patients increasing, making it the third most common malignancy in western countries reaches 14%, which is probably in the world and the second one in Europe [1]. According primarily the result of radical surgery in oligometa- to data from Surveillance, Epidemiology, and End Results static disease (metastasectomy). The median survival (SEER) colorectal cancer is disseminated in 22% of pa- for patients receiving fluoropyrimidine, oxaliplatin and tients during the diagnosis [2]. In addition, about 30–40% irinotecan-based sequential palliative chemotherapy is of patients in stage III will relapse within five years. about 20 months.

326 Kinga Krawiec et al., Short bowel syndrome after panitumumab

The addition of molecular targeted drugs to the 2013, the patient experienced symptoms of mechanical standard mentioned above contributes to the improve- gastrointestinal obstruction once again. Intraoperatively, ment in the treatment results. In cancer cells, about half intra-abdominal adhesions were found together with the of patients have activating mutations of the KRAS (exons intestinal loop drawn into a massive pelvic inflammatory 2, 3, 4) and NRAS genes (exons 2, 3, 4), and about 10% in infiltration, which was probably a late complication of the BRAF gene [3–5]. These are negative predictors for radiation therapy. Ileo-transverse anastomosis was per- efficacy of treatment with panitumumab and cetuximab, formed. In September 2015, another surgery took place which are both anti-EGFR (epidermal growth factor due to vaginal-intestinal fistula symptoms. Loops of the receptor) monoclonal antibodies. These medications small intestine were dissected distally from the bypass can be used in mutations-negative patients. Despite anastomosis, leaving the invaginated stumps. different antibody isotypes (panitumumab — IgG2 and In November 2017, a positron emission tomogra- cetuximab — IgG1), no differences in their effectiveness phy (PET) with 18-fluorodeoxyglucose (18-FDG) was were demonstrated [6]. performed. The recurrence of the disease was found Initially, the benefit from using anti-EGFR antibod- in a form of a new lesions — in the bed after complete ies in the third-line therapy was demonstrated in patients mesorectal resection (SUV max. FDG 5.2) and perito- with wild-type KRAS tumours — in monotherapy the re- neal implants (SUV max. FDG = 6.7). sponse was observed in 13% of patients, and the median At admission to the chemotherapy department, the OS increased from 4.8 months to 9.5 months compared patient was in very good general condition PS0 (PS, with best supportive care [7]. Studies assessing the com- performance status) but slightly underweight (BMI bination of antibodies with first-line chemotherapy not 18.9, body weight 43 kg). The patient reported pain in only showed a positive effect on life extension of such the anal area and loose stools since the last surgery; treatment, but also enabled the determination of further however, with good appetite, and stable body weight. negative predictive factors as KRAS as well as NRAS Physical examination revealed the presence of a massive and BRAF mutations. The combination of anti-EGFR hernia in the area of the stoma and numerous, movable antibodies with first-line chemotherapy increases the axillary lymph nodes enlarged to 1 cm. The patient was median OS to 26 months and progression-free sur- a smoker. She did not report any chronic diseases. The vival (PFS) to 10 months compared to chemotherapy family history of cancer was negative. In laboratory tests: (20 months and 8 months, respectively) [8, 9]. bone marrow, liver, and kidney functions were normal; The most common side effects of anti-EGFR anti- there were increased values of carcinoembryonic (CEA, bodies are skin reactions caused by disturbed prolifera- 13.92 ng/mL) and carbohydrate antigen (Ca 19-9 anti- tion, differentiation and migration of keratinocytes as gen; 43.3 U/mL). well as stimulation of the non-specific immune response Due to the lack of KRAS, NRAS, and BRAF gene [10]. Symptoms covering skin and its appendages caused mutations and chronic diarrhea, which could poten- by these antibodies are defined as skin toxicity. tially be exacerbated by irinotecan, it was decided to introduce FOLFOX chemotherapy in combination with panitumumab. After the second drug administration Case report she developed a G1 acne-like rash on face and torso, G2 hand-foot syndrome, and G1 diarrhoea. Oral antibi- In February 2018, a 55-year-old female patient with otic therapy with doxycycline at the dose of 2 × 100 mg, inoperable recurrence of rectal cancer was admitted to topical treatment of skin lesions with vitamin A, E and the chemotherapy ward to start systemic treatment. The cholesterol ointment and loperamide 4 × 4 mg were in- malignancy was primary diagnosed in March 2012 when, troduced. After the 4th cycle, the skin lesions intensified due to gastrointestinal obstruction in the course of rectal (G2 rash and G3 hand-foot syndrome), so the topical cancer, a double-barrel sigmoideostomy was performed. treatment was enriched by 10% urea ointment. After Due to extension of the disease the patient underwent the 5th cycle, the patient’s general condition worsened. induction chemotherapy with capecitabine (04–07.2012; The symptoms of short bowel syndrome connected with 10.2012–03.2013) and after that she received preopera- diarrhoea increased to grade G2 leading to electrolyte tive chemoradiotherapy (07–08.2012). In May 2013, the disturbances. In addition, trophic changes in the abdomi- patient underwent laparotomy. Intraoperatively, rectal nal skin in the area of the stoma (G3) appeared, which tumour infiltrating the uterus, part of vagina, and the made considerable difficulties while taking care of it. It anterior abdominal wall was found. As a consequence was necessary to prolong the intervals between infusions low anterior rectal resection by Hartmann method with of cytostatics. Parenteral hydration and correction of complete mesorectal resection and hysterectomy was electrolyte disturbances were introduced simultaneously performed. In pathological examination tubular adeno- with continuation of current symptomatic treatment. carcinoma G2 ypT2N0 was diagnosed. In September Due to the severity of diarrhoea, atropine with diphe-

327 Oncology in clinical practice 2019, Vol. 15, No. 6 noxylate 2.5 mg + 0.025 mg 3 × 2 tablets and morphine In this case, skin toxicity was manifested not only as 10 mg every four hours were added to the loperamide a rash characteristic for anti-EGFR drugs, but also as treatment. A slight improvement was obtained after dryness and trophic changes of the abdominal skin in using racecadotril 100 mg three times a day. the area of the stoma and hand-foot syndrome; these First evaluation of treatment effectiveness, based additional symptoms significantly impaired patient’s on the CT scan, revealed cancer stabilisation. However, quality of life. A skin ulceration in the area of the stoma during this time the patient lost 16% of baseline body made sticking an ostomy pouch impossible, which was weight (BMI 15.7), and increased her risk associated extremely troublesome due to diarrhoea. In turn, the with nutritional status (NRS, Nutritional Risk Score) increased hand-foot syndrome worsened patient’s which was rated 4 — as an indication for nutritional daily activities. treatment. Due to the lack of formal possibilities to Hand-foot syndrome occurs in 6–64% of patients return to targeted therapy after discontinuation, it treated for cancer, and its frequency depends on the was decided to continue systemic treatment along with type of systemic treatment used. Erythema, oedema, symptomatic medications and the use of medical food. hyperkeratosis, and signs of dysesthesia usually occur In subsequent CT scans, disease stabilization main- in G1–2 severity. In turn, the G3 degree is associated tained, but clinically due to exacerbation of skin toxicity with flaking skin, as well as blistering and ulceration a temporal brake from panitumumab administration was accompanied by severe pain that significantly affect made. Ointments with hydrocortisone (hydrocortisone, work and self-service. Hand-foot syndrome is most often urea 10%, boric acid 1%) and gentamicin were added to a complication of capecitabine, liposomal doxorubicin, symptomatic treatment. Further adverse reactions were docetaxel, or fluorouracil [15]. In the presented case, accompanied by prolonged asymptomatic neutropaenia previous long-term capecitabine chemotherapy was and G2 peripheral polyneuropathy. During the 16th likely to affect the appearance and severity of hand-foot oxaliplatin infusion a severe allergic reaction occurred. syndrome. In addition, oxaliplatin exacerbated the It was manifested by pruritus and redness located on symptoms of polyneuropathy. the skin of the limbs. Treatment of skin reactions depends on their severity By January 2019, the patient’s PS (PS3) and quality and includes the use of moisturizers, vitamin K oint- of life deteriorated significantly. Because of this and ments, protective skin filters (SPF > 15 UVA and UVB), due to cachexia and unacceptable toxicity treatment creams containing steroids, and oral antibiotics. If the was stopped after 16 infusions. For the further care patient develops a G ≥ 3 skin reactions or skin toxicity the patient was referred to the Oncological Outpatient is deemed unacceptable, it is recommended to suspend Clinic. In a CT scan performed in March 2019, the anti-cancer drugs temporarily and, after a restoration, disease was still stable. The patient died in May 2019, continue the therapy in a reduced dose if possible. In without confirmation of cancer progression. some patients, the side effects of anti-EGFR drugs disappear only after permanent discontinuation of therapy. The strategy for management of this skin toxicity Discussion includes not only treatment but also prophylaxis. Cur- rently, prophylactic antibiotic therapy with tetracyclines Skin toxicity most commonly manifested as acne-like or with drugs for external use is not a standard procedure rash, periungual inflammation, dryness, and itching of because there is no clear evidence of a reduction in skin the skin occurs in up to 96% of patients receiving pani- complications frequency. However, there are reports tumumab along with chemotherapy. During FOLFOX that such a modification may not only reduce the risk of chemotherapy with panitumumab, skin rash G ≥ 3 was G2–4 skin toxicity by up to 50% but is also likely to have observed in 38% of patients, compared to 2% of pa- a positive impact on the quality of life, mainly during tients receiving chemotherapy alone. However, it has the initial phase of immunotherapy [16, 17]. been shown that there are no significant differences Triple-drug therapy with panitumumab is associated in the quality of life of patients depending on whether with higher incidence of G ≥ 3 diarrhoea (18% vs. 9%) they have G0–2 or G ≥ 3 skin complications [11]. On [12]. Diarrhoea complicating systemic treatment with the other hand, the development of G2–4 skin toxicity, panitumumab is known to be less common in patients as opposed to G0–1, correlates with good response to undergoing prophylactic antibiotic therapy (56% treatment. In the first group of patients, higher medians vs. 85%), which probably results from anti-inflammatory of OS and PFS are noted [12–14]. In most patients, and antibacterial effects of tetracyclines [17]. skin complications disappear during therapy; however, Numerous anti-diarrhoeal medications were used in in some of them, as in the presented case, they persist the presented case, unfortunately with poor therapeutic with significant intensity and may lead to treatment effect. Literature indicates that in the described situation discontinuation. some improvement may be achieved by H2 receptor

328 Kinga Krawiec et al., Short bowel syndrome after panitumumab blockers or proton pump inhibitors which reduce diar- program (Novemeber 2019) allows for interruption in rhoea in patients with short bowel syndrome [18]. In the cytotoxic treatment but interval between antibody infu- presented patient short bowel syndrome was related to sions can not be longer than 8 weeks. In this regard, it both current systemic therapy and previous treatment is extremely important to carry out a proper qualifica- consisting of surgeries, chemotherapy, and radiation tion before administration of triple therapy including therapy, which led to reduction in length of the intestine anti-EGFR antibodies. and impairment of its function. Short bowel syndrome is defined as a reduction in the absorption of nutrients resulting from excessive shortening or functional dis- References orders of the intestine. It is manifested by debilitating diarrhoea, leading to malnutrition and both water and 1. Bray F, Ferlay J, Soerjomataram I, et al. Global cancer statistics 2018: GLOBOCAN estimates of incidence and mortality worldwide for 36 electrolyte disorders. Treatment of this syndrome should cancers in 185 countries. CA Cancer J Clin. 2018; 68(6): 394–424, doi: take place in specialist centers. It is based on parenteral 10.3322/caac.21492, indexed in Pubmed: 30207593. 2. Howlader N, Noone AM, Krapcho M, et al. SEER Cancer Statistics nutrition with simultaneous enteral nutrition, aimed at Review, 1975–2016, National Cancer Institute. Bethesda, MD, https:// maintaining the function of intestine and preventing seer.cancer.gov/csr/1975_2016/, based on November 2018 SEER data submission, posted to the SEER web site, April 2019. atrophy of the intestinal villi. 3. Xie MZ, Li JL, Cai ZM, et al. Impact of primary colorectal Cancer Limited availability of outpatient clinics that spe- location on the KRAS status and its prognostic value. BMC Gastro- cialize in nutritional treatment is a hindrance to cancer enterol. 2019; 19(1): 46, doi: 10.1186/s12876-019-0965-5, indexed in Pubmed: 30917791. patients. Modification of therapy by adding adequate 4. Zhao B, Wang Lu, Qiu H, et al. Mechanisms of resistance to anti-EGFR nutritional treatment is bound to improve the general therapy in colorectal cancer. Oncotarget. 2017; 8(3): 3980–4000, doi: 10.18632/oncotarget.14012, indexed in Pubmed: 28002810. condition of the patients in whom short bowel syndrome 5. Tran B, Kopetz S, Tie J, et al. Impact of BRAF mutation and microsat- led to cachexia and abandoning chemotherapy. ellite instability on the pattern of metastatic spread and prognosis in metastatic colorectal cancer. Cancer. 2011; 117(20): 4623–4632, doi: It is estimated that as many as 10–20% of cancer 10.1002/cncr.26086, indexed in Pubmed: 21456008. patients die due to malnutrition, and only 30–60% of 6. Price TJ, Peeters M, Kim TW, et al. Panitumumab versus cetuximab the ones at risk receive nutritional support (i.e. oral sup- in patients with chemotherapy-refractory wild-type KRAS exon 2 metastatic colorectal cancer (ASPECCT): a randomised, multicentre, plements or parenteral nutrition or enteral nutrition). open-label, non-inferiority phase 3 study. Lancet Oncol. 2014; 15(6): One of the European multicenter studies estimated 569–579, doi: 10.1016/S1470-2045(14)70118-4, indexed in Pubmed: 24739896. that nearly 40% of cancer patients receive incorrect 7. Jonker DJ, Karapetis CS, Harbison C, et al. K-ras mutations and classification of nutrition level, resulting in the lack of benefit from cetuximab in advanced colorectal cancer. N Engl J Med. 2008; 359(17): 1757–1765, doi: 10.1056/NEJMoa0804385, indexed adequate nutritional intervention [19]. in Pubmed: 18946061. According to the guidelines of the European Socie 8. Douillard JY, Oliner KS, Siena S, et al. Panitumumab-FOLFOX4 ty for Clinical Nutrition and Metabolism (ESPEN), treatment and RAS mutations in colorectal cancer. N Engl J Med. 2013; 369(11): 1023–1034, doi: 10.1056/NEJMoa1305275, indexed long-term parenteral nutrition should be offered in in Pubmed: 24024839. bowel failure if: 1) enteral nutrition is insufficient, 2) 9. Cutsem EV, Lenz HJ, Köhne CH, et al. Fluorouracil, Leucovorin, and Irinotecan Plus Cetuximab Treatment andRASMutations the predicted survival is longer than 2–3 months, 3) it in Colorectal Cancer. J Clin Oncol. 2015; 33(7): 692–700, doi: is anticipated that parenteral nutrition may stabilise 10.1200/jco.2014.59.4812. 10. Jost M, Kari C, Rodeck U. The EGF receptor — an essential regulator or improve the patient’s performance status and qual- of multiple epidermal functions. Eur J Dermatol. 2000; 10(7): 505–510, ity of life [20]. In addition, BMI in the range of 18.5– indexed in Pubmed: 11056418. –20.0 kg/m2 means the patient is at the risk of malnutri- 11. Siena S, Tabernero J, Bodoky G, et al. Quality of life during first-line FOLFOX4 ± panitumumab in wild-type metastatic colorectal carci- tion with an indication for the introduction of nutritional noma: results from a randomised controlled trial. ESMO Open. 2016; treatment. BMI below 18.5 kg/m2 is diagnosed as malnu- 1(2): e000041, doi: 10.1136/esmoopen-2016-000041, indexed in Pubmed: 27843597. trition with the need for urgent nutritional intervention. 12. Douillard JY, Siena S, Cassidy J, et al. Final results from PRIME: ran- Anti-EGFR monotherapy is less likely to cause domized phase III study of panitumumab with FOLFOX4 for first-line treatment of metastatic colorectal cancer. Ann Oncol. 2014; 25(7): life-threatening complications in comparison with 1346–1355, doi: 10.1093/annonc/mdu141, indexed in Pubmed: chemotherapy. However, cumulative toxicity coming 24718886. from combination of targeted drugs and chemotherapy 13. Saltz LB, Meropol NJ, Loehrer PJ, et al. Phase II trial of cetuximab in patients with refractory colorectal cancer that expresses the epidermal may impair the quality of life in a significant way. More growth factor receptor. J Clin Oncol. 2004; 22(7): 1201–1208, doi: over it may create the need for dose reduction or drug 10.1200/JCO.2004.10.182, indexed in Pubmed: 14993230. 14. Douillard JY, Rong A, Sidhu R. RAS mutations in colorectal cancer. N discontinuation which in turn reduces the chances of Engl J Med. 2013; 369(22): 2159–2160, doi: 10.1056/NEJMc1312697. obtaining desired therapeutic effects. In Poland, cetuxi- 15. Kowalska M, Kowalik A, Góźdź S. Dermatologic adverse events associated with chemotherapy and targeted anticancer therapy. Przegląd mab and panitumumab treatment is financed under the Dermatologiczny. 2016; 2: 127–138, doi: 10.5114/dr.2016.59135. Ministry of Health’s drug program. If the antibody used 16. Ocvirk J, Heeger S, McCloud P, et al. A review of the treatment options in the first line is discontinued due to toxicity, the drug for skin rash induced by EGFR-targeted therapies: Evidence from randomized clinical trials and a meta-analysis. Radiol Oncol. 2013; program does not allow its re-use in the third line even 47(2): 166–175, doi: 10.2478/raon-2013-0014, indexed in Pubmed: if its ineffectiveness has not been proven. Updated drug 23801914.

329 Oncology in clinical practice 2019, Vol. 15, No. 6

17. Lacouture ME, Mitchell EP, Piperdi B, et al. Skin toxicity evalua- ESPEN guidelines on chronic intestinal failure in adults. Clin Nutr. tion protocol with panitumumab (STEPP), a phase II, open-label, 2016; 35(2): 247–307, doi: 10.1016/j.clnu.2016.01.020, indexed in randomized trial evaluating the impact of a pre-Emptive Skin Pubmed: 26944585. treatment regimen on skin toxicities and quality of life in patients 19. Arends J, Baracos V, Bertz H, et al. ESPEN expert group recom- with metastatic colorectal cancer. J Clin Oncol. 2010; 28(8): mendations for action against cancer-related malnutrition. Clin Nutr. 1351–1357, doi: 10.1200/JCO.2008.21.7828, indexed in Pubmed: 2017; 36(5): 1187–1196, doi: 10.1016/j.clnu.2017.06.017, indexed in 20142600. Pubmed: 28689670. 18. Pironi L, Arends J, Bozzetti F, et al. Home Artificial Nutrition & Chronic 20. Bozzetti F, Arends J, Lundholm K, et al. ESPEN guidelines on paren- Intestinal Failure Special Interest Group of ESPEN, Home Artificial teral nutrition: non-surgical oncology. Clinical Nutrition. 2009; 28(4): Nutrition & Chronic Intestinal Failure Special Interest Group of ESPEN. 445–454, doi: 10.1016/j.clnu.2009.04.011.

330 CASE REPORT

Wojciech Michalski1, Grażyna M Poniatowska1, Joanna G Jońska-Gmyrek1, Karol E Nietupski1, Anna Z Cencelewicz2, Andrzej Mróz3, Witold Gerke2, Agnieszka Chreptowicz2, Tomasz Demkow1, Paweł J Wiechno1 1Urooncology Department, Maria Sklodowska-Curie Memorial Cancer Centre and Institute of Oncology, Warsaw, Poland 2Oncological Gastroenterology Department, Maria Sklodowska-Curie Memorial Cancer Centre and Institute of Oncology, Warsaw, Poland 3Pathology and Laboratory Diagnostics Department, Maria Sklodowska-Curie Memorial Cancer Centre and Institute of Oncology, Warsaw, Poland

hCG-secreting malignancies — diagnostic pitfalls

Address for correspondence: ABSTRACT Lek. Wojciech Michalski We present a case of a 34-year-old male patient referred to our Uro-oncology Department with a suspicion of Klinika Nowotworów Układu Moczowego a metastatic germ cell tumour, owing to enlarged left testicle and elevated b-hCG concentration (39 mIU/mL). Centrum Onkologii — Instytut Impaired performance status caused by extensive pulmonary and liver metastases, accompanied by significant im. Marii Skłodowskiej-Curie w Warszawie lymphadenopathy, necessitated prompt management. However, a testicular tumour was excluded on ultrasound ul. Roentgena 5, 02–781 Warszawa imaging; a hydrocele only was found. The b-hCG concentration was not increasing (37 mIU/mL). We found a diag Phone: (+48 22) 546 20 57 nosis of an extragonadal germ cell tumour doubtful, and a liver biopsy was performed. Due to the patient’s quick e-mail: [email protected] deterioration, we decided to commence pre-phase chemotherapy with cisplatin and etoposide, which resulted in a significant clinical improvement. The pathological examination, along with immunoassays, revealed undif- Oncology in Clinical Practice 2019, Vol. 15, No. 6, 331–335 ferentiated cholangiocarcinoma, and the patient continued chemotherapy with a biliary tract cancer regimen, DOI: 10.5603/OCP.2019.0040 i.e. cisplatin and gemcitabine. Unfortunately, the clinical response was short-lived; the disease progressed, the Copyright © 2019 Via Medica patient was offered best supportive care and died two months after the diagnosis. ISSN 2450–1654 The case underpins the literature review with respect to differential diagnosis of an elevated hCG concentration. In particular, we discuss ectopic secretion in non-trophoblastic and non-germinal malignancies and the causes of false positive assays. Key words: human chorionic gonadotropin (hCG), germ cell tumour, paraneoplastic syndrome

Oncol Clin Pract 2019; 15, 6: 331–335

Introduction or cerebrum, along the body’s midline. Because the cure rate and prognosis are excellent even in the Human chorionic gonadotropin (hCG) is a glyco- metastatic cases, the issues of prompt diagnosis and protein hormone produced by trophoblast during preg- adequate treatment are of utmost importance [2, 3]. In nancy. In oncology, it serves as a marker of gestational selected patients, the diagnosis of GCT can be solely trophoblastic disease (GTD) and germ cell tumours established on the basis of elevated tumour marker (GCT). Additionally, hCG in its various forms has been concentrations, i.e. a-foetoprotein (AFP) and/or found in tissues of non-trophoblastic and non-germinal b-hCG [3]. Therefore, it is crucial to be aware of and malignancies [1], where it promotes tumour growth and avoid pitfalls that may mislead a physician and postpone invasion. Serum hCG reactivity may therefore pose the correct diagnosis. diagnostic difficulties. We present a case of hCG-secreting cholangiocarci- GCTs account for the majority of malignancies noma, referred to our centre with a suspicion of GCT. in young men. Usually testicular in origin, they may Possible scenarios of paraneoplastic secretion and false also develop in the retroperitoneum, mediastinum, positive hCG assays are also reviewed.

331 Oncology in clinical practice 2019, Vol. 15, No. 6

Case report of CK7 expression) or gastric carcinoma (Figures 1–3). Germ cell tumours were ultimately excluded. On gas- A 34-year-old male patient was admitted to a respiratory medicine centre with a four-month history of persistent, unproductive cough and dyspnoea, first on exertion and then at rest. A chest computed tomography (CT) scan revealed disseminated bilateral lung nodules, thickened bronchial walls, ground-glass opacity, enlarged heart, pericardial effusion (14 mm), as well as fractured sternum and 2nd left rib. Abdominal and pelvic CT scans showed abdominal and retroperitoneal lymphadenopathy (38 mm and 17 mm, respectively), multiple liver metastases (max. 40 mm), and agenesis of the left kidney. No abnormalities apart from a max- illary sinus polyp were found on CT scan of the head. Moreover, the patient gave a six-month history of left testicle enlargement; on ultrasound (US) the picture was characteristic of a testicular hydrocele, but the presence of a tumour could not be ruled out. Serum hCG con- Figure 1. Undifferentiated cholangiocarcinoma, HE staining, centration of 39 mIU/mL (normal < 5 mIU/mL) gave mag. 200 × rise to a suspicion of a germ cell tumour. At this stage, in February 2019, the patient was referred to our centre. On admission, he presented with cough and dyspnoea, ECOG performance status 2, and pulse oximetry of

88% (94% on O2). hCG concentration was 37 mIU/mL (normal < 5 mIU/mL), and a-foetoprotein (AFP) and lactate dehydrogenase (LDH) concentrations were within normal limits. Blood count and chemistry as well as coagulation parameters showed no important abnormalities. Scrotal US revealed a left testicular hydrocele (15 mL) and no suspicious tumours. Haemodynamically insignificant pericardial effusion and normal contractil- ity of cardiac muscle (left ventricle ejection fraction of 65%) were found on echocardiography. The case was presented at a multi-disciplinary clinical meeting. Due to a relatively low increase in hCG concentration together with massive metastases, the diagnosis of an extragonadal germ cell tumour was du- Figure 2. Undifferentiated cholangiocarcinoma, CK19 (+) bious. We agreed that a pathological diagnosis should be established; one of the liver metastases was chosen for a core biopsy. Once the biopsy had been performed, we decided to commence pre-phase chemotherapy due to the patient’s steady clinical deterioration. Cisplatin (20 mg/m2) and etoposide (100 mg/m2) were administered on days 1–2, with prophylaxis of the acute tumour lysis syndrome (ATLS) and thromboprophylaxis. The pre-phase resulted in a rapid improvement with respect to dyspnoea and pulse oximetry (94–98% with no O2 supply). The pathology report revealed an undifferentiated (G3) adenocarcinoma with high mitotic activity. Immu- nostaining was as follows: CKAE 1/3 (+), CK19 (+), CK7 (–), CK20 (–), SALL4 (–), PLAP (–), b-hCG (–), CD 30 (–), CDX2 (–). It was characteristic of cholangiocarcinoma (highly-aggressive type? — untypical lack Figure 3. Undifferentiated cholangiocarcinoma, CK7 (–)

332 Wojciech Michalski et al., hCG-secreting malignancies troscopy, gastric and duodenal inflammatory lesions of GCT diagnosis, we would have continued with four were biopsied; chronic gastritis/duodenitis was diag- cycles of standard BEP or VIP chemotherapy. Even nosed pathologically. with another tumour histology, which finally proved the This led to the final diagnosis of cholangiocarcinoma case, cisplatin and etoposide would have been likely to (TNM 8th edition: cTx cN1 pM1; clinical stage IV). The decrease the tumour volume before adapting further chemotherapy regimen was changed to GP (gemcitabine treatment to the pathology outcome. 800–1000 mg/m2 days 1, 8 and cisplatin 30 mg/m2 days hCG is a protein composed of two subunits: a, com- 1, 8; to be repeated every three weeks). Only two cycles mon to all glycoprotein hormones; and b, responsible were administered. Although substantial, the clinical for its specific structure and activity [1]. Different forms improvement was short-lived. Dyspnoea recurrence and of the hormone are encountered in vivo, e.g. the native performance status decline (ECOG 4) was observed. hCG, hyperglycosylated hCG (hyp-hCG), nicked-hCG, With best supportive care, the patient died two months or the free b-subunit. Apart from the role played in after the diagnosis. pregnancy, hCG is capable of promoting angiogenesis, supressing macrophage activity, blocking apoptosis (hyp-hCG), promoting choriocarcinoma invasion, as Discussion well as enhancing malignant transformation, growth, and invasion of non-trophoblastic malignancies (b-subunit Germ cell tumours (GCT), however rare, account and hyp-hCG) [1]. The hormone variants may be de- for the most common malignancies in males aged tected both in serum and cancer tissue. 15–40 years [2]. The highest incidence rates are observed Elevated in all cases of gestational trophoblastic in developed countries (11.8 per 100,000 in Norway) [3]. disease, hCG serves as an ideal marker, contributing Therefore, given the patient’s age, clinical presentation, to diagnosis, treatment monitoring, and follow-up. and an elevated hCG concentration, the suspicion of hCG-secreting germ cell tumours account for 40–50% GCT in the patient described was justified. However, of non-seminomas and 15–20% of seminomas tumours once a testicular tumour was ruled out on US, the prob- [1]. In non-seminomas tumours, the hCG concentration ability of GCT decreased, because only 5% of GCT are is one of the prognosis factors. extragonadal (EGGCT) [2]. Importantly, EGGCTs typi- Other malignancies very often express and secret cally arise in the body’s mid-line, e.g. retroperitoneum, hCG [4–21]; the protein is synthesised either by the mediastinum, or cerebrum [2]. This, in turn, was not whole tumour cell population or by a subclone of undif- the case in our patient. Massive pulmonary and liver ferentiated cells. Most frequently, the b-subunit is pro- metastases were accompanied by relatively small retrop- duced [1]. Many authors point out that hCG synthesis is eritoneal lymphadenopathy (17 mm) and no mediastinal a factor of poor prognosis. Examples of non-gestational lymphadenopathy. Still, such a presentation could have and non-germinal neoplasms secreting hCG are shown resulted from an aggressive non-seminomatous GCT, in Table 1. Many others, however, have been reported e.g. choriocarcinoma, a histological component more in the literature. likely to give visceral metastases with a small or even Truly elevated serum hCG concentrations may be burned-out primary testicular tumour. In this case, observed in hypogonadal men [22] and postmenopausal however, the hCG concentration would have been much women [23]. The pituitary gland, normally secreting higher, corresponding with the tumour burden. Overall, small amounts of the hormone, is stimulated to hCG we considered the possible diagnosis of GCT doubtful production in the event of a marked decrease in sex hor- and decided on the liver biopsy. mones concentrations. A two-week hormone replace- Some GCT patients are not fit enough to start treatment therapy should suffice to assess whether this is the ment with full doses of combination chemotherapy. This case in our patient [23, 24]. Another reason, sometimes usually stems from a massive tumour volume with sig- difficult to elicit from the patient, is self-administering nificantly elevated marker concentrations and a high risk of hCG. Male athletes who abuse anabolic steroids of bleeding (e.g. choriocarcinoma) as well as impaired withdraw them at intervals and switch to hCG in order performance status and organ dysfunction. To avoid to stimulate endogenous testosterone production and fatal complications, a pre-phase chemotherapy should prevent testicular atrophy [25]. be administered, for instance 2–3 days of cisplatin and In oncological daily practice, it is worth remembering etoposide or single-agent low-AUC carboplatin. Once that markers may be secreted from the tumour mass af- the patient has improved, full-dose chemotherapy must ter chemotherapy initiation, i.e. during the first cycle, or be started [3]. Understandably, there are scarce data even from necrotic tissues after the completion of treat- available on this topic. We decided to administer such ment [26]. Germ cell tumour patients with persistent induction treatment to our patient, without liver biopsy elevated markers after first-line chemotherapy should be results, given his rapidly deteriorating status. In case closely followed up and scheduled for prompt residual

333 Oncology in clinical practice 2019, Vol. 15, No. 6

Table 1. Examples of non-gestational, non-germinal hCG- tive hCG assay in the urine sample may explain the false -secreting neoplasms with the reported hCG concentrations positivity of the serum [28]. However, even in case of Primary site, histology Serum hCG true positive serum, the hCG concentration in urine may be too low to be detected [24]. [mIU/mL] Reports of false positive hCG assays due to cannabi- Lung adenocarcinoma [4] 7660 noid use can also be found in the literature [29], although Non-small cell lung cancer [5] 4261 not confirmed by some authors [30]. Nevertheless, his- Solitary fibrous tumour of the pleura [6] 2174 tory taking should cover this aspect as well. Gastric signet-ring cell carcinoma [7] 458 In our patient, hCG immunostain in the liver biopsy Gallbladder adenocarcinoma [8] 558 specimen was notably negative despite serum positivity. This may have been due to a small sample or the fact that Colorectal Cancer [9] 903.7 only a subclone of cancer cells produced b-hCG. Another Phyllodes tumour of the breast [10] 58 explanation may be rapid secretion of hCG outside the Cervical squamous carcinoma [11] 50.05 cancer cells and into circulating blood, hence leaving an Mucinous adenocarcinoma of the ovary [12] 227 undetectable amount in the cytoplasm. Low sensitivity Endometrial carcinoma [13] 201 of the assays used may have added to the outcome [15]. Urinary bladder high-grade transitional cell 95 The differential diagnosis of GCT, other malig- carcinoma [14] nancies, and false-positive hCG assays is of utmost importance. In selected cases of substantial tumour Nephroblastoma (Wilms tumour) [15] 469 burden, extensive visceral metastases, and impending Columnar cell variant of papillary thyroid 2800 organ failure, the diagnosis of GCT may be established carcinoma [16] on the basis of unequivocally elevated serum markers Cribriform-morular variant of thyroid papillary 139 (hCG, AFP). This may pose serious difficulties because carcinoma [17] there is no objective concentration cut-off value. In High-grade osteosarcoma [18] 2177 the literature reviewed, the highest paraneoplastic Liposarcoma with rhabdomyosarcomatous 843 hCG result was 7660 mIU/mL [4]. On the other hand, differentiation [19] a typical clinical presentation, along with very high Osteoblastoma [20] 24.7 GCT marker concentrations and a need for immediate Giant cell tumour of the bone [21] 263 chemotherapy, sanctions treatment initiation without histological confirmation. hCG — human chorionic gonadotropin In conclusion, the subtleties of GCT marker interpretation, given the expected radical treatment outcome, tumour resection unless there is an unequivocal increase support referring such patients to high-volume centres in marker concentration, which justifies second-line of excellence [2, 3]. chemotherapy. Another possibility of a rapid serum hCG (or any marker) increase is re-infusion with autologous peripheral blood stem cell (PBSC) transplant [27] in pa- References tients undergoing high-dose chemotherapy. PBSCs are harvested at the beginning of induction chemotherapy, 1. Sisinni L, Landriscina M. The Role of Human Chorionic Gonadotropin as Tumor Marker: Biochemical and Clinical Aspects. Adv Exp Med Biol. when serum markers are elevated. Their concentrations, 2015; 867: 159–176, doi: 10.1007/978-94-017-7215-0_11, indexed in decreased or normalised in responders, may increase Pubmed: 26530366. 2. Oldenburg J, Fosså SD, Nuver J, et al. ESMO Guidelines Working again after the transplant, but such a phenomenon is Group. Testicular seminoma and non-seminoma: ESMO Clinical transient and concordant with a marker’s half-life [27]. Practice Guidelines for diagnosis, treatment and follow-up. Ann Oncol. The results of hCG assays may also be false posi- 2013; 24 Suppl 6: vi125–vi132, doi: 10.1093/annonc/mdt304, indexed in Pubmed: 24078656. tive for various reasons. Heterophilic antibodies (HA), 3. Honecker F, Aparicio J, Berney D, et al. ESMO Consensus Conference frequently found in sera, may appear as a result of on testicular germ cell cancer: diagnosis, treatment and follow-up. Ann Oncol. 2018; 29(8): 1658–1686, doi: 10.1093/annonc/mdy217, infections or contact with foreign (e.g. animal) tissues indexed in Pubmed: 30113631. [24]. They are capable of interfering with two-sided 4. Lazopoulos A, Krimiotis D, Schizas NC, et al. Galactorrhea, mastodynia and gynecomastia as the first manifestation of lung adenocarcinoma. (‘sandwich’) assays, hence giving false positive out- A case report. Respir Med Case Rep. 2019; 26: 146–149, doi: 10.1016/j. comes. A similar mechanism is related to additives or rmcr.2018.12.001, indexed in Pubmed: 30603606. preservatives in blood collection tubes [24]. Commercial 5. Cirit Koçer B, Erdoğan Y, Akıncı Özyürek B, et al. b-HCG secretion by a non-small cell lung cancer: a case report. Tuberk Toraks. 2016; 64(1): kits of heterophilic blocking reagents (HBR) are avail- 69–72, indexed in Pubmed: 27266288. able to bind HA in the sample and prevent this effect; 6. Kugasia IR, Alkayem M, Patel JB. A rare case of b-hCG production by a solitary fibrous tumor of the pleura. Am J Case Rep. 2014; such kits are used at our centre. HA molecules are too 15: 518–522, doi: 10.12659/AJCR.891171, indexed in Pubmed: big to be filtered in kidney glomeruli; therefore, a nega- 25420430.

334 Wojciech Michalski et al., hCG-secreting malignancies

7. Ben Kridis W, Ben Hassena R, Charfi S, et al. Gastric signet-ring cell 19. Maryamchik E, Lyapichev KA, Halliday B, et al. Dedifferentiated Lipo- carcinoma with hypersecretion of b-Human chorionic gonadotropin sarcoma With Rhabdomyosarcomatous Differentiation Producing HCG: and review of the literature. Exp Oncol. 2018; 40(2): 149–151, indexed A Case Report of a Diagnostic Pitfall. Int J Surg Pathol. 2018; 26(5): 448– in Pubmed: 29949529. 452, doi: 10.1177/1066896918760192, indexed in Pubmed: 29532681. 8. Leostic A, Tran PL, Fagot H, et al. Elevated human chorionic go- 20. Morris CD, Hameed MR, Agaram NP, et al. Elevated b-hCG associ- nadotrophin without pregnancy: A case of gallbladder carcinoma. ated with aggressive Osteoblastoma. Skeletal Radiol. 2017; 46(9): J Gynecol Obstet Hum Reprod. 2018; 47(3): 141–143, doi: 10.1016/j. 1187–1192, doi: 10.1007/s00256-017-2647-0, indexed in Pubmed: jogoh.2017.12.005, indexed in Pubmed: 29292237. 28396962. 9. Louhimo J, Carpelan-Holmström M, Alfthan H, et al. Serum HCG beta, 21. Lawless ME, Jour G, Hoch BL, et al. Beta-human chorionic gonad- CA 72-4 and CEA are independent prognostic factors in colorectal otropin expression in recurrent and metastatic giant cell tumors of cancer. Int J Cancer. 2002; 101(6): 545–548, doi: 10.1002/ijc.90009, bone: a potential mimicker of germ cell tumor. Int J Surg Pathol. indexed in Pubmed: 12237895. 2014; 22(7): 617–622, doi: 10.1177/1066896914534466, indexed in 10. Reisenbichler ES, Krontiras H, Hameed O. Beta-human chorionic Pubmed: 24831855. gonadotropin production associated with phyllodes tumor of the 22. Lempiäinen A, Hotakainen K, Blomqvist C, et al. Increased human cho- breast: an unusual paraneoplastic phenomenon. Breast J. 2009; rionic gonadotropin due to hypogonadism after treatment of a testicular 15(5): 527–530, doi: 10.1111/j.1524-4741.2009.00772.x, indexed in seminoma. Clin Chem. 2007; 53(8): 1560–1561, doi: 10.1373/clin- Pubmed: 19624411. chem.2007.088518, indexed in Pubmed: 17644799. 11. Mustafa A, Bozdag Z, Tepe NB, et al. An unexpected reason for 23. Cole LA, Sasaki Y, Muller CY. Normal production of human chorionic elevated human chorionic gonadotropin in a young woman. Cervical gonadotropin in menopause. N Engl J Med. 2007; 356(11): 1184–1186, squamous carcinoma. Saudi Med J. 2016; 37(8): 905–907, doi: doi: 10.1056/NEJMc066500, indexed in Pubmed: 17361004. 10.15537/2016.8.14529, indexed in Pubmed: 27464870. 24. Ballieux BE, Weijl NI, Gelderblom H, et al. False-positive serum 12. Wagner V, Winn H, Newtson A, et al. hCG production by mucinous human chorionic gonadotropin (HCG) in a male patient with a ma- adenocarcinoma of the ovary in a reproductive aged woman. Gyne- lignant germ cell tumor of the testis: a case report and review of the col Oncol Rep. 2018; 26: 102–104, doi: 10.1016/j.gore.2018.10.012, literature. Oncologist. 2008; 13(11): 1149–1154, doi: 10.1634/theon- indexed in Pubmed: 30533474. cologist.2008-0159, indexed in Pubmed: 18984875. 13. Grenache DG, Moller KA, Groben PM. Endometrial adenocarcinoma 25. Aherne NJ, Small CA, McVey GP, et al. Abnormal hCG levels in a pa- associated with elevated serum concentrations of the free beta tient with treated stage I seminoma: a diagnostic dilemma. World J subunit of human chorionic gonadotropin. Am J Clin Pathol. 2004; Surg Oncol. 2008; 6: 68, doi: 10.1186/1477-7819-6-68, indexed in 121(5): 748–753, doi: 10.1309/LMR6-YEJL-P6QC-DX93, indexed in Pubmed: 18578862. Pubmed: 15151215. 26. Beck SDW, Patel MI, Sheinfeld J. Tumor marker levels in post-che- 14. Ahmed M, Kanji A, Begum T. Gynaecomastia: an unusual present- motherapy cystic masses: clinical implications for patients with ing symptom of bladder cancer. BMJ Case Rep. 2015; 2015, doi: germ cell tumors. J Urol. 2004; 171(1): 168–171, doi: 10.1097/01. 10.1136/bcr-2015-210649, indexed in Pubmed: 26113595. ju.0000099714.16082.78, indexed in Pubmed: 14665869. 15. Gupta AK, Charlton A, Prelog K, et al. b-HCG Elevation in Wilms Tu- 27. Inoue M, Koga F, Kawakami S, et al. False tumor marker surge evoked by mor: An Uncommon Presentation. Pediatr Blood Cancer. 2016; 63(6): peripheral blood stem cell transplantation. Oncologist. 2008; 13(5): 526–529, 1105–1106, doi: 10.1002/pbc.25930, indexed in Pubmed: 26894993. doi: 10.1634/theoncologist.2007-0253, indexed in Pubmed: 18515737. 16. Gu H, Sui S, Cui X, et al. Thyroid carcinoma producing b-human cho- 28. Patel KK, Gronowski AM. Heterophile antibody interference in qual- rionic gonadotropin shows different clinical behavior. Pathol Int. 2018; itative urine/serum hCG devices: Case report. Clin Biochem. 2016; 68(4): 207–213, doi: 10.1111/pin.12639, indexed in Pubmed: 49(9): 729–731, doi: 10.1016/j.clinbiochem.2015.12.018, indexed in 29446856. Pubmed: 26968106. 17. Alikhan M, Koshy A, Hyjek E, et al. Discrepant serum and urine b-hCG 29. Garnick MB. Spurious rise in human chorionic gonadotropin induced results due to production of b-hCG by a cribriform-morular variant of by marihuana in patients with testicular cancer. N Engl J Med. 1980; thyroid papillary carcinoma. Clin Chim Acta. 2015; 438: 181–185, doi: 303(20): 1177, doi: 10.1056/NEJM198011133032014, indexed in 10.1016/j.cca.2014.08.026, indexed in Pubmed: 25181612. Pubmed: 7421935. 18. Tuy BE, Obafemi AA, Beebe KS, et al. Case report: elevated serum 30. Braunstein GD, Thompson R, Gross S, et al. Marijuana use does not beta human chorionic gonadotropin in a woman with osteosarcoma. spuriously elevate serum human chorionic gonadotropin levels. Urolo- Clin Orthop Relat Res. 2008; 466(4): 997–1001, doi: 10.1007/s11999- gy. 1985; 25(6): 605–606, doi: 10.1016/0090-4295(85)90290-0, indexed 008-0173-z, indexed in Pubmed: 18288544. in Pubmed: 2990078.

335 CASE REPORT

Aleksandra Piórek1, Dariusz M Kowalski1, Adam Płużański1, Olga Stanowska2, Maciej Krzakowski1 1Department of Lung and Thoracic Cancers, The Maria Sklodowska-Curie Institute — Oncology Centre in Warsaw, Poland 2Department of Pathology and Laboratory Diagnostics, The Maria Sklodowska-Curie Institute — Oncology Centre in Warsaw, Poland

Adenoid cystic carcinoma of the lung — a case report

Address for correspondence: ABSTRACT Lek. Aleksandra Piórek Adenoid cystic carcinoma (ACC) is a malignant neoplasm that frequently originates from the salivary glands Klinika Nowotworów Płuca of the head and neck. The majority of pulmonary adenoid cystic carcinomas develop centrally in the trachea. i Klatki Piersiowej Primary ACC of the lung arising from the bronchial glands is a rare disease and accounts for only 0.09–0.2% Centrum Onkologii — Instytut of all primary lung neoplasms. Although their growth rate is often indolent, they sometimes show aggressive im. Marii biologic behaviour. Local invasion with perineural infiltrations, and lymph node and hematogenous metastases Skłodowskiej-Curie w Warszawie have been reported for some of these neoplasms. Treatment options for advanced disease are limited. We herein e-mail: [email protected] report a case of a 56-year-old male patient with adenoid cystic carcinoma of the lung, who received conventional Oncology in Clinical Practice chemotherapy and endobronchial irradiation. This review focuses on the role of palliative tretament in the mana 2019, Vol. 15, No. 6, 336–338 gement of metastatic ACC. DOI: 10.5603/OCP.2019.0041 Key words: adenoid cystic carcinoma, lung, chemotherapy Translation: dr n. med. Dariusz Stencel Copyright © 2019 Via Medica Oncol Clin Pract 2019; 15, 6: 336–338 ISSN 2450–1654

Case report kidney (largest 34 × 33 mm). The patient was qualified to high dose rate (HDR) endobronchial brachytherapy In July 2016, a 56-year-old man diagnosed with ad- using the iridium isotope Iridium-192. A total of 20 Gy enoid cystic carcinoma (ACC) of the left lung with an in four fractions at weekly intervals was given to the af- initial clinical stage of cT3N2M0 was admitted to the fected bronchial sections. The treatment was completed Department of Lung and Thoracic Cancers, The Maria in August 2016. After 15 months, the disease progressed. Sklodowska-Curie Institute — Oncology Centre in War- Four chemotherapy cycles were used according to the saw. Previously, in another centre, the patient received carboplatin/paclitaxel regimen, and the disease was six cycles of chemotherapy according to the PN regimen stabilised. In December 2018, a CT scan showed a new (cisplatin and vinorelbine) — treatment was completed in lesion in the 6/7 liver segment and numerous metastatic May 2016. On admission, the patient was in good general changes in both kidneys. The patient received four cycles condition (category 1 — according to the World Health of chemotherapy according to the PE scheme (cisplatin Organisation classification), but had reported shortness of and etoposide) and achieved disease stabilisation. Treat- breath and haemoptysis since about two weeks previously. ment was complicated by grade 2 hearing impairment No significant abnormalities were found in the laboratory (CTCAE version 5.0). The last control visit took place tests. Physical examination of pulmonary fields revealed in July 2019; the disease is still stabilised. impaired percussion sound on the left side and weakening of respiratory murmur on the same side. Chest computed tomography (CT) showed complete atelectasis of the left Discussion lung with left main bronchus amputation and the presence of a lymph node package under tracheal bifurcation of Primary ACC of the lung arising from the bronchial size 30 × 17 mm as well as lesions in the right lung and left glands is a rare disease and accounts for only 0.09–0.2%

336 Aleksandra Piórek et al., Lung ACC — a case report of all primary lung neoplasms [1]. Although their growth clinical stage IIIB and three with stage IV at baseline [3]. rate is often indolent, they sometimes show aggressive In the next two studies, patients with stage IV accounted biologic behaviour. Local invasion with perineural infil- for 8.3% (1) and 10% (3), respectively [5, 8]. trations, and lymph node and hematogenous metastases The treatment of choice is radical surgery, if feasi- have been reported for some of these neoplasms [2]. ble. Palliative treatment, on the other hand, includes Among 34 patients observed in the Beijing centre, chemotherapy, radiotherapy, prosthesis, and other 21 (61.8%) primary lesions were located in the trachea palliative surgery. Several studies have demonstrated or main bronchus, 11 (32.3%) tumours were below the the benefit of radiation therapy in terms of controlling lobular bronchi, and only 2 (5.9%) were in the pulmo- the primary tumour and ensuring a good palliative ef- nary parenchyma [3]. The relatively low incidence of fect in up to 75% of patients treated [9]. Resolution of ACC in peripheral parts of the lung is probably closely haemoptysis and reduction of dyspnoea were reported related to the distribution of glandular cells [4]. Occur- in 72.2% and 56.3% of irradiated patients, respectively rence of glands gradually decreases with the degree of [9]. Brachytherapy appears to be an effective and safe bronchial branching and accounts for only 11.3% in 6th method of palliative ACC treatment [10, 11]. One of the order bronchi, and then decreases close to zero [4]. ACC papers describes the use of endotracheal and endobron- localised outside the trachea should be distinguished chial irradiation in a young woman diagnosed with ACC. from primary and metastatic lung tumours. In com- There was a reduction of discomfort and improved respi- parison with other primary lung cancer, ACC tends to ratory function confirmed in lung function tests, and the occur in younger patients and with equal frequency in response to treatment continued for almost a year [10]. men and women [3]. Smoking does not appear to be an ACC is considered as a cancer with low sensitivity to che- aetiological factor for ACC. Often, the first symptom motherapy. There are few data in the literature regarding of the disease is cough, but in many patients the disease systemic treatment of this group of patients. Among the is detected by an incidentally performed imaging test. previously mentioned patients in stage IV, attempts were However, demographic data, clinical presentation, and made to use chemotherapy [3]. The first patient received radiological picture of changes are often diverse and free a regimen including gemcitabine (1250 mg/m2 on days from any characteristics. Histopathological examination 1 and 8) and cisplatin (75 mg/m2 on day 1), but the disease remains the only diagnostic tool that differentiates progressed after two treatment cycles due to enlargement ACC from other lung neoplasms. The morphological of the primary lesion and mediastinal lymph nodes. The picture is characteristic — there are two types of cells: second patient received vinorelbine (25 mg/m2 on days ductal cells with scant cytoplasm and angulated hyper- 1 and 8) and cisplatin (75 mg/m2 on days 1–3), achiev- chromatic nucleus, stained with cytokeratin (CK7); and ing symptom relief and disease stabilisation in imaging myoepithelial cells of basaloid appearance stained with tests. One patient received erlotinib, but after three myoepithelial markers (p63, SMA, calponin) — this months of treatment the disease progressed within the biphasic character emphasised by immunohistochem- mediastinal lymph nodes. Systemic treatment was also istry is crucial in differential diagnosis. The cells form used among patients with disease disseminated during cribriform, tubular, and solid structures. The percentage the follow-up period [3]. Data on treatment regimens of solid pattern determines the degree of histological are presented in Table 1. In the study described, among differentiation. Cancer typically extensively infiltrates the presented patients receiving palliative chemotherapy, along the nerve trunk. In doubtful cases, it is possible only one showed sensitivity to treatment with paclitaxel to perform immunohistochemical staining with the and cisplatin. Another study described the efficacy of MYB antibody — a positive reaction indicates MYB a combination of carboplatin and paclitaxel, and another gene translocation characteristic for ACC, which can be confirmed by fluorescence hybridisation in situ (FISH) [5, 6]. Usually, ACC of the lung grows slowly; however, Table 1. Combination chemotherapy in advanced ACC of the lung [3] in some cases there is a more aggressive course with Chemotherapy regimen Treatment line a tendency of local infiltration and, less frequently, paclitaxel 175 mg/m2, day 1; 1 lymph node involvement. In addition, after various pe- cisplatin 75 mg/m2, days 1–3 riods of disease-free time local or systemic relapses can gemcitabine 1250 mg/m2, days 1 and 8; 1 occur [2]. Among the large group of patients treated at cisplatin 75 mg/m2, days 1–3 the Mayo Clinic in 1972–2002 distant metastases were 2 observed in 40.5% [7]. In 15 ACC patients the tumour vinorelbine 25 mg/m , days 1 and 8; 1 cisplatin 75 mg/m2, days 1–3 metastasised mainly to the lungs, brain, chest wall, and liver [7]. Initially advanced disease is described very paclitaxel 175 mg/m2, day 1; 2 2 rarely. In the previously cited study, inoperable patients cisplatin 75 mg/m , day 1 constituted 23% (8), of whom five were diagnosed with pemetrexed 500 mg/m2, day 1 2

337 Oncology in clinical practice 2019, Vol. 15, No. 6 case that was sensitive to uracil-tegafur and cisplatin in carcinoma. Gen Thorac Cardiovasc Surg. 2010; 58(2): 82–86, doi: 10.1007/s11748-009-0467-4, indexed in Pubmed: 20155344. combination with radiation therapy [4, 12]. 5. Zhu F, Liu Z, Hou Y, et al. Primary salivary gland-type lung cancer: The presented patient received systemic treatment clinicopathological analysis of 88 cases from China. J Thorac Oncol. three times — in each case doublet chemotherapy with 2013; 8(12): 1578–1584, doi: 10.1097/JTO.0b013e3182a7d272, indexed in Pubmed: 24389442. a platinum derivative. After each treatment patient 6. Togashi Y, Dobashi A, Sakata S, et al. MYB and MYBL1 in adenoid obtained clinical benefit and disease stabilisation was cystic carcinoma: diversity in the mode of genomic rearrangement and transcripts. Mod Pathol. 2018; 31(6): 934–946, doi: 10.1038/s41379- found on imaging tests. The use of endobronchial irra- 018-0008-8, indexed in Pubmed: 29410490. diation resulted in the relief of symptoms and disease 7. Molina JR, Aubry MC, Lewis JE, et al. Primary salivary gland-type lung cancer: spectrum of clinical presentation, histopathologic control for over a year. The treatment was well tolerated. and prognostic factors. Cancer. 2007; 110(10): 2253–2259, doi: 10.1002/cncr.23048, indexed in Pubmed: 17918258. 8. Lee JH, Jung EJ, Jeon K, et al. Treatment outcomes of patients with adenoid cystic carcinoma of the airway. Lung Cancer. 2011; 72(2): References 244–249, doi: 10.1016/j.lungcan.2010.08.011, indexed in Pubmed: 20828861. 1. Kawashima O, Hirai T, Kamiyoshihara M, et al. Primary adenoid cystic 9. Makarewicz R, Mross M. Radiation therapy alone in the treatment carcinoma in the lung: report of two cases and therapeutic consid- of tumours of the trachea. Lung Cancer. 1998; 20(3): 169–174, doi: erations. Lung Cancer. 1998; 19(3): 211–217, doi: 10.1016/s0169- 10.1016/s0169-5002(98)00018-x, indexed in Pubmed: 9733051. 5002(97)00098-6, indexed in Pubmed: 9631369. 10. Boedker A, Hald A, Kristensen D. A method for selective endobronchial 2. Kang DY, Yoon YS, Kim HK, et al. Primary salivary gland-type lung and endotracheal irradiation. J Thorac Cardiovasc Surg. 1982; 84(1): cancer: surgical outcomes. Lung Cancer. 2011; 72(2): 250–254, doi: 59–61, indexed in Pubmed: 6283277. 10.1016/j.lungcan.2010.08.021, indexed in Pubmed: 20884075. 11. Price JC, Percarpio B, Murphy PW, et al. Recurrent adenoid cystic 3. Hu MM, Hu Y, He JB, et al. Primary adenoid cystic carcinoma of carcinoma of the trachea: intraluminal radiotherapy. Otolaryngol the lung: Clinicopathological features, treatment and results. Oncol Head Neck Surg. 1979; 87(5): 614–623, indexed in Pubmed: 228226. Lett. 2015; 9(3): 1475–1481, doi: 10.3892/ol.2015.2859, indexed in 12. Allen AM, Rabin MS, Reilly JJ, et al. Unresectable adenoid cystic Pubmed: 25663934. carcinoma of the trachea treated with chemoradiation. J Clin Oncol. 4. Shimizu J, Oda M, Matsumoto I, et al. Clinicopathological study 2007; 25(34): 5521–5523, doi: 10.1200/JCO.2007.13.7273, indexed of surgically treated cases of tracheobronchial adenoid cystic in Pubmed: 18048830.

338 REPORT

Magdalena Miedzińska Department of Clinical Oncology/Chemotherapy, Elbląska Hospital, MAGODENT Sp. z o.o., Warsaw, Poland

EOTTD Meeting in Berlin, July 5–6, 2019

Address for correspondence: ABSTRACT Lek. Magdalena Miedzińska At the beginning of July 2019 international conference of the European Organization for the Treatment of Tropho- Oddział Onkologii Klinicznej/Chemioterapii blastic Disease (EOTTD) took place in the one of the largest university hospitals in Europe, the Charité hospital in Szpital Elbląska, MAGODENT Berlin. The main goal of this year’s EOTTD conference was to emphasize the role of instant and correct clinical, ul. Szamocka 6, 01–748 Warszawa biochemical, pathomorphological, immunohistochemical and genetic diagnosis, conducting intensive, compli- e-mail: [email protected] ant with recommendations treatment and the need to assess the quality of life of patients. National registers, the

Oncology in Clinical Practice set-up of reference centers and their cooperation should serve to achieve these goals. 2019, Vol. 15, No. 6, 339–341 Key words: gestational trophoblastic disease, gestational trophoblastic neoplasm DOI: 10.5603/OCP.2019.0037 Translation: dr n. med. Dariusz Stencel Oncol Clin Pract 2019; 15, 6: 339–341 Copyright © 2019 Via Medica ISSN 2450–1654

On July 5–6, 2019 another international EOTTD During the lectures, the current recommendations (The European Organization for Treatment of Tropho- and treatment options for GTN were presented, with blastic Disease) conference took place. The meeting well-established cytostatics and their combinations place was one of the largest university hospitals in Eu- depending on the risk score [2]. In the low-risk group rope, i.e. the Charité hospital in Berlin, and its host was (0–6 points), monotherapy is recommended: metho- Jalid Sehouli — professor of gynecology and oncology. trexate or dactinomycin. In the high-risk group (from As always, the meeting was chaired by prof. Michael 7 points), multi-drug chemotherapy with the EMA-CO Seckl from London. In total, 52 physicians and scientists, regimen (etoposide, methotrexate, dactinomycin — cy- including four from Poland, took part in the conference. clophosphamide, vincristine) with possible 2–3 induction The only report from Poland was the speech of Dr. Grze- EP cycles (etoposide, cisplatin) or EP-EMA regimen gorz Szewczyk on the second day of the conference in (etoposide, cisplatin — etoposide, methotrexate, dac- the session: “New GTD center updates what is working tinomycin). Particular attention should be paid to pa- and what needs fixing?”. tients from the so-called “ultra-high risk” group (above The first day was dedicated to lecture sessions, and 12 points), where the tumor doubling time is only a few the second was the day of workshop meetings. The days and it is necessary to start immediate, intensive activity of the EOTTD group began in 2009. Its main treatment. The option available and used in special cases goal was to bring together specialists dealing with Ges- is high-dose chemotherapy with peripheral blood stem tational Trophoblastic Disease (GTD) and Gestational cell transplantation, which, despite its effectiveness, Trophoblastic Neoplasm (GTN) and create current requires extreme caution due to possible complications, recommendations [1]. The disease mainly affects young including death [3]. women and despite common advanced clinical stage it In connection with biological premises [4] and initial should always be treated as potentially curable. How- encouraging results of immunotherapy with use of im- ever, despite good prognosis, it is estimated that every mune response checkpoints inhibitors, most commonly year around 2,100 patients diagnosed with GTN die pembrolizumab [5], the French center in 2017 began due to inadequate medical care, which is mainly due a multi-center phase II clinical study TROPHIMMUN, to ignorance of biology and the course of the disease, aiming to assess the efficacy and toxicity of avelumab as well as a limited group of specialists involved in its in the treatment of chemotherapy-resistant GTN pa- diagnosis and treatment. tients. Avelumab is anti-PD-L1 (programmed death

339 Oncology in clinical practice 2019, Vol. 15, No. 6 ligand 1) monoclonal antibody and was administered Institute of Mother and Child in Warsaw, where, with at a dose of 10 mg/kg every 2 weeks until normalization the consent of the National Oncological Gynecology of hCG concentration, followed by an additional three Consultant and with the support of the Polish Society consolidation cycles. Preliminary results of the study will of Oncological Gynecology, in 2017 the Trophoblast be presented during the ISSTD (The International So- Disease Treatment Center was created, to which more ciety for the Study of Trophoblastic Diseases) congress and more women are reporting , usually after searching in Toronto in October this year. the center on the internet. Based on epidemiological The next most widely discussed issues were the data, it is estimated that in Poland there are about rarest GTN subtypes, i.e. Placental Site Trophoblas- 600 cases of GTD every year and 60 to 80 cases of tic Tumor (PSTT) and Epithelioid Trophoblastic GTN. This small amount results in a large dispersion Tumor (ETT). A characteristic feature of these dis- of patients and the resulting small practical experience eases, which significantly impedes and delays proper of individual doctors. Grzegorz Szewczyk, in addition diagnosis, is usually a long time interval from the to presenting statistical data and development plans for preceding pregnancy, calculated in months or even the Center, has recently presented a registry regarding years. A detailed algorithm is presented depending patients with GTD, thanks to which it will be possible in on the stage of cancer and the main prognostic fac- the future to assess both the morbidity and the results tor, which is the time since the previous pregnancy of GTN treatment in our country more precisely (www. (the cut-off value was set at 48 months), as well as trofoblast.imid.med.pl). Apart from Poland, speakers the desire to preserve fertility. Because of the usu- from Ireland, Serbia, Sweden and Ukraine presented ally high chemoresistance, surgery is the preferred their centers. treatment option, and if chemotherapy is needed, the Traditionally, on the second day, workshops took EP/EMA or TP/TE multi-drug regimens (paclitaxel, place in subgroups: clinicians and far fewer pathomor- cisplatinum/paclitaxel, etoposide) are used [6, 7]. It phologists, biochemists and nurses. In the group of was recommended to report PSTT and ETT cases to clinicians I participated in, apart from organizational the international register, which has already collected matters, the focus was on agreeing treatment recom- data on over 300 patients from 13 countries (http:// mendations for patients with disease progression or stdc.group.shef.ac.uk/psttuhr). relapse after treatment with EMA-CO multi-drug One of the sessions was devoted to patients’ quality chemotherapy (postulated II line scheme is TP/TE, of life and widely understood psychosocial issues. Very and III line treatment is pembrolizumab, which would interesting lectures was on fertility after GTN and replace high-dose chemotherapy with peripheral blood cognitive impairment after chemotherapy. However, stem cell transplantation) and an algorithm for the diag the presentations prepared by two patients after GTN nosis of atypical placental site nodule (APSN), which treatment met with the greatest interest. They made us were previously considered benign, and as it turns out — doctors aware how the diagnostic process and finally can be associated with the development of PSTT in the diagnosis and subsequent treatment affect not only as much as 10–15% and ETT. In each subgroup, the the patient’s health, but also her entire functioning in role of integrating the community of people dealing the family and society as well as her relatives. On the with patients diagnosed with GTD was highlighted other hand, it was very encouraging to meet directly in order to exchange experiences and create research healthy women with GTN diagnosed in the past and opportunities. The final effect of the workshop are to after undergoing intensive, multi-stage and long-term be recommendations that, after agreeing with ESGO treatment. One patient belonged to the high-risk group (The European Society of Gynecological Oncology) and and the other to the group of “ultra-high risk” with brain IGCS (The International Gynecologic Cancer Society), metastases. Making possible something which seems are to be published at the end of this year and then to be impossible, e.g. to achieve complete recovery updated every three years. in patients with very advanced disease and numerous The main postulate of this year’s EOTTD conference metastatic lesions adds motivation to action and to was to emphasize the role of rapid and correct clinical, continue treatment despite subsequent progression and biochemical, pathomorphological, immunohistochemi- treatment toxicity. It should be emphasized, that GTN cal and genetic diagnosis, intensive treatment in accord- at every stage of treatment should always be treated as ance with the recommendations and the need to assess potentially curable. the quality of life of patients. National registers, creation The next session was the reports of representatives of reference centers and their cooperation should serve of the newly established national trophoblast disease to achieve the above objectives. treatment centers. The Polish center, as last year, Next year’s EOTTD conference will take place in was presented by doctor Grzegorz Szewczyk from the Porto, the next in 2021 is planned in Warsaw.

340 Magdalena Miedzińska, EOTTD Meeting in Berlin, 5–6.07.2019

References es is ubiquitous and independent of clinical outcomes. Int J Gynecol Cancer. 2017; 27(3): 554–561, doi: 10.1097/IGC.0000000000000892, indexed in Pubmed: 28060141. 1. Bolze PA, Attia J, Massardier J, et al. EOTTD group. Formalised con- 5. Ghorani E, Kaur B, Fisher RA, et al. Pembrolizumab is effective for sensus of the European Organisation for Treatment of Trophoblastic drug-resistant gestational trophoblastic neoplasia. Lancet. 2017; Diseases on management of gestational trophoblastic diseases. Eur 390(10110): 2343–2345, doi: 10.1016/S0140-6736(17)32894-5, inde- J Cancer. 2015; 51(13): 1725–1731, doi: 10.1016/j.ejca.2015.05.026, xed in Pubmed: 29185430. indexed in Pubmed: 26092638. 6. Frijstein MM, Lok CAR, van Trommel NE, et al. Management and 2. FIGO Oncology Committee report: FIGO staging for gestational tro- prognostic factors of epithelioid trophoblastic tumors: Results from phoblastic neoplasia 2000. Int J Gynecol Obstet. 2002; 77(3): 285–287, the International Society for the Study of Trophoblastic Diseases doi: 10.1016/s0020-7292(02)00063-2. database. Gynecol Oncol. 2019; 152(2): 361–367, doi: 10.1016/j. 3. Frijstein MM, Lok CAR, Short D, et al. The results of treatment with ygyno.2018.11.015, indexed in Pubmed: 30473257. high-dose chemotherapy and peripheral blood stem cell support for 7. Gadducci A, Carinelli S, Guerrieri ME, et al. Placental site trophoblastic gestational trophoblastic neoplasia. Eur J Cancer. 2019; 109: 162–171, tumor and epithelioid trophoblastic tumor: Clinical and pathological doi: 10.1016/j.ejca.2018.12.033, indexed in Pubmed: 30731277. features, prognostic variables and treatment strategy. Gynecol Oncol. 4. Bolze PA, Patrier S, Massardier J, et al. PD-L1 expression in premalig- 2019; 153(3): 684–693, doi: 10.1016/j.ygyno.2019.03.011, indexed in nant and malignant trophoblasts from gestational trophoblastic diseas- Pubmed: 31047719.

341