UCSF Radiation Oncology Update: Predicting Benefit from Advanced Radiation Technologies

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The Department of Radiation Oncology at the University of California, San Francisco School of Medicine present

April 23 - 24, 2021

Course Directors

Sue Yom, MD, PhD, MAS Catherine Park, MD Mary Helen Barcellos-Hoff, PhD University of California, San Francisco

University of California, San Francisco School of Medicine Acknowledgement of Commercial Support

This CME activity was supported in part by educational grants from the following:

Siemens Medical

Exhibitors

Accuray Bayer Boston Scientific Brainlab MIM Software Inc. Q-Fix RaySearch Laboratories RefleXion Medical Regeneron Siemens Healthineers Varian Medical Systems

University of California, San Francisco School of Medicine Presents

UCSF Radiation Oncology Update: Predicting Benefit from Advanced Radiation Technologies

Overview This year’s course is focused on the role of advanced technologies in radiation oncology, especially the challenging issue of selecting patients who stand to benefit most. The course will feature discussions of IMRT, SBRT, MRI, and particle therapy. We will discuss proposed clinical, radiologic and biologic selection methods which are gaining importance as systemic therapies become increasingly tolerable, potent, and complex. This course offers numerous practical case-based review sessions allowing for self-assessment and interaction with expert panelists.

Educational Objectives Upon completion of this program, attendees should be able to:

• Describe molecular, immunologic, and imaging-based stratification of brain tumors; • Integrate hormone therapy and precise radiation therapy in treating prostate cancer; • Cite 3 major recent findings related to immunotherapy and oncogene addiction in lung cancer; • Name 3 predictors of breast cancer response; • Name two ways to reduce morbidity in head and neck cancer patients; • Identify MR predictors of prognosis and early response in gastrointestinal cancer.

ACCREDITATION

The University of California, San Francisco School of Medicine (UCSF) is accredited by the Accreditation Council for Continuing Medical Education to provide continuing medical education for physicians.

UCSF designates this live activity for a maximum of 15.25 AMA PRA Category 1 Credits™. Physicians should claim only the credit commensurate with the extent of their participation in the activity.

This CME activity meets the requirements under California Assembly Bill 1195, Continuing Education and Cultural and Linguistic Competency.

NURSES: For the purpose of recertification, the American Nurses Credentialing Center accepts AMA PRA Category 1 Credit™ issued by organizations accredited by the ACCME.

PHYSICIAN ASSISTANTS: AAPA accepts category 1 credit from AOACCME, Prescribed credit from AAFP, and AMA PRA Category 1 Credit™ from organizations accredited by the ACCME.

PHARMACY: The California Board of Pharmacy accepts as continuing professional education those courses that meet the standard of relevance to pharmacy practice and have been approved for AMA PRA Category 1 Credit™.

General Information

Attendance Verification/Sign-In Sheet / CME Certificates In order to receive credit, you must log into the live stream at least once during the course dates of April 23 - 24, 2020. Once you have logged on you can view the sessions in real time or review anything that you might have missed as the program will be recorded. Recorded presentations will be available for 30 days post course.

After the meeting, you will receive an email from [email protected] with a link to complete your online Course Evaluation/Electronic CME Certificate. Please make sure that you add this email to your safe senders list. Upon completing the online survey, your CME certificate will be automatically generated to print; you will also receive a copy by email. For smartphone users, you may want to take a photo of your certificate as some settings prevent you from emailing the certificate.

The link will be available for approximately 30 days after the last day of the course. However, after that date the link will expire and you will no longer be able to claim your credits online. You must then contact the Office of CME at [email protected] to receive your certificate and a $15 administrative fee may be applied.

Speaker Survey The Speaker Survey can be completed in real time during the course and is separate from the Evaluation/CME Certificate. A link to the Speaker Survey will also be provided in the Zoom Webinar chat box.

Virtual Exhibit Hall We invite you to join our supporting exhibitors in the virtual exhibit hall. A link to the exhibit hall will be provided in the Zoom Webinar chat box.

Federal and State Law Regarding Linguistic Access and Services for Limited English Proficient Persons

I. Purpose. This document is intended to satisfy the requirements set forth in California Business and Professions code 2190.1. California law requires physicians to obtain training in cultural and linguistic competency as part of their continuing medical education programs. This document and the attachments are intended to provide physicians with an overview of federal and state laws regarding linguistic access and services for limited English proficient (“LEP”) persons. Other federal and state laws not reviewed below also may govern the manner in which physicians and healthcare providers render services for disabled, hearing impaired or other protected categories

II. Federal Law – Federal Civil Rights Act of 1964, Executive Order 13166, August 11, 2000, and Department of Health and Human Services (“HHS”) Regulations and LEP Guidance. The Federal Civil Rights Act of 1964, as amended, and HHS regulations require recipients of federal financial assistance (“Recipients”) to take reasonable steps to ensure that LEP persons have meaningful access to federally funded programs and services. Failure to provide LEP individuals with access to federally funded programs and services may constitute national origin discrimination, which may be remedied by federal agency enforcement action. Recipients may include physicians, hospitals, universities and academic medical centers who receive grants, training, equipment, surplus property and other assistance from the federal government.

HHS recently issued revised guidance documents for Recipients to ensure that they understand their obligations to provide language assistance services to LEP persons. A copy of HHS’s summary document entitled “Guidance for Federal Financial Assistance Recipients Regarding Title VI and the Prohibition Against National Origin Discrimination Affecting Limited English Proficient Persons – Summary” is available at HHS’s website at: http://www.hhs.gov/ocr/lep/ .

As noted above, Recipients generally must provide meaningful access to their programs and services for LEP persons. The rule, however, is a flexible one and HHS recognizes that “reasonable steps” may differ depending on the Recipient’s size and scope of services. HHS advised that Recipients, in designing an LEP program, should conduct an individualized assessment balancing four factors, including: (i) the number or proportion of LEP persons eligible to be served or likely to be encountered by the Recipient; (ii) the frequency with which LEP individuals come into contact with the Recipient’s program; (iii) the nature and importance of the program, activity or service provided by the Recipient to its beneficiaries; and (iv) the resources available to the Recipient and the costs of interpreting and translation services.

Based on the Recipient’s analysis, the Recipient should then design an LEP plan based on five recommended steps, including: (i) identifying LEP individuals who may need assistance; (ii) identifying language assistance measures; (iii) training staff; (iv) providing notice to LEP persons; and (v) monitoring and updating the LEP plan.

A Recipient’s LEP plan likely will include translating vital documents and providing either on-site interpreters or telephone interpreter services, or using shared interpreting services with other Recipients. Recipients may take other reasonable steps depending on the emergent or non- emergent needs of the LEP individual, such as hiring bilingual staff who are competent in the skills required for medical translation, hiring staff interpreters, or contracting with outside public or private agencies that provide interpreter services. HHS’s guidance provides detailed examples of the mix of services that a Recipient should consider and implement. HHS’s guidance also establishes a “safe harbor” that Recipients may elect to follow when determining whether vital documents must be translated into other languages. Compliance with the safe harbor will be strong evidence that the Recipient has satisfied its written translation obligations.

In addition to reviewing HHS guidance documents, Recipients may contact HHS’s Office for Civil Rights for technical assistance in establishing a reasonable LEP plan.

III. California Law – Dymally-Alatorre Bilingual Services Act. The California legislature enacted the California’s Dymally-Alatorre Bilingual Services Act (Govt. Code 7290 et seq.) in order to ensure that California residents would appropriately receive services from public agencies regardless of the person’s English language skills. California Government Code section 7291 recites this legislative intent as follows:

“The Legislature hereby finds and declares that the effective maintenance and development of a free and democratic society depends on the right and ability of its citizens and residents to communicate with their government and the right and ability of the government to communicate with them.

The Legislature further finds and declares that substantial numbers of persons who live, work and pay taxes in this state are unable, either because they do not speak or write English at all, or because their primary language is other than English, effectively to communicate with their government. The Legislature further finds and declares that state and local agency employees frequently are unable to communicate with persons requiring their services because of this language barrier. As a consequence, substantial numbers of persons presently are being denied rights and benefits to which they would otherwise be entitled.

It is the intention of the Legislature in enacting this chapter to provide for effective communication between all levels of government in this state and the people of this state who are precluded from utilizing public services because of language barriers.”

The Act generally requires state and local public agencies to provide interpreter and written document translation services in a manner that will ensure that LEP individuals have access to important government services. Agencies may employ bilingual staff, and translate documents into additional languages representing the clientele served by the agency. Public agencies also must conduct a needs assessment survey every two years documenting the items listed in Government Code section 7299.4, and develop an implementation plan every year that documents compliance with the Act. You may access a copy of this law at the following url: http://www.spb.ca.gov/bilingual/dymallyact.htm

Faculty List

Course Directors

Catherine Park, MD Professor and Chair

Mary Helen Barcellos-Hoff, PhD Professor and Vice Chair

Sue Yom, MD, PhD, MAS Professor and Conference Chair

Conference Manager

Alan Taniguchi, MS

Visiting Faculty

Megan Daly, MD Associate Professor, Radiation Oncology UC Davis Health Sacramento, CA

William Hartsell, MD Medical Director, Northwestern Medicine Proton Center Warrenville, IL

William Regine, MD Professor and Chair, Radiation Oncology University of Maryland Baltimore, MD

David Thomson, MD. FRCR Consultant Oncologist The Christie NHS Foundation Trust University of Manchester Manchester, UK

Richard Valicenti, MD Professor and Chair, Radiation Oncology UC Davis Health Sacramento, CA

UCSF Course Faculty

Mekhail Anwar, MD, PhD Associate Professor

Steve Braunstein, MD, PhD Associate Professor

Jason Chan, MD Assistant Professor

UCSF Course Faculty (continued)

Felix Feng, MD Professor

Mary Feng, MD Professor

Shannon Fogh, MD Associate Professor

Jonathan George, MD, MPH Associate Professor Otolaryngology - Head and Neck Surgery

Alexander Gottchalk, MD, PhD Professor

Matthew Gubens, MD Associate Professor, Medical Oncology

Patrick Ha, MD Professor, Otolaryngology - Head and Neck Surgery

Julian Hong, MD, MS Assistant Professor

Ella Jones, PhD Specialist, Radiology and Biomedical Imaging

Hyunseok Kang, MD Associate Professor, Medical Oncology

Kavita Mishra, MD Associate Professor

Osama Mohamad, MD, PhD Assistant Professor

Jean Nakamura, MD, PhD Professor

Nicolas Prionas, MD, PhD Assistant Professor

David Raleigh, MD, PhD Assistant Professor

Mack Roach III, MD Professor, Radiation Oncology & Urology

Penny Sneed, MD Professor Emeritus

Zhen Jane Wang, MD Professor, Radiology and Biomedical Imaging

Anthony Wong, MD, PhD Assistant Professor

Florence Yuen, NP Nurse Practitioner Disclosures

The following faculty speakers, moderators, and planning committee members have disclosed they have no financial interest/arrangement or affiliation with any commercial companies who have provided products or services relating to their presentation(s) or commercial support for this continuing medical education activity:

Mekhail Anwar Jean Nakamura Jason Chan Catherine Park Steve Braunstein Nicolas Prionas William Hartsell David Raleigh Ella Jones Richard Valicenti Kavita Mishra Anthony Wong Osama Mohamad Florence Yuen

The following faculty speakers have disclosed a financial interest/arrangement or affiliation with a commercial company who has provided products or services relating to their presentation(s) or commercial support for this continuing medical education activity. All conflicts of interest have been resolved in accordance with the ACCME Standards for Commercial Support:

Megan Daly Research Grants EMD Serono; Genentech, Merck

Felix Feng Consultant Astellas, Janssen, Myovant, Roivant, Blue Earth Diagnostics Co-founder PFS Genomics Scientific Advisory Board SerImmune Diagnostics Spouse Grant Funding Varian, AstraZeneca.

Mary Feng Research Grants Varian, UpToDate Breast, Sarcoma Chapter, Zenith Epigenetics Consultant Myovant Sciences, Riovant Sciences, Astellas Pharma Stock SerImmune

Shannon Fogh Consultant Accuray

Matthew Gubens Consultant AstraZeneca. Sanofi Research Grants Amgen, Celgene, JNJ, Merck, Novartis, OncoMed, Trizell

Patrick Ha Advisory Board Bristol-Myers Squibb, Loxo Oncology, Rakuten Medical Educational funding Stryker, Johnson and Johnson, Medtronic, Axogen

Hyunseok Kang Scientific Advisory Board Bayer, Achilles Therapeutics Consultant PIN Therapeutics, MitoImmune Research funding Kura Oncology, Elevar Therapeutics, Exelisis, Eli Lilly, PDS Biotechnology, NeoImmune Tech, Prelude Therapeutics

William Regine Stock Shareholder/ Xcision Intellectual Property Rights

Mack Roach Consultant Merck, Genomic Health, Myriad, Globe Life Svc Honoraria PCRI, AvidXchange

David Thomson Advisor Merck Sharp & Dohme

Zhen Jane Wang Stockholder Nextrast

Sue Yom Research Grants Merck, Bristol-Myers Squibb, BioMimetix, Genentech Book royalties UpToDate, Springer

This UCSF CME educational activity was planned and developed to: uphold academic standards to ensure balance, independence, objectivity, and scientific rigor; adhere to requirements to protect health information under the Health Insurance Portability and Accountability Act of 1996 (HIPAA); and, include a mechanism to inform learners when unapproved or unlabeled uses of therapeutic products or agents are discussed or referenced.

This activity has been reviewed and approved by members of the UCSF CME Governing Board in accordance with UCSF CME accreditation policies. Office of CME staff, planners, reviewers, and all others in control of content have disclosed no relevant financial relationships. UCSF Radiation Oncology Update: Predicting Benefit from Advanced Radiation Technologies Live Stream Course Friday – Saturday, April 23-24, 2021 All times are Pacific Daylight Time (PDT) FRIDAY, APRIL 23, 2021 8:00 AM Day 1 Announcements Sue Yom, MD, PhD, MAS BRAIN AND SPINE TUMORS • Moderator: Steve Braunstein, MD, PhD 8:10 1. Definitive and Postoperative Steve Braunstein, MD, PhD Radiation for Brain Metastases in the Era of Targeted Therapy and Immunotherapy 8:30 2. Imaging-based Precision Re- Shannon Fogh, MD Irradiation for Brain Tumors 8:50 3. Stereotactic Approaches for Spine Jean Nakamura, MD Reirradiation 9:10 4. Meningioma: Molecular and Imaging- David Raleigh, MD, PhD based Prognostication 9:30 5. CNS Case-based Learning: Steve Braunstein, MD, PhD Self-Assessment Session with Penny Sneed, MD Shannon Fogh, MD Jean Nakamura, MD, PhD David Raleigh, MD, PhD 10:30 Break GENITOURINARY CANCERS • Moderator: Osama Mohamad, MD 10:50 6.MRI, SBRT, Proton Therapy, and Mack Roach, MD Hormone Therapy for Prostate Cancer: What’s Best and What’s Next? 11:10 7.The Status of Postoperative Richard Valicenti, MD Radiation: Hypofractionation? Hormone Therapy? 11:30 8.Genomic Profiling for Therapy Felix Feng, MD Selection in Prostate Cancer 11:50 9.Updates on SBRT and HDR Osama Mohamad, MD Brachytherapy for Localized Prostate Cancer 12:10 PM Lunch 1:10 10.Multimodality Management of Anthony Wong, MD, PhD Bladder Cancer 1:30 11.GU Case-based Learning: Osama Mohamad, MD with Self-assessment Session Mack Roach III, MD Richard Valicenti, MD Felix Feng, MD Anthony Wong, MD, PhD Julian Hong, MD, MS

UCSF Radiation Oncology Update: Predicting Benefit from Advanced Radiation Technologies Live Stream Course Friday – Saturday, April 23-24, 2021 All times are Pacific Daylight Time (PDT) FRIDAY, APRIL 23, 2021 (continued)

THORACIC CANCERS • Moderator: Sue Yom, MD, PhD, MAS 2:30 12.Lung SBRT: Risky Situations and Megan Daly, MD the Role of Immunotherapy 2:50 13.Stage III Non-small Cell Lung Sue Yom, MD, PhD, MAS Cancer: Radiation Therapy in the Context of Oncogene Addiction and Immunotherapy 3:10 PM Break 3:30 14.Small Cell Lung Cancer: Evolving Jason Chan, MD Applications of Radiation Therapy and Immunotherapy 3:50 15.Optimizing Management of Matthew Gubens, MD Oncogene Driven Oligometastasis 4:10 16.Thoracic Case-based Learning: Sue Yom, MD, PhD, MAS Self-assessment Session with Megan Daly, MD Jason Chan, MD Matthew Gubens, MD 5:10 PM Adjourn

SATURDAY, APRIL 24, 2021

8:00 AM Day 2 Announcements Sue Yom, MD, PhD, MAS BREAST CANCER • Moderator: Nicolas Prionas, MD, PhD 8:10 17.Molecular Predictors of Outcome for Catherine Park, MD Ductal Carcinoma in situ 8:30 18.Hypofractionated Radiation Therapy Nicolas Prionas, MD, PhD for Breast Cancer 8:50 19. PET- and MRI-based Predictors of Ella Jones, MD Response to Neoadjuvant Chemotherapy 9:10 20.Skin Care Interventions that Make a Florence Yuen, NP Difference 9:30 21. Breast Case-based Learning: Self- Nicolas Prionas, MD, PhD assessment Session with Catherine Park, MD Ella Jones, PhD Florence Yuen, NP 10:30 AM Break

PROTON THERAPY • Moderator: Kavita Mishra, MD 10:50 22.Proton Therapy at the Christie NHS David Thomson, MD and Europe 11:10 23.The Proton Therapy Landscape in William Hartsell, MD the U.S. and What Comes Next 11:30 24.The Future of Proton Therapy William Regine, MD Innovation and Value 11:50 Q&A with Speakers Sue Yom, MD, PhD, MAS 12:10 PM Lunch HEAD AND NECK CANCERS • Moderator: Hyunseok Kang, MD 1:10 25.Contouring and Treatment Planning Jason Chan, MD Consensus 1:30 26.Targeted Therapy vs Hyunseok Kang, MD Immunotherapy for Head and Neck Cancers 1:50 27.Principles of Oral Cavity Surgery Patrick Ha, MD and Morbidity Reduction 2:10 28.Comprehensive Thyroid Cancer Jonathan George, MD, MPH Management 2:30 Break 2:50 29. HN Case-based Learning: Self- Jason Chan, MD with assessment Sue Yom, MD, PhD, MAS Hyunseok Kang, MD Patrick Ha, MD Jonathan George, MD, MPH GASTROINTESTINAL CANCERS • Moderator: Mary Feng, MD 3:50 30.SBRT for Pancreatic Cancer: Mary Feng, MD Evidence and Practical Tips 4:10 31.Organ Preservation in Rectal Cancer Mekhail Anwar, MD, PhD 4:30 32.MRI Response Assessment in Jane Wang, MD Rectal Cancer 4:50 33.Gastrointestinal Case-based Mary Feng, MD with Learning: Self-assessment Session Mekhail Anwar, MD, PhD Jane Wang, MD

5:10 PM Adjourn

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Definitive and PostOp RT Brain Metastasis Management Review for Brain Metastases  Supportive care only (QUARTZ randomized trial of OSC +/- WBRT, Mulvenna P, Lancet 2016) in the Era of Targeted Therapy  WBRT for diffuse brain metastases (NRG and Immunotherapy CC001 trial of memantine +/- hippocampal avoidance, Brown PD, J Clin Oncol 2020) 4/23/2021  SRS alone for limited brain mets (NCCTG 0574 SRS +/- WBRT, Brown PD, JAMA 2016) Steve Braunstein, M.D. Dept. of Radiation Oncology  Surgery & postop RT for single or dominant University of California San Francisco brain met too large or sx for SRS (or for dx)

 56 yo woman with widely metastatic EGFR Targeted Therapy & Immunotherapy L858R mutated lung adenocarcinoma; excellent response to gefitinib  1yr later 3 brain mets; changed to osimertinib

Monoclonal Antibodies  No brain RT or SRS so far 1.4 yr later Brain met dx 5 wks later 1.4 yrs later Protein Kinase Inhibitors

Courtesy of CC BY 4.0

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 77 yo man c melanoma brain/liver/lung/ST mets Immunorx for Melanoma Brain Mets  Large met resected; 8 mm residual + 8 mm R fr met  Ipi/nivo x 4 then maintenance nivolumab x 2 yrs CHECKMATE-204, Tawbi HA et al, NEJM 2018  NED 4 years after brain met dx; never had RT  94 patients with asx brain mets Start of ipi/nivo 5 wks later 4 yrs later  Ipilimumab (anti CTLA4) + nivolumab (anti PD-1) q 3 wks x 4 then maintenance nivolumab q 2 wks  Brain mets resp: 26% CR, 30% PR, 2% stable  Median time to response 2.3 mo  9-month intracranial FFP 60% & survival 83%  55% grade 3-4 toxicity; 7% CNS grade 3-4 toxicity (e.g., HA, brain edema); one death from immune-related myocarditis

Immunorx for Melanoma Brain Mets BRAF/MEK Inhibitors for Melanoma Brain Mets CHECKMATE-204, Tawbi HA et al, NEJM 2018 COMBI-MB, Davies MA et al, Lancet Oncol 2017  Multi-center phase II trial; asx or sx brain mets  Oral dabrafenib (BRAF inh) + trametinib (MEK inh) 90% of  Brain met response in 56% of 108 patients with responses asx mets and 59% of 17 patients with sx mets ongoing at time of  Median resp. duration 6.5 mo; survival 10.8 mo analysis (Hold BRAF inhibitors x 1-3 days before and 1 day after SRS/RT)

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Melanoma Brain Met Decision Tree Brain Mets from Lung Cancer with Driver Mutations symptomatic  50-60% of patients with EGFR mutation or ALK and/or bulky? rearrangement and ~1/3 of ROS1-positive pts No Yes develop brain metastases (c/w ~20% overall) ipi + nivo x 4 BRAF-mutant?  Most patients with sx or asx brain mets (TKI naïve or on less-brain-penetrating TKIs) will then nivo No Yes respond to brain-penetrating TKIs (durable  In the absence of severe mass effect requiring response; conventional dabrafenib + surgery, surgery +/- RT can be deferred to limit better than therapies trametinib morbidity single (Do not give TKIs agent) (rapid response; concurrent with RT) short duration)

ALK-positive Brain Mets: No prior TKI ALK-positive Brain Mets: Prior TKI

Global phase III trial, Peters S et al, NEJM 2017 Global phase II trial, Solomon BJ, Lancet Oncol 2018 Prior Intra- Intra- Median  Lorlatinib: 3rd generation ALK/C-ROS1 TKI SRS or cranial cranial response designed to overcome ALK resistance mutations n WBRT response CR duration and to penetrate the blood-brain barrier. Alectinib 64 26 81% 38% 17.3 mo Prior Intra- Intra- Median SRS or cranial cranial response Crizotinib 58 21 50% 5% 5.5 mo n WBRT response CR duration Global phase III trial, Camidge DR et al, NEJM 2018 Lorlatinib 81 26 63% --% 14.5 mo Prior Intra- SRS or cranial n WBRT response ROS1-positive Brain Mets Brigatinib 40 18 83%  Entrectinib, or if unavailable, crizotinib Crizotinib 41 19 33%  Lorlatinib after progression on crizotinib

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EGFR-mutated Brain Mets: EGFR-mutated Brain Mets: No prior TKI No prior TKI

FLAURA phase III trial, Soria JC et al, NEJM 2018 Waterfall plot of best CNS PFS response to osimertinib (HR = 0.48; p = 0.014)  Pt subset had asx or stable treated brain mets Osimerinib Reungwetwattana T et al, J Clin Oncol 2018 Aug n = 61

Prior Intra- Median SRS or cranial CNS n WBRT response PFS Standard TKI n = 67 Osimertinib 61 15 91% NR Standard* 67 16 68% 13.9 mo *Gefitinib or erlotinib Months Reungwetwattana T et al, J Clin Oncol 2018

EGFR-mutated Brain Mets: EGFR-mutated Brain Mets: Does added RT improve survival? Does added RT improve survival?

 Retrospective reviews* Magnuson JCO 2017  Emerging data in the & large meta-analyses† osimertinib era suggest worse overall suggests the ability to survival for brain met defer CNS RT in patients treated with selected patients EGFR-TKI without without compromise in upfront SRS or WBRT, CNS-PFS BUT they were in the pre-osimertinib era Thomas et al. 2021 UCSF, Stanford, U Colorado * Magnuson WJ et al, JCO 2017 Apr;35(10):1070 † Wang C et al, Lung Cancer 2018 Aug; 122:94 † Du XJ et al, Front Oncol 2018 Dec; 8:603

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Brain Mets from Lung Cancer HER2+ Breast Caner Brain Mets: without Driver Mutations ,† ‡ st nd KEYNOTE-189, Gandhi L et al, NEJM 2018; 378(22):2078 Lapatinib* or neratinib + capecitabine 1 -or 2 -line rx Brain met Median Median  Cis- or carboplatin n response PFS OS followed by Pembro combo *LANDSCAPE 44 66% 5.5 mo? ?? pemetrexed †Meta Analysis 661 29% 4.1 mo? 11.2 mo maintenance + ‡Lapatinib-naïve 37 49% 5.5 mo 13.3 mo pembrolizumab vs ‡Prior lapatinib 12 33% 3.1 mo 15.1 mo placebo Placebo combo  Longer survival Overall(%) Survival T-DM1; PARP, CDK 4/6, HER2, VEGFR, PI3K inhibitors; and PFS, overall bevacizumab + carbo or cisplatin and in patients Months with brain mets c Hazard ratio for death 0.49 overall (p<0.001): *Bachelot T et al, Lancet Oncol 2013; 14:64 0.36 with brain mets at baseline † Petrelli F et al, Eur J Cancer, 2017; 84:141 pembrolizumab 0.53 without brain mets at bastline ‡Freedman RA et al, J Clin Oncol 2019; 37:1081

HER2+ Brain Mets: SummarySummary Addition of Tucatinib  Brain met pts are living longer (mult rx over time) HER2CLIMB, Lin N et al, J Clin Oncol 2021; 38:2610-19  Melanoma brain mets w/o need for surgery  Upfront combination ipi/nivo if asx (durable)  Upfront dabrafenib/trametinib if sx & BRAF mutant (rapid response; not as durable)  Lung adeno CA with driver mutations  Alectinib, brigatinib, or lorlatinib if ALK-positive  Osimertinib if EGFR-mutant  HER2 + breast cancer brain mets  Lapatinib or neratinib or tucatinib + capecitiabine  Tucatinib + Trastuzumab + Capecitabine  Risk of adverse radiation effect increased  Efficacy in patients with both active and stable BM

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Imaging –based Precision Re- Disclosures Irradiation for Brain Tumors

Consultant for Accuray Inc

Shannon Fogh Associate Professor and Site Director of UCSF Health School of Medicine Quality Microsystems

Importance of Imaging in Radiation Oncology

• Time to treatment and delays in treatment: Timing/Delays in Treatment

Quality of Imaging for contouring disease and critical structures

Fusion

Quality of Radiologist

1 4/14/2021

MRI at Diagnosis MRI at Time of Presentation

Delays from Imaging to Treatment Importance of Imaging in Radiation Delivery in the Radiosurgery Age: Oncology Prognosis and Implications

Change in surgical cavity

Rapid growth of an aggressive tumor, particularly if it is subtotal resection We reviewed all treatment demographics, clinical outcomes, and workflow timing, including time from MRI, CT simulation, insurance authorization and consultation to the start of SRS for brain metastases.

A total of 82 patients with 151 brain metastases treated with SRS were evaluated. The median time from consultation, Swelling worse or improved insurance authorization, CT simulation, and MRI for treatment planning were15, 7, 6, and 11 days to SRS. Local freedom from progression (LFFP) was lower in metastases with MRI 10 ≥14 days before treatment (p = 0.0003, log rank). The 6 and 12 month LFFP were 95% and 75% for metastasis with interval <14 days from MRI to treatment compared to 56% and 34% for metastases with MRI ≥14 days before treatment. On multivariate analysis, LFFP Midline shift improved after resection remained significantly lower for lesions with MRI ≥14 days at SRS (p = 0.002, Cox proportional hazards, hazard ratio 3.388, 95% confidence 14 interval 1.577-7.273).

Delays from MRI to SRS treatment delivery for brain metastases appears to reduce local control and in some cases may affect survival. Future studies should monitor the timing from imaging acquisition to treatment delivery. Our experience suggests that the time from MRI to treatment should 18 be <14 days.

2 4/14/2021

Importance of Radiologist Input

Postsurgical changes of prior right parietal craniotomy with subjacent resection cavity in the right precuneus. No change in susceptibility artifact along the right occipital biopsy tract and in the right precuneus resection cavity. Enhancement along the anterior margin of the resection cavity in areas of previously demonstrated reduced diffusion, consistent with evolving postoperative changes.

No significant change in infiltrative mass-like T2/FLAIR hyperintensity primarily centered in the right posterior cingulate gyrus and right hippocampus with multiple areas of patchy enhancement, mildly reduced diffusion, and increased cerebral blood flow. Regions of patchy enhancement appears slightly more conspicuous compared to the prior study, some of which may be secondary to differences in contrast timing.

IMPRESSION:

Compared to MRI from 8/17/2019, no evidence of tumor progression. Continued evolution of postsurgical changes in the right precuneus with similar extent of residual glioblastoma centered in the right posterior cingulate gyrus and right hippocampus.

3 4/14/2021

Potential Pathways of Spread

• Infiltration of cerebellar peduncle

• Cerebral peduncle

• Corpus collosum

• Anterior/ posterior commisure

Recurrent GBM

Post treatment surveilance:

- MRI

- Gadolinium enhanced MRI remains gold standard

- Serial imaging q2-3 months but factors determining frequency include adjunct therapy regimens, clinical trial enrollment, new symptoms, health status and patient compliance

4 4/14/2021

Pseudo-progression following chemoradiation for GBM

Imaging studies:

- MR spectroscopy - Can supplement MR imaging studies

- Perfusion MR imaging - Assessment of tumor vascularity Post Op 1 mo 3 mo 6 mo 18 mo

Hou et al., Neurosurg Focus: 2006.

Imaging advances? Recurrent High Grade Gliomas

• Advances in genetic and molecular classification of tumors will ultimately lead to new targets for molecular imaging using methods such as PET and spectroscopy. This is exciting but still very experimental.

• Advances in MRI based physiologic imaging are already moving clinical brain tumor imaging of beyond gadolinium enhanced MRI. These include measures of tumor perfusion (DSC, ASL) and cellularity (diffusion) that have the potential to impact clinical practice. The immediate future may take the form of multivariate- imaging metrics. Hou et al., Neurosurg Focus: 2006.

5 4/14/2021

Perfusion imaging and tumor grade Perfusion Imaging: Pseudo-progression vs. Recurrence Radiation Injury IDH mutation status: associated with tumor hypoxia/reduced angiogenesis PG T1 DSC ASL PG T1 … predicted by rCBV from DSC perfusion imaging

12 mo 24 mo Recurrent Glioma DSC PG T1 ASL

14 mo Adapted from Jing et al., Exp Ther Med., 2016 Kickingerederet al, Nature Sci Rep. 2015

Pseudo-response following Avastin for recurrent GBM Diffusion Imaging: Pseudo-response vs Response

Post Avastin

Pre Avastin Post Avastin

Diff

PG T1 PG T1

Pre Rx 4 wks post 12 wks post ADC Courtesy Dr. Daniel Chow, Courtesy Dr. Daniel Chow, UCI UCI

6 4/14/2021

Imaging studies: Role of Fusion

• (123)I-alpha-methyl-tyrosine (IMT) single-photon computed emission tomography (SPECT)

• (11)C-methionine positron emission tomography (MET- PET)

Hou et al., Neurosurg Focus: 2006. Hou et al., Neurosurg Focus: 2006.

Real-Time Pre-Treatment Review Limits Real-Time Pre-Treatment Review Limits Unacceptable Deviations on a Cooperative Unacceptable Deviations on a Cooperative Group Radiotherapy Technique Trial: Group Radiotherapy Technique Trial: Quality Assurance Results of RTOG 0933 Quality Assurance Results of RTOG 0933

• Purpose/Objectives—RTOG 0933 was a phase II • Methods and Materials trial of hippocampal avoidance during whole-brain . Prior to enrolling patients, all treating physicians and sites were required to successfully complete a “dry-run” credentialing test. radiotherapy for patients with brain metastases. . Treating physicians were credentialed based on accuracy of MRI- Results demonstrated improvement in short-term CT fusion and hippocampal and normal tissue contouring, and sites memory decline, as compared to historical controls, were credentialed based on protocol-specified dosimetric criteria. and preservation of quality of life. Integral to the . Using the same criteria, pre-treatment centralized review of conduct of this trial were quality assurance processes enrolled cases was conducted. . Physicians enrolling 3 consecutive patients without unacceptable inclusive of pre-enrollment credentialing and pre- deviations were permitted to enroll further patients without treatment centralized review of enrolled cases. pretreatment review, although their cases were reviewed posttreatment.

7 4/14/2021

ResultsResults ResultsResults

• Of the 82 cases reviewed prior to treatment as part of the real-time rapid review process, 21 • Reasons for unacceptable contouring deviations cases (25%) from 12 different institutions were: received a score of Deviation Unacceptable: . Hausdorff distance for hippocampal contour in excess • 11 cases had unacceptable deviations of of 7mm (11 cases) . Incorrect contouring of optic chiasm/nerves (7 cases) contouring only and incorrect MRI/CT fusion (2 cases). • 5 cases had unacceptable deviations of IMRT planning and 5 cases had unacceptable deviations of both contouring and IMRT planning.

Contours and Deviations Axial

• Fusion: ALWAYS review the fusion generated by • Infidibulum dosi/physics •4th ventricle • Focus on Anatomic land marks: • Lateral ventricle . Dural surfaces: Falx Cerebri, Tentorium • Third ventricle . Ventricular system: Line up to choroid plexus (often partially calcified on CT) • Cerebral aquaduct . Skeletal anatomy: use bone windows for sella/clivus • Falx cerebri

8 4/14/2021

CoronalCoronal

• Falx Cerebri • Lateral Ventricle • Third Ventricle

9 4/14/2021

SagitalSagital Future Directions

• Corpus Collosum •4th ventricle • Imaging advances • Tentorium Cerebellum • Documentation of treatment volumes for review

• Consensus on volumes

10 Disclosure

2021 UCSF Radiation Oncology Update I have no relevant financial relationships with any companies related to the content of this course. Stereotactic Approaches for Spine Re-irradiation

Jean Nakamura, M.D. Professor, Department of Radiation Oncology

4/23/2021

Educational Objectives Evolving SBRT to address challenges in spinal metastases

. Review recent data informing spine SBRT practice . Evolving management of metastatic disease ‐ Focus on significance of histology and epidural disease

‐ Focal techniques that permit local control and . Discuss practice considerations for spinal re-irradiation functional preservation

‐ Defining more precisely which patients stand to benefit with spine SBRT and how to achieve optimal outcomes

1 | [footer text here] SBRT outcomes: Radioresistant vs. Radiosensitive Histologies SBRT: Radioresistant vs. Radiosensitive histologies Zeng, et al. Journal of Neuro-Oncology 2021

Zeng, et al. Journal of Neuro-Oncology 2021

‐ Does histology influence outcome after SBRT? . Potentially contribute to local control . Potential implications for SBRT dosing

‐ Single institution, prospectively maintained database analysis of 1394 spinal segments in 605 pts

‐ Radioresistant: renal cell, melanoma, sarcoma, GI, thyroid spinal metastases ‐ Radiosensitive: Prostate cancer

‐ Most received 24‐28 Gy in 2 fractions

Significance of RR histology and Epidural disease Significance of RR histology and Epidural disease Zeng, et al. Journal of Neuro-Oncology 2021 Zeng, et al. Journal of Neuro-Oncology 2021

. RR 1Y Local failure 19.2% . RS 1Y Local failure 3.2% . PTV V90 were similar between RR and RS cohorts . RR 2Y Local failure 22.4% . Spinal cord point max also similar . RS 2Y local failure 8.4% . Epidural progression present in 40% of local failure

. RR time to local failure (median) 6.1 months . RS time to local failure (median) 15.5 months

. 2Y vertebral compression fracture ~13%

2 | [footer text here] Significance of RR histology and Epidural disease SBRT and Epidural disease Zeng, et al. Journal of Neuro-Oncology 2021 Rothrock JNSG 2020

. Retrospective study 31 pts 2014‐2018 . Epidural disease and radioresistant histology predicted . High grade epidural spinal disease was defined as grade 2 ESCC – which is defined by radiographic deformation of the spinal cord by for greater local failure metastatic disease . Myelogram used‐ no margin ‐ Pts with RR histologies also were more likely to have . Fused MRI –1 mm expansion on spinal cord paraspinal disease extension . Thecal sac is contoured, defined as cord + remaining CSF visible thru ‐ Epidural disease in RR cohort was borderline significant (p myelogram or T2 = 0.053)

SBRT and Epidural disease Rothrock JNSG 2020 Re‐irradiation: Critical structure tolerances . Varied fractionations: . 9 Gy x 3 most common . Challenges associated with spinal irradiation . 6 Gy x 5 . 7 Gy x 5 ‐ spinal targets traverse multiple anatomic compartments . 12 Gy x 3 ‐ cervical levels: head and neck structures ‐ thoracic: esophagus, lung . Spinal dmax: 24 Gy/3, 30 Gy/5 fx. ‐ lumbosacral: kidneys, bowel . Coverage of PTV usually reduced by cord constraint ‐ spinal cord, cauda equina

. 1Y LRF 10.4% . 2Y cumulative incidence of LRF 22% . No serious SBRT‐related complications

3 | [footer text here] Experimental evidence supports increasing inter-RT time increases Critical structure definition: tolerance to re-irradiation Spinal cord contouring

. True spinal cord (MRI defined) + margin (1.0‐2.0 mm typically) ‐MRI or CT myelogram ‐differences in positioning between diagnostic MRI and planning CT can complicate co‐registration

. Spinal canal ‐ identifiable on CT ‐ Depending on spinal level may provide variable margin on cord ‐ Beware of epidural disease

KK Ang IJROBP Vol 50, Number 4, 2001

ISRS Practice Guidelines 2017 Experimentally‐determined spinal cord repair kinetics

. 50% recovery of occult injury induced by 44 Gy at 1 year . 60% at 2 years • Based on literature reviews . 65‐70% after 3 or more years • Predominantly retrospective, single institution studies, low . These prospectively collected data provide evidence that spinal quality (level III) cord repair occurs • Re‐irradiation technique : Image‐guided IMRT or SRS . Anecdotal, small scale clinical data also consistent with this • Fractionation : most commonly involved three –five fractions • 1Y local control – 75% • Crude rate of radiation myelopathy –1.2%

KK Ang IJROBP Vol 50, Number 4, 2001

S Myrehaug J Neurosurg Spine 2017

4 | [footer text here] HyTEC 2019: Re‐irradiation SBRT

Sahgal, …. Jackson IJROBP 2019 IJROBP 2011

81 lesions in 60 pts with metastatic epidural spine metastases who previously received EBXRT to spine

SBRT 8 Gy x 3 if tumor not in contact with cord 5-6 Gy x 5 if tumor is in contact with cord

Median F/U = 12 months Median EBXRT dose: 30 Gy in 10 fractions Median time from EBXRT to recurrence = 20 months Median OS = 11 months HyTec Organ-specific Paper: Spinal cord dose tolerance to Stereotactic Body Radiation Therapy A. Sahgal, 93% with stable/improved disease JH Chang, et. al. IJROBP ePub October 2019

HyTEC 2019: Re‐irradiation SBRT HyTEC 2019 Guidelines

Sahgal, …. Jackson IJROBP 2019 Sahgal, …. Jackson IJROBP 2019 Pooled data from multiple studies Common practices: Re‐irradiation Parameter Guideline PRV margins of 1-3 mm on spinal cord Cumulative thecal sac Dmax ⦤ 70 Gy SBRT thecal sac Dmax ⦤ 25 Gy Minimum interval to re-irradiation at least 5 - 6 months minimum time interval HyTec Organ-specific Paper: Spinal cord dose tolerance to Stereotactic Body Radiation Therapy A. Sahgal, 5-6 months JH Chang, et. al. IJROBP ePub October 2019

5 | [footer text here] What are current limitations in the literature? Summary

. Driven by institutional practice (hence heterogeneously applied . Recent data point to the challenge of addressing epidural guidelines) disease, which represents an opportunity for SBRT approaches . Radioresistant histologies may also warrant specific strategies . Low resolution data . Re‐irradiation of spinal metastases is an issue that we will ‐ What patient features influence risk? continue to see . Possibilities: Spinal level, target volume, epidural disease, . Spinal cord repair permits cumulative doses that exceed standard presence/absence of cord compression (edematous cord), fractionation spinal cord constraints fractionation . Follow up/ OS short (commonly < 12 months) . What exactly is the upper limit? To be determined . Cord constraints continue to be refined . Pooling data/direct dosimetric comparisons between studies is very . 5‐6 month interval between initial and re‐irradiation dosing challenging

6 | [footer text here] 4/20/2021

Meningiomas: Molecular and radiologic prognostication Meningiomas are tumors of the cerebral and spinal meninges

David R. Raleigh, MD, PhD Assistant Professor Robert and Ruth Halperin Endowed Chair in Meningioma Research Brain Tumor Center Principal Investigator and Preclinical Therapeutics Core Director Departments of Radiation Oncology and Neurological Surgery University of California San Francisco [email protected] raleighlab.ucsf.edu Meningioma organoid Stereotactic meningioma sampling

Louveau et al. Nature (2015)

WHO grade does not encapsulate the biologic diversity of Meningioma overview meningioma

• Most common primary brain tumor (38%) • WHO grade 1 (75%) WHO grade I meningioma • >34,000 new cases annually in the United States – ≤3 mitoses/HPF • WHO grade 3 atypical (15-20%) • No formal staging system – 4-19 mitoses/HPF • Little consensus on optimal treatment – Brain invasion – 3+ of necrosis, sheeting, macronucleoli, • No effective chemotherapies or molecular agents hypercellularity, small cells

• Molecular drivers are poorly understood • WHO grade 4 anaplastic (1-5%) – ≥20 mitoses/HPF Wen et al. Neuro Oncol (2010) Rogers et al. J Neurosurg (2015) – Frank anaplasia Brastianos et al. Neuro Oncol (2019) Ostrom et al. Neuro Oncol (2020) Louis et al. Acta Neuropatholog (2016)

1 4/20/2021

Qualitative radiologic features are prognostic for meningioma Quantitative radiomic features are prognostic for meningioma outcomes outcomes

Morin et al. Neurooncol Adv (2019) Morin et al. Neurooncol Adv (2019)

Multiplatform genomic profiling and magnetic resonance RTOG 0539 imaging identify mechanisms underlying meningioma biology

• Phase II trial of observation for low-risk meningiomas or radiotherapy for intermediate- and high-risk meningiomas

Strata Description Treatment Low risk Grade I meningioma status post GTR or STR Observation Intermediate risk (i) Recurrent grade 1 or (ii) primary grade 2 meningioma status post GTR 54 Gy in 30 Fx (1 cm CTV) High risk (i) Recurrent grade 2, (ii) grade 2 status post STR, or (iii) grade 3 meningioma 60 Gy in 30 Fx (1-2 cm CTV) • Trial closed with 244 patients enrolled • First successful cooperative group trial for meningioma

Rodgers et al. IJROBP (2016) Rodgers et al. J Neurosurg (2018) Magill and Vasudevan et al. Nat Commun (2020) Rodgers et al. IJROBP (2020)

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UCSF intermediate- and high-risk meningioma outcomes UCSF meningioma radiotherapy and radiosurgery paradigms

• WHO grade 1 • Phase III trials of GTR ± radiotherapy for WHO grade 2 –GTR: Observation meningioma – STR: Observation versus adjuvant radio(therapy/surgery) – NRG BN-003 – 50.4-54Gy/28-30Fx versus 15Gy/1Fx – ROAM (EORTC 1308)

• WHO grade 2 (atypical) – GTR: Controversial – STR: Adjuvant radiotherapy (or, less likely, radiosurgery) • Histologic features predict local control of WHO grade 2 – 59.4Gy/33Fx versus 15Gy/1Fx meningioma after surgery and adjuvant radiotherapy

• WHO grade 3 (anaplastic) – Adjuvant radiotherapy irrespective of extent of resection – 60Gy/30Fx versus 15-18Gy/1Fx

• Anisotropic CTV expansions along the dura – WHO grade 1: 0 cm – WHO grade 2: 1-2 cm – WHO grade 3: 2 cm – Brain invasion: 0.2-0.5 mm

Susko et al. Neurosurg (In press) Chen et al. J Neurosurg (2018)

Meningioma short somatic variants correlate with tumor location There are 15 distinct histologic variants of meningiomas and histology

Psammomatous Angiomatous Papillary Chordoid and Secretory Secretory Meningothelial and transitional TRAF7 mutation AKT1E17K mutation

Clark et al. Science (2013) Brastianos et al. Nat Genet (2013) Sahm et al. Acta Neuropatholog (2013) Ruess et al. Acta Neuropatholog (2013) Clark et al. Nat Genet (2015) Courtesy of Arie Perry Youngblood et al. J Neurosurg (2019)

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DNA methylation profiling identifies groups of meningiomas with Meningioma DNA methylation grouping reveals biologic drivers distinct clinical outcomes and therapeutic vulnerabilities

Harmanci et al. Nat Commun (2017) Olar et al. Acta Neuropathol (2017) Sahm et al. Lancet Oncol (2017) Vasudevan et al. Cell Reports (2018)

Meningioma DNA methylation grouping reveals biologic drivers Meningioma DNA methylation grouping reveals biologic drivers and therapeutic vulnerabilities and therapeutic vulnerabilities

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Summary Acknowledgements

• Molecular and radiologic features elucidate meningioma outcomes – MIB1 labeling index, DNA methylation profiling, targeted gene expression profiling – ADC, sphericity, intratumor heterogeneity The Raleigh Laboratory UCSF Neurological Surgery UCSF Biochemistry & Biophysics Harish Vasudevan Mitch Berger Jeremy F. Reiter, MD, PhD • UCSF meningioma treatment paradigms Charlotte Eaton Philip Theodosopoulos John Liu Funding – Surgery Abrar Choudhury UCSF Neuro-Pathology NIH NCI R01 CA262311 Vikas Dagubbati Arie Perry NIH NCI R01 CA251221 – Radiosurgery William Chen David Solomon NIH NCI R01 CA255369 – Radiotherapy with anisotropic CTV margins CJ Lucas Melike Pekmezci NIH NINDS R01 NS106155 Kyounghee Seo NIH NCI K08 CA212279 – Clinical trials and molecular therapy Tim Casey-Clyde UCSF Neuro-Oncology NIH NICHD R21 HD106238 Sydney Lastella Nicolas Butowski DOD NFRP NF200021 o CKD4/6 inhibitors Minh Nguyen Nancy Ann Oberheim Bush UCSF Wolfe Meningioma Program Project o Radiosurgery + immunotherapy UCSF Marcus Program in Precision Medicine UCSF Radiation Oncology UCSF Neuro-Radiology UCSF Catalyst Awards Program Catherine Park Javier Villanueva-Meyer UCSF Brain Tumor SPORE Research Award Penny Sneed Steve Braunstein

5 

70 yo ♀, 50 pk-yr tob hx, COPD, CNS Case-Based Learning: 1 wk of expressive aphasia and mild Brain Metastasis R-sided weakness Postoperative Rx MRI: 7 x 5 x 5 4/23/2021 hetero. enhancing L frontal mass Penny K. Sneed, M.D. (atyp meningioma vs PNET vs ependymoma Dept. of Radiation Oncology vs metastasis) University of California San Francisco CT C/A/P negative

Indications for Surgery Path: poorly-differentiated carcinoma Day 1 postop MRI confirmed GTR  Single (or dominant) lesion  Histologic diagnosis in question  Large (not easily controllable with SRS/SBRT  Symptomatic  Lesion surgically accessible  Patient medically suitable for surgery Pre-gad T1 Post-gad T1 DWI

 

What postoperative brain management A. Observation would you recommend for this patient? 50-60% risk of local recurrence by 6-12 mo (Patchell RA, JAMA 1998; Kocher M [EORTC], J Clin Oncol 2011; Mahajan A, Lancet Oncol 2017) A. Observation B. Whole brain radiotherapy only B. Whole brain radiotherapy only Compared with SRS, yields better local and intracranial C. SRS or SBRT only control, but more neurocognitive deterioration without improving survival time (Brown PD, Lancet Oncol 2017) D. WBRT + SRS or SBRT C. SRS or SBRT only E. Wait for further testing, and consider Preferred choice according to NCCTG/N107C/ CEC・3 immunotherapy or targeted therapy randomized trial (Brown PD, Lancet Oncol 2017)

D. WBRT + SRS or SBRT NCCTG N107C/CEC3 Trial

Not studied in combination in postop setting; for Brown PD, et al. Lancet Oncol, 2017; 18:1049-1060 definitive rx, SRS alone results in less neurocognitive decline without compromising survival time (Brown PD,  Resection + postop WBRT vs. SRS JAMA 2016) E. Wait for further testing, and consider  194 pts randomized; 48 instit. in US & Canada immunotherapy or targeted therapy  WBRT 30 Gy/10 fx or 37.5 Gy/15 fx Immunotherapy or targeted therapy may be reasonable  12-20 Gy to cavity + 2 mm; higher dose to any in the postop setting for melanoma or EGFR, ALK, or unresected mets ROS1 NSCLC extrapolating from experience in patients with small, asymptomatic brain mets. Need data.

 

NCCTG N107C/CEC3 Trial Resection Cavity Post-Op SBRT Brown PD, et al. Lancet Oncol, 2017; 18:1049-1060 Eitz KA et al, JAMA Oncology 2020 Median 6-mo 6-mo✪ 6-mo survival intracranial surgical cognitive  581 resection cavities in 558 patients treated to n time control bed control deterioration median of 30 Gy in 5 fxs at 6 int’l institutions SRS 98 12.2 mo 55% 80% 52%  Median F/U 12.3 mo; MST 21.2 mo WBRT 96 11.6 mo 81% 87% 85%  One-year results: p=0.70 p<0.0001 p= 0.00031 p=0.00068 . 84% local control  Among 54 long-term survivors with testing @ ≥ 1 yr, . 46% distant brain failure cognitive deterioration in 37% of SRS pts vs. 89% of WBRT patients . 13% leptomeningeal disease (higher risk with larger PTV)  No difference in risk of LMD (7% vs 5% at 12 mo) . 8.6% clinical radiation necrosis  20% of SRS patients had salvage WBRT

PET/CT neg.; unkn 1º; no actionable mutations Local recurrence 6 mo later Further shrinkage of cavity on MRI @ 5 wks SRS 18.5 Gy / 1 fraction Linac SBRT to 25 Gy / 5 fractions

30 Gy 25 Gy 20 Gy 15 Gy 18.5 Gy 10 Gy 9 Gy axial coronal

 

SA-CME Question

In the NCCTG N107C/CEC3 trial of postoperative SRS vs WBRT, which outcome was significantly improved in the SRS arm? A. Overall survival time B. Risk of cognitive deterioration [lower] C. Surgical bed control D. Intracranial control E. None of the above

 4/22/2021

CNS Case-Based Learning: CNS Case-Based Learning Brain Metastasis Postoperative Rx

4/23/2021

Penny K. Sneed, MD, David R. Raleigh, MD PhD, Jean L. Nakamura, MD, Shannon E. Fogh, MD, Steve E. Braunstein, MD PhD

Dept. of Radiation Oncology University of California San Francisco

70 yo ♀, 50 pk-yr tob hx, COPD, Indications for Surgery 1 wk of expressive  Single (or dominant) lesion aphasia; mild R-sided weakness  Histologic diagnosis in question MRI: 7 x 5 x 5  Large (not easily controllable with hetero. enhancing SRS/SBRT L frontal mass  Symptomatic (atyp meningioma vs  Lesion surgically accessible PNET vs ependymoma vs metastasis)  Patient medically suitable for surgery CT C/A/P negative

1 4/22/2021

Day 1 postop MRI confirmed GTR What postoperative brain treatment Path: poorly differentiated carcinoma would you recommend for this patient?

A. Observation B. Whole brain radiotherapy only C. SRS or SBRT only D. WBRT + SRS or SBRT E. Wait for further testing, and consider Pre-gad Post-gad DWI immunotherapy or targeted therapy

A. Observation D. WBRT + SRS or SBRT 50-60% risk of local recurrence by 6-12 mo (Patchell Not studied in combination in postop setting; for RA, JAMA 1998; Kocher M [EORTC], J Clin Oncol 2011; definitive rx, SRS alone results in less neurocognitive Mahajan A, Lancet Oncol 2017) decline without compromising survival time (Brown PD, B. Whole brain radiotherapy only JAMA 2016) E. Wait for further testing, and consider Compared with SRS, yields better local and intracranial control, but more neurocognitive deterioration without immunotherapy or targeted therapy improving survival time (Brown PD, Lancet Oncol 2017) Immunotherapy or targeted therapy may be reasonable C. SRS or SBRT only in the postop setting for melanoma or EGFR, ALK, or ROS1 NSCLC extrapolating from experience in patients Preferred choice according to NCCTG/N107C/ CEC・3 with small, asymptomatic brain mets. Need data. randomized trial (Brown PD, Lancet Oncol 2017)

2 4/22/2021

NCCTG N107C/CEC3 Trial NCCTG N107C/CEC3 Trial Brown PD, et al. Lancet Oncol, 2017; 18:1049-1060 Brown PD, et al. Lancet Oncol, 2017; 18:1049-1060  Resection + postop WBRT vs. SRS Median 6-mo 6-mo 6-mo survival intracranial surgical cognitive  48 instit US & Canada; 194 pts randomized; 12-20 Gy n time control bed control deterioration to cavity+2 mm; higher dose to any unresected mets Overall Survival Cognitive-decline-free Surv SRS 98 12.2 mo 55% 80% 52% (>1 SD ↓ in at least WBRT 96 11.6 mo 81% 87% 85% p = 0.703 1/6 tests) p=0.70 p<0.0001 p= 0.00031 p=0.00068

SRS p < 0.0001  Among 54 long-term survivors with testing @ ≥ 1 yr, WBRT HR 0.47 cognitive deterioration in 37% of SRS pts vs. 89% of SRS WBRT patients  No difference in risk of LMD (7% vs 5% at 12 mo) WBRT  20% of SRS patients had salvage WBRT

Resection Cavity Post-Op SBRT Further shrinkage of cavity on MRI @ 5 wks PET/CT neg.; unkn. 1º; no actionable mutations Soliman H et al, Neurosurgery 2019 Linac SBRT to 25 Gy / 5 fractions  137 resection cavities in 122 patients treated to median of 30 Gy in 5 fxs (range, 25-35 Gy)  CTV incl cavity edge and dura with 0.5-1 cm margin along meninges; PTV 2 mm 30 Gy  Median F/U 16 mo; MST 17 mo 25 Gy  One-year results: 20 Gy . 84% local control 15 Gy . 45% distant brain failure 10 Gy . 22% leptomeningeal disease (higher risk with breast cancer and STR)

3 4/22/2021

Local recurrence 6 mo later SA-CME Question SRS 18.5 Gy / 1 fraction In the NCCTG N107C/CEC3 trial of postoperative SRS vs WBRT, which outcome was significantly improved in the SRS arm? A. Overall survival time B. Risk of cognitive deterioration [lower] C. Surgical bed control 18.5 Gy D. Intracranial control 9 Gy E. None of the above axial coronal

SA-CME Question In the NCCTG N107C/CEC・3 trial of post- CNS Case-Based Learning: operative SRS vs WBRT, which outcome was significantly improved in the SRS arm? Recurrent Meningioma X A. Overall survival time (12.2 vs 11.6 mo, NS) ✓ B. Risk of cognitive deterioration (Neurocognitive deterioration at 6 months 52% for SRS vs 85% for WBRT, p=0.00031) X C.Surgical bed control (80% vs 87% at 6 mo) X D.Intracranial control (55% vs 81% at 6 mo)

Brown PD, et al. Lancet Oncol, 2017; 18:1049-1060

4 4/22/2021

Case presentation Case presentation

• 33 year-old female with a history of right frontal meningioma, Presentation Recurrence Present day WHO grade I, status post gross total resection 10 years ago

• Now presenting with an symptomatic radiographic multifocal recurrence in the resection cavity

• Gross total resection of atypical meningioma, WHO grade II, with MIB1 labeling index of 10%

Audience survey CME question

• What adjuvant treatment would you favor in this case? • Which of the following statements are not applicable to the design of the NRG BN-003 and EORTC 1308 (ROAM) trials? A. Close imaging surveillance A. Atypical meningioma B. DNA methylation profile to establish molecular risk

C. Adjuvant radiotherapy to a total dose of 54Gy with a 1.5-2 cm B. Randomized phase III isotropic CTV expansion around the resection cavity C. GTR ± adjuvant radiotherapy D. Adjuvant radiotherapy to a total dose of 59.4-60Gy with a 1.5-2 cm anisotropic expansion around the resection cavity D. MIB1 labeling index 7%

Brastianos et al. Advances in multidisciplinary therapy for meningiomas. Neuro Oncol 2019

5 4/22/2021

CME question CNS Case-Based Learning: • Which of the following statements are not applicable to the design of the NRG BN-003 and EORTC 1308 (ROAM) trials? Spine Metastasis

A. Atypical meningioma

B. Randomized phase III

C. GTR ± adjuvant radiotherapy

D. MIB1 labeling index 7%

Brastianos et al. Advances in multidisciplinary therapy for meningiomas. Neuro Oncol 2019

Case Presentation

• Pt is a 61 yo M dx w/ MM

• 2 years prior: neck pain, C4 involvement ‐> radiotherapy at OSH

• Present: c/o L neck pain, L arm weakness

• PET/CT – multiple FDG avid and lytic lesions

• Exam: Complete flaccid weakness of L arm, sparing of L hand 0/5 L deltoid, 0/5 L biceps

6 4/22/2021

Challenge: Bulky epidural disease, contact with the spinal cord

OSH SBRT to C4 4 Gy x 5 Audience survey: What approach would you favor in this case?

A. No further radiotherapy B. Resection, consider post‐op radiotherapy C. Intensity modulated radiotherapy D. SBRT single fraction E. SBRT multiple fractions

7 4/22/2021

Audience survey: If re‐irradiation, what approach/fractionation would you CME Question: which of below statements are in the HyTec use? Guidelines regarding re‐irradiation SBRT?

A. AP/PA 8 Gy x 1 A. Keep Spinal cord Dmax 20 Gy in 1 fraction B. 3DCRT 3 Gy x 10 B. Keep Spinal cord Dmax 20 Gy in 2 fractions C. IMRT 3 Gy x 10 C. PRV margins of 1‐3 mm on the spinal cord are typical D. SBRT single fraction D. Minimum time interval to re‐irradiation should be at least 5‐6 months E. SBRT multiple fractions E. C and D

HyTec Organ‐specific Paper: Spinal cord dose tolerance to Stereotactic Body Radiation Therapy A. Sahgal, JH Chang, et. al. IJROBP ePub October 2019

SBRT ARCS, 5 Gy x 5 to 72% IDL C3‐5

CME Question: which of below statements are true regarding re‐irradiation SBRT?

A. Keep Spinal cord Dmax 20 Gy in 1 fraction B. Keep Spinal cord Dmax 20 Gy in 2 fractions C. PRV margins of 1‐3 mm on the spinal cord are typical D. Minimum time interval to re‐irradiation should be at least 5 months E. C and D

HyTec Organ‐specific Paper: Spinal cord dose tolerance to Stereotactic Body Radiation Therapy A. Sahgal, JH Chang, et. max mean al. IJROBP ePub October 2019 C‐cord 22.95 Gy 6.16 Gy

8 4/22/2021

CNS Case-Based Learning: Case Presentation Multiple Brain Metastases • Pt is a 41 yo M dx w/metastatic FIGO IVB endometrial ca • Therapy: Peritoneal, renal, lung metastases, on lenvatinib/pembrolizumab

• Presentation: complex seizure

• Imaging: CT/MRI brain: 3.5 cm enhancing R frontal lobe mass

• Exam: ECOG 0, AOx3, motor/sensory intact

Audience survey: Post‐resection, what approach would you favor in this case?

A. Whole brain radiotherapy B. Hippocampal avoidance whole brain radiotherapy C. Single session radiosurgery D. Multi (3‐5 fractions) session radiosurgery E. Observation

9 4/22/2021

>20 total additional lesions

CME Question: Which of the following statements regarding adjuvant CME Question: Which of the following statements regarding adjuvant whole brain radiotherapy dose (30 Gy in 10 fractions vs 37.5 Gy in 15 whole brain radiotherapy dose (30 Gy in 10 fractions vs 37.5 Gy in 15 fractions) were concluded from the post‐hoc analysis of N107C trial? fractions) were concluded from the post‐hoc analysis of N107C trial?

A. WBRT 30 Gy/10 fractions had worse intracranial tumor control A. WBRT 30 Gy/10 fractions had worse intracranial tumor control B. WBRT 30 Gy/10 fractions had more high‐grade toxicity B. WBRT 30 Gy/10 fractions had more high‐grade toxicity C. WBRT 37.5 Gy/15 fractions yielded better surgical bed control C. WBRT 37.5 Gy/15 fractions yielded better surgical bed control D. WBRT 37.5 Gy/15 fractions improved overall survival D. WBRT 37.5 Gy/15 fractions improved overall survival E. WBRT 30 Gy vs 37.5 Gy had equivalent time to cognitive impairment E. WBRT 30 Gy vs 37.5 Gy had equivalent time to cognitive impairment

Trifiletti et al. Optimizing Whole Brain Radiation Therapy Dose and Fractionation: Results From a Prospective Phase 3 Trial (NCCTG N107C [Alliance]/CEC.3). IJROBP 2020.

10 4/22/2021

Trifiletti et al. IJROBP 2020

11 4/22/2021

Tsao et al. Cochrane Database of Systemic Reviews 2018

Hippocampal Avoidance WBRT

30Gy/10Fx

DH100%≤9Gy DHmax 16Gy

Practical Radiation Oncology 2012 Gondi et al. SNO 2019

12 4/22/2021

Parotid Avoidance WBRT Lacrimal Avoidance WBRT

Wang et al. JAMA Oncol 2019 Wang et al. IJROBP 2019

CNS Case-Based Learning: High Grade Glioma

30 Gy in 10 fractions with 9 Gy in 3 fractions boost to surgical bed

13 4/22/2021

Case Presentation

• Pt is a 44 yo F p/w R sided weakness, L cingulate lesion s/p biopsy f/b STR. Path c/w GBM, IDH wt

High Grade Glioma Case • Therapy: 60 Gy EBRT with concurrent/adj Temozolomide

Case continued

• Completed 6 cycles of adjuvant Temodar

• 1 yr later evidence of progression on interval imaging

14 4/22/2021

Audience survey: What approach would you favor in this case of recurrent glioblastoma?

A. Optimal supportive care B. Bevacizumab alone C. CCNU alone D. Radiosurgery E. Hypofractionated external beam radiotherapy

CME Question: Which of the following statements regarding re‐ irradiation of high grade glioma is correct?

A. OS following re‐irradiation is independent of performance status B. Smaller retreatment volumes are associated with poorer outcome C. Shorter time between radiation courses yields improved OS D. Median OS >20 months from re‐irradiation in favorable patients E. Older patient age at re‐irradiation is associated with improved OS

15 4/22/2021

CME Question: Which of the following statements regarding re‐ irradiation of high grade glioma is correct?

Kessel et al. PLOS ONE. 2017; Chapman et al. Neuro Oncol Pract 2019 Chapman et al. Neuro Onc Pract 2019

Chapman et al. Neuro Onc Pract 2019

16 4/22/2021

Disclosures:

The speaker acknowledges receiving (last 12 mo.):

Consulting Fees from: Merck (2021), Genomic Health

(2021), Myriad (2020), Globe Life Svc (2020) Mack Roach III, MD MRI, SBRT, Proton Therapy and Professor Radiation Hormone Therapy for Prostate Cancer: Honoria from: PCRI (2020) and AvidXchange (2021) Oncology & Urology, UCSF What is Next?

Oncologic Outcomes after Localized Prostate Goals to Discuss in the context of RT (20 min.): Cancer Treatment: Associations with Pretreatment Prostate Magnetic Resonance Imaging Findings. 1. MRI Webmer et al. J of Urol. 205:1055-62, 2021. a) Anatomy: (Roach 1996), post RT pattern of failure (Pucar 2007), MRI-targeted Bx (Ahdoot, 2020) b) Predicting outcomes (Webmer 2021) c) Response: (post RT metabolic changes (Pickett …Roach, 2004) d) Treating the Dil & FLAME (2021) (Pickett … Roach 1999; Xia …Roach, 2001)

2. SBRT (Osama Mohamad will cover this topic)

3. Protons vs?? “SHIPP”: Estimated probabilities of prostate (Stereotactic Heavy Ions vs Protons vs Photons) cancer specific survival after 4. Hormone Therapy (“OG” style, i.e. not “next generation ADT) definitive treatment of localized a) LHRH vs LHRH + Anti-androgen? prostate cancer stratified by MRI b) Duration? Timing? category (modified from Webmer et I. Intermediate Risk al. J of Urol 2021). II. High Risk

1 4/22/2021

Focal Boost to the Intraprostatic Tumor in External Beam Proton versus intensity-modulated radiotherapy Radiotherapy for Patients With Localized Prostate Cancer: Results From the FLAME Randomized Phase III Trial. Kerkmeijer JCO 2021 for prostate cancer: patterns of care and early … Focal Lesion Ablative Microboost in Prostate Ca. trial, 571 pts with Int - HR prostate ca. … (2009-15). toxicity. Yu et al. JNCI 105:25-32, 2012 … 77 Gy (fractions of 2.2 Gy) to the entire prostate. VS … simultaneous integrated focal boost up to 95 Gy (up to 2.7 Gy) to intraprostatic lesion visible on MRI. Organ at risk constraints were prioritized over the focal boost dose. 27k men; 553 (2%) PRT & 27,094 (98%) IMRT. … primary end point 5-yr bDFS … DFS, DMFS, PCSS, OS, toxicity, and health-related quality of life. Pts receiving PRT younger, healthier … more affluent ... Med …reimbursement … $32k for PRT & $18.5 for IMRT. PRT was associated with a … reduction in GU toxicity at 6 mo. compared with IMRT (but not) at 12 mo. Conclusions: … PRT is substantially more costly … no difference in (late) toxicity in a comprehensive cohort … with prostate cancer at 12 mos post-treatment.

Initial toxicity, quality-of-life outcomes, and dosimetric impact in randomized phase 3 trial of hypofractionated versus standard fractionated proton therapy for low-risk prostate cancer. Vargas et al. Advances in Rad Onc, 2018

“A man should look for what is,

and not for what he thinks should be.”

Albert Einstein

2 4/22/2021

Table 1. Figure 14. Some examples and reviews of unique features of the response to particle beam exposures Cumulative incidence of subsequent primary cancers by treatment group after carbon radiotherapy, photon radiotherapy, or surgery for localized prostate cancer: a propensity score-weighted, retrospective, cohort study.

Mohamad et al. 2019

Seven Major Challenges - “RESIDUE”: SHIPP 1. Radiobiology to address uncertainty in optimal fraction (Stereotactic Heavy Ions vs Protons vs Photons) sizes and doses and RBE (biological) 2. Exchange of technology, funding and infrastructure SBRT for Unfavorable Int. Risk Prostate Cancer between academic centers, health care payers, industry and funding agencies (operational) Heavy Ions (Carbon)* vs Protons** vs Photons 3. Size/weight of accelerators & gantries A Prospective Phase II Randomized Trial# (engineering/physics) 4. Integration of technology to advance key areas from beam acceleration and delivery, through treatment 1. Large retrospective & prospective population based series planning and image guidance (engineering/physics) 2. HYPO-RT-PC Trial 5. Define the patient population to be studied; that is, “who 3. RTOG 0938 (5 vs 12 fractions completed) really needs PBRT” (clinical) 6. Uncertainties of dose and range at the end of the Bragg 4. 12 Fx carbon experience & ongoing Phase I-II trial peak (physics) 5. Preliminary results of 2 Phase I – II trials Proton trials 7. Evidence of clinical cost-effectiveness (societal) 6. Results of RTOG 9413 Adjuvant ADT

NEW CLINICAL AND RESEARCH PROGRAMS IN PARTICLE BEAM RADIATION THERAPY – THE UCSF PERSPECTIVE Roach Et Al. IJPT (2016)

3 4/22/2021

Sequence of hormonal therapy and radiotherapy field size in unfavourable, localized prostate cancer (NRG/RTOG 9413): long–term results of a randomized, phase 3 trial. Roach et al. Lancet Oncol 2018 NHT ADT then RT

NHT vs AHT (4 mo.) PORT

Sequence of hormonal therapy and radiotherapy field size in unfavourable, localised prostate cancer (NRG/RTOG 9413): long-term results of a randomised, phase 3 trial. Roach et al. Lancet 2018

* (n=2157) Objectives: The “feasibility” (endpoints) ASCENDE RT vs CIRT 2016 1) “Feasibility”: 100% a. Design the study and launch trial for Localized Prostate 90% Cancer (why this site?) 80% b. IGRT QA for delivery of protons or carbon ions across 70% international sites ~ photons. c. Model funding travel & cost of RT abroad 60% 2) Proof of principle “surrogate” endpoints: 50% a. PSA failure, PSA Nadir 40% • NCCN High‐risk: 69% vs 56% (D’Amico) 30% 4) QOL endpoints: • Gleason sum ≥8: 40% vs 31% a. Health‐related QoL (bowel, urinary domains) 20% • iPSA >20 ng/mL: 19% vs 17% b. Changes in sexual function. 10% • cT3a: 29% vs 23% Grade 3 toxicity: 2.5% vs 0%?? If successful, expand to Phase III Trial to: 0% 1 2 3 4 5 6 7 8 9 10 1. RBE: photons vs protons vs carbon 135791113151719212325(years) 2. Improved dose distribution: photons vs particles ASCENDE RT CIRT (Japan) *Nomiya et al. Radiotherapy & Oncology 121(2016) 288-293

15 16

4 4/22/2021

Meta-analysis of RTOG Trials Q & A: duration of ADT (Patients Treated on Prospective Phase III Randomized Trials for Localized Dz!)

1. Duration of ADT in Int. & High Risk Prostate Ca.?

a) 6 vs 4 months?

b) 4 mo. vs 28 mo.

c) 18 vs 36 months?

Full Disclosure: I consulted for almost every company who made hormonal drugs in the past. No Current Conflicts Roach et al. IJROBP 2000

Disease Specific Survival by Risk Groups Distribution of Risk Groups by Treatment Type RT Alone (n=1500) (Roach et al. IJOBP 47, 609-15, 2000) 1.0

GS=2-6, T1-2 0.6 0.8

GS=2-6, T3; GS=7, T1-2 survival rate 0.4 GS=7, T3; GS>7, T1-2

Group 1 53/363 Group 2 84/443 Group 3 92/338 Group 4 154/324 GS>7, T3/n+ 0.0 0.2

012345678910111213141516 years since randomization From Roach et al. IJROBP 47: 617-627, 2000

Roach et al. IJROBP 2000

5 4/22/2021

Disease Specific Survival for Risk Group 2 Disease Specific Survival Risk Groups 3 & 4 1.0 1.0 0.8 0.6 survival rate survival 0.4 survival rate RT alone 84/443 G&F (4 mons) 1/70 RT alone 246/662 long G 9/114 G&F (4 mons) 49/145 0.2 long G 41/241

From Roach et al. IJROBP 47: 617-627, 2000 0.0 0.0 0.2 0.4 0.6 0.8 0123456789101112

years since randomization 0123456789101112

years since randomization From Roach et al. IJROBP 47: 617-627, 2000

From Roach et al. IJROBP 47: 617-627, 2000

RTOG 9910 RTOG 9910: Neoadjuvant Androgen Suppression Duration Patient Characteristics

8-wk AS  RT+ AS 28-wk AS  RT+ AS Characteristic (N=752) (N=738) Tumor stage, no. (%) T1b-T2 706 (94) 695 (94) T3-4 46 (6) 43 (6) Gleason score, no. (%) 2 - 6 202 (27) 201 (27) 7 466 (62) 464 (63) 8 - 10 84 (11) 73 (10) Serum PSA, ng/mL (%) ≤20 685 (91) 667 (90) >20 - 100 67 (9) 71 (10) 1. 4 to 6 mos improves OS vs 0 (DFCC, RTOG 9408, TROG) NCCN Risk Group, no. (%) 2. 4 mos improves CSS vs 0 (RTOG 8610, RTOG 9408) Intermediate 634 (84) 621 (84) High 110 (15) 112 (15) 3. No evidence > 4 months is required for Intermediate Risk Patients

6 4/22/2021

Duration of Suppression Before Radiotherapy for Localized Prostate Cancer: Radiation Therapy Group Randomized Clinical Trial 9910. Pisansky et al. JCO 33: 332-339, 2015 Systematic review and meta-analysis of monotherapy compared with combined androgen blockade for patients with advanced prostate RTOG 9910: Neoadjuvant Androgen Suppression and Duration carcinoma. Samson et al. Cancer, 95: 361-376, Disease-Specific Survival Biochemical Failure – Phoenix

99% 96%

98% 95% Events 8-week AS 192 28-week AS 185 P=0.78

HR=0.81 (0.48-1.39) 27% survival (%) survival Events 19%

Disease-specific 8-week AS 30 27% 28-week AS 24 16%

P=0.45 Biochemical failure (%)

Year after randomization Year after randomization Patients at risk Patients at risk 8-week AS 752 725 690 677 639 609 569 531 474 350 8-week AS 752 706 644 593 540 491 448 402 347 250 28-week AS 737 718 686 664 642 610 582 539 456 307 28-week AS 737 712 669 614 559 517 475 411 328 211

Neoadjuvant Androgen Suppression Duration: Adverse Events

Grade ≥2 Adverse Event Incidence, %

Early

8-week AS  RT 28-week AS  RT

Endocrine (e.g. flushing) 27 46

Gastrointestinal 18 20

Genitourinary 27 31

Sexual (e.g. erectile dys.) 10 22 MAB Monotherapy

Overall 58 76

Bicalutamide 150 mg plus standard care vs standard alone for early prostate cancer. McCleod et al. BJU Intl. 2005

Item MAB % Mono % (n/N) (n/N) Fisher’s exact test

Urination 11.3 26.3 p = 0.023 difficulty (9/80) (20/76)

Limited 12.0 28.0 p = 0.012 activities (10/83) (23/82) due to urination trouble

7 4/22/2021

Combined androgen blockade (CAB) versus luteinizing eau European Association of Urology hormone-release hormone (LHRH) agonist monotherapy Duration of Androgen Deprivation Therapy in High-risk Prostate for androgen deprivation therapy. Cancer: A Randomized Phase III Trial Nabid et al. European Urol. (In Press 2018) World Journal of Urology (2020) 38:971-979. Park et al. RESULTS AND LIMITATIONS: … The 5-yr OS rates … 91% for Table 2 long arm (88-95%) and 86% for short arm (83-90%), p=0.07. QoL Comparison of quality of life at post-ADT 3 months (Intent-to-treat) analysis … in six scales and 13 items favoring 18 mo ... EORTC QLQ-C30, Mean, SD CAB (n=35) LHRH-M (n=34) p-value CONCLUSIONS: … 36 mo is not superior to 18 mo of ADT. ADT Physical function 80.2. (13.9) 76.1 (19.2) 0.31 combined with RT can potentially be reduced to 18 mo in

Cognitive function 87.6. (16.3) 83.3. (17.9) 0.281 selected men without compromising survival or QoL …. PATIENT SUMMARY: In this study … high-risk prostate cancer Fatigue 23.8. (14.8) 24.5 (15.7) 0.849 patients treated with radiotherapy and either 36 or 18 mo of Pain 4.8. (9.5) 16.2. (19.5) 0.003 ADT. … no difference in survival between the two groups, with

Quality of Life 58.8. (18.3) 57.6 (19.7) 0.792 the 18-mo group experiencing a better quality of life.

eau eau European Association of Urology European Association of Urology

Duration of Androgen Deprivation Therapy in High-risk Prostate Duration of Androgen Deprivation Therapy in High-risk Prostate Cancer: A Cancer: A Randomized Phase III Trial Randomized Phase III Trial Nabid et al. European Urol. (2018) Nabid et al. European Urol. (In Press 2018)

Multivariable Cox Regression analysis for overall survival

HR (95% CI) P value

36 vs 18 months 0.92 (0.65-1.3) 0.6

Age 1.05 (1.03-1.07) 0.002

PSA >20 0.97 (0.66-1.43) 0.9

Gleason score 8-10 1.21 (0.81-1.81) 0.3

T3-T4 1.38 (0.96-2.0) 0.08

ITT (Intention to treat)

8 4/22/2021

eau European Association of Urology

Duration of Androgen Deprivation Therapy in High-risk Prostate Cancer: A Randomized Phase III Trial Nabid et al. European Urol. (2018) Issues: 1. Underpowered (n=630) vs ~1000 EORTC a. OS at 5 years p=0.07 with 36 > 18 mo. b. PSA control favors 36 mo. at 15 years (p=0.02 ) c. Known factors to not significant e.g. T-stage, PSA d. 78% of deaths non-prostate ca. 2. HR = single factor (PSA> 20 ng/ml (43%),

1. MRI Conclusions: a) Anatomy: (Roach 1996) b) Treatment to the DIL (Pickett … Roach 1999; Xia …Roach 2001 ( FLAME) c) Response: (post RT metabolism (Pickett …Roach, 2006)

2. SBRT (not what Osama Mohamad will cover) a) Population based data “I skate to where the puck is going to be, b) Prospective Data (RTOG 0938)

3. Protons vs?? SHIPP:(Stereotactic Heavy Ions vs Protons vs Photons) not to where it has been” 4. Hormone Therapy (“OG” style) a) LHRH vs LHRH + Anti-androgen? CAB! – Wayne Gretsky b) Duration? Timing? I. Intermediate Risk 4 months II. High Risk - “Long term”(not 18 months)

9 4/23/2021

Topics The Status of Post‐prostatectomy Radiation: Timing, • Post‐RP early salvage RT vs. adjuvant RT Dose, Next Generation Imaging, and more • Effective and safe RT dose Richard K Valicenti, MD, MA, FASTRO • The status of hypofractionation Chair and Professor of Radiation Oncology • Next generation imaging for treatment selection • ADT and pelvic RT for post‐prostatectomy salvage

RAVES Trial: Radiotherapy-Adjuvant Versus Early Salvage RAVES: Disease Control (Median FU 6.1 years) Eligibility: Stratification: One or more of these risk factors after RP: • Pre-op PSA • Positive margin • Margin positivity • Extra-prostatic extension • SVI • SVI • Gleason Score Institution

Undetectable PSA (<0.1)

RANDOMISATION 1:1

Ajuvant RT Active surveillance within 4-6 months of RP PSA > 0.2

Early Salvage RT

1 4/23/2021

RADICALS: Biochemical PFS ARTISTIC Meta‐analysis: Summary RADICALS‐RT GETUG‐AFU 17 RAVES Accrual period 11/2007‐12/2016 04/2008‐06/2016 03/2009‐12/2015 Eligibility criteria Positive margins Positive margins Positive margins pT3a/pT3b/pT4 pT3a/pT3b pT2/pT3a/pT3b Gleason 7‐10 RT schedule 66/33 or 52.2/20 66/33 64/32 ART timing < 6m of RP <6m of RP <6m of RP Trigger for eSRT PSA>0.1 ng/ml and rising PSA>0.20 ng/ml and PSA >0.20 ng/ml or 3 consecutive rising PSA rising levels eSRT timing < 2m of trigger PSA ASAP after PSA relapse <4m of trigger PSA and before PSA=1ng/ml Primary outcome FFDM EFS FfBF Trial design Superiority Superiority Non‐inferiority

Patient Characteristics Raves GETUG‐AFU 17 RADICALS ARTISTIC: Event‐free survival (PSA‐driven) Patients randomized 333 424 1396

Median follow up 73 months 47 months 60 months Trial HR (95% CI) Weight (%) Median Age (range) 64 (44‐76) 64 (37‐77) 65 (39‐79) Radicals 1.10 (0.81 – 1.49) 63

Pre‐operative PSA (median) 7.4 Not collected 7.9 GETUG‐AFU 17 1.27 (0.56 – 2.87) 9 pT2 76 (23%) 0 339 (24%) RAVES 1.11 (0.71 –1.75 29 pT stage 3a/b 257 (77%) 411 (97%) 1047 (75%) Overall 1.12 (0.88 – 1.42) 100 pT4 0 8 (2%) 9 (1%) Gleason score <6 16 (5%) 43 (10%) 96 (9%) ART better eSRT better1 7 266 (80%) 337 (79%) 1065 (76%) >8 51 (15%) 40 (9%) 235 (17%) Positive margins 224 (67%) 418 (99%) 882 (63%) Potential absolute difference of 1% at 5‐years (in favor of eSRT) Seminal vesicle involvement 43 (19%) 90 (21%) 259 (19%) (95% CI: 1% in favor of ART to 4% in favor of eSRT)

Extracapsular extension 257 (77%) 422 (100%) 954 (68%)

2 4/23/2021

Does Post-op RT Dose Matter? SAKK 09/10 (ASCO 2021) Study N Doses bPFS Toxicity Comments Xin et al 71 66 Gy 74.9% (4 yr) Acute or late 67% salvage • pT2/T3N0M0, R0‐1 (adjuvant – pT3/4 73 72 Gy 82.6% (4 yr) NSS 87% WPRT • Rising PSA level: >0.1‐ 2.0 ng/mL or salvage > 0.2) P=0.299 No ADT • PSA persistence excluded > 0.4 ng/mL GS 8-10 benefited Swiss SAKK 09/10 170 64 Gy N.A. G2, 3GU: 13%, 0.6% No impact on urinary • Cancer spread excluded by conventional imaging 174 70 Gy 16.6%, 1.7% continence R 6yr FBP GU G2/3 GI G2/3 G2, 3 GI: 16%, 0.6% 15.4%, 2.3% A NSS N 70 Gy in 35 with 3D‐CRT or IMRT 61.3% 26%/4% 20%/2% D Arm 1 King 10,034 60 Gy 38.5% N.A. 2% RFS improvement for each (meta-analysis) 70 Gy 58.4% Gy O M Arm 2 62.3% 21%/8% 7%/4% Bernard et al 364 >66.6 Gy 61% (5yr) N.A. No ADT 64 Gy in 32 with 3D‐CRT or IMRT (salvage) 64.8-66.6 Gy 54% (5yr) Suggest RT dose I < 64.8 Gy 43% (5yr) > 66.6 Gy Z NS NS p=0.009 P=0.04 E Cozzarini et al 334 > 70.2 Gy 83% (5yr) G2,3 GU: 11.5%, 2% adjuvant; < 70.2 Gy 71% (5yr) 10.5%, 4% 23% AHT P=0.001 G2 GI: 14%, 17.5% 45% NHT

Recurrence Outside of the CTV as Defined by EORTC Guidelines

3 4/23/2021

Falcon Trial: Change in Clinical Decision Results EMPIRE‐1 Trial: Failure Analysis

Change in clinical decision Type of change A. Jani, ASTRO 2020 Management plans were revised post‐ “Major” scan for 66/104 (64%) subjects ‐ Salvage treatment TO systemic non‐curative 58/104 (56%) had a positive Hypothesis: Radiotherapy *PRIMARY therapy: 16/66 (34%) outcomes improve due to: ENDPOINT 3Y‐FFS: 18F‐fluciclovine scan 16 ‐ Salvage treatment TO 63.0% vs 75.5% P=0.003 (Z test) 46/104 (44%) negative watchful waiting: 16/66 • Excluding pts with extra- pelvic subjects (24%) disease 4Y‐FFS: 66 • Changing treatment field 51.2% vs 75.5% P < 0.001 (Z test) “OTHER” decisions & target definition ‐ Planned radiotherapy was 16 modified for 23/66 (35%) 23 ‐ Modality change in 11/66 • Median FU (17%) 11 • Overall: 2.48 Y • Non-failing pts: 3.06 Y PET vs. Non‐PET Guided PSA response 88% vs. 72%

NRG/RTOG 0534 RCTs Evaluating ADT + RT vs. RT after RP Study No. Stage inclusion PSA Outcome Median • Negative conventional imaging (Study period) Requirement f/u (yrs) • pT2/T3 +/‐ R+ N0M0 RTOG 9601 840 pT3N0, 0.2-4.0 ng/mL 12-yr BR: 44%(PBRT+LTAD) 12 (1998-2003) pT2R1N0 vs. 68%(PBRT); P<0.001 R • Entry PSA level: 0.1‐ 2.0 ng/ml 12-yr DM:14.5%(PBRT+STAD) 5yr FFP 5 yr FFDM vs. 23%(PBRT); P=0.005 A 12-yr OS 76% (PBRT+LTAD) N PBRT (64.8 ‐70.2 Gy) 71% 91.7% vs.71% (PBRT); P=0.04 Arm 1 D GETUG-16 743 pT2-pT4N0 0.2-2.0 ng/mL 5-yr PFS: 80% (PBRT+STAD) 5.3 (2006-2010) vs. 62% (PBRT); P<0.05 O Arm 2 PBRT + STAD(4‐6 months) 81% 94.4% 5-yr OS: 96% (PBRT=STAD) M vs. 95% (PBRT); NS Arm 3 RTOG 0534 1734 pT3N0, 0.1-2.0 ng/mL 5-yr FFP: 71% (PBRT) vs. 5.4 I PLNRT (45 Gy) + PBRT(to 64.8 ‐ 87% 95.2% (2008-2015) pT2R1N0 81%(PBRT+STAD) vs. Z 70.2Gy) + STAD (4‐6 months) 87%(PBRT+PLNRT+STAD); P<0.001 E All SS. 3 vs. 1 SS. 5-yr DM: PBRT+ADT vs. PBRT +PLNRT+STAD;NS

4 4/23/2021

NRG-GU006 Schema New ASTRO/AUA Guideline Statement STEP 1 S Arm 1 (Blinded)* (Standard; Evidence Strength: Grade A) REGISTRATION T Surgical Margins External Beam Radiation: E Positive vs. Negative 64.8 to 70.2, 1.8 Gy/36‐39 fractions Submission of tissue for P R Decipher analysis Plus S A Clinicians should offer hormone therapy to patients 2 Pre‐SRT PSA Note: Decipher analysis results must be T N Blinded placebo daily for 6 months (~180 days) to <0.5 ng/mL vs. ≥0.5‐ completed before Step 2 randomization R D start on Day 1 of radiation therapy (+/‐ 2 weeks) can occur. 1.0 ng/mL treated with salvage radiotherapy (postoperative PSA R A O E If Decipher results have already been T M obtained, in lieu of tissue, results must G I I Arm 2 (Blinded)* be submitted to GenomeDX for I PAM50 Molecular ≥0.20 ng/mL). validation. External Beam Radiation: S F Z Subtype (per Decipher 64.8 to 70.2, 1.8 Gy/36‐39 fractions T Y E analysis) Plus R Luminal B vs. (Luminal A A/Basal/Unknown) Blinded apalutamide daily for 6 months (~180 T days) to start on Day 1 of radiation therapy (+/‐ 2 I Ongoing research may someday allow personalized weeks) O N selection of hormone or other therapies within

* patient subsets.

Summary • Early salvage post‐RP RT is as effective as adjuvant RT but with less side effects and better QOL

• Dose escalation salvage (72 Gy) for pT3/4N0 (> 0.2 ng/mL) prostate cancer does not improve bNED survival or overall survival but increases GII/III GI toxicity

• Traditional risk stratification criteria are not sufficient to individualize post‐operative dose‐ intensification Thank you!

• Advance imaging to define a patient‐specific target may be necessary to that end and can set the conditions for future study

• NRG/RTOG 0534 with the results of twoT other RC provide a new clinical standard for the use of ADT with salvage post‐prostatectomy radiation therapy Questions? • Pelvic RT with ADT and fossa RT appears beneficial in comparison to fossa RT but advantage over ADT and fossa RT requires additional study or may be justified for selected patients

5 Genomic Testing for Therapy Selection Disclosures in Prostate Cancer . In the last year, I have consulted for Astellas, Janssen, Myovant, Roivant, and Blue Earth Diagnostics. . I am co-founder of PFS Genomics, a molecular diagnostics company in the breast cancer space. Felix Feng, MD . I am on the scientific advisory board for SerImmune Diagnostics. Professor of Radiation Oncology, Urology and Medicine . My wife receives grant funding from Varian and AstraZeneca. George and Judy Marcus Distinguished Professor Vice Chair, Department of Radiation Oncology . Thankfully I do not have any conflicts of interest with any prostate Director, Benioff Initiative for Prostate Cancer cancer genomics company! University of California at San Francisco

Chair, Genitourinary Cancer Committee, NRG Oncology

Genomic Tests are in NCCN Guidelines for Prostate Cancer Outline

Decipher is now .Prognostic biomarkers for newly diagnosed insurance-reimbursed for all non-metastatic prostate cancer prostate cancer .Prognostic/predictive biomarkers for recurrent

Oncotype, Prolaris, prostate cancer and Promark are primarily validated in low and intermediate risk patients

All have been demonstrated to increase prognostic value when added to clinical features

1 4/20/2021 [ADD PRESENTATION TITLE: INSERT TAB > HEADER & FOOTER > NOTES AND HANDOUTS] Highlights of 3 Gene Expression Classifier Tests Why I Tend to Prefer Decipher: • Data, data, data. Broadly validated (over 130 papers) (Genomic Health): Quantitative real‐ Threshold: Low vs high risk = probability • Data, data, data. While Oncotype measures expression of time PCR 17 genes on a scale of 0‐100 of adverse surgical pathology >20% 17 genes and Prolaris measures 46, Decipher captures the expression of 46,000 genes (but the Decipher score is based on 22 genes). (Myriad Genetics): Quantitative real‐time Threshold: Low vs high risk = 10 year PCR 46 genes on a scale of 1‐10 mortality risk >3% • I tend to see mostly intermediate or high-risk patients. Decipher is more validated in these settings. (Oncotype and Prolaris more validated in lower risk patients). (GenomeDx Biosciences): Microarray 22 RNA biomarkers on a Threshold: Low vs int vs high risk • First prostate cancer genomics test to be approved for any scale of 0‐1 (5 yr met risk ~ 2% vs 6% vs 22%) patient with non-metastatic disease

Decipher is Prognostic Across the Spectrum of Prostate Cancer Prognosis in Localized Prostate Cancer Patients Using NCCN Risk Groups

Jairath N, European Urology 2021 Multivariable hazard ratios shown

7 Spratt D et al, JCO 2018

2 4/20/2021 [ADD PRESENTATION TITLE: INSERT TAB > HEADER & FOOTER > NOTES AND HANDOUTS] Prognosis in Localized Prostate Cancer Performance of Decipher in Intermediate Risk Patients Using Clinical Features & Decipher Patients Treated with Definitive Radiotherapy

Low clinical-genomic risk group tumors had no metastatic events

Spratt D et al, JCO 2018 Berlin A et al, IJROBP 2018

Performance of Decipher in Intermediate Risk Patients Treated with Definitive Radiotherapy

PIs: Neil Desai & Ale Berlin NRG GU Chair: Felix Feng AUC Coin flip = 0.50 NCCN = 0.54 Clinical-genomic = 0.89

Berlin A et al, IJROBP 2018

3 4/20/2021 [ADD PRESENTATION TITLE: INSERT TAB > HEADER & FOOTER > NOTES AND HANDOUTS] Validation of Decipher in NRG/RTOG trials in high-risk Validation of Decipher in NRG/RTOG trials in high-risk prostate cancer patients treated with RT + ADT prostate cancer patients treated with RT + ADT

RTOG 94-13: Hazard Ratio Hazard Ratio Hazard Ratio Model Variable P-value P-value P-value RT + 4 months ADT (95% CI) (95% CI) (95% CI) DM BF OS GC score 1.24 (1.12 - 1.38) <0.001* 1.11 (1.03 - 1.20) 0.004* 1.14 (1.06 - 1.21) <0.001* RTOG 92-02: RT + 4 months ADT Age 1.02 (0.98 - 1.06) 0.40 0.99 (0.96 - 1.01) 0.28 1.07 (1.04 - 1.10) <0.001* MVA: GC score + Log2 pre-treatment 1.02 (0.84 - 1.25) 0.82 1.21 (1.06 - 1.39) 0.006* 1.02 (0.90 - 1.16) 0.75 vs Clinical PSA RT + 28 months ADT T3-T4 vs. T1-T2 1.41 (0.83 - 2.39) 0.21 1.09 (0.77 - 1.54) 0.62 1.16 (0.84 - 1.60) 0.36 Gleason 8-10 vs. <8 2.32 (1.33 - 4.06) 0.003* 1.21 (0.85 - 1.73) 0.30 1.34 (0.95 - 1.89) 0.09 RTOG 99-02: Hazard ratios of genomic classifiers were per 0.1 unit increased. Studies as strata. RT + 24 months ADT GC is an independent prognostic biomarker for distant metastases, biochemical failure, and overall survival when baseline clinical variables were accounted for. Distant Metastases Overall Survival

Study PIs: Paul Nguyen and Felix Feng Study PIs: Paul Nguyen and Felix Feng

Decipher can identify a subset of high-risk prostate cancer PREDICT-RT (NRG GU009): A Prospective Phase III Trial using Decipher patients at low risk for metastatic progression to Intensify or De-Intensify Treatment for High Risk Patients

DECIPHER Trial PIs: Paul Nguyen & Oliver Sartor SCORE Arm 1: NRG GU Committee Chair: Felix Feng Stratification RT + intermed Low or Decipher score term ADT Intermed Boost Type Pelvic Txt(Y/N) Arm 2: RANDOMIZE Eligibility RT + LTADT Previously untreated high- risk prostate cancer (by NCCN criteria) Arm 1: RT + LTADT Stratification Primary Endpoint: MFS High Boost Type Sample Size: 2478 patients Pelvic Txt(Y/N) Arm 2: RT = radiation therapy, RANDOMIZE RT + LTADT + LTADT = long term androgen deprivation therapy abi/apalutamide Low genomic risk group tumors had no metastatic events Nguyen P et al, PCAN 2017 1 5

4 4/20/2021 [ADD PRESENTATION TITLE: INSERT TAB > HEADER & FOOTER > NOTES AND HANDOUTS] Validation of Outline Decipher in the Post-Prostatectomy .Prognostic biomarkers for newly diagnosed Setting: prostate cancer

.Prognostic/predictive biomarkers for recurrent prostate cancer

Decipher may Identify Patients who Benefit from Can Decipher be used to Identify Who Should Receive Anti- Adjuvant vs Salvage Radiotherapy Androgen Therapy with Salvage Radiotherapy?

NRG/RTOG 9601: A Phase III Trial Shipley et al, NEJM 2017 Patients with low Decipher scores Patients with high Decipher scores

R S Recurrent PCa Entry PSA A T (1.5 ng/mL) Placebo (PSA 0.2-4.0) N R Post-Surgery D (2 years) A Nadir PSA O T Salvage RT AND M I Prior ADT I Bicalutamide F Margin Z pT3 or Y (2 years) pT2 with (+) margin status E

Sample size: 760 patients Primary endpoint: Overall survival (HR 0.77, p=0.04) Median follow up: 13 years

Den et al, JCO 2015 1 9

5 4/20/2021 [ADD PRESENTATION TITLE: INSERT TAB > HEADER & FOOTER > NOTES AND HANDOUTS] 22-gene Decipher classifier risk stratifies all outcomes Decipher remains a significant predictor of outcome in a multivariable model

Variable Hazard ratio (95% CI) P‐value Hazard ratio (95% CI) P‐value Hazard ratio (95% CI) P‐value Distant Metastases Prostate Cancer Specific Mortality Overall Survival Distant Metastases PCSM OS DecipherGC score score 1.17 (1.05 - 1.32) 0.006* 1.39 (1.20 - 1.63) <0.001* 1.17 (1.06 - 1.29) 0.002* Treatment vs. Placebo 0.62 (0.39 ‐ 0.97) 0.037* 0.53 (0.30 ‐ 0.92) 0.024* 0.82 (0.57 ‐ 1.19) 0.293 High High <0.001 Intermediate Intermediate Age 65+ vs. 65‐ 1.30 (0.83 ‐ 2.06) 0.247 1.52 (0.88 ‐ 2.66) 0.136 1.95 (1.33 ‐ 2.91) Low Low * Black vs. non‐Black 0.88 (0.28 ‐ 2.13) 0.798 0.86 (0.17 ‐ 2.73) 0.827 1.35 (0.57 ‐ 2.77) 0.467 High Intermediate Gleason 8‐10 vs. ≤72.11 (1.24 ‐ 3.47) 0.007* 2.53 (1.38 ‐ 4.49) 0.003* 1.87 (1.20 ‐ 2.85) 0.007* Low T3 vs. T2 1.42 (0.82 ‐ 2.58) 0.220 2.01 (0.97 ‐ 4.62) 0.061 1.24 (0.79 ‐ 1.97) 0.350 Entry PSA 1.16 (0.88 ‐ 1.49) 0.264 1.37 (1.01 ‐ 1.80) 0.041* 1.08 (0.84 ‐ 1.35) 0.530 Positive surgical margins 0.71 (0.44 ‐ 1.16) 0.167 1.26 (0.68 ‐ 2.44) 0.465 0.98 (0.64 ‐ 1.53) 0.919 Non‐nadir vs. nadir PSA 1.31 (0.62 ‐ 2.51) 0.456 2.10 (0.92 ‐ 4.26) 0.074 1.98 (1.13 ‐ 3.30) 0.019* (<0.5ng/ml) Hazard ratios of GC were per 0.1 unit increased.

Feng et al, JAMA Oncology, 2021 Feng et al, JAMA Oncology, 2021

The absolute benefit from hormone therapy The absolute benefit from hormone therapy is smaller in the low Decipher risk groups is smaller in the low Decipher risk groups

Entire cohort Early salvage RT (PSA <0.7 ng/mL)

12-year distant metastases 12-year PCSM 12-year OS 12-year distant metastases 12-year PCSM 12-year OS

Decipher risk group Decipher risk group

Feng et al, JAMA Oncology, 2021 Feng et al, JAMA Oncology, 2021

6 4/20/2021 [ADD PRESENTATION TITLE: INSERT TAB > HEADER & FOOTER > NOTES AND HANDOUTS] SPARTAN: A Phase III Trial of Apalutamide vs Placebo in Patients Decipher Score is Associated with Non-Metastatic Castration Resistant PCa with Response to Apalutamide Apalutamide + ADT 1207 high risk 2:1 Randomization High Decipher scores Low Decipher scores nmCRPC patients Placebo + ADT Patients with both high Primary End Point: MFS and low Decipher scores 100 benefited from the

80 addition of apalutamide, APA, 40.5 mos 233 patients with (median) but those with high 60 archived samples Decipher scores benefited profiled with more. 40 PBO, 16.2 mos Decipher (median) 20 HR, 0.28 (95% CI, 0.23-0.35)

Metastasis-Free Survival (%) Survival Metastasis-Free P < 0.0001 0 Feng, Thomas, Saad et al, 04 81216 20 24 28 32 36 40 44 JAMA Oncology in press Months No. at risk APA 806 713 652 514 398 282 180 96 36 16 3 0 Median time between biopsy and treatment randomization ~ 6 years. PBO 401 291 220 153 91 58 34 13 5 1 0 0 Smith MR, et al. N It is remarkable that a biomarker is associated with response 6 years later! Engl J Med. 2018

Developing Predictive Biomarkers for Androgen PAM50 Clustering Readily Identifies Luminal (A and B) and Basal Subtypes in Prostate Cancer Deprivation Therapy: Lessons from the Breast Cancer Field

PAM50: a clinically utilized genomic test that identifies breast cancer subtypes (luminal A/B & basal) to determine who should receive hormone therapy.

Now validated Hypothesis: in >20,000 Zhao et al, prostate The PAM50 classifier can be applied to prostate cancer JAMA Oncology cancer patients to determine sensitivity to ADT. 2017 samples

7 4/20/2021 [ADD PRESENTATION TITLE: INSERT TAB > HEADER & FOOTER > NOTES AND HANDOUTS] Luminal B Prostate Cancers Exhibit the Greatest The Next Step: Incorporating Predictive Biomarkers Response to Androgen Deprivation Therapy (ADT) into Clinical Trials NRG GU006 national trial: Luminal A Eligibility Luminal B or Basal PSA recurrent post-RP with Stratification PSA ≥0.1 and ≤1.0 ng/mL Arm 1 1. Molecular and at least one of the Salvage RT + 6 months subtype following risk features: of placebo (Luminal B vs non-Luminal B) • Gleason score 4+3 or Arm 2

2. One vs. RANDOMIZE greater multiple risk Salvage RT + 6 months • Persistent PSA elevation features of apalutamide after RP • Pathologic pT3 disease

Zhao et al, JAMA Oncology 2017 Trial PIs: F Feng & D Spratt Patients matched by clinical and pathologic features This trial accrued much faster than expected: Patients do not want androgen deprivation therapy Physicians want a predictive test determining who should receive ADT Zhao et al, JAMA Oncology 2017

Ongoing transcriptional profiling of randomized trials Conclusions

RTOG 96-01 (JAMA Onc, 2021) When to give ADT for recurrence . New molecular tests have been developed to identify CHAARTED (ASCO GU, 2020) Whether to give chemo for mets prostate cancer patients with poor prognosis; these have been incorporated into phase III trials for patients with newly SPARTAN (JAMA Onc, 2021) Whether to give apalutamide for TITAN (ASCO 2020) non-met and metastatic disease diagnosed or recurrent disease. STAMPEDE When to give abiraterone for met . The Decipher test may identify who should receive ADT ENZAMET Whether to give enzalutamide for with salvage RT for a PSA recurrence, and who may derive ENZARAD non-met and metastatic disease greater benefit from apalutamide in the nmCRPC setting. RTOG 9202, 9902, and 9413 How to give ADT with radiation for intermed or high-risk PCa . Additional tests are being evaluated to help personalize RTOG 0126, 9910, and 9408 other treatment decisions for prostate cancer patients.

8 4/20/2021 [ADD PRESENTATION TITLE: INSERT TAB > HEADER & FOOTER > NOTES AND HANDOUTS] Acknowledgments

Feng lab Collaborators George Zhao Osama Mohamad (UCSF) Carissa Chu Julian Hong (UCSF) Melody Xu Anthony Wong (UCSF) Laura Chang Mack Roach (UCSF) David Quigley Dan Spratt (Michigan) Will Chen Paul Nguyen (Dana Farber) Vishal Kothari Phuoc Tran (Hopkins) Travis Barnard Rpbert Den (TJU) Hui Li Ale Berlin (PMH) Rajdeep Das Neil Desai (UTSW) Denise Playdle Jeff Karnes (Mayo) Adam Foye Ted Schaeffer (Northwestern) Haolong Li Howard Sandler (Cedars) Zach Kornberg Bill Shipley (MGH) Decipher Troy Robinson FUNDING SUPPORT Alan Pollack (Miami) Elai Davicioni Jonathan Chou Adam Dicker (TJU) NIH (R01 CA230516, R01 CA227025, Seagle Liu Paul Lloyd Eric Small (UCSF) R01 CA235641, R01 CA240582) Rebecca Huang Marc Perry Thomas Hope (UCSF)) Department of Defense Ting Wei Janssen Prostate Cancer Foundation Lisa Chesner Shibu Thomas AACR/SU2C Ruhollah Moussavi Michael Gormley Benioff Initiative for Prostate Cancer Research Margaret Yu

9 4/20/2021 [ADD PRESENTATION TITLE: INSERT TAB > HEADER & FOOTER > NOTES AND HANDOUTS] & " .

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NCBD analysis of primary therapy for MIBC Updates in radiation therapy for Large bladder cancer unmet need UCSF refresher 2021 for curative therapy

Anthony C. Wong, MD/PhD Assistant Professor UCSF Radiation Oncology

Gray et al, Euro Urol 2012

NCCN supports RT in intact and post‐op setting

Radiation therapy for MIBC

NCCN Bladder guidelines, v3.2021

1 4/23/2021

Bladder‐preserving trimodality therapy (TMT) Bladder preservation vs radical cystectomy

No successfully completed randomized trials comparing modalities Maximal Within 6 Concurrent Comparing pooled RTOG data to neoadjuvant chemo/RC meta‐analysis: weeks chemo + RT transurethral OS/5Y DSS/5Y DM/5Y Cyst CystOS CystDSS G3 late tox GI/GU resection of CMT 57% 71% 31% 21% 45% 60% 2%/6% NAC‐RC 50% bladder tumor ‐UVA, worse OS after CMT: T stage, hydronephrosis, older age, incomplete TURBT (TURBT) ‐MVA, worse OS after CMT: Older age ‐UVA and MVA, higher CR rate: Visibly complete TURBT

Mak et al, JCO 2014 Vale, Euro Uro 2005 NCCN Bladder guidelines, v3.2021

TMT vs RC: Propensity‐score matched outcomes Patient selection for TMT Associated with worse outcomes after TMT: ‐Hydronephrosis ‐Carcinoma in Situ ‐Incomplete TURBT

Kulkarni et al, JCO 2017 Giacalone et al, Euro Urol 2017

2 4/23/2021

BC2001: HR‐QOL after TMT BC2001: HR‐QOL after TMT

• No significant difference in QOL with concurrent chemotherapy or RT only • No significant difference in QOL with whole bladder boost vs reduced high • Compliance reasonable (70% of expected questionnaires at 1 year, 60% of expected at 5 years) volume boost (pre‐IMRT and IGRT era) • QOL impaired at end of treatment but returns to baseline at 1 year Huddart et al, Euro Urol 2020 Huddart et al, Euro Urol 2020

Radiation therapy paradigms GemX: ChemoRT for elderly/frail patients MGH approach: ‐Induction chemoRT (40‐45 Gy)  interim cystoscopy at 2‐3 weeks If CR  consolidative chemoRT to 60‐66 Gy Otherwise  radical cystectomy

Alternative approach: ‐ChemoRT (60‐66 Gy)  surveillance cystoscopy at 2‐3 months

RT options: Elective pelvic RT (39.6‐45 Gy) – Benefit of elective nodal radiation unclear Overall survival Late toxicity Whole bladder vs tumor bed boost (60‐66 Gy) – BC2001: no significant difference Phase II single arm (N = 78 cT2‐T4 MIBC) ‐NeoGemX cohort received neoadjuvant chemo Daily vs BID RT – NRG RTOG 0712: no significant difference ‐Gemcitabine 100 mg/m2 weekly, RT 52.5 Gy/20 fractions to whole bladder with 3D‐CRT Conventional vs moderate hypofx– BC2001/BCON: possible advantage to hypofractionation ‐Cystoscopic CR/3m 92%, severe colitis in 1 patient requiring ostomy

Thompson et al, IJROBP 2017; Choudhury et al, JCO 2011

3 4/23/2021

HYBRID: RT only for chemo‐ineligible patients

Post‐cystectomy RT

Single center prospective Phase 2 RCT (N = 65, MIBC any stage) ‐Elderly, sick population not candidates surgery or daily RT due to comorbidity ‐36 Gy in 6 weekly fractions using 3D CRT “plan of the day” vs standard planning ‐1‐year invasive LRR‐free 86% ‐Median OS 18.9 months, 2 year OS 40% Huddart et al, IJROBP 2020

Rationale for adjuvant RT Rationale for adjuvant RT

UPenn Model

• Low‐risk: pT2

• Intermediate‐risk: pT3+ with negative margins AND ≥10 LNs dissected

• High‐risk: pT3+ with positive margins OR <10 LNs dissected

Baumann et al, IJROBP 2016 Baumann et al, Bladder Cancer 2017

4 4/23/2021

Clinical trials—no Phase III data available yet Egyptian Phase II RCT—adj CRT vs chemo

Caveats: • Problematic trial design (chemo only arm added late to Phase III RCT, 1:1:4 randomization) • Non‐urothelial histology in 45‐50%, although unplanned subset analysis showed similar benefit in urothelial only cohort

Baumann et al, Bladder Cancer 2017 Zaghloul et al, JAMA Surgery 2017

IMPART: IMRT for bladder cancer

• PTV1/2 (bladder and elective nodes) 52 Gy/32 fractions

• PTV3 (bladder tumor bed) 64 Gy/32 fractions

• PTV4 (involved nodes) Recent advances in bladder RT 60 Gy/32 fractions

• Prospective Phase 2, n = 38 • Primary endpoint—meeting dose constraints • Secondary endpoints—acute/late toxicity, pelvic relapse‐free survival, OS Tan et al, Clin Onc 2020

5 4/23/2021

IMPART: IMRT for bladder cancer IMPART: IMRT for bladder cancer

• G3+ GU/GI Acute toxicity 26% • 76% met primary endpoint of meeting pre‐determined dose constraints, 97% had RT per protocol, 92% completed treatment • Late G3+ toxicity 5% at 1 year (cystitis/hematuria), none at 2 years • Median OS 1.9 years, 5‐year OS 34%

Tan et al, Clin Onc 2020 Tan et al, Clin Onc 2020

HYBRID: Image‐guided adaptive RT HYBRID: Image‐guided adaptive RT

• Phase 2 RCT comparing adaptive (“plan of the day”) vs standard planning for ultrahypofractionated (6 Gy x 6 weekly) bladder 3D CRT

• Primary endpoint non‐GU G3+ acute toxicity: 6% adaptive vs 13.3% standard • Key secondary endpoint combined 3‐month local control: 81.3% (88% adaptive vs 74% standard)

Huddart et al, IJROBP 2020 Huddart et al, IJROBP 2020

6 4/23/2021

RAIDER: Adaptive radiation dose‐escalation BC2001/BCON: Conventional vs hypofract

• International 2‐stage phase 2 RCT • Standard WBRT arm: • Hypofractionation Whole bladder 64 Gy/32 fx or 55 Gy/20 fx reduced invasive LRF (HR • Standard adaptive arm: 0.71) Whole bladder 52 Gy/32 or 46/20 fx Reduced high volume boost to 64 Gy/32 fx or 55 Gy/20 fx • Dose escalated adaptive arm: Whole bladder 52 Gy/32 or 46/20 fx Reduced high volume boost to 70 Gy/32 fx or 60 Gy/20 fx

• 1st stage primary endpoint: Meeting normal tissue constraints • 2nd stage primary endpoint: G3+ toxicity 6‐18 months post‐RT

• Appears to have met accrual goal 345 patients in 2020, awaiting results

Hafeez et al, BMJ Open 2020; Huddart ASCO GU 2020 Choudhury et al, Lancet Onc 2021

BC2001/BCON: Conventional vs hypofract BC2001/BCON: Conventional vs hypofract

• Numerically increased G3‐4 bladder/rectal • No benefit in OS toxicity in hypofractionated arm

• Worse FACT‐BL QOL at end of treatment in hypofx arm, but difference not statistically significant at 1 year or later endpoints

• Authors suggest 55 Gy/20 is new standard of care, but: • Not randomized • “A meta‐analysis is to a randomized trial what meta‐physics is to physics” –Ralph Weichselbaum

Choudhury et al, Lancet Onc 2021 Choudhury et al, Lancet Onc 2021

7 4/23/2021

Biomarker‐driven TMT clinical trials

• RETAIN bladder trial—Fox Chase

Bladder RT future directions

Geynisman et al, ASCO 2021

Biomarker‐driven TMT clinical trials Biomarker‐driven TMT clinical trials

• 50% of AS cohort experienced recurrence at median 15 months F/U (2 locally advanced/mets, 5 MIBC, 7 NMIBC) • Mutation distribution: RB1 (50%), ATM (42%), ERCC2 (31%), FANCC (4%) • Recurrence in 62% with RB1 mut, 25% with ERCC2 mut • Overall 55% retained bladder (89% in AS cohort) • Conclude risk‐adapted approach permits AS • Currently opening at Fox Chase/JHU RETAIN‐2: neoadjuvant chemo‐ immunotherapy

Geynisman et al, ASCO 2021 Geynisman et al, ASCO 2021

8 4/23/2021

Bladder RT and immunotherapy DUART: concurrent durva+RT early results

• Phase 2 single arm powered to detect improvement in 1‐year PFS from 50% (RT alone historical) to 75% • Concurrent durvalumab+RT followed by adjuvant durvalumab • Median age 74, 62% cT2+, 62% inoperable, 31% cN+ • Median follow‐up 16 months • PFS/1Y 73%, median PFS 18.5 months • OS/1Y 84%, OS/2Y 77% • No correlation between clinical outcomes and PD‐L1 expression

Solanki et al, Euro Urol 2019 Joshi et al, GU ASCO 2021

TMT and immunotherapy TMT and immunotherapy

Courtesy J. Efstathiou Courtesy A. Solanki

9 4/23/2021

Summary

• Trimodality therapy (maximal TURBT followed by chemoradiotherapy) is an underutilized modality in patients with MIBC • Patients with the best outcome after TMT are those with complete cystoscopic resection and without hydronephrosis or CIS • Quality of life after TMT returns to baseline in most patients at 1 year • Concurrent low‐dose gemcitabine or radiation therapy only may be offered to patients to frail to receive cisplatin or mitomycin • Image‐guided IMRT and adaptive RT are feasible • Adjuvant radiotherapy may be considered for patients with high‐risk features after radical cystectomy (pT3‐4, positive margins, positive nodes) • Ongoing clinical trials are establishing the role of kris ‐adapted therapy and immunotherapy in bladder‐preserving TMT

10 Learning objectives

Genitourinary Case-based 1. Understand treatment options for ‘early-risk’ prostate cancer and Review considerations for different RT modalities. 2. Discuss the current role of radiotherapy and hormone therapy in Osama Mohamad, MD PhD high-risk and node-positive prostate cancer. 3. Discuss the current role of radiotherapy in the setting of metastatic Panel: Felix Feng MD, Julian Hong MD, I-Chow Hsu MD, Mack Roach MD, Anthony Wong MD PhD, Richard Valicenti, MD prostate cancer and the role of metastasis-directed therapy. 4. Discuss the role of radiotherapy and hormone therapy in recurrent prostate cancer after prostatectomy. 4/23/2021

Case 1 Initial Work up

. 69 yo previously healthy man presents with a PSA of 7.2, up from 3.5 last . TRUS for staging with biopsy: year. ‐ 30 cc gland without hypoechoic lesions, ECE, nor SVI. . He has no family history of prostate cancer, is highly active, and has no ‐ Pathology revealed GS 3+3 disease in 3/6 cores on the L and GS 3+4 disease in major urinary issues (IPSS 8). His sexual function is adequate without 1/6 cores on the R, total 4/12 cores involved. medications (SHIM 20). ‐ Risk stratification: . DRE at the urologist office reveals a smooth 35 cc gland without nodularity. . PSA 7.2 . cT1c . GG 2

1 | [footer text here] 2019 NCCN risk classification Treatment options

. He met with a local surgeon who offered him radical prostatectomy and referred him to a radiation oncologist at UCSF

. Treatment options “discussed” at UCSF:

Favorable intermediate ‐ Conventional radiotherapy risk: ‐ Moderate hypofractionation - Per Briganti’s nomogram, risk of LN ‐ Stereotactic radiotherapy (SBRT in 4-5 fractions) involvement is 2% ‐ HDR brachytherapy (2 fractions) ‐ LDR brachytherapy ‐ Surgery ‐ Active surveillance

NCCN Guidelines Prostate Cancer, v1.2019 6

In men with ‘favorable’ intermediate-risk prostate cancer, which PACE-B: Acute CTCAE toxicity for gastrointestinal (A) and of the following statements are true: genitourinary systems

A. Active surveillance, although appropriate in certain patients, is not listed as an option in NCCN guidelines B. Biochemical control with SBRT is >90% at 5 years C. SBRT for prostate cancer is well tolerated with limited GI/GU toxicity D. B and C E. All of the above

7 8 Brand et al. Lancet Oncology 2019

2 | [footer text here] High Dose Rate Brachytherapy as monotherapy Panel discussion: SBRT Special Considerations

- Does a history of TURP affect decision to undergo SBRT? - What about IPSS score of 25? - Would you recommend SBRT for unfavorable intermediate risk prostate cancer? Do you use ADT with SBRT?

Panel: Would you recommend HDR for unfavorable intermediate risk prostate cancer (GS 4+3 or >50% cores positive)?

9 10 Dutta, SW. Exp Rev Med Dev. 2018.

Case 1: Treatment Dose: 36.25 Gy (7.25 Gy/fx, 5 fxs qod) to prostate+5mm (except 3mm posteriorly) with Case 2 SIB 40 Gy (8 Gy/fx, 5 fxs qod) to Prostate . He was eventually offered SBRT or Tracking: 3 gold fiducials . A 72 yo man presents with a PSA of 23. HDR monotherapy without ADT TRUS biopsy reveals GS 4+5 disease on the IGRT: CBCT (vs. CyberKnife tracking) . He has a history of lethal prostate cancer in his father (died of L and GS 4+3 disease on the R, total 9/18 metastatic cancer at age 69) . He elected for SBRT and received 40 cores involved. Gy in 5 fractions . He has no major medical comorbidities and good functional status . He tolerated the treatment well. He . IPSS 9 and SHIM 8. developed acute G2 GU and G1 GI . DRE reveals a 30 cc gland with bilateral nodularity without toxicities. lateral sulcus obliteration. . TRUS confirms 30 cc gland with bilateral hypoechoic lesions . He is doing well now, 2 years since and without ECE/SVI.

treatment with PSA of 0.04, and no . Risk stratification -> NCCN high risk disease: late toxicities. ‐ PSA 23 ‐ cT2c ‐ GS 4+5

11 Presentation Title

3 | [footer text here] 2019 NCCN risk classification Case 2

. Prostate MRI reveals PIRADS 5 lesion in the anterior transitional zone in the mid gland 0.9 x 2.1 x 2.1 cm; and a PIRADS 5 lesion in

High risk disease: the left posterolateral peripheral zone at base 1.4x2.0x1.2 cm CT A/P with contrast and NM bone scan are negative for ‐ rT2c nodal and distant metastases. ‐ No ECE, SVI, bone lesions nor LNs

NCCN Guidelines Prostate Cancer, v1.2019

Case 2: Panel discussion Case 2: Update

. Is there a role for PET imaging in high-risk prostate cancer? . PET PSMA was not available nearby and Medicare did not pay for PET axumin . No further imaging was done

4 | [footer text here] Case 2 Case 2: Panel discussion

. His surgeon offered radical prostatectomy and pelvic LND The patient meets with a radiation oncologist and decides on and referred him to radiation oncology? radiotherapy.

Regarding the use of hormone therapy in men with high-risk PCS IV: 18 vs 36 months ADT prostate cancer treated with external beam radiation therapy and ADT: a- 36 months improves overall survival at 10 years compared to 18 months b- 36 months reduces biochemical failure at 10 years but impairs testosterone recovery compared to 18 months c- 18 months reduces prostate-cancer specific mortality compared to 6 months d- Both a and b Primary endpoints: Overall survival and e- Both b and c quality of life

19 Nabid et al, Euro Urol 2018

5 | [footer text here] TROG 03.04 (RADAR study; 6 vs 18 months ADT): improved in PCSM in Case 2: Panel discussion the 18 months arm

What is your recommendation for? ‐ Role for Abiraterone + prednisone in high-risk prostate cancer? ‐ Role for Docetaxel?

Denham et al, Lancet Oncol 2019

Case 2: Case 2: continued

. A 72 yo man with NCCN high risk disease prostate cancer, PSA 23, cT2c, . He elects to proceed with long-term ADT (neoadjuvant, GS 4+5. concurrent and adjuvant) and pelvic IMRT + HDR . Is there any benefit for dose-escalation with brachytherapy boost? brachytherapy boost. . Should we treat the pelvis? . Should we dose escalate the MRI visible disease?

6 | [footer text here] ASCENDE-RT Results RTOG 0321 At 10 years Late G3 GI tox: 1% • 125 patients: T1c-T2c, GS≤6 and PSA btwn 10-20; Late G3 GU tox: 4% All pts DE-EBRT LDR-PB Survival Outcomes OR T1c-T3b, GS≥7 and PSA≤20 No G4/G5 toxicities NCCN risk (N=398) (n=200) (n=198) 7-yr b-PFS Toxicity Outcomes • Median FU: 10 yr

Intermediate 122 (31%) 63 (31%) 59 (30%) • DE-EBRT 75% • Treatment: DE-EBRT LDR-PB P EBRT, 45 Gy in 25 fx, to prostate/SVs or whole • LDR-PB 86% ‐ High 276 (69%) 137 (69%) 139 (70%) Acute Toxicities pelvis (if lymphatic risk>15%) 9-yr b-PFS G2+ GU 16% 33% <0.0001 G2+ GI 14% 9% NS ‐ HDR-B, 19 Gy in 2 fx within 24 hr, to prostate • DE-EBRT 62% Late Toxicities (5 yr) only or prostate+ECE/SVI if T3a or T3b G3+ GU 6% 20% <0.001 • LDR-PB 83% ‐ ADT permitted if clinically indicated G3+ GI 3% 8% NS • Primary Endpoint: Late Grade 3+ GU and GI 5-yr b-PFS 86% Toxicities 10-yr b-PFS 77% No difference btwn groups in MFS, OS, PCSS NCCN Risk Group N (%) Intermediate 95 (76%) 5-yr OS 95% High 20 (16%) 10-yr OS 76% Very High 10 (8%)

25 Morris et al, IJROBP 2017 26 Hsu et al, IJROBP 2020

POP-RT Results RTOG 9413 vs GETUG 01 vs POP-RT

Acute Toxicities: • No significant difference in GU Primary or GI tox Endpoint: 5-year BFFS Late Toxicities: WPRT: 95% • Increased G2+ GU PORT: 81% tox with WPRT P < 0.001 (20% vs 9%) • No significant difference in G2 + GI tox

27 Murthy et al, JCO 2021 28

7 | [footer text here] Case 2: (a “slight” twist) patient Case 2: Panel discussion paid for PET PSMA For N+ disease, discuss: . A 72 yo man presents with NCCN high risk ‐ ADT: disease prostate cancer, PSA 23, cT2c, GS 4+5. . Timing of ADT and RT? . Duration of ADT? . PSMA PET/CT, done at UCSF, showed: . Role for Abiraterone+prednisone? ‐ L and R external iliac LNs with focal uptake

‐ Stage IV prostate cancer: T2c N1 M0 ‐ Radiation: . Pelvic RT technique and dose? . Prostate RT boost technique and dose?

Case 2: (another twist) Case 2: Panel discussion

. A 72 yo man presents with prostate cancer, PSA 23, cT2c, GS . Do you recommend primary tumor RT in patients with M1 4+5. disease?

. CT C/A/P and bone scan revealed: sclerotic 2 cm lesion in L3 ‐ What dose and fractionation do you use? and a 1.5 cm left iliac lesion . PSMA PET/CT at UCSF confirmed above findings, and another R 7th rib lesions . Biopsy of the L3 lesion confirms metastatic prostate cancer.

8 | [footer text here] Which of the following is true regarding radiation to the primary tumor in men with newly diagnosed metastatic prostate cancer STAMPEDE Arm H: Prostate RT in M1a-b prostate cancer receiving ADT?

A. Prostate radiotherapy improves overall survival in all men with metastatic prostate cancer B. Prostate radiotherapy improves overall survival in men with low metastatic burden C. In the Stampede trial of primary prostate irradiation, the pelvis received 45Gy Primary endpoint: Overall survival and the prostate+SV received 79.2Gy D. A and C E. B and C

Parker et al, Lancet 2018 33

STAMPEDE Arm H: Results In men with oligometastatic prostate cancer, which of the following statements are supported by prospective clinical trials?

Overall survival (low M1 burden) Overall survival (high M1 burden) A. There is a significant reduction in quality of life after metastasis directed therapy B. Median ADT-free survival after ablative metastasis-directed therapy is 3-year 81% vs 73% 3-year 53% vs 54% approximately around 21 months C. Total consolidation of PSMA avid disease improves outcomes D. All of the above E. Only B and C

No effect on symptomatic local events (44% vs 42%)

9 | [footer text here] STOMP trial: Metastasis-directed therapy (30Gy/10fr) ORIOLE: Outcomes of Observation vs Stereotactic Ablative Radiation for Oligometastatic Prostate Cancer - Phase II, 62 pts with oligorecurrent, hormone sensitive cancer Median ADT-free survival 21 months vs 12 months - 3 mets, detected on choline-PET - Randomized to observation vs MDT (surgery vs SBRT) - Primary endpoint: ADT-free survival

- Findings: - 55% nodal recurrence - Median f/u: 3 yrs - LC 100% at 2 years - No G2+ toxicity

Ost et al, JCO 2017 38 Phillips, R, Jama Onc. 2020

Case 3 Case 3: Panel discussion

. 63 yo man with no major medical comorbidities, PSA 11, . Do you recommend ultrasensitive PSA testing? biopsy GS 3+4, cT1c and negative metastatic work up s/p RP/PLND . Do you recommend adjuvant RT now? . Pathology showed pT3bN0 disease, ECE/SVI+, GS 4+3, negative surgical margins, 0/8 LNs (4 on each side). . Is genomic testing useful for decision making in this case? . Initial post-op PSA is <0.1. . 3 months after surgery, he is using one pad a day (mostly for reassurance, minimal SUI) . PSA remains <0.1.

10 | [footer text here] Case 3 The ARTISTIC meta-analysis of RAVES, RADICALS, and GETUG-17

. pT3bN0, GS 4+3, negative margin . Post-op PSA <0.1 . Decipher score is 0.69

42 Claire Vale et al. Lancet 2020.‹

Case 3 Case 3: Panel discussion

. pT3bN0, GS 4+3, negative margin . What is the role of imaging in biochemical relapse after . Post-op PSA <0.1 surgery? . Decipher score is 0.69 ‐ MRI? . Ultrasensitive PSA <0.006 (3 months after surgery). ‐ Transrectal ultrasound? ‐ PET? What kind? At what PSA levels?

. He was recommended adjuvant RT but declined . He returns 1 year later with PSA 0.19

11 | [footer text here] Case 3: PSMA PET In men undergoing salvage radiation therapy for biochemical relapse, which of the following statements is true?

. PET PSMA did not show any evidence of local, regional, or A. The addition of short-term ADT to prostate bed radiation therapy improves distant disease progression-free survival and overall survival B. The addition of short-term ADT and pelvic LN radiotherapy to prostate bed . MRI and U/S did not show any evidence of local recurrence radiation improves progression-free survival and freedom from distant metastasis C. The addition of short-term ADT and pelvic LN radiation to prostate bed radiation results in higher rates of late GI/GU toxicity D. Prostate bed radiation dose escalation from 64 to 70 Gy improves distant metastasis but does not affect overall survival

RTOG 9601: Salvage RT +/- Bicalutamide for 2 years Adding ADT to salvage RT (RTOG 9601)

Shipley et al, NEJM 2017 Shipley et al, NEJM 2017

12 | [footer text here] GETUG-16: Salvage RT +/- Goserelin for 6 months Case 3: Panel discussion

. In which patients receiving salvage RT is elective pelvic LN recommended?

Carrie et al, Lancet Onc 2016

RTOG 0534 (SPPORT) RTOG 0534 (SPPORT) Freedom from progression

Pollack, et al, ASTRO 2018

13 | [footer text here] RTOG 0534 (SPPORT) Case 3: Panel discussion Freedom from metastasis

. What dose do you use for salvage RT to the prostate bed? Increased G2+ GI and G2+/3+ hematologic acute toxicity, and late G2+ hematologic toxicity with PLNRT

Pollack, et al, ASTRO 2018

Case 3 SAKK 09 10 . pT3bN0, GS 4+3, negative margin . Post-op PSA <0.1 Rates of late grade 2 and 3 genitourinary toxicity did not significantly differ though . Decipher score is 0.69 late grade 2 and 3 gastrointestinal toxicity . Ultrasensitive PSA <0.006 (3 months after surgery). was more common in patients receiving dose‐intensified RT (35 (20%) and 4 (2.3%) vs. 12 (7.3%) and 7 (4.2%); . He was recommended adjuvant RT but declined p=0.009). . He returns 1 year later with PSA 0.19-> Eventually decided to receive early salvage RT with 6 months ADT. He received 45 Gy to the pelvis, 70.2 Gy to the prostate bed, in 39 fractions.

ASCO GU 2021 56

14 | [footer text here] Case 3: the final twist Case 3: Panel discussion

. For isolated pelvic LN relapse on PSMA : . A 51 year-old man with pT3bN0, GS 4+3, negative margin, 0/9 LN prostate cancer. ‐ Is there a role for SBRT vs. full pelvic RT? Define your target Post-op PSA <0.1, minimal incontinence at volume? 3 months. Decipher 0.69. Ultrasensitive ‐ Would you recommend ADT? How long? PSA <0.006, rises to 0.21 at 1 year. . PSMA PET showed isolated 7 mm R external iliac LN recurrence.

Case 3

. He completes salvage prostate bed/pelvic RT with SIB to the involved LN. He receives 12 months ADT. His PSA “ becomes undetectable. Thank you.

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Disclosures Lung SBRT: Risky Situations and the Role of Immunotherapy • Disclosures: Research Funding ‐ EMD Serono, Genentech, Merck

Megan E. Daly MD Associate Professor of Clinical Radiation Oncology University of California Davis Comprehensive Cancer Center

Timeline of the Development of SBRT/SABR Overview 2021 and Beyond: 2010: RTOG 0236 -Optimal treatment for 2003: Indiana Phase I published (Timmerman et 2015: RTOG 0915 published (Timmerman published (Videtic et central and ultracentral al, JAMA), establishing tumors et al, Chest) SBRT as a standard-of-care al, IJROBP) comparing • Current Status of Lung SBRT 2001: Early German 4 fraction to single -Adjuvant Immunotherapy lung/liver SBRT experience for medically inoperable (3 randomized trials) stage I NSCLC fraction SBRT for published (Wulf et al, peripheral early stage -Role in operable patients • Use of SBRT for central and ultracentral tumors Strahlenther Onkol) NSCLC • Use of SBRT in interstitial lung disease • SBRT + Immunotherapy for early‐stage NSCLC 1995 2000 2005 2010 2015 2020

2004: RTOG 0236 1998: Early Japanese SBRT 2019: RTOG opens, testing 3 fraction experience published (Uematsu et 0813 (central SBRT in medically al, Cancer) 2015: STARS/ROSEL tumors) inoperable, early stage, pooled analysis of published peripheral NSCLC randomization between 1995: First published SBRT 2009: RTOG 0813 SBRT and lobectomy for opens, testing 5 operable early stage experience (Blomgren et al, 2003: Stanford publishes first fraction SBRT for NSCLC published Acta Oncologica) prospective North American Phase I centrally located early (Chang et al, Lancet SBRT trial using single fraction lung stage NSCLC Oncology) treatment (Whyte et al, Annals of Thoracic Surgery)

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Discussion: SBRT for Central Tumors Prospective Outcomes using SBRT for Central and Ultracentral tumors • Frequently defined by the guidelines established in the RTOG 0813 (JCO 2019) HILUS Trial (JTO 2021) early IU SBRT trials: within 2 cm of the proximal Eligibility Within 2 cm of PBT or PTV Within 1 cm of mainstem or lobar bronchus bronchial tree, defined as the distal 2 cm of the trachea, touching mediastinal pleura the mainstem and lobar bronchi Prescription Dose 50‐60 Gy in 5 fractions 56 Gy in 8 fractions • RTOG 0813 also included tumors with PTV touching/ Isodose Line 60‐90% 65‐70% overlapping mediastinal pleural Dose constraint(s) to Max <105% of prescription dose Max to contralateral mainstem bronchus/ • Term “ultracentral” not standardized, but typically refers Proximal Bronchial <4cc of non‐adjacent wall to 18 trachea<48.8 Gy to tumors with PTV touching or overlapping PTB, Tree Gy Guideline max< 56 Gy to ipsilateral mainstem trachea, esophagus, +/‐ great vessels bronchus Dose constraints to Max < 105% of Rx dose None great vessels <10 cc non‐adjacent wall to 47 Gy Observed Toxicity 15 grade 3+ AE (15%) 22 grade 3+ AE (33.8%) 4 grade 5 AE (4%) –All 10 grade 5 AE (15.4%), 6 hemoptysis hemoptysis

HILUS Trial Hilus Trial: Dose to main bronchus/trachea • Prospective multicenter phase II trial for tumors located ≤1cm from the PBT (lumen) in EQD2 and risk of grade 5 bleed • Primary endpoint local control and secondary endpoint toxicity • 7 Gy x 8 was prescribed to the 67% isodose encompassing the PTV • Patients were stratified to group A (tumors ≤1cm from the main bronchi/trachea) or group B (all other tumors) • Sixty‐five patients (group A/group B, n=39/26) were evaluable • Grade 3‐5 toxicity in 22 patients, including 10 cases of treatment related death • Dose and tumor distance to the main bronchi/trachea were significant risk factors. • Dose modeling showed D0.2cc to the main bronchi/trachea as the strongest predictor for lethal bronchopulmonary hemorrhage

Lindberg K et al. The HILUS‐trial –a prospective Nordic multi‐center phase II study of ultra‐central lung tumors treated with Lindberg K et al. The HILUS‐trial –a prospective Nordic multi‐center phase II study of ultra‐central lung tumors treated with stereotactic body radiotherapy, Journal of Thoracic Oncology (2021) stereotactic body radiotherapy, Journal of Thoracic Oncology (2021)

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Retrospective Ultracentral Lung Tumor Outcomes SUNSET Trial for Ultracentral NSCLC Yau VK et al, Chaudhuri et Tekatli H. et al, JTO 2016 Nguyen et al, Wang et al, WCLC 2017 al, Lung Practical WCLC 2018 Cancer 2015 Radiation • Defines “ultracentral” as PTV touching or Oncology overlaping the central bronchial tree, Eligibility Tumor directly GTV directly PTV overlapping trachea or Tumor directly GTV abutting esophagus, pulmonary vein, or abuts overlaps abutting central PBT abuts overlaps PBT, proximal pulmonary artery PBT, trachea, airway trachea, or bronchial esophagus, or esophagus, tree (PBT)or • Time to event continual reassessment pulmonary trachea; or PTV method vein/artery intersecting esophagus • Prescript 50-60 Gy in 5 50 Gy in 4-5 60 Gy in 12 fractions 40-60 Gy in 3-8 45-60 in 5-15 Currently accruing ion Dose fractions fractions fractions fractions N= 26 7 47 14 88 • Primary Endpoint: MTD Observe 8% grade 2-3. None 38% grade 3+ toxicity, 14% grade 3+ 21.6% grade d No grade 4-5 21% possible or likely tx- toxicity (7% grade 3+ toxicity Toxicity toxicity related death including 5) (11.3% grade 15% pulmonary 5) hemorrhage Guiliani et al. Lung Cancer 2018 19, e529-e532DOI:

SBRT with Interstitial Lung Disease ASPIRE‐ILD (PI: David Palma MD PhD)

Study N Radiation Pneumonitis Rates Bahig et al (Montreal). PRO 2016 28 32% grade 3+ 21% grade 5 Ueki et al (Kyoto), JTO 2015 20 55% grade 2+ 10% grade 3+ Glick et al (Princess Margaret), CLC 2018 39 20.5 grade 2+ 10.3% grade 3+ 5.1% grade 5 Yamaguchi et al (Kitakyushu), Lung Cancer 2013 16 (subclinical) 19% grade 2+ 12.5% grade 4+ Onishi et al (Japanese multi‐institution), Cancers 2018 242 6.9% grade 5 Finazzi T et al (Amsterdam), WCLC 2019 24 20.8% grade 3+ 12.5% grade 5

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Potential Benefits of Combining RT and Rationale for Immunotherapy in Early Stage NSCLC Immunotherapy

• SBRT is less immunosuppressive than conventionally fractionated RT or • Surgical lobectomy is standard‐of‐care for fit patients with early stage, resectable NSCLC surgery • Adjuvant chemotherapy indicated for high‐risk factors, improves OS • SBRT specifically can even be immunostimulatory and deplete immunosuppressive cells • Adjuvant immunotherapy of interest to further improve outcomes, reduce toxicity profiles • RT can improve antigen presentation by antigen presenting cells • ECOG‐ACRIN EA5142 ANVIL phase III trial completed accrual • SBRT specifically can release high levels of tumor antigens • SBRT is standard‐of‐care for medically inoperable, early stage NSCLC and can achieve • SBRT upregulates immunogenic cell surface markers (ie. MHC‐1) excellent local control (>90%), but regional and distant failures remain significant (15‐25%) • SBRT can induce immunogenic cell death • Adjuvant chemotherapy is typically not used following SABR (limited data, chemo is not well • RT and especially SBRT can increase homing of immune cells to tumor tolerated in this typically frail, inoperable population with multiple medical comorbidities) • Immunotherapy may allow for fewer nodal and distant failures and be well tolerated when • RT can recruit regulatory T cells (Tregs) given before, during, or after SBRT for early stage NSCLC • RT can shift tumor‐associated macrophages polarization from M2 to M1 • RT can induce secretion of danger signals and cytokines (ie. TNFalpha) • RT can upregulate cell‐surface expression of PD‐L1

RT + Immunotherapy: The Importance of Timing Radiation‐Induced Immune Activation • Homing of cytotoxic T lymphocytes to the tumor • MSKCC retrospective study of microenvironment melanoma patients treated with • Maturation of dendritic ipilimumab and non‐brain cells directed RT • Down‐regulation of immunosuppressive cells • Median OS: 9 months when RT like myeloid derived given during induction vs. 39 suppressor cells months when RT given during • Secretion of cytokines maintenance • Shifting tumor associated macrophage polarization to M1

Barker CA, et al. Cancer Immunol Res. 2013;1(2):92-98. Daly ME, et al. J Thorac Oncol. 2015;10(12):1685‐93.

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Figure Lessons from Stage IV NSCLC: Secondary Analysis of KEYNOTE‐001 Lessons Learned from Stage IV NSCLC –PEMBRO‐RT (Pembro for Stage IV NSCLC) ‐ Effect of Prior RT on Response Trial • Multicenter phase 2 study (PEMBRO‐RT) of 76 patients with advanced NSCLC randomized to pembrolizumab (200 mg/kg Q3 wks x 24 months) alone or after SBRT (8 Gy x 3) to a single tumor • Overall response rate 18% vs. 36% (p=0.07) • Disease control rate 48% vs. 72% • Median PFS 1.9 vs. 6.6 months (p=0.19) • PFS and OS significantly approved among PD‐L1‐ negative subgroup • Median OS 7.6 vs 15.9 months (p=0.16) • No increase in treatment‐related toxicities with SBRT

Shaverdian N, et al. Lancet Oncol. 2017;18(7):895-903.

Early Phase Trials Evaluating SABR+ Checkpoint SWOG/NRG S1914 Schema Blockade in Early‐Stage NSCLC

Study Phase N Checkpoint inhibitor Royal Marsden II 31 Adjuvant nivolumab x 12 months ASTEROID (Vastra II 216 Adjuvant durvalumab x 12 months Gotaland Region) UC San Diego I/II 56 Concurrent + adjuvant durvalumab, 6 cycles UCLA iSABR I/IIR 105 Neoadjuvant, concurrent and adjuvant durvalumab x 5 cycles

total (start 5 days prior to SABR) Stratification factors: ‐ Location (central vs MD Anderson IIR 140 Concurrent and adjuvant nivolumab 4 cycles total peripheral) ‐ Size (<4 cm vs ≥4 cm) UC Davis I 33 Neoadjuvant (2 cycles) concurrent and adjuvant atezolizumab, ‐ Zubrod PS (0‐1 vs 2) 6 cycles total

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PACIFIC 4 / RTOG 3515 KEYNOTE 867

N=630 Up to 28 Days Primary Inclusion Criteria 1:1 Durva 1500mg q 4 SBRT (45‐54 Gy) + Concurrent and • Clinical Stage I/II node Patient wks x 24 mos Endpoint: Screening Adjuvant Placebo Q3 weeks for up to 12 negative (T1 – T3 N0) SOC PFS • Medically inoperable or Baseline Scan definitive R SBRT months Placebo q 4 wks x Eligible stage I‐IIA refuse surgery Submit Tumor 24 mos • ECOG PS 0-2 samples Key Node negative • All comers Stratifications: Secondary 1:1 •By size NSCLC patient •Central vs. Endpoint: (n=530) peripheral OS SBRT (45‐54 Gy) + Concurrent and Lung Adjuvant Pembrolizumab Q3 weeks for Additional Key points • NSCLC proven by histology / cytology Cancer up to 12 months • Tissue submission mandated –core preferred but will accept FNA samples for translational analysis Co‐Primary Endpoints: • SOC SBRT taking place during screening. SBRT planning can occur before study enrollment Mortality • Randomization within 7 days of completion of SOC SBRT • Event‐Free Survival • Overall Survival Slide Courtesy of Cliff Robinson MD

Conclusions Thank you!

• SBRT for ultracentral lung tumors remains high risk. Close attention to maximum and volumetric dose constraints to critical structures, including bronchus, vessels, esophagus, and others remains crucial. Risk benefit discussions with patients are important

• SBRT in patients with ILD is high risk and should be considered in the context of individual patient risk/benefit profile and other treatment options

• SBRT/Immune Checkpoint Blockade combinations are under investigation in several randomized phase III trials for early stage, medically inoperable NSCLC

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Disclosures STAGE III NON-SMALL CELL LUNG CANCER: 2017-2021 RADIATION THERAPY IN THE CONTEXT OF Includes all nondisputed payments from openpaymentsdata.cms.gov ONCOGENE ADDICTION AND IMMUNOTHERAPY ■ Paid to my institution – Research grants: Genentech, Merck, Bristol- Sue Yom, MD, PhD, MAS, FASTRO Myers Squibb, BioMimetix UCSF Radiation Oncology ■ Paid to me – Book royalties: UpToDate, Springer

Non-small Cell Lung Carcinoma – no longer Treatments for NSCLC considered a single disease ■ Surgery – Lobectomy, pneumonectomy, sublobar resection – Percutaneous ablation procedures, e.g. RFA – Intrabronchial ablation procedures, e.g. PDT ■ Radiotherapy – External beam RT – standard or accelerated Many combinations of hypofractionation – SBRT – primary or oligometastatic site(s) the above modalities. But only the last two ■ Chemotherapy categories are – Platinums – Non-platinum agents biomarker driven. ■ Targeted therapy – Small molecule inhibitors – Anti-angiogenic therapies ■ Immunotherapy Travis WD J Thor Oncol 2015; Hilley Lancet 2016 3 4

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Biologically based therapies for Stage IV NSCLC FDA approved agents for stage IV NSCLC • Anti-Angiogenics • Pre-2000: Nothing – Bevacizumab – Ramucirumab nd rd • ~ 2002-2005: Gefitinib/Erlotinib for 2 /3 line • Anti-EGFR • ~ 2005-2007: Bevacizumab added to chemo – Erlotinib; Gefitinib; Afatinib; Osimertinib (EGFRm+) • ~ 2008-2009: Cetuximab added to chemo (FLEX trial) – Necitumumab • Other TKI’s • ~ 2010-2015: Select biomarker-driven oral agent > Chemo – Crizotinib; Lorlatinib (ALK+, ROS1+) – Gefitinib/Erlotinib/Afatinib for EGFRm+ – Entrectinib (ROS1+) – Crizotinib/Ceritinib for ALK+ – Ceritinib; Brigatinib; Alectinib (ALK+) – Dabrafenib/Trametinib (BRAF V600E) – ~ 2013-2017: Anti-ALK and ROS therapies – Selpercatinib; Pralsetinib (RET) • ~ 2015 - present: Immunotherapy (Anti-PD1/PDL1) • Immunotherapy (anti-PD1/PDL1) – Nivo > Docetaxel for 2nd line – Nivolumab – Pembro > chemo for 1st line with PDL1 > 50% – Pembrolizumab – Atezolizumab

5 6 – Durvalumab (stage III)

Examples of biomarker trials in stage IV NSCLC Prior adjuvant EGFR TKI trials for stage I-III Chemo vs. Pembro Chemo vs. Erlotinib PDL1 > 50% ■ RADIANT EGFR Mutation – Stage IB to IIIA disease – Randomized phase III, erlotinib vs placebo – Adjuvant erlotinib associated with longer DFS in post hoc analysis but NS – 37% of relapses in the patients on erlotinib involved NEITHER the CNS PRACTICE • OPTIMAL study: PFS ■ EVAN 13.1 vs. 4.6 mo • Keynote 024 Study: – Stage IIIA CHANGING PFS 10.3 vs 6 mo • (OS NS due to salvage) – Randomized phase II, erlotinib vs vinorelbine/cisplatin

Zhou C Lancet Oncol 2011; Reck M NEJM 2016 – Sig better 2 year DFS with adjuvant erlotinib 7

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NOT PRACTICE CHANGING ADJUVANT/CTONG1104 trial 10.7 month improvement in DFS – sig PRACTICE CHANGING? – Stage II to IIIA disease 75.5 versus 62.8 months OS - nonsig adjuvant trial of osimertinib – Randomized phase III, gefinitib vs vinorelbine/cisplatin – Longer DFS with adjuvant gefitinib – Overall survival nonsig, recurrence in the CNS was common

Wu Y, ASCO 2017; Lancet Oncol 2018 9

ADAURA adjuvant trial of osimertinib DFS: HR of 0.17 favoring osimertinib ■ Stage IB to IIIA ■ Double blind placebo controlled phase III, for EGFRm–positive (Ex19del or L858R) ■ Trial started after optional completion of adjuvant chemotherapy (45% didn’t get any); no postop radiation à high relapse rate in placebo arm ■ Osimertinib (80 mg once daily) or placebo for 3 years ■ $200,000 annual cost per patient Background:

• FLAURA trial in advanced NSCLC showed that patients who received osimertinib upfront lived 7 months longer than patients treated with erlotinib or gefinitib

• Osimertinib works against exon 19 deletions and exon 21 L858R but also works against T790M mutation associated with resistance – also better CNS penetration Wu. N Engl J Med. 2020 Lovly C, ESMO 2020.

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LIBRETTO-001: Efficacy With Selpercatinib in Patients With RET Fusion–Positive NSCLC For advanced stage NSCLC

Best Tumor Response by IRC in Patients With ■ Durability of response • FDA has approved selpercatinib (May 2020) and pralsetinib Prior Platinum Doublet CT (n = 105) in pretreated patients 40 (September 2020) for patients with metastatic RET fusion–positive – DoR: 17.5 mos NSCLC. 20 – PFS: 16.5 mos 0 • Broad NGS testing to detect RET fusions along with alterations in – Antitumor activity EGFR, ALK, ROS1, BRAF V600E, NTRK, and METex14 is -20 observed regardless recommended at diagnosis of stage IV NSCLC. of prior therapy -40 • IHC and FISH have significant false negative and false positive ■ Treatment naive (n = rates. -60 ORR, % (95% CI) 64 (54-73) 39) § CR 2 • RNA NGS might be more effective in detecting fusions like -80 § PR 62 – ORR: 85% § SD 29 RET, NTRK and ALK. Maximum Change in Tumor Size (%) Size Tumor in Change Maximum -100 § PD 4 Prior anti–PD-(L)1 therapy – DoR and PFS not § NE 4 No prior anti–PD-(L)1 therapy Prior multitargeted kinase inhibitor, reached To Crizotinib in Treating Patients With Stage IB-IIIA Non-small Cell Lung Cancer That Has including those with anti-RET activity Drilon. NEJM. 2020;383:813. Been Removed by Surgery and ALK Fusion Mutations (An ALCHEMIST Treatment watch Trial) - NCT02201992

LungART Phase III Trial LungART Phase III Trial

Inclusion: • Required to have at least 3 dissected intrapulmonary/hilar nodes and at least 3 from proximal mediastinal nodal stations • ENE in an isolated mediastinal node ineligible, but ENE eligible if within a complete lymph node dissection • Excluded bronchial margin with carcinoma in situ, or positive pleural lavage cytology

Contouring/planning: • Bronchial stump, hilar region, and involved mediastinal pleura (stations 4, 7, 10) always included in CTV plus all pathologically involved nodal stations • Expanded 1 cm for motion to rCTV then 0.5 laterally and 1 cm sup-inf to PTV • Lungs V20 ≤ 31% after lobectomy and ≤ 22% after pneumonectomy Le Pechoux, ESMO 2020. • 30% of heart ≤ 35 Gy

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LungART Phase III Trial DFS components (First event)

Control PORT

All DFS events* 152 144

Mediastinal relapse 70 (46.1%) 36 (25.0%)

Brain metastasis 27 (17.8%) 34 (23.6%)

Other metastasis 71 (46.7%) 71 (49.3%)

Death 8 (5.3%) 21 (14.6%)

*Patients can have more than one event at the same time

Le Pechoux, ESMO 2020.

NRG-RTOG 0617 Stage III Lung

Tissue for EGFR but Register & no integral Stratify: biomarker 60 Gy + Paclitaxel/Carboplatin

PS (0 vs. 1)

PET staging 74 Gy + Paclitaxel/Carboplatin (yes vs. no) R

Histology (squamous 60 Gy + Paclitaxel/Carbo/Cetuximab vs. non-sq) Rigorous credentialing RT (3D vs. for 3D and IMRT) IMRT 74 Gy + Paclitaxel/Carbo/Cetuximab

P. I. : J. Bradley

5 4/23/21

RTOG 0617: 74 Gy vs 60 Gy for NSCLC Could Immune System DVH Have Affected Outcome?

■ EDIC = Effective Dose to Immune System Radiation Dose Question Cetuximab Question 60 Gy vs. 74 Gy (RT/Chemo vs. RT/Chemo-Cetux) ■ function of DVH to heart, lungs, great vessels and total body (integral) DVH

28.7 vs. 20.3 mo. 25 vs. 24 mo. !"#$ 3 (/) #6" Median Survival Median Survival = &. () ∗ +," + &. &. ∗ +/" + &. 01 + &. 21 ∗ &. .1 ∗ ∗ 2 P=0.004 P=0.29 4 7) ∗ (&

• EDIC range: ~ 2 to 12. Detrimental effect of 74 Gy No benefit (nor detriment) to • Not surprisingly, EDIC scores were significantly through 2 years Cetuximab higher in the 74 Gy arm than the 60 Gy arm

Bradley J, Lancet Oncol 2015 21 22 Jin J, ASTRO 2017

EDIC Outcomes from NRG 0617 PACIFIC TRIAL

■ Correlation of EDIC with Covariate Comparison HR (95%CI) p Note that PDL1 was neither an eligibility nor stratification factor

OS ‘beat’ lung Vx or heart Esophagitis Grade <3 1.55 (1.13, 0.006 Vx or GTV as a prognostic grade 3 (RL) vs 2.13) Eligibility biomarker. Grade≥3 • Stage III NSCLC • PS 0-1 S Durvalumab 10 mg/kg Received No (RL) vs 0.65 (0.47, 0.90) 0.01 • Definitive Chemo-RT done q2 weeks for up to 1 year full chemo Yes T • 54-66 Gy R v 2 EDIC Continuous 1.17 (1.09, <0.0001 • V20<35% Age v Gender 1.25) • 2+ cycles of platinum A to N=713 R 1 + 2nd agent T v Smoking • Doing well Modeling of • NEPD I Placebo Relationship between • No Grade 2 RP F q2 weeks for up to 1 year EDIC and survival • No active Grade 2 Y suggests that EDIC > 10 AE’s • Co-primary endpoints: PFS and OS approaches incurability. • Ready to Go • Independent Central Review of Imaging • <14 days (amended to <42).

23 Jin J, ASTRO 2017 24

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Subgroup Analyses of Pacific

PACIFIC trial: advent of immunotherapy ■ Notable Findings: No obvious benefit in EGFRm+ pts. ■ Possible trend to greater benefit for pts with (pre-RT) PDL1 > 25% ■ EU approval based on PDL1 ≥ 1%

• Median duration of follow-up was 33.3 mos Antonia SJ et al. N Engl J Med 2017 • 48.2% of patients have died as of 1/31/19 • 44.1% on Durva arm vs. 56.5% on placebo arm Gray JE, JTO 2020 25 26

Subgroup Analyses of Pacific ■ Notable Findings: No obvious benefit in EGFRm+ pts. Possible trend to PACIFIC Trial: Timing of Durvalumab greater benefit for pts with (pre-RT) PDL1 > 25% ■ EU approval based on PDL1 ≥ 1% ■ Original design required randomization within 14 days after RT. – Amended to allow up to 42 days. ■ Secondary analysis (NEJM Supplement) showed better efficacy of Durva in the <14 days cohort: – HR 0.39 in favor of Durva for 1-14 day Pts. – HR 0.63 in favor of Durva for 15-42 day Pts. ■ Supports the hypothesis that intense RT/CRT may induce PDL1 and/or other factors priming for immunotherapy.

Gray JE, JTO 2020 27 Antonia SJ et al. N Engl J Med 2017

7 4/23/21

ICI Studies in Stage III NSCLC: Does radiation dose escalation matter in the mostly conventional RT schedules wake of PACIFIC? ■ CheckMate73L: nivo/CCRT+nivo-ipi vs • At median followup of 25.2 months, intrathoracic progression occurred in 37% nivo/CCRT+nivo vs CCRT+durva of patients in durvalumab arm and 48% of those in placebo arm ■ PACIFIC2: CCRT/durva+durva vs CCRT/placebo+placebo • But toxicity is more concerning in patients receiving duvalumab – increased risks of pneumonitis and patients have less reserve to tolerate subtle or overt ■ ALCHEMIST (Alliance/ECOG): Postop Nivo vs. cardiac toxicity observation (includes IB/II) • Need for more novel forms of dose escalation ■ Big10 Consortium: CCRT + nivo-ipi vs. nivo • More targeted – give the dose to specific high risk subvolumes • More personalized – give the dose to those who can tolerate it better ■ NRG-LU004: Phase I RT/durva (no chemo)

NRG-RTOG 1106 Study of Adaptive, ‘Dose-dense’ Chemo-RT

Std. Chemo-RT Std. Chemo-RT Not sig different S (50 Gy/5 wks) (10 Gy/1wk) T X R 1 v IIIA vs. B to NEW PET A v T-size R 2 during Wk 4 T v Histology I Adaptive F Accel. Chemo-RT Chemo-RT Y (46.2 Gy/4 wks) (up to 34.2 Gy/2 wks N= 117 --> 80.4 Gy) Primary endpoint: Local-Regional PFS

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Not sig different RTOG 0617 Exploratory Analysis of miRNA profile as a ‘Predictive’ Biomarker ■ Patients with ‘high risk’ miRNA signature benefited from high BED, but ‘low risk’ miRNA patients did not benefit.

BED < 100Gy, low risk, MST = 33.4 Months (N=38) 100 BED < 100Gy, high risk, MST = 9.9 Months (N=33) BED ≥ 100Gy, low risk, MST = 38.9 Months (N=15) • miRNA 80 BED ≥ 100Gy, high risk, MST = 19.3 Months (N=14)

signature 60 based upon

Not sig different pre-RT OS(%) 40 serum levels • BigART increased in-field primary 20 2/3rds of patients had tumor control by 17% and in-field 0 the low risk signature 0 12 24 36 48 60 72 84 96 108 locoregional control by 11% and would not benefit Months • Validates U Michigan model from dose escalation predicting 1% improved LRC per Gy) Sun Y (Kong FM), IJROBP 2018 34

TKI vs ICI induced interstitial lung disease PA A LAD SVC circumflex

RV A RA LV LA

Lmain RCA ant circumflex

TKI pneumonitis incidence 1.12% for all-grade, apical 0.61% for high-grade, and 0.20% for grade 5 septal – Suh, Lung Cancer Sep 2018 lat inf More common in patients with prior exposure to ICI Cadranet, European Respiratory Review 2019

9 4/23/21

Future directions: more frequent or continuous Future directions: PET tracers targeting hypoxia? adaptive replanning of radiation? • 18F-FMISO = most extensively studied PET tracer for imaging hypoxia • For 18F-FDG, radiation causes decrease of tracer uptake and tumor SUVmax • highly lipophilic with slow plasma clearance, low tumor-to-background ratio but increases background uptake due to radiation-induced inflammation • F-MISO results have not yet been reported from RTOG 1106 • à When is best time to adapt? second vs fourth week of treatment? • Second-generation nitroimidazole derivatives: more hydrophilic, lower • Image-guided radiotherapy systems allow increasing automation lipophilicity, higher tumor-to-background ratio • CBCT-Linac systems: daily delineation of target volumes and automated daily • 18F-fluoroazatiomycin arabinoside (18F-FAZA) dose evaluation • 18F-fluoroerythronitroimidazole (18F-FETNIM) • MRI-Linac systems: daily assessment of functional parameters derived from • 18F-flortanidazole (18F-HX4) perfusion, diffusion, and spectroscopy imaging • PET-Linac systems: clinical use has not yet been fully reported • 4Cu-ATSM • bioreductive enzymes reduce Cu (II) to Cu (I) in hypoxic conditions, which dissociates from ATSM and is trapped within the hypoxic cell

Stage III NSCLC: Summary

■ A lot has changed since RTOG 0617. – Sensitivity to risks of combined toxicities with TKI and ICI – Priority on CNS control and immune function – Continuing evaluation of lung and heart dose-volume issues ■ New standard of care for non mutant = Concurrent chemoRT → Durvalumab ■ Tissue markers (EGFR, PDL1, ALK/ROS1, BRAF, RET): unclear role in Stage III but it is becoming more standard to test tissue. --> NGS? ■ Radiation dose escalation remains worthy of further study but requires re-evaluation in the context of TKIs and immunotherapy. ■ Future? – Non-invasive biomarkers e.g. liquid biopsies/dynamic monitoring. – Improve current functional imaging e.g. not just PETCT. – Improve Immunotherapy approaches (e.g. dual ICI, biomarker driven ICI, concurrent vs or followed by maintenance ICI). – Include Oligometastatic Stage IV disease in ‘Quasi-Definitive’ Intent Trials.

10 Disclosures

. None

Small Cell Lung Cancer: Evolving Applications of Radiation Therapy and Immunotherapy

Jason Chan, MD UCSF Radiation Oncology Assistant Professor

Current Role of RT in SCLC Current Role of RT in SCLC

ASCO 2021 (Daly et al.)

Despite PCI and TRT in guidelines, these indications seem to be falling out of favor

NCCN v2.2021 3 NCCN v2.2021 4 ME Daly, N Ismaila, RH Decker, K Higgins, D Owen… - Journal of Clinical Oncology, 2021 KA Higgins, CB Simone II, A Amini, IJ Chetty… - Journal of Thoracic …, 2021

1 | [footer text here] Systemic Therapy in SCLC Evolving Applications of RT + IO

. Add IO to CRT backbone in LS-SCLC? . Replace PCI with HA-PCI or omit altogether after IO? . Intra-cranial salvage with focal or comprehensive RT? . Any role for consolidative RT? . Possible role of immune modulation with RT?

5 NCCN v2.2021 6

Evolving Applications of RT + IO NRG-LU005 LS-SCLC: PHASE II/III RANDOMIZED STUDY OF CHEMORADIATION VERSUS CHEMORADIATION PLUS ATEZOLIZUMAB

. Add IO to CRT backbone in LS-SCLC? ARM 1 EP q3w x 4 cycles . Replace PCI with HA-PCI or omit altogether after IO? R Thoracic RT 45 Gy BID or 66 Gy QD LS-SCLC A . Intra-cranial salvage with focal or comprehensive RT? N STRATIFICATION D . Any role for consolidative RT? RT BID vs. QD O Chemo (Cis vs. Carbo) M ARM 2 . Possible role of immune modulation with RT? Sex (M vs. F) I EP q3w x 4 cycles ECOG (0-1 vs. 2) Z Thoracic RT 45 Gy BID or 66 Gy QD E Atezolizumab q3w x 1 year

7 8 PI Kristin Higgins, MD

2 | [footer text here] STIMULI ADRIATIC LS-SCLC: Consolidative ICI LS-SCLC: Consolidative ICI

9 Owonikoko, ASCO 2018 10 About UCSF - Data Updated August 2017

Evolving Applications of RT + IO NRG-CC003 Randomized Phase II/III Trial of Prophylactic Cranial Irradiation with or without Hippocampal Avoidance for Small Cell Lung Cancer

. Add IO to CRT backbone in LS-SCLC? ARM 1 . Replace PCI with HA-PCI or omit altogether after IO? R PCI (25 Gy in 10 fractions) LS-SCLC or ES-SCLC A Baseline neurocognitive . N Intra-cranial salvage with focal or comprehensive RT? assessment D O . Any role for consolidative RT? STRATIFICATION M Stage: LS vs. ES ARM 2 I . Possible role of immune modulation with RT? Age: < 60 or ≥ 60 PCI with IMRT Hipoocampal Z Memantine: Yes vs. No Avoidance (25 Gy in 10 fractions E Hippocampi Dmax ≤ 13.5 Gy Hippocampi D100% < 7.5 Gy

11 12 PI Vinai Gondi, MD

3 | [footer text here] MAVERICK Evolving Applications of RT + IO “MRI Brain Surveillance Alone Versus MRI Surveillance and Prophylactic Cranial Irradiation (PCI): A Randomized Phase III Trial in Small-Cell Lung Cancer” . Add IO to CRT backbone in LS-SCLC? . Replace PCI with HA-PCI or omit altogether after IO? . Intra-cranial salvage with focal or comprehensive RT? . Any role for consolidative RT? . Possible role of immune modulation with RT?

Brain Metastases Salvage Tx WBRT or SRS up to treating physician

13 PI Chad G Rusthoven, MD 14

SRS vs. WBRT for SCLC Evolving Applications of RT + IO

. FIRE-SCLC (Retrospective): benchmark for SRS outcomes . Add IO to CRT backbone in LS-SCLC? . ENCEPHALON (Heidelberg): SRS vs. WBRT for 1-10 brain . Replace PCI with HA-PCI or omit altogether after IO? mets (Randomized Ph II) . Intra-cranial salvage with focal or comprehensive RT? . Dana Farber: SRS for 1-6 brain mets (Single arm) . Any role for consolidative RT? . MDACC: SRS for 1-5 brain mets (Single arm) . Possible role of immune modulation with RT?

15 CG Rusthoven, M Yamamoto, D Bernhardt, DE Smith… - JAMA oncology, 2020 16

4 | [footer text here] Role of TRT and PCI Unclear with IO IMpower133 Patterns of Failure

IMpower133 (EP ± Atezolizumab) CASPIAN (EP ± Durvalumab) *No benefit in adding Tremelimumab to EP + Atezo

“The most dominant pattern of progression in both treatment arms • Curative-intent TRT not permitted but • PCI received by 11% in both arms of IMpower133 was in initial sites of disease” “palliative” thoracic RT allowed and 8% in control arm of CASPIAN

JW Goldman, M Dvorkin, Y Chen, N Reinmuth, K Hotta… - The Lancet Oncology, 2021 17 L Horn, AS Mansfield, A Szczęsna, L Havel… - New England Journal of …, 2018 18 Higgins, ASTRO 2020 SV Liu, M Reck, AS Mansfield, T Mok, A Scherpereel… - Journal of Clinical Oncology, 2021

Caution: PCI and TRT Questionable Prior to IO Caution: Extra-CNS Consolidation Questionable Prior to IO RTOG 0937: PCI ± Thoracic and RT to 1-4 extra-cranial mets Takahashi et al. Slotman et al.

No OS benefit to PCI in ES- Did not meet primary SCLC. Most favor MRI endpoint of 1y OS benefit surveillance since this study but 2y OS benefit observed Fewer failures, more toxicity (including one G5 pneumonitis), no OS benefit

19 T Takahashi, T Yamanaka, T Seto, H Harada… - The Lancet Oncology, 2017 20 EM Gore, C Hu, AY Sun, DF Grimm, SS Ramalingam… - Journal of Thoracic …, 2017 BJ Slotman, H van Tinteren, JO Praag, JL Knegjens… - The Lancet, 2015

5 | [footer text here] Caution: RT-associated lymphopenia Phase I: Thoracic RT with Pembro after induction chemo in ES-SCLC

• Appears safe Efficacy perhaps limited by 1) induction without IO, 2) including PD after induction, and 3) combining with Extracranial or prolonged courses of RT increase the risk of severe lymphopenia, anti-PD1 which is associated with poorer survival in patients treated with checkpoint inhibitors IMRT 45 Gy in 15 fractions to PTV SIB to GTV up to 52.5 Gy allowed LRG Pike, A Bang, BA Mahal, A Taylor, M Krishnan… - International Journal of …, 2019 21 A Abravan, C Faivre-Finn, J Kennedy, A McWilliam… - Journal of Thoracic …, 2020 22 JW Welsh, JV Heymach, D Chen, V Verma… - Journal of Thoracic …, 2020 N Joseph, A McWilliam, J Kennedy, K Haslett, J Mahil… - Radiotherapy and Oncology, 2019

NRG-LU007 (RAPTOR) Evolving Applications of RT + IO ES-SCLC: Randomized Phase II/III Trial Of Consolidation Radiation + Immunotherapy

ARM 1 . Add IO to CRT backbone in LS-SCLC? Atezolizumab maintenance ES-SCLC R . Replace PCI with HA-PCI or omit altogether after IO? SD or PR after EP + A ARM 2 Atezo x 4-6c N Atezolizumab maintenance + . Intra-cranial salvage with focal or comprehensive RT? D Standard RT: QD up to 5 sites STRATIFICATION O Thoracic or Liver RT: 45 or 30 Gy . Any role for consolidative RT? Sites receiving RT M Extra-Thoracic RT 30 or 20 Gy (fields 1-3 vs. > 3) I . Possible role of immune modulation with RT? PR vs. SD Z ECOG (0-1 vs. 2) E

*PCI optional

23 PI Quynh-Nhu Nguyen, MD 24

6 | [footer text here] Major need to extend IO benefit in SCLC Mutation spectrum of SCLC SCLCs have high TMB but benefits of IO are generally modest, maybe due to low PD-L1 expression . Poor prognosis with early recurrences IMpower133 . No ICI predictive biomarkers in routine clinical practice ‐ No clear correlation with PD-L1 TPS/CPS or TMB . Limited second line therapy options ‐ Lurbinectedin ORR 35%; PFS 3.5 mo ‐ EP Re-Challenge ORR 49% PFS 4.7 mo ‐ Topotecan ORR 17% to 25%; PFS 2.7-4.1 mo

J Trigo, V Subbiah, B Besse, V Moreno, R López… - The Lancet Oncology, 2020 M Peifer, L Fernández-Cuesta, ML Sos, J George… - Nature genetics, 2012 25 N Baize, I Monnet, L Greillier, M Geier, H Lena… - The Lancet Oncology, 2020 26 C Shao, G Li, L Huang, S Pruitt, E Castellanos… - JAMA network open, 2020 SV Liu, M Reck, AS Mansfield, T Mok, A Scherpereel… - Journal of Clinical Oncology, 2021

ASCL1, NEUROD1, and POU2F3 expression defines 4 SCLC subtypes

• SCLC-I experiences greatest benefit from the addition of anti- PD-L1 to chemotherapy

• SCLC-N models are sensitive to multiple Aurora kinase (AURK) inhibitors Questions? • SCLC-A models are sensitive to [email protected] multiple B-cell lymphoma 2 (BCL2) inhibitors • SCLC-P models are sensitive to PARP inhibitors

27 About UCSF - Data Updated August 2017

7 | [footer text here] Disclosures

. Consulting ‐ AstraZeneca, Sanofi Optimizing Management of Oncogene Driven . Research Funding (to institution) Oligometastasis in Lung Cancer ‐ Amgen, Celgene, JNJ, Merck, Novartis, OncoMed, Trizell UCSF Radiation Oncology Update 2021

. I will discussing non-FDA approved treatment/ indications Matthew Gubens, MD, MS during my presentation today (research findings) Associate Professor, Thoracic Oncology

April 23, 2021

Some definitions and distinctions

. Oligometastatic ‐ Synchronous ‐ Metachronous . Oligoresidual . Oligoprogressive

. Oligoblennia-- deficiency of mucus (1853) . Oligandrous-- having fewer than 20 stamens

3 4

1 | [footer text here] Meta-analysis of oligometastatic NSCLC Meta-analysis of oligometastatic NSCLC

. Included NSCLC with . In validating set, multivariable hazard ratio for OS: ‐ 1-5 synchronous mets ‐ Synchronous 3.02 vs metachronous 1 ‐ Metachronous mets (diagnosed >= 2 mos after primary) ‐ N stage: N3 8.28 vs N2 1.93 vs N1 1.69 vs N0 1 ‐ Controlled primary tumor (surgery or RT) ‐ T stage NS ‐ Locally ablative treatments to all mets ‐ Brain mets NS . N=757 from published studies, where investigators reached out ‐ Lung met NS to authors, with 20/30 patient datasets collected ‐ Histology: other 6.26 vs large cell 2.39 vs squam 1.86 vs adeno 1

5 Ashworth AB et al, Clin Lung Ca, 2014. 6 Ashworth AB et al, Clin Lung Ca, 2014.

Meta-analysis of oligometastatic NSCLC SABR COMET

. Issues ‐ Not prospective, not randomized ‐ Not randomized ‐ No data on systemic therapy . And only 1st gen targeted therapies . And no immunotherapy . More studies needed…

7 Ashworth AB et al, Clin Lung Ca, 2014. 8 4/14/2021

2 | [footer text here] SABR-COMET SABR-COMET

Issues • Heterogeneity across tumor types • Role of systemic treatment • Number of oligo sites • SABR-COMET3 • SABR-COMET10 Median OS: 50 vs 28 mo Median PFS: 11.6 vs 5.4 mo HR 0.47, p=0.006 HR 0.48, p=0.001

9 Palma et al, JCO 2020. 10 Palma et al, JCO 2020

Gomez trial– LAT in NSCLC oligometastatic disease Gomez trial– LAT in NSCLC oligometastatic disease

. Multicenter, randomized phase 2 trial . Stopped early by DSMC after 49 pts assigned: significant PFS . Stage IV NSCLC, 3 or fewer mets benefit . No progression at 3+ mos after front-line systemic therapy . PFS 14.2 vs 4.4 mos, p=0.022 . Randomized 1:1 . OS 41.2 vs 17.0 mos, p=0.017 ‐ Maintenance therapy/observation ‐ Local consolidative therapy to all sites (surgery allowed) . Primary endpoint: PFS . Secondary endpoints: OS, toxicity, new lesions

11 Gomez et al, JCP 2019. 12 Gomez et al, JCO 2019 4/14/2021

3 | [footer text here] Gomez trial– LAT in NSCLC oligometastatic disease NORTHSTAR trial: EGFR-specific

. MDACC . (also Univ of Colorado, UCSF, MSKCC, UCLA) . N=143 pts for 120 able to be . 0-1 nonregional mets: n=32 randomized . 2-3 nonregional mets: n=17 . 80% power to detect an improvement of 8 . No mutation: n=41 mos in mPFS from . EGFR: n=6 (3/3) 14 to 22 mos

13 Gomez et al, JCO 2019. . EML4-ALK: n=2 (2/0) 14

Phase 3 trials underway Phase 3 trials underway internationally

. N=400 . SARON ‐ Randomized phase 3, OS endpoint . Maintenance is ‐ 1-5 lesions in up to a max of 3 organs pemetrexed, ‐ N=340 pembrolizumab, . SABR-COMET 3 docetaxel, . SABR-COMET 10 gemcitabine, or erlotinib

15 16

4 | [footer text here] What about oligoprogression? What about oligoprogression?

. University of Colorado . Shanghai Pulmonary Hospital, retrospective ‐ ALK fusion +, n=38 (on crizotinib) ‐ EGFR mutation +, n=206 (on erlotinib) ‐ EGFR mutation +, n=27 (on erlotinib) ‐ <=5 lesions during TKI therapy . PFS1: ALK pts 9.0m, EGFR pts 13.8m . 124 were CNS . At progression, 25/51 suitable for local therapy . PFS1: 10.1m ‐ Defined as non-LM CNS and/or <=4 sites of extra CNS PD . PFS2: 18.3m . PFS2 (in 25 pts, 24 after rads, 1 after surgery): 6.2m . OS: 37.4m

17 Weickhardt AJ et al. J Thorac Onc 2012 18 Xu Q et al. J Cancer, 2019.

What about oligoprogression on 3rd gen agents?

. MSKCC, retrospective ‐ EGFR mutation +, n=25 (on osimertinib– 3 1L) ‐ <=5 lesions during TKI therapy . 124 were CNS . PFS2: 4.9m . Time from local tx to systemic change: 7.8m

19 Wang C et al. IJROBP, 2019 20

5 | [footer text here] Treatment of oligometastatic disease

. For oligometastatic/oligoresidual disease ‐ Clear PFS benefit to local ablative therapy to oligo(residual) disease . OS data in NSCLC forthcoming in large trials ‐ Suggestion of more robust benefit in EGFR mutated NSCLC . NORTHSTAR trial accruing (including at UCSF) . For oligoprogressive disease ‐ No randomized data in oligoprogressive disease with EGFR (and other) targeted therapy, but fairly compelling rationale and data

6 | [footer text here] 4/23/21

Case 1: non-small cell lung cancer, non-operative Self-Assessment CME • 62 yo man with new cough • CXR showed pneumonia and RLL opacity Session: Thoracic • Persistent cough led to CT showing RLL mass Sumi Sinha, MD and Sue Yom, MD, PhD, MAS with • PET/CT Megan Daly, MD, Jason Chan, MD, Matthew Gubens, • Hypermetabolic RLL mass with narrowing of the MD, and Alexander Gottschalk, MD, PhD bronchus intermedius and right middle lobe bronchus • Hypermetabolic lymphadenopathy in right hilum, subcarina, and upper right paratracheal

PETCT images Case 1, cont.

• Bronch bx of station 7: adenocarcinoma • TTF-1+, CK 7+, CK 20- • Guardant 360 • BRAF+, TP53+ • No EGFR, ALK, MET, RET • Foundation One • TPS 80% (high expression) • MRI brain - no metastatic disease

1 4/23/21

Points of discussion Case 1, cont.

• Should molecular testing be offered/allowed • Patient wanted to try any means to achieve for stage III patients? surgical candidacy • What implications does this have for • Started dabrafenib 150 mg bid and therapy? trametinib 2 mg daily • Developed rash • Neoadjuvant targeted therapy? • Surgical candidacy determination? • After 6 weeks, had dose reduction to dabrafenib 100 mg bid and trametinib 1.5 mg daily • CT scan: reduction in tumor bulk

Post-induction CT Case 1, cont.

• Started 1st cycle of cisplatin/ etoposide + concurrent RT • 2nd cycle was switched to carboplatin/etoposide due to tinnitus • delayed two weeks due to neutropenia

2 4/23/21

RT plan Post-chemoRT PETCT

Definitive intent stage III Heart mean 28.12 (goal<26) Heart V40 30% (goal<50%) Lung mean 14.19 (goal<17) Lung V20 of 22% (goal<30%) Esoph mean 33.93 (goal<34)

Case 1, cont. Case 1, cont.

• Points of discussion • Started durvalumab q2w at 5 weeks • Should this patient continue to maintenance PDL1 • After 6 months (12 cycles), started high dose blockade? steroid due to pneumonitis • Should this patient go back to BRAF-MEK therapy? • Restarted 2 more cycles of durva then discontinued • Should this patient receive nothing further given his due to pneumonitis complete response?

Of note in PACIFIC: • All patients started durvalumab within 42 days after CRT • Exploratory analysis indicates starting ≤14 days after CRT was associated with OS advantage Faivre-Finn, Annals of Oncology (2018) 29 (suppl_8): viii488-viii492

3 4/23/21

Classic dosimetric Radiation-related pneumonitis indices for RP • Usually emerges within first 3 months after radiation Risk of grade 2+ pneumonitis by 24 months: • Related to geographic region of RT field • V20 < 22%: 0% risk • Driven by cytotoxic damage to type II pneumocytes and vascular • V20 22%-31%: 7% risk endothelial cells • V32% - 40%: 13% risk • V20 >40%: 36% risk

Hanania et al. Chest (2019) Jul; 156(1):150-162 Graham et al. IJROBP 1999 Yorke et al. IJROBP 2002

PACIFIC: Study Design ClinicalTrials.gov number: NCT02125461 Phase III, Randomized, Double-Blind, Placebo-Controlled, PACIFIC: Updated OS results Multicenter, International Study

• Patients with stage III, locally advanced, 1–42 days unresectable NSCLC who post-cCRT have not progressed Durvalumab Coprimary endpoints 10 mg/kg q2w for following definitive • PFS by BICR using platinum-based cCRT up to 12 months RECIST v1.1* (≥2 cycles) N=476 • OS • 18 years or older 2:1 randomization, stratified by age, sex, and Key secondary • WHO PS score 0 or 1 smoking history endpoints N=713 • Estimated life expectancy • ORR (per BICR) of Placebo • DoR (per BICR) ≥12 weeks 10 mg/kg q2w for up to 12 months • Safety and tolerability • Archived tissue was • PROs collected N=237

All-comers population Paz-Ares L. Presented at 2017 ESMO Congress; Madrid, Spain; September 9, 2017. Abstract LBA1_PR. Gray et al, ASCO 2019, abstract 8526 • Median duration of follow-up was 33.3 mos • 48.2% of patients have died as of 1/31/19 • 44.1% on Durva arm vs. 56.5% on placebo arm

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PACIFIC: Incidence and Clinical Significance of Pneumonitis (CTCAE Protocol (v4.0)) PACIFIC: Pneumonitis Management During Trial

Pneumonitis* or Durva Placebo Radiation Pneumonitis1,2 Immune-Mediated Any grade 33.9% 24.8% Durva Placebo Immune-mediated pneumonitis (N=51 of Pneumonitis§ 475 patients) Grade 3 3.4% 3.0% Any grade 10.7% 6.8% Grade 5 (death) 1.1% 1.7% Grade 3 1.7% 2.6% Leading to dose delay or interruption† 5.1% 3.0% Grade 5 0.8% 1.3%

§ • Corticosteroids (N=44) Leading to dose discontinuationǂ 4.8% 2.6% Immune-mediated pneumonitis or interstitial lung disease, including fatal cases, defined as requiring use of systemic corticosteroids and with no clear alternate etiology, occurred in patients receiving IMFINZI in clinical studies2 Note: No Grade 4 events of pneumonitis or radiation pneumonitis were reported in either group * Includes acute interstitial pneumonitis, interstitial lung disease, pneumonitis, and pulmonary fibrosis • High-dose corticosteroids, ≥ 40 † Includes pneumonitis only and occurring in >5% of patients ǂ Includes pneumonitis only and occurring in >1% of patients mg prednisone per day (or 1. Antonia SJ, et al. N Engl J Med. 2017;377:1919-1929. equivalent) (N=28) 2. IMFINZI Product Monograph. AstraZeneca Canada Inc. Jan 28, 2019. • Also received infliximab (N=2) • Any-grade rates 9% higher with durvalumab than in control arm but grade 3 and 5 rates lower • In trials of IO alone vs placebo, the difference of any Resolution (N=27) pneumonitis was only 3-4% suggesting interaction with RT 17 18 IMFINZI Product Monograph. AstraZeneca Canada Inc. Jan 28, 2019.

Alliance 31101/RTOG 1306

6 weeks UCSF

4-8 weeks U Colorado

Singapore

~8000 patients

5 4/23/21

Case 1, cont. Follow-up PETCT

• Increased prednisone from 5 mg back to 20 mg given worsening pulm symptoms • CT - no evidence of cancer recurrence, improvement in pneumonitis • Went to pulm rehab and now transitioning to PT • Remains NED

Case 2: non-small cell lung cancer, operative • 75 y.o. female with 3 weeks scant hemoptysis • PMH of chronic afib with pacemaker, on anticoagulation with Coumadin • CXR showed LLL mass • 10/18/17 CT chest: LLL mass 6.9x5.0cm, cavitary and thick- walled, spiculated, with extensive pleural contact, effacement of subpleural fat. Tiny satellite nodule, 4mm. AP window nodes up to 10.5mm and pretracheal node 9mm, precarinal node 10mm. Mild L hilar LAD, 11mm. Small portocaval nodes. Bullous emphysema, severe and bullous at the apices. Small pleural effusion. • PET/CT: LLL mass with SUV 19.8. Hypermetabolic LAD in L post mediastinum, SUV 11.8, about 10mm. Mod to severe emphysema.

6 4/23/21

Case 2, cont. Case 2, cont.

•PFTs: FVC 2.47 (87% pred), FEV1 • Seen by surgery – considered surgical candidate, but would recommend induction chemo or 1.84 (86% pred) DLCO 13.04 (65% enrollment on trial, referred for screening pred) • CT brain: No evidence of disease •CT guided bx of lung mass • Enrolled in PembroX clinical trial of preoperative • Pathology: Squamous cell carcinoma neoadjuvant pembrolizumab x 2c • CK7+ CK20- p63+ TTF1- • Developed half-cup/day hemoptysis, requiring IR embolization with coil of a branch of left • No molecular diagnostics done pulm artery (2 subsegmental branches)

Defining hyperprogression Discussion points

• Is this patient manifesting hyperprogression? How can you tell?

Frelaut, Int J Mol Sci, 2019

• Original definition: RECIST progression and at least two-fold increase in Tumor Growth Rate at 8 weeks (Champiat et al, Clin Cancer Res, 2017)

• Depending on exact definition (tumor growth rate, RECIST, presence of new lesions), affects 4-29% of solid tumor patients on immunotherapy

7 4/23/21

Case 2, cont. Discussion points

• Left lower lobe lobectomy and nodal dissection • Should this patient receive adjuvant • Moderately differentiated SCC, >10% residual viable tumor - no LVI, no PNI chemotherapy? • Parenchymal and bronchial margins negative; no • Should this patient receive adjuvant visceral pleural invasion; closest margin 15 mm radiation? • 3/20 nodes • Stations examined: 5, 6, 7, 8, 9, 10, 11 • Stations involved: 7, 11 • Size of largest metastatic deposit: 1.1 cm • No ENE • AJCC 8th edition staging: ypT3N2 • Post-operative nausea/vomiting, improved with Reglan

Case 2, cont.

• Completed 2 cycles adjuvant carboplatin and paclitaxel, discontinued due to SOB, hypotension, declining performance status • CT c/a/p: LUL mediastinal pleural thickening (reactive vs metastatic), new subacute L rib fractures s/p LLL lobectomy, stable RML 5 mm nodule Lung mean 8.93 Gy Heart mean 22.84 Gy • Postoperative RT to bronchial stump and L Lung V20 12% Pacemaker 0.74 Gy mediastinal nodes Esophagus mean 23.35 Gy Liver V30 5%

8 4/23/21

Open questions

• CTV = bronchial • Whether to give adjuvant chemotherapy in surgical stump, 4, 7,10, ±1-2, ±3, ±5, ±6, patients who have received neoadjuvant ±8 immunotherapy and/or chemotherapy • Lung V20 ≤ 31% after lobectomy • Whether to give adjuvant postoperative radiation in • Lung V20 ≤ 22% surgical patients who have received neoadjuvant after pneumonectomy immunotherapy and/or chemotherapy • Heart V30 ≤ 35% • Cord max ≤ 45 Gy

2017 Protocol modified: Target accrual of 500 patients to show a 12% difference in 3 yr DFS from 30% in control arm to 42% in PORT arm (power of 80%, alpha 5%)

No difference in DFS Found Case 2, cont.

• 5 month posttreatment CT Chest: Stable 5 mm RML nodule and LUL pleural thickening. • 8 month CT brain: NED. • 11 month CT chest: RML nodule stable. No LAD. Trace L pleural effusion.

Routine PORT no longer standard of care

Questions which will not be answered regarding need for PORT: • Multiple nodes/stations, gross ENE • Nodes which have responded to neoadjuvant therapy

9 4/23/21

NEOSTAR results (NCT03158129)

• 44 pts randomized to 3 cycles of IO prior to surgery • Stages IA 8 (18%), IB 15 (34%), IIA 7 (16%) IIB 5 (11%); IIIA 9 (20%) • 34 pts had surgery, 7 not resected, 3 pending • Among all 44 patients, 10 major path responses overall (24%) with 6 path CRs (15%) • Among 34 resections, major path response rate was 29% (nivo 20%, nivo-ipi 43%) • ORR was 22%; 15% of pts had PD (3 N, 3 NI) • Complications included 2 bronchopleural fistulas and 8 air leaks with one death due to BPF post steroid-treated pneumonitis; one each of G3 pneumonia, hypoxia, hypermagnesemia; one G3 diarrhea • % of viable tumor was lower in tumors with PD-L1 >1% vs PD-L1 ≤1% (median 20% vs 80%, p = .046) Cascone, Abstract #8504, ASCO 2019

Case 3: Oligometastasis Case 3, cont.

• 54 yo man with cough • Increased cough a few months later with pain in left chest wall and left scapula. Unable to talk due to coughing. • Had LUL lobectomy • After inconclusive workup, CT chest demonstrated • 4.1 cm moderate-to-poorly differentiated mediastinal LN enlargement and mass in left chest wall adenosquamous carcinoma • Biopsy demonstrated recurrent disease • 0.3 cm to vascular margin (otherwise negative margins) • Started palliative RT to chest wall and mediastinum to 15 Gy • 0/3 peribronchial, lobar, and hilar nodes in 5 fractions (of intended 30 Gy in 10 fractions) • AJCC 8th edition: pT2bN0M0, stage IIA • Stopped RT and came to UCSF for second opinion • Original surgery specimen profiling: no evidence of EGFR, ALK, ROS1 • 4 cycles of adjuvant carboplatin/pemetrexed or BRAF alterations and PD-L1 = 50% • Foundation Med: MET exon 14 splice site, MDM2 amplification, CDKN2A/B loss, MTAP loss, MS stable, TMB low (3 Muts/Mb)

10 4/23/21

Discussion points Case 3, cont. • Began cisplatin and etoposide with concurrent RT • Should he receive immunotherapy, MET directed • RT given with definitive intent to all sites of disease therapy, chemotherapy, or radiation therapy? (mediastinal mass and chest wall disease): 66 Gy in • If he receives radiation, to what sites and dose? 30 fractions to GTV, 60 Gy in 30 fractions to PTV • Cough and pain dramatically improved

Lungs

Heart

Case 3, cont.

• Three weeks after CRT completion, started immunotherapy with durvalumab • 3 month PET with no evidence of recurrence • 8 month CT c/a/p: NED, post-RT changes

Schroeder et al. Transl Lung Cancer Res. 2019;8(Suppl 2):S184–S191

11 4/23/21

European Society for Radiotherapy and Oncology (ESTRO) and European Organisation for Research Definitions of and Treatment of Cancer (EORTC) oligometastatic disease Areas of controversy

• ESTRO-ASTRO • Adrenal and brain synchronous mets are consensus document: considered a special category but should • Consensus supported the ability to deliver others be eligible for aggressive therapy? safe, clinically meaningful • Should patients with driver mutations be radiotherapy as a considered a special category eligible for minimum requirement for defining OMD in the aggressive therapy? context of radiotherapy • Systemic therapy induced OMD was identified as a distinct state Lievens et al, Accessed at: https://www.astro.org

Guckenberger et al, Lancet Oncol 2020

Case 4: Small cell lung cancer Case 4, cont. • Patient presented with dry cough for several weeks • Brain MRI was negative • CT chest was obtained • PET/CT confirmed activity of LUL dominant lesion and extensive supraclavicular, mediastinal, and hilar lymphadenopathy as well as satellite nodule • EBUS biopsy of 4R node demonstrated metastatic SCLC

12 4/23/21

SCLC staging per AJCC Next steps in treatment?

Why immunotherapy in SCLC? IMPOWER133

Alexandrov et al Nature 2013

Horn et al., NEJM 2018

13 4/23/21

CASPIAN Consolidative thoracic RT in ES-SCLC EP +/- Durvalumab

CREST, Slotman et al., Lancet 2015 • ES patients who responded to chemo, PS 0-2 • 30 Gy in 10 fx + PCI 13 months vs. 10 months (given same time) vs. PCI only • Primary endpoint of 1 year OS not met, but significant difference at 2 years (13% vs 3%)

Paz-Ares et al., Lancet 2019

Consolidative thoracic RT in ES- Consolidative thoracic RT in ES- SCLC in setting of changing SOC SCLC in setting of changing SOC • Neither IMPOWER133 nor CASPIAN allowed Takahashi et al., Lancet Oncol 2017 • ES-SCLC patients responding to chemo consolidative thoracic radiation • Required negative brain MRI • PCI no longer always given for ES-SCLC • No OS difference, though brain metastases reduced • PCI falling out of favor in EXTENSIVE STAGE patients well monitored with MRIs (remains standard of care for limited stage)

14 4/23/21

Safety of thoracic RT with ChemoRT + immunotherapy Immunotherapy combination will be tested in LS-SCLC

• Of 78 total patients, only 7 grade 4 events in 4 patients

RT volumes for consolidative Case 5: Thymoma thoracic RT CREST trial: • 50 y.o. female with cough “The planning target volume • CXR showed a mediastinal mass included the post- chemotherapy • CT showed a 14 cm size mediastinal mass in contact volume with a 15 mm margin to with pericardium and left anterior chest wall, account for without lymphadenopathy microscopic disease and setup errors. • Core biopsy showed a lymphocyte-rich thymoma Hilar and mediastinal nodal (historical name for B1) stations that were considered involved pre-chemotherapy were always included, even in case of response”

15 4/23/21

Case 5, cont. CT scan • Induction chemotherapy with cyclophosphamide, doxorubicin, carboplatin, and prednisone (CAPP) due to marginal resectability • After 2 cycles of CAPP, significant decrease in size of mass coming away from chest wall, but no further response at 4 cycles

Case 5, cont. Postoperative radiation • Median sternotomy • En bloc radical resection of 20 cm mediastinal mass • Postoperative intensity-modulated radiation • Mass was not adherent to the chest wall but was in extensive contact with the pericardium and adherent to pleura of left upper lobe therapy, 5040 cGy in 28 fractions • Resection of anterolateral pericardium and phrenic nerve • En bloc resection of the left upper lobe lingula via wedge • Bovine pericardial reconstruction was used • Left diaphragm was plicated • Pathology: • Well differentiated type B1 thymoma • No LVI, no PNI • Questionable microscopic transcapsular invasion, although this could not be fully assessed due to disruption of the specimen – per pathology T2N, Masaoka stage IIA • Masaoka stage III if pericardial invasion although pericardium was not seen on pathologic review

16 4/23/21

(Chemo)radiation for thymic Discussion points malignancies • When is postoperative RT warranted for thymoma? • Did this patient benefit from neoadjuvant chemotherapy? When should neoadjuvant chemotherapy be given? • Is radiation a reasonable treatment in this situation?

Case 5, cont. Case 5, cont.

• Patient is a von Hippel-Lindau disease carrier and • Found on surveillance chest CT, 5 years later underwent screening abdominal CT • Tumors and cysts in kidney, pancreas, genital tract • Clear cell renal cell carcinoma, pancreatic neuroendocrine tumor, and adrenal pheochromocytomq • Hemangioblastomas in brain and spinal cord; retinal angiomas • Endolymphatic sac tumors of inner ear • Noncancerous tumors in liver and lungs • 2.5 years after thymoma, she was diagnosed with T1aN0 grade 2 clear renal cell carcinoma • Had robotic assisted laparoscopic left partial nephrectomy without incident

17 4/23/21

Discussion points Case 5, cont. • We observed these tumors for almost 2 years • What is the best management of drop metastases? without emergence of other sites • What is the natural history of thymoma after drop metastases?

Case 5, cont.

• Stereotactic radiation (SBRT) to three pleural lesions, 5000 cGy in 5 fractions to all three sites

Min Max Mean Min Max Mean

Fifteen months later, patient remains NED – pleural thickening, mild left renal atrophy

18 4/23/2021

DUCTAL CARCINOMA IN SITU: RISK ASSESSMENT

Catherine Park, M.D. April 24 2021

British Journal of Cancer (2019) 121:285–292; https://doi.org/10.1038/s41416‐019‐0478‐6

Evolutionary models have been proposed to describe the clonal progression of DCIS into IBC

In situ hybridization

DCIS lesion Normal duct

vessel

s IBC stroma DCIS

EDA+ angiogenesis FN British Journal of Cancer (2019) 121:285–292; https://doi.org/10.1038/s41416‐019‐0478‐6 Remodeling of ECM

1 4/23/2021

AGENDA

1.Incidence and natural history of pure DCIS 2.Trials that Selected GOOD RISK DCIS • RCT and Single Arm 3.Risk Stratification • Molecular Diagnostics • Oncotype DCIS • PRELUDEDX • MSKCC nomogram 5.Prospective Observation Trials

Outcomes are worse in patients with DENSE TILS

Increase in screening--> 30% rise in cancer incidence

eFigure 1. Twenty-year breast cancer-specific survival after DCIS, by age of diagnosis

 SEER data base of 18 registries, 1988-2011, N=108,196 individuals Cancer.gov

2 4/23/2021

NSABP B-17 Effect of radiotherapy on BCS mortality

PROSPECTIVE RANDOMIZED TRIALS OF RT FOR DCIS DCIS: MANY TREATMENT OPTIONS

Median IBTR follow up Risk  Treatment options for DCIS Trials N (years) No RT RT reduction P 1 Wide excision +/- RT +/- endocrine therapy NSABP B17 813 17.25 35% 20% 47-52% <0.001 ~50% Risk Mastectomy EORTC 108532 1010 15.8 31% 18% 48% <0.001 Reduction Bilateral mastectomy UK, Aust, NZ3 475 12.7 26% 9% 69% <0.0001 Radiation: WBI, hypofractionated, APBI SweDCIS4 1046 17 32% 20% 37.5% <0.001  Survival is excellent with all; IBTR varies dramatically

1Wapnir, et al. J Natl Cancer Inst 2011; 103:478 2Donker, et al. J Clin Oncol 2013; 31:4054 3Cuzick, et al. Lancet Oncol 2011;12:21 (Only those not receiving tamoxifen, and randomized to No RT or RT are included) 4Warnberg, et al. J Clin Oncol 2014; 32:3613

3 4/23/2021

Can we OMIT RT in highly selected patients with favorable DCIS?

 RTOG 9804—Randomized trial for Good-Risk DCIS

 ECOG-ACRIN E5194—Prospective WEA for Good-Risk DCIS

Tamoxifen optional (~62%)

Median f/u= 7 yrs 6.7 vs 0.9% LR

Median f/u 12 yrs 30% of patients received tamoxifen

4 4/23/2021

ECOG 5194 12 year update Wide Excision Alone: ECOG 5194: 5 yr update

Low-intermediate grade High grade Size <2.5 cm Size <1.0 cm Margins >3mm Margins >3mm 24.5% Ipsilateral breast events (IBEs) for cohort 1 14.4% and cohort 2. Cohort 1 was defined as low- or intermediate-grade ductal carcinoma in situ 18.0 % (DCIS), tumor size 2.5 cm or smaller. 10.5% Cohort 2 was defined as high-grade DCIS, tumor size 1.0 cm or smaller.

Hughes et al, JCO VOL 27 NUMBER 32 NOVEMBER 10 2009

Selection of Patients with DCIS for Optimal Risk Assessment: Clinical Tools Management is Complex

• Heterogeneity in biology/extent . Molecular Assays:

• Difficulties assessing size and margins . Oncotype DCIS . PreludeDx • Protracted natural history (especially for low grade lesions) requires long follow up . Nomograms--MSKCC

• Inability to predict clinical outcome can lead to over- or under-treatment

5 4/23/2021

San Antonio Breast Cancer Symposium – December 6-10, 2011 Oncotype DCIS Score as a Predictor of Local Molecular Diagnostic to Predict Risk Recurrence: ECOG E5194 Subgroup Analysis

 Ipsilateral local recurrence:  DCIS Score HR (per 50 units) = 2.31 (95% CI: 1.15, 4.49,p=.02)  Adjusted for tamoxifen

 Ipsilateral invasive recurrence:  DCIS Score HR (per 50 units) = 3.68 (95% CI: 1.34, 9.62,p=.01)  Unadjusted

Patient Characteristics Validation Study: Ontario Cohort Ontario Cohort (N=571) Age ≥ 50 years 459 (81%)

Nuclear Grade Low 55 (10%) Intermediate 332 (58%) High 184 (32%)

Comedo Necrosis 350 (61%) Solid Subtype 358 (63%) Tumor Size < 10 mm 150 (26%) > 10 mm 140 (25%) Missing 281 (49%)

Multifocality* 114 (20%)

ER+ by RT-PCR 541 (95%) HER2+ by RT-PCR 100 (17.5%)

*Presence of at least 2 foci of DCIS in the same quadrant at least 5 mm apart Sikand et al. J Clin Path, 2005

6 4/23/2021

Study Design Ontario Cohort Outcomes

Study population  Population based cohort of cases diagnosed with pure DCIS in Ontario 1994-2003  Breast-conserving surgery alone  Negative resection margins

Statistical Analytical Plan  Pre-specified study objectives, Laboratory assays, Endpoints  Oncotype DCIS Score  Continuous variable (0 – 100)  3 pre-specified risk groups: Low < 39 Intermediate 39 –54 High > 55 Statistics  Cox proportional hazards models  Kaplan-Meier estimates to evaluate 10-year risk of recurrence by DCIS risk group (log rank tests used to compare risk groups) 7

Kaplan-Meier 10 yr Risk of LR by DCIS Score Factors Associated with LR: Multivariable Risk Group Analysis

7 4/23/2021

Comparison of Ontario Cohort to E5194 Cohort: K-M 10 year LR Multivariable Cox models for any local recurrence

EFFECT OF TUMOR SIZE and AGE

Study Design *A surgeon and a radiation oncologist independently completed pre‐ and post‐assay questionnaires about their recommendations for each patient. *Secondary objectives were to summarize patient clinicopathologic characteristics, to determine the distribution of DCIS Score results across the cohort and across clinicopathologic factors, and to evaluate the effect of DCIS Score results on physician estimates of local recurrence risk. *An exploratory objective was to assess changes in patient decisional conflict and anxiety using validated tools, pre‐ and post‐assay.

8 4/23/2021

Distribution of DCIS score by Risk Group Distribution of DCIS Score by clinical-pathologic factors

The number of patients with DCIS Score results in the low (blue), intermediate (yellow), and high (green) ranges are reported,along with mean (SD) and median (IQR) DCIS Score results for each risk group.DCIS ductal carcinoma in situ, SD standard deviation, IQR interquartile range

Pre- and Post- assay radiotherapy recommendations

Low Intermediate High

• Swe-DCIS trial (n=1046, 1987- 1999) • BCS; randomized to RT/no RT • PRELUDE DX • 7 biomarkers: HER2, PR, Ki67, COX2, p16/INK4A, FOXO A1, and SIAH2 • Performed on 584 cases • Requires at least 4 of 7 biomarkers to complete assay

9 4/23/2021

PRELUDEDX

BCS=BLUE BCS+RT=ORANGE

The 10‐year absolute risks of IBC and IBE for patients with a DS of 3 or less (low risk) had an average 10‐year IBC risk of 4% (95% CI, 0%–9%) and IBE risk of 8% (95% CI, 0%– 14%),adjusted for year of diagnosis

PREDICT REGISTRY STUDY The PREDICT Registry Study

Protocol Synopsis Protocol Synopsis, continued Study Groups/ Female patients with DCIS, 25 years and older. Patients must have Cohorts histologically confirmed ductal carcinoma in situ (DCIS) in a single breast NCT Number NCT03448926 without evidence of invasive cancer (presence of lobular carcinoma in situ (LCIS) or other benign breast disease in addition to DCIS is acceptable) Brief Title The PREDICT Registry  Prospective Registry to Evaluate the effect Primary Percent of Cases w/ Changes in Treatment Recommendation [Time: 5 years] Outcome The study will collect details on physician treatment recommendations of DCISionRT on treatment decisions in Official Title A Prospective Registry Study to Evaluate the Effect of the DCISionRT Test on Measures before and after availability of the genomic test (DCISionRT) results. The Treatment Decisions in Patients with DCIS Following Breast Conserving data elements include type of surgery (lumpectomy, therapeutic (n=2500) patients undergoing BCS for mastectomy, contralateral prophylactic mastectomy), type of radiation primary DCIS Therapy therapy (none, IORT, APBI, whole breast RT) and endocrine therapy (yes, no). The main measure will be percent of cases in which treatment recommendations are changed after the test results become available.  Primary outcome: % of cases with changes Brief Summary This is a prospective cohort study for patients diagnosed with ductal carcinoma in situ (DCIS) of the breast. The primary objective of the study is to create a de- Secondary Function of Demographic Factors [Time Frame: 5 years] in treatment recommendations at 5 years Outcome Percent of patients for which the recommended treatments change after identified database of patients, test results, treatment decisions and outcomes Measures DCISionRT results are known as a function of demographic factors (age  Secondary outcome: that can be queried to determine the utility of the DCISionRT test in the groups <40, 40-50 and >50; ethnicity; family history) diagnosis and treatment of ductal carcinoma in situ of the breast. Function of Tumor Factors [Time Frame: 5 years]  Function of demographic factors (age, Percent of patients for which the recommended treatments change after DCISionRT results are known as a function of tumor factors (tumor size, ethnicity, FHx) grade, architecture, necrosis, palpability, surgical margins, hormone Study Design Prospective Observational Cohort [Patient Registry] receptor status).  Function of Tumor factors: (size, grade, architecture, necrosis, palp, margins, ER) Acta Oncologica, 2006; 45: 536543 Miami Breast Cancer Conference® - March 5-8, 2020

10 4/23/2021

DCIS Nomogram MULTIVARIABLE ANALYSIS: FACTORS MSKCC Nomogram ASSOCIATED WITH IBTR

Adjusted P . Based on 1681 patients Variable HR value . 10 clinical/pathologic/treatment variables Age (per year) Continuous 0.98 0.03 Family history No 1.00 0.07 . Estimates probability of IBTR at 5 and 10 years Yes 1.34 after BCS Initial Radiologic 1.00 0.09 . External validation presentation Clinical 1.39 Nuclear grade Low 1.00 0.25 Intermediate/high 1.30 Necrosis Absent 1.00 0.50

Rudloff U, et al., J Clin Oncol 2010 Present 1.13 Rudloff et al., 2010, J Clin Oncol

DCIS Nomogram DCIS Nomogram MULTIVARIABLEResults ANALYSIS: FACTORS Results ASSOCIATED WITH IBTR NOMOGRAM

Variable Adjusted P value HR Margin status Negative ≥2mm 1.00 0.002 Close/positive 1.73 Number of excisions ≤2 1.00 0.03 ≥3 1.68 Time period 1991-1998 1.00 0.0006 1999-2006 0.57 Radiation therapy Yes 1.00 <0.0001 No 2.67 Endocrine therapy Yes 1.00 0.003 No 2.11 Rudloff et al., 2010, J Clin Oncol

11 4/23/2021

DCIS NOMOGRAM EXTERNAL ACTIVE SURVEILLANCE in DCIS

VALIDATIONS TRIAL COMET LORIS LORD LORETTA US UK Netherland JCOG s Japan Author Year Institution AUC/C-index Design RCT RCT Patient Single arm Yi 2012 MDACC 0.63-0.65 preference Univ Hosp Leuven Age >40 >48 >45 >40, <75 Sweldens 2014 0.67 Belgium Endocrine Possible Possible Not allowed Tamoxifen Natl Cancer Centre Rx Wang 2014 0.67 Singapore Primary 2,5,7 yrs 10 yrs 10 yrs 5,10 yrs Collins 2015 Harvard 0.68 outcome Opened 2017 2014 2017 2017

Target 1200 Closed 1240 340 (accrual (600) 166 (40) (60) 2020)

PCORI: COMET STUDY

12 4/23/2021

SUMMARY:

 For patients with low risk disease, aggressive therapies have limited absolute benefit  Individualized risk estimation based on clinical/pathologic factors and molecular analysis: Selection criteria for ‘low risk’ in clinical trials (ECOG 5194, RTOG 9804) MSKCC Nomogram PreludeDx Oncotype Dx  The level of acceptable risk to omit hormone or radiation therapy is not defined

13 Learning Objectives

. Establish breast cancer as a malignancy with low alpha/beta ratio

. Review the literature establishing hypofractionated whole breast radiotherapy as the Hypofractionated radiotherapy standard of care for breast cancer: less is more . Describe the experience with ultra-hypofractionated whole breast radiotherapy

Nicolas D. Prionas, MD PhD . Define which patients are most appropriate for partial breast irradiation Department of Radiation Oncology University of California, San Francisco . Review the variable cosmetic outcomes with partial breast irradiation 4/23/2021

Outline

. Radiobiology . PBI (EBRT) ‐ Alpha/beta of breast cancer ‐ NSABP B39 ‐ Florence Trial . Hypofractionated whole breast RT ‐ RAPID ‐ UK START Pilot ‐ OCOG/Whelan ‐ IMPORT LOW Radiobiology ‐ UK START A&B ‐ TROG 07.01 . PMRT ‐ Chinese hypofractionated trial . Ultra hypofractionated whole breast RT ‐ UK FAST ‐ UK FAST FORWARD

1 | [footer text here] Linear Quadratic Model UK START Pilot

. 1986-1998; N=1410; T1-3 N0-1

. Arms: 50 Gy (2Gy/fx), 39 Gy (3 Gy/fx), 42.9 Gy (3.3 Gy/fx)

. Primary endpoint: late change in breast appearance

𝜶 ~𝟑𝑮𝒚 𝜷

Gunderson, Tepper, editors. Clinical Radiation Oncology. 3rd ed. 2012 Yarnold el al, Radiation Oncology 2005

Breast Cancer 𝛼/𝛽2.88

8 Qi XS, White J, Li XA. Is α/β for breast cancer really low? Radiother Oncol. 2011 Aug;100(2):282-8.

2 | [footer text here] Trial Years Pts Dose (Fraction Size) Local Recurrence (10 yr) OS 50 Gy/25 fx (2 Gy) 12.1% RMH/GOC 1986-1998 1410 42.9 Gy/13 fx (3.3 Gy) 9.6% No diff. 39 Gy/13 fx (3 Gy) 14.8%

50 Gy/25 fx (2 Gy) 7.5% OCOG 1993-1996 1234 No diff. Whole breast irradiation 42.5 Gy/16 fx (2.66 Gy) 7.4% 50 Gy/25 fx (2 Gy) 7.4% START A 1998-2002 2236 41.6 Gy/13fx – 5 wks (3.2 Gy) 6.3% No diff. 39 Gy/13 fx – 5 wks (3 Gy) 8.8% 50 Gy/25 fx (2 Gy) 5.5% No diff. START B 1999-2001 2215 40 Gy/15 fx – 3 wks (2.67 Gy) 4.3%

Yarnold el al, Radiation Oncology 2005; Haviland et al, Lancet 2013; Whelan et al, NEJM 2010

Hypofractionation - ASTRO Consensus Freedom from marked Trial Years Pts Dose (Fraction Size) P-value change (5⍭ or 10 yr) 50 Gy/25 fx (2 Gy) 90.2% RMH/GOC 1986-1998 1410 42.9 Gy/13 fx (3.3 Gy) 84.4% <0.001 39 Gy/13 fx (3 Gy) 93.4% 50 Gy/25 fx (2 Gy) 71.3% OCOG 1993-1996 1234 NS 42.5 Gy/16 fx (2.66 Gy) 69.8% 50 Gy/25 fx (2 Gy) 60.1%⍭ START A 1998-2002 2236 41.6 Gy/13fx – 5 wks (3.2 Gy) 58.4%⍭ NS 39 Gy/13 fx – 5 wks (3 Gy) 66.1%⍭ 50 Gy/25 fx (2 Gy) 60.6% NS START B 1999-2001 2215 40 Gy/15 fx – 3 wks (2.67 Gy) 65.6%

UK START B – photographic change - 42.2% vs 36.5% favoring Hyporactionation

Yarnold el al, Radiation Oncology 2005; Haviland et al, Lancet 2013; Whelan et al, NEJM 2010

3 | [footer text here] TROG 07.01 UK FAST

. 2007-2014; N=1608; 5-yr results . 2004-2007; N=915; 10-yr results . Arms: 28.5 Gy or 30 Gy/5 fx (once weekly) vs 50 Gy/25 fx . Non-low risk DCIS ‐ <50 yo . >50 yo, T1-2 (<3 cm), N0 . Primary endpoint: photographic breast ‐ >50 yo and palpable, multifocal, >1.5 cm, grade 2-3, necrosis, comedo histology, Outcome Conventional Hypofx P-value appearance margin <10 mm 5-yr FFLR 94% 94% NS No Boost Boost

. Arms: 5-yr FFLR 93% 97% <0.001 Fibrosis 6% 15% NS ‐ 50 Gy / 25 fx vs 42.56 Gy / 16 fx ‐ +/- boost (16 Gy / 8 fx)

. Primary endpoint: time to local recurrence

13 Chu et al. SABCS 2020. Brunt et al. Ten-Year Results of FAST: A Randomized Controlled Trial of 5-Fraction Whole-Breast Radiotherapy for Early Breast Cancer. J Clin Oncol. 2020; 38:3261-3272.

UK FAST – Increased risk of induration UK FAST FORWARD

. 2011-2014; N=352; 5-year follow-up

. >50 yo, T1-2 (<3 cm), N0

. Arms: 40 Gy/15 fx vs 27 Gy or 26 Gy/5 fx (one week)

. Primary endpoint: IBTR

. More breast induration and edema with hypofx

15 FAST Trialists group, Agrawal RK et al. First results of the randomised UK FAST Trial of radiotherapy hypofractionation for treatment of early breast cancer (CRUKE/04/015). Radiother Oncol. 2011 Jul;100(1):93-100.

4 | [footer text here] Outcome 40 Gy 27 Gy 26 Gy P-Value Induration 0.8% 2.3% 1.6% 0.013 Edema 1.5% 3.4% 2.4% 0.032 Partial breast irradiation Marked 20.4% 27.5% 24.7% 0.048 hardness

ASTRO APBI Consensus Guidelines Accelerated Partial Breast Irradiation – NSABP B-39

. 2005-2013; N=4216

. <3.0 cm, 0-3 nodes (DCIS allowed) ‐ 24% DCIS, 65% pN0, 10% pN1

. Arms ‐ Traditionally fractionated whole breast (50 Gy/25 fx) +/- boost ‐ APBI (34-38.5 Gy/10 fx bid, brachy or EBRT)

. 10 year outcomes favor WBI ‐ Cumulative incidence of IBTR (3.9% vs 4.6%) ‐ Recurrence free interval (93.4% vs 91.8%, p=0.02) ‐ No difference in DDFI or OS

. Toxicity Equivalence CANNOT be concluded. ‐ Any grade 3 toxicity (10% APBI vs 7% WBI) ‐ No difference in patient or MD scored cosmesis

Correa et al. Accelerated Partial Breast Irradiation: Executive summary for the update of an ASTRO Evidence-Based Consensus Statement. Pract Radiat Oncol. 2017 Mar - Apr;7(2):73-79. PMID: 27866865. Vicini et al. Long-term primary results of accelerated partial breast irradiation after breast-conserving surgery for early-stage breast cancer: a randomised, phase 3, equivalence trial. Lancet. 2019

5 | [footer text here] Florence Trial Accelerated Partial Breast Irradiation – RAPID Trial . 2006-2011; N=2135 . 2005-2013; N=520

. <3.0 cm, node negative (micromets allowed) . >40 yo, IDC <2.5 cm, 0-3 nodes (85% pN0) ‐ 82% invasive, 70% <1.5 cm, 99% pN0, 90% ER+

. Arms . Arms ‐ 50 Gy in 25 fx whole-breast ‐ 50 Gy /25 fx OR 42.5 Gy/16 fx +/- boost ‐ 30 Gy in 5 fx APBI qod ‐ 38.5 Gy/10 fx bid (brachy or EBRT)

. 10-year outcomes . 8 year outcomes ‐ Cumulative incidence of IBTR (2.5%, 3.7%) ‐ Cumulative incidence of IBTR (3.0% APBI vs 2.8% WBI) ‐ OS 91.9% in both ‐ No difference in DFS or OS ‐ CSS (96.7%, 97.8%)

. Toxicity . Toxicity ‐ Acute grade 2+ (28% APBI vs 45% WBI) Non-inferiority confirmed. ‐ APBI had less acute and late toxicity ‐ Late grade 2+ (32% APBI vs 13% WBI) ‐ APBI had better cosmesis rated by patient and MD ‐ 7-year, nurse-reported fair-poor cosmesis more common with APBI (36% vs 19%)

Whelan et al. External beam accelerated partial breast irradiation versus whole breast irradiation after breast conserving surgery in women with ductal carcinoma in situ and node-negative breast cancer (RAPID): a randomised controlled trial. Lancet. 2019.

IMPORT LOW (Lancet 2017) Local Recurrence . 2007-2018; N=674 Trial Years Pts Dose (Fraction Size) OS (5⍭ - 10 yr) 50 Gy/25 fx (2 Gy) . >50 yo, IDC <3 cm, 0-3 nodes (97% pN0) [N=674] 3.9% NSABP B39 2005-2013 4216 38.5 Gy/10 fx bid (3.85 Gy) No different 4.6% 34 Gy/10 fx bid (3.4 Gy) brachy . Arms (all in 15 fx) ‐ 40 Gy whole-breast 50 Gy/25 fx (2 Gy) 2.5% No different Florence 2005-2013 520 ‐ 36 Gy whole breast and 40 Gy partial breast 30 Gy/5 fx qod (6 Gy) 3.7% ‐ 40 Gy partial breast 50 Gy/25 fx (2 Gy) or 2.8% RAPID 2006-2011 2135 42.56 Gy / 16 fx (2.66 Gy) No different . 5-year outcomes 3.0% ‐ Cumulative incidence of IBTR (1.1%, 0.2%, 0.5%) 38.5 Gy/10 fx bid (3.85 Gy) 40 Gy/15 fx (2.67 Gy) 1.1%⍭ ⍭ No different . 5-year toxicity (patient reported) favors PBI IMPORT Low 2007-2010 674 36 Gy/15 fx (2.67 Gy) 0.2% ⍭ ‐ Appearance changes (47.7%, 36.7%, 35.1%) Non-inferiority confirmed. 40 Gy/15 fx PBI (2.67 Gy) 0.5% ‐ Firmness (35.3%, 21.0%, 15.3%)

Yarnold el al, Radiation Oncology 2005; Haviland et al, Lancet 2013; Whelan et al, NEJM 2010

6 | [footer text here] NCCN - APBI Freedom from marked Trial Years Pts Dose (Fraction Size) P-Value change (5⍭ or 10 yr) 50 Gy/25 fx (2 Gy) Cosmesis similar (patient) NSABP B39 2005-2013 4216 38.5 Gy/10 fx bid (3.85 Gy) P<0.05 APBI cosmesis worse (MD) 34 Gy/10 fx bid (3.4 Gy) brachy SIMILAR/WORSE

50 Gy/25 fx (2 Gy) 85.4% Florence 2005-2013 520 BETTER P=0.001 30 Gy/5 fx qod (6 Gy) 100% (patient report)

50 Gy/25 fx (2 Gy) or 81% RAPID 2006-2011 2135 42.56 Gy / 16 fx (2.66 Gy) WORSE P=0.001 64% 38.5 Gy/10 fx bid (3.85 Gy) 40 Gy/15 fx (2.67 Gy) 52.3%⍭ BETTER IMPORT Low 2007-2010 674 36 Gy/15 fx (2.67 Gy) 63.3%⍭ P=0.007 40 Gy/15 fx PBI (2.67 Gy) 64.9%⍭

Hypofractionated PMRT – Chinese trial

. Post-mastectomy, T3-4N2-3 (N=820)

. 6-9 MeV, 5 mm bolus

. Arms ‐ Conventional (50 Gy / 25 fx) Post-Mastectomy Radiotherapy ‐ Hypofx (43.5 Gy / 15 fx) . Median follow-up 58.5 months

. 5-year local recurrence (8.3 vs 8.1%)

. No difference in overall toxicity ‐ Except less acute grade 3 skin toxicity (8 vs 3%)

7 | [footer text here] FABREC trial – Hypofractionated PMRT after reconstruction Conclusions

. T1-3N+ s/p mastectomy with immediate expander/implant reconstruction . Alpha-beta ratio for breast cancer is low (~3 Gy).

. Hypofractionated whole breast radiotherapy is the standard of care for all patients where WBI is . Arms; Post-mastectomy RT +/- IMNs indicated. ‐ Conventional: 50 Gy / 25 fx ‐ Hypofx: 42.56 Gy / 16 fx (39.9 Gy / 15 fx to SCV) . Hypofractionated WBI improves cosmesis.

. Ultra-hypofractionated regimens exist, but may have worse induration and should be employed carefully . Outcome measures (elderly, low KPS). ‐ Primary: patient reported, 6 month physical well being ‐ Secondary: Oncologic, clinical, and cosmetic . ASTRO APBI suitable patients are >50 yo, Tis or T1 (<2.5 cm), node negative, ER+, resected with negative margins.

. External beam APBI regimens are an option, but cosmetic outcomes are controversial.

Canadian Hypofractionation (OCOG 93010)

. 1993-1996; N=1234

. T1-2N0 s/p lumpectomy + ALND, surgical margins(-)

. Separation <25 cm

. Arms: 42.56Gy/16fx vs 50Gy/25fx (no boost)

. No difference in LR (~6%), DFS, or cosmesis @10 yr

. Good to excellent cosmesis (69.8% vs 71.3%), low grade 3 skin toxicity (2.5% vs 2.7%)

32 Whelan et al. JNCI 2002, NEJM 2010.

8 | [footer text here] UK START B MD Anderson Hypofractionation

. 1999-2001 . N=2215 women . pT1-3N0-1 (89.7% T1, 75.2% pN0) . Patients who were not well represented on other trials . 7.7% mastectomy • N=287 . START A – 39Gy/13fx vs 41.6Gy/13fx vs 50Gy/25fx (optional 10 Gy boost, 61%) • 76% were overweight or obese . START B – 40Gy/15fx vs 50Gy/25fx (optional 10 Gy boost, 43%) • 70.3% C cup or larger . Physician assessed cosmesis . Breast shrinkage, telangiectasia, and edema less with hypofx . 42.5Gy/16fx vs 50Gy/25fx + boost

@10 years 40 Gy 50 Gy . At 6 months LR 3.8% 5.2% ‐ Hypofx had less dermatitis, pruritis, breast pain, fatigue, lack of energy and LRR 4.3% 5.5% trouble meeting family needs DR 12.3% 16.0%* All‐cause mortality 15.9% 19.2%*

33 Haviland et al. Lancet Onc. 2013.

9 | [footer text here] Acknowledgements Radiology • Scott Graham Breast Cancer Advocates • Nola Hylton • Chloee Wendorf • Susie Brain • Dian Heditsian • Bonnie Joe • Michael White • MRI and PET Imaging Markers For Kim Ray • Jim Slater Funding Support • Deep Hathi • Salma Javin • Mt. Zion Health Fund Prediction of Treatment Response in • Margarita Watkins • Henry VanBrocklin • Breast Oncology Program • Wen Li Breast Care Center • Breast Cancer Patients • David Newitt Give Breast Cancer a Boot • Laura Esserman • Youngho Seo • Susan G. Komen SAC110017 Ella F. Jones, PhD • Rita Mukhtar • Ben Franc • NIH/NCI U01CA151235 [email protected] • Jo Chien • Rob Flavell • NIH/NCI P01CA210961 • Ruby Gao 4/20/2021 • Miguel Pampaloni • NIH/NCI R01CA227763 • Julissa Melina‐Vega • Courtney Lawhn‐Heath • DOD W81XWH‐18‐1‐0671 Breast cancer patients and their families 4/20/2021 2

Learning objectives Neoadjuvant chemotherapy (NAC) in breast cancer National Surgical Adjuvant Breast and Bowel Project (NSABP): protocol B‐18 and B‐27 . How imaging markers are used in the neoadjuvant treatment trial . No difference in disease‐free survival or overall survival in patients . MRI markers for the prediction to treatment response and recurrence receiving neoadjuvant chemotherapy with AC or AC + taxane compared to free survival those receiving adjuvant therapy

. Use of PET molecular imaging markers to inform assess early treatment . Opportunities Clinical Trial Model response and drug selection • Assess the intact primary tumor and refine treatment • Understand tumor biology in responseAdjuvant to treatment Neoadjuvant • DevelopEndpoint new tools for prognosticSurvival assessment Primary tumor • Accelerate new drug development response Timeline Years (5‐20) Months

Rastogi et al., JCO, 2008

3 4

1 4/20/2021 [ADD PRESENTATION TITLE: INSERT TAB > HEADER & FOOTER > NOTES AND HANDOUTS] Contrast‐enhanced MR Imaging I‐SPY 1/ACRIN 6657 PI: Esserman and Hylton Pre‐contrast (t ) t Functional tumor volume 0 1 t2 . Functional tumor volume (FTV) has been used to pCR and RCB monitor treatment response in breast cancer patients Anthracycline (AC) Taxane (T)

. Using a three‐time point acquisition strategy (t0,t1 MR1 MR2 MR3 MR4 and t2) at the time of contrast injection, a signal‐ enhancement‐ratio (SER) map is generated . FTV is the sum of all the voxels meeting the FTV1 FTV2 FTV3 FTV4

enhancement threshold in the SER map pCR = pathologic complete response RCB = residual cancer burden Hylton, Magn Reson Imaging Clin N Am. 1999 Hylton et al., Radiology, 2012

5 6

I‐SPY 1/ACRIN 6657 Key Findings I‐SPY 2 TRIAL PI: Esserman & Berry . MRI volume (FTV) was a strong Investigation of Serial Studies to Predict Your Therapeutic Response with Imaging And MoLecular Analysis predictor of pCR and RCB at all FTV2 time point • I‐SPY 2 is a response‐ adaptive phase II trial testing . FTV was a stronger predictor of novel agents for breast recurrence free survival (RFS) cancer than pCR • Drugs “graduate” from I‐SPY 2 when they reach a . FTV2 had the highest overall C Bayesian predictive statistic when combined with probability of achieving 85% RCB success in a subsequent 300‐ patient phase III trial . FTV (highest quartile cut point) >3000 patients registered • MRI response is used to discriminate differences in >1500 patients completed surgery adjust patient randomization 14 agent combinations completed survival outcomes and the ratio and to estimate the 7 drug graduated FTV4 predictive probabilities optimal timing of MR imaging Hylton et al., Radiology, 2012 measurement differ by subtype Hylton et al., Radiology, 2016

7 8

2 4/20/2021 [ADD PRESENTATION TITLE: INSERT TAB > HEADER & FOOTER > NOTES AND HANDOUTS] Forego chemo for Dedicated breast PET (Db‐PET) I‐SPY 2.2 Schema excellent responders

. Imaging of the primary breast tumor during treatment can provide critical prognostic and predictive Randomization Surgery information . High sensitivity of dbPET can detects tumors at low dose of radiotracers (൑5 mCi) allowing longitudinal studies with minimum radiation exposure . A 39-year-oldHigh‐resolution breast imaging capability from dedicated breast PET, we will be able to captureDbPET early treatment was cancerresponse patient as well with as high quality imaging features that are of prognostic value able to resolve an agglomerate of the agglomerate Pre‐NAC (T0) Early‐NAC (T1)Mid‐NAC (T2) Post‐NAC (T3) ER+/PR+/HER2+ highlighting the tumors imaged by multifocality and 18 [ F]FDG-wbPET at heterogeneity of dbPET dbPET Randomize to targeted treatment the pre-treatment the primary for poor responders timepoint. tumor.

9 wbPET dbPET 10

Initial experience with FDG‐dbPET Initial experience with dbPET . Patient characteristics 32 yo female BRCA 1 carrier with a 2 lesions in the right and 1 in the left • 32 yo female BRCA 1 carrier with 3 biopsy confirmed lesions TN . 2 lesions in the right breast SUVmax • ER+/PR‐, HER2‐ Overall FTV TN: 19.5 73.2 cc ER+: 19.1 • Triple negative (TN) ER+ . 1 lesion in the left breast • Triple negative (TN) Overall FTV SUVmax . A dose of 5 mCi of FDG was administered and the patients was imaged in 89.5 cc TN: 15.3 the prone position at 45 min post‐injection MRI examinations at later time points showed a more dramatic response to therapy in the TN tumor and near complete 11 12pathologic response was documented at mastectomy Jones et al., Clinical Breast Cancer, 2017

3 4/20/2021 [ADD PRESENTATION TITLE: INSERT TAB > HEADER & FOOTER > NOTES AND HANDOUTS] Results Early detection of treatment response dbPET DCE‐MRI Patient Characteristics 3 weeks of Tx 3 weeks of Tx 100 100 Pre‐treatment 30 30 Age 42.5 ABC mean (range) (29‐63) Subtype

HR+/HER2‐ 4 _T0 _T1

HR+/HER2+ 2 Responder SUVmax SUVmax HR‐/HER2+ 1 %Chg MTV0_1 %Chg SUVmax0_1 TN 5 D E F Ki67 47.8 0 0 ‐100 -100 mean (range) (17.5‐80.0) ≤1 >1 ≤1 >1 ≤1 >1 ≤1 >1 RCB RCB RCB≤1 (pCR) 7 RCB RCB responder RCB>1 (non‐pCR) 3 Non ‐

13 14

FES for imaging ER+ breast cancers Whole body FES‐PET of ER+ breast cancers ~70% breast cancers are ER+ 18F-FES PET imaging of 33 patients to evaluate • Equivocal lesions FDA APPROVED • ER status in metastatic disease Estradiol [18F]Fluoroestradiol • Origin of metastases A form of estrogen (FES) • 18F-FES PET improved diagnostic understanding in 88% of the patients and • FES was developed for PET imaging of ER status led to therapy change in 48% of the patients • Earlier clinical studies show that FES uptake in tumor correlates with the level of ER expression in biopsy samples and is predictive to endocrine treatment response Bone scan FES‐PET • These initial findings substantiate the utility of FES‐PET as an in vivo assay to select appropriate treatment for ER+ patients

15 16 Minturn et al., Radiology, 1988 Kruchten et. al JNM, 2012

4 4/20/2021 [ADD PRESENTATION TITLE: INSERT TAB > HEADER & FOOTER > NOTES AND HANDOUTS] FES‐PET Imaging of ER+ Breast Cancer Initial experience of FES‐dbPET imaging Response to tamoxifen, fulvestrant, aromatase inhibitor (AI) . Patients with biopsy confirmed ER+ (>90%) and HER2‐ breast cancers were imaged with dbPET and standard breast dynamic contrast‐ enhanced magnetic resonance imaging (DCE‐MRI) . A dose of 5 mCi of FES was administered and patients were imaged in the prone position at 45 min post‐injection

Linden et. al Clin. Cancer Res., 2011 Jones et al., NPJ Breast Cancer, 2019

17 18

Results Pre‐treatment ILC Pre‐treatment IDC FES‐dbPET Imaging of patients >90% ER+ . Todate,wehaveimaged DCE‐MRI FES‐dbPET DCE‐MRI FES‐dbPET 14 breast cancer patients with >90% ER+ and HER2‐ using [18F]FES‐dbPET ACABB Patient A Patient C . Patient age ranged from 23 to 76, with a range of Ki67 from 1 to 30%

Patient D . While all patients have Patient B >90% ER+, they exhibit Patient C: Well circumscribed Diffused FES uptake pattern in ILCs different imaging pattern pattern in IDC Patient D: No FES uptake due to SUVmax = 15.83 SUVmax = 5.02 prior treatment with tamoxifen

19 20

5 4/20/2021 [ADD PRESENTATION TITLE: INSERT TAB > HEADER & FOOTER > NOTES AND HANDOUTS] FES‐dbPET Imaging of Response Summary Patient #1 . MRI FTV is a reliable marker to monitor neoadjuvant treatment response A B C . The use of FDG‐dbPET along with breast MRI may present an opportunity to guide earlier treatment redirection . FES‐dbPET has varying FES uptake pattern in ILC and IDC ER+ breast cancer diseases . SUVmax = 15.83 SUVmax = 6.11 Baseline FES‐uptake may inform treatment planning for ER+ breast cancer. Treatment induced change of FES‐uptake can be used to inform response and Patient #2 F subsequent treatment DEF

21 SUVmax = 35.24 SUVmax = 6.35 22

Future directions

. In addition to FTV, MRI background parenchymal enhancement and apparent THANK YOU diffusion coefficient from diffusion weighted imaging are currently being explored as multivariate predictors . Compare FDG‐dbPET with MRI for assessing the early detection of treatment response . FES uptake to inform treatment selection in ER+ breast cancers. FES‐dbPET will also be used assess the efficacy of new selective ER degrader (SERD) Montgomery Street . Invasive lobular carcinoma is mostly ER+, we believe that FES‐dbPET uptake will provide important information of this breast cancer subtype . The high spatial resolution of dbPET and MRI may afford high quality radiomic features to correlate with molecular signatures to inform tumor biology Women’s Imaging Center

6 4/20/2021 [ADD PRESENTATION TITLE: INSERT TAB > HEADER & FOOTER > NOTES AND HANDOUTS] 4/22/2021

General Skin Guidelines No Standard of Care

• Cleanse Skin Care Interventions that • Mild Soap and water; Dove TM, Neutrogena TM, skintegrity spray TM • Pat the skin dry make a difference • No rubbing, No wash cloths, no exfoliation • Moisturize Florence Yuen, RN, AOCNP, CWCN‐AP • Avoid irritants (alcohol, gels, lanolin, tea tree oil) • NO TAPE • Protect the skin from sun and friction • Deodorant/Antiperspirant use ALLOWED

Herst et al 2014 Wooding et al 2017 Morgan 2014 (Mepitel film ) (Mepitel film ) (Mepitel film) Prevention and Reduction of Severe Radiation Skin Reactions Randomized phase 3, clinical Feasibility Study Descriptive/Case reports • Multinational Association For • Mepitel film trial Supportive Care in Cancer • High potency topical steroid 78 (Breast) patients 36 (Head & Neck) patients 3(Breast) external beam photon (MASCC) Skin Group 2013 cream External beam from China and New Zealand external beam IMRT • Oncology Nursing Society (ONS) 2020 ‐No moist desquamation ‐Up to 37% decreased rates of ‐Significant reduction in ‐92% reduction in skin moist desquamation dermatitis reactions ~28% reduction in skin ‐Duration of reactions ‐Easy to apply reaction decreased. ‐Negligible bolus effect ‐Facial stubble decreased Support Care Cancer: 2013 Oct 21, (10) 2933‐48 when left in place for adherence of the film ONF 2020, 47(6) 654‐670 treatment. ‐Higher overall treatment ‐Replaced weekly as needed dose ~60 Gy

1 4/22/2021

Mepitel Film Mepitel Film TM 5 Weeks 50 Gy

No other skin care required if the film is in place Advantages Dis‐advantages Should be smooth with no bubbles • Can be effective in preventing and • Does not always stay in place Replace every 7 to 10 days decreasing the severity of moist Leave in place if it not lifting • Potential moisture trapping Should be smooth with no bubbles desquamation Remove if moderate erythema, puritis or • Reduces friction • Application rash develops beneath • Decreases evaporative losses • Acquisition • No additional skin care required if • Molynecke xrt site is covered • Improved sense of satisfaction among patient

A Randomized Trial of Mometesone furoate 0.1% Prophylactic treatment with a potent Mometesone Furoate Cream Reduces acute corticosteroid cream ameliorates radiodermatitis, Radiation Dermatitis in Patients Receiving Breast independent of radiation schedule. Radiation Therapy: Results of a Randomized Trial to Reduce High Grade Acute Radiation Dermatitis • N =202, simple mastectomy & • N= 120, BCS and chest wall in Breast Cancer Patients Receiving Post BCS, randomized • Daily mometesone cream Mastectomy Radiation. • Applied from start to radiation for • daily betamethasone cream vs 5 weeks or until moist 124 patients 68 % reconstructed BID essex cream desquamation Moist desquamation was ~55% in the entire cohort. • MF significantly reduced incidence of 43.8% vs 66.7% compared to control cream (Eucerin) • Both arms had benefit Reduced skin toxicity scores. MF arm had a lower incidence of maximum skin toxicities and longer time to development of grade 3 • Moist desquamation in 4.8% vs 15.5% • 61 (steroid) vs 141 (control) dermatitis • Reduced impairment of quality of BID application day 1 to 14 days post treatment or development of moist desquamation patients developed significant life (Dermatology Life Quality reactions. Index) Conclusions: Breast cancer patients receiving MF during PMRT experienced significantly reduced rates • Hypo‐fractionated patients of moist desquamation in comparison with a control cream. developed less skin reactions vs standard A. Ho et al. Int J Rad Oncol Biol Phys 2018;101;325‐333 Hindley, A et al. Int J of Radiation Oncology Biology Physics Ulff E. et al Radiother Oncol. 2017;122(1)50 2014;vol 90(4), 748‐755

2 4/22/2021

Mometesone 0.1% “Manuka” Honey Hypo‐fractionation 40 Gy w/ daily bolus Leptospermum Scoparium

• low pH (acidic) and high osmolarity hinders microbe growth • Facilitates wound hydration • Anti‐inflammatory • Antibacterial effect against gram‐positive, gram‐negative, anaerobes and MRSA • No resistance to date • Autolytic debridement (desquamation) Mometesone daily (pm)/moisturizer (day)and • Wound and burn literature—improved faster healing and scarring vs silvadene skintegrity spray Start of treatment and 1 week post (week 4)

Ref: Hixon, K. et al. 2019. Advances in wound care. A critical review and perspective of honey in tissue engineering and Ref: Ho, A. 2018 (J.ijrobp). Randomized trial of mometasone 0.1% to reduce high grade clinical wound healing. dermatitis in breast cancer patients receiving PMRT. Ref: Jull AB et al. 2015 Honey as a tropical treatment for wounds. Cocharan Database

Manuka Honey Application Risk Stratification

• Lower Risk • Higher Risk • Smaller breast size (50Gy • Use of bolus/sensitizers • PMRT • Reconstruction • Fungating mass

3 Learning Objectives

1. Understand the role of pathologic and molecular predictors of in-breast Breast Cancer Case-based tumor recurrence for the treatment of DCIS. 2. Define the current role and risks of partial breast irradiation in primary and Learning Session recurrent early stage breast cancer. 3. Specify basic constraints and associated toxicities for IMRT/VMAT for Moderator: breast/chest wall radiotherapy. Nicolas Prionas, MD PhD 4. Understand the potential efficacy of hypofractionated post-mastectomy Panelists: radiotherapy. Catherine Park, MD, Ella Jones, MD, Olivier Morin, PhD 5. Discuss the role of radiotherapy after complete response to neoadjuvant 4/23/2021 chemotherapy and review enrollment criteria for ongoing trials.

Case 1 – DCIS Work-up

. 60 yo woman, otherwise healthy . Bilateral screening mammogram followed by left diagnostic mammogram. No palpable finding. . Gyn Hx ‐ Age at menarche: 13 - Breast fed: 2 months . Fine pleomorphic calcifications in the upper ‐ Age at menopause: 50 - Birth Control Pills: 2 years outer left breast, spanning 3 cm (BI-RADS 4) ‐ Gravida/Para: G3P2 - Hormone Replacement Therapy: none ‐ Age at first delivery: 27 - Prior mammograms: all negative . Stereotactic core biopsy ‐ Intermediate-high grade DCIS . Family Hx: ‐ Post-biopsy mammogram showed clip ‐ Mother with breast CA and recurrence after Tamoxifen x5 years (died of displaced by 0.7 cm other causes)

1 | [footer text here] Artificial Intelligence/Machine Learning in Breast Cancer Screening AI System for Breast Cancer Screening

Discussion . What is the current role of AI/ML in breast cancer screening?

. How can AI best be incorporated into the Diagnostic Radiology work-flow?

USA UK False positive reduction 5.7% 1.2% False negative reduction 9.4% 2.7%

• In UK, AI reduced workload of second reader by 88%.

McKinney, S.M., Sieniek, M., Godbole, V. et al. International evaluation of an AI system for breast cancer screening. Nature 577, 89–94 (2020). https://doi.org/10.1038/s41586-019-1799-6

Breast MRI for DCIS - example Phase 1 Phase 2 Phase 3

Discussion . How do you approach the interpretation of breast MRI for DCIS?

Phase 4 Phase 5 Phase 6

2 | [footer text here] Surgery Post-op complications

. Left lumpectomy #1, wire-localized: ‐ 4.5 x 2.0 x 6.5 cm specimen. . Post-operative course was ‐ Intraop specimen imaging showed the wire, but no complicated by recurrent biopsy clip. hematoma requiring drainage, ‐ Pathology negative. Biopsy site change was not identified. packing, and ultimately wound- vac. . Left lumpectomy #2, Magseed-guided: ‐ High grade DCIS, measuring 0.6 cm. ‐ Comedonecrosis present . She re-presented for ‐ Margins within 0.1 cm medially. radiotherapy 2 months post- ‐ ER+ (strong, >98%), PR+ (weak to strong, 80%) ‐ Her2 negative by FISH (1.2 Avg ratio Her2:Cent17) operatively.

SACME1: For completely resected (margins >2 mm) high grade SACME1: For completely resected (margins >2 mm) high grade DCIS, <1 cm in size, what would you cite as the 12-year risk of any DCIS, <1 cm in size, what would you cite as the 12-year risk of any in-breast tumor recurrence without adjuvant therapy? in-breast tumor recurrence without adjuvant therapy?

A. <5% A. <5% B. 10-15% B. 10-15% C. 20-30% C. 20-30% D. 50% D. 50% E. 75% E. 75%

3 | [footer text here] Predictors of invasive Prognostic nomograms/calculators recurrence after DCIS Scoring system 123 . Van Nuys Prognostic Tumor size (mm) ൑ 15 16-40 ൐ 40 - Race (African American) Index Margin (mm) ൐ 10 1-9 ൑ 1 Path/grade Grade 1- Grade 1- Grade 3 +/- - Premenopausal 2/Necrosis- 2/Necrosis+ necrosis Age >60 40-60 <40 - Palpable Overall Score 4-6 7-9 10-12 10-year LR 1% 20% 50% -High grade 10-year RFS 97% 73% 34% . MSKCC Nomogram - Necrosis ‐ Age, Family Hx, palbability, grade, No Tx Endocrine RT Endocrine + RT - p16 high 10 year necrosis, margins, re- 30% 16% 13% 6% IBTR -Her2+ excision, era of surgery,

Silverstein MJ. The University of Southern California/Van Nuys prognostic index for ductal carcinoma in situ of the breast. Am J Surg. 2003 Oct;186(4):337-43. Predictors of an Invasive Breast Cancer Recurrence after DCIS: A Systematic Review and Meta-analyses. Visser et al. Cancer Epidemiol Biomarkers Prev. May 1 2019 Nomogram for Predicting the Risk of Local Recurrence After Breast-Conserving Surgery for Ductal Carcinoma In Situ. Rudloff et al. J Clin Oncol. 2010 Jul 12.

Omission of Radiotherapy for DCIS DCIS - EBCTCG

. ECOG-ACRIN E5194 (2009, update 2015): ‐ Single arm trial (lumpectomy w/o RT) ‐ 2 cohorts (tamoxifen used by ~30%) . DCIS G1-2, size <=2.5cm, margins >=3mm (12 year IBTR 14%) . DCIS G3, size <=1cm, margins >=3mm (12 year IBTR 25%)

. RTOG 9804 (2015) ‐ RCT lumpectomy +/- RT (tamoxifen in ~60%) ‐ DCIS G1-2, size <=2.5cm, margins >=3mm ‐ Closed due to poor accrual (n=636 of 1790 planned) ‐ 12-year IBTR (11% vs 3%)

Solin et al. Surgical Excision Without Radiation for Ductal Carcinoma in Situ of the Breast: 12-Year Results From the ECOG-ACRIN E5194 Study. J Clin Oncol. 2015 Nov 20;33(33):3938-44. EBCTCG. Overview of the Randomized Trials of Radiotherapy in Ductal Carcinoma In Situ of the Breast. J Natl Cancer Inst Monogr. 2010 Oct.

4 | [footer text here] Oncotype DCIS OncotypeDCIS – Our patient

. 12 gene assay

. Developed from DCIS cases from NSABP B14, NSABP B20, Kaiser, Genomic Health, Marin General

. Applied to ECOG E5194 patients, validated on Ontario DCIS cohort

. 10-year risk of ipsilateral breast event ‐ Low grade – 10.6% ‐ Intermediate grade – 26.7% ‐ High grade – 25.9%

Solin et al. A multigene expression assay to predict local recurrence risk for ductal carcinoma in situ of the breast. J Natl Cancer Inst. 2013 May 15;105(10):701-10.

Gene expression assays in DCIS Combining Oncotype DCIS and Clinicopathologic Features

. Combined analysis of ECOG 5194 and Ontario DCIS cohort [N=773] Discussion . Excluded positive margins and multifocality . How do you currently incorporate gene expression assays (e.g. OncotypeDCIS) into treatment decisions for DCIS?

. Does the use of gene expression assays and recurrence risk scores have a role in risk-adapted imaging surveillance of DCIS?

. Do gene expression assays add value to a Medomics profile, beyond clinicopathologic information, to help predict outcomes and adapt management?

Rakovitch, E et al. “Refined estimates of local recurrence risks by DCIS score adjusting for clinicopathological features: a combined analysis of ECOG-ACRIN E5194 and Ontario DCIS cohort studies.” Breast cancer research and treatment vol. 169,2 (2018): 359-369.

5 | [footer text here] 60 yo with left upper outer high grade DCIS (0.6 cm) with SACME2: When comparing accelerated external beam partial breast irradiation close margin and post-op wound complications (38.5 Gy in 10 fractions BID) and hypofractionated whole breast irradiation Discussion (42.5 Gy in 16 fraction), APBI has ______acute grade 2+ toxicity and ______. What are her best treatment options? late grade 2+ toxicity. ‐ Observation A. similar, similar ‐ Endocrine therapy alone B. lower, lower ‐ Traditionally fractionated whole breast RT (50 Gy in 25 fx) +/- endocrine therapy C. higher, higher ‐ Hypofractionated whole breast RT (40.05 Gy in 15 fx) +/- endocrine therapy D. lower, higher

‐ Hypofractionated partial breast RT (40.05 Gy in 15 fx) +/- endocrine therapy E. higher, lower

‐ Accelerated partial breast radiotherapy (38.5 Gy in 10 fx BID) +/- endocrine therapy

SACME2: When comparing accelerated external beam partial breast irradiation DCIS - EBCTCG (38.5 Gy in 10 fractions BID) and hypofractionated whole breast irradiation (42.5 Gy in 16 fraction), APBI has ______acute grade 2+ toxicity and ______late grade 2+ toxicity.

A. similar, similar B. lower, lower C. higher, higher D. lower, higher E. higher, lower

EBCTCG. Overview of the Randomized Trials of Radiotherapy in Ductal Carcinoma In Situ of the Breast. J Natl Cancer Inst Monogr. 2010 Oct.

6 | [footer text here] IMPORT LOW (Lancet 2017) Accelerated Partial Breast Irradiation – RAPID Trial

. Multicenter, randomized, non-inferiority trial . Multicenter, phase 3 RCT, non-inferiority design

. <3.0 cm, node negative (micromets allowed) [N=2135] . >50 yo, IDC <3 cm, 0-3 nodes (97% pN0) [N=674]

. Arms . Arms (all in 15 fx) ‐ Traditionally fractionated whole breast (50 Gy /25 fx OR 42.5 ‐ 40 Gy whole-breast Gy/16 fx) +/- boost ‐ APBI (38.5 Gy/10 fx bid, brachy or EBRT) ‐ 36 Gy whole breast and 40 Gy partial breast ‐ 40 Gy partial breast . 82% invasive, 70% <1.5 cm, 99% pN0, 90% ER+

. Partial breast: Tumor bed + 1.5 cm CTV + 1.0 cm PTV . 8 year outcomes ‐ Cumulative incidence of IBTR (3.0% APBI vs 2.8% WBI) . 5-year outcomes ‐ No difference in DFS or OS ‐ Cumulative incidence of IBTR (1.1%, 0.2%, 0.5%)

. Toxicity . 5-year toxicity (patient reported) favors PBI ‐ Acute grade 2+ (28% APBI vs 45% WBI) Non-inferiority confirmed. ‐ Appearance changes (47.7%, 36.7%, 35.1%) Non-inferiority confirmed. ‐ Late grade 2+ (32% APBI vs 13% WBI) ‐ Firmness (35.3%, 21.0%, 15.3%) ‐ 7-year, nurse-reported fair-poor cosmesis more common with APBI (36% vs 19%)

Accelerated Partial Breast Irradiation – NSABP B-39 ASTRO APBI Consensus Guidelines

. Phase III RCT, equivalence trial

. <3.0 cm, 0-3 nodes (DCIS allowed) [N=4216]

. Arms ‐ Traditionally fractionated whole breast (50 Gy/25 fx) +/- boost ‐ APBI (34-38.5 Gy/10 fx bid, brachy or EBRT)

. 24% DCIS, 65% pN0, 10% pN1

. 10 year outcomes favor WBI ‐ Cumulative incidence of IBTR (4.6% vs 3.9%) ‐ Recurrence free interval (93.4% vs 91.9%, p=0.02) ‐ No difference in DDFI or OS Equivalence CANNOT be concluded. . Toxicity ‐ Any grade 3 toxicity (10% APBI vs 7% WBI)

7 | [footer text here] 60 yo with left upper outer high grade DCIS (0.6 cm) with Ongoing DCIS Trials close margin and post-op wound complications Discussion . LORIS DCIS trial (UK) . COMET trial (US) ‐ Randomized non-inferiority trial ‐ Women age 40 or older . When delivering partial breast irradiation what techniques can ‐ Women age 46 or greater ‐ Low-intermediate grade DCIS Mammographic low-intermediate grade DCIS ‐ ‐ Arms: Active surveillance +/- HT vs Local therapy help with target delineation?  resected (surgery + radiation) +/- HT ‐ Arms: Active surveillance (yearly) vs RT, HT, or both

. How do you account for tissue rearrangement after . LORD (Low-Risk DCIS) trial (EORTC) . Observational studies incorporating reconstruction? ‐ Randomized non-inferiority trial Oncotype DCIS ‐ Women age 45 or greater ‐ Pure low grade DCIS ‐ Arms: Active surveillance vs conventional treatment (WLE, WLE+RT, mastectomy, endocrine therapy)

Case 2 – Recurrence 64 yo with prior left whole breast RT for high grade DCIS, now with in-breast invasive recurrence, cT1cN0, ER+PR+Her2-, Ki67 5% . Our patient undergoes adjuvant left whole breast radiotherapy (50 Gy in 25 fractions) with tangent fields Discussion . What are her best treatment options? . She returns 4 years later with screen-detected in-breast tumor recurrence ‐ Lumpectomy and observation

. Diagnostic mammogram and ultrasound\ ‐ Mastectomy ‐ 1.1 cm spiculated mass ‐ Axilla negative ‐ Lumpectomy and whole breast re-irradiation

. Ultrasound-guided core biopsy ‐ Lumpectomy and partial breast re-irradiation ‐ Invasive ductal carcinoma, 1.1 cm, grade 2, ER+PR+Her2-, Ki67 5%

8 | [footer text here] RTOG 1014 – PBI for reirradiation Case 3 - Locally advanced . Phase 2, single arm, prospective trial . 60 yo woman with palpable mass in left axilla

. Recurrence >1 year after RT, <3 cm in size, 0-3 nodes, margin negative . Ultrasound left axilla: 3.1 x 2.2 x 1.8 cm lymph resection [N=58] node.

. Prior RT: 50 Gy/25 fx . US-guided core biopsy of the left axillary node: ‐ Mammary carcinoma with mucinous and neuroendocrine differentiation, ER+(>95%), . Reirradiation PR+(75%), Her2-, Ki67 30%. ‐ Dose: 45 Gy in 30 fx (1.5 Gy BID) ‐ Target: Cavity + 1.5 cm CTV + 1.0 cm . Diagnostic left mammogram PTV (avoid 5 mm from skin) ‐ Heterogeneously dense breast tissue. ‐ Pleomorphic calcifications in a linear segmental . 5-year cum incidence of recurrence: 5.2% distribution in the outer central left breast spanning 6 cm, extending to the sub-nipple area. . Toxicity: 26.3% Grade 2, 7% Grade 3

Arthur et al. Effectiveness of Breast-Conserving Surgery and 3-Dimensional Conformal Partial Breast Reirradiation for Recurrence of Breast Cancer in the Ipsilateral Breast: The NRG Oncology/RTOG 1014 Phase 2 Clinical Trial. JAMA Oncol. 2020;6(1):75–82.

. MR breast: ‐ 7.5 cm broad swath of non-mass enhancement throughout the 60 yo woman with IDC of the left breast, cT3N3bM0, grade 2, inferolateral quadrant of the left breast. ER+PR+Her2-, receiving neoadjuvant AC-T . MRI-guided vacuum-assisted core biopsy ‐ IDC, grade 2, with LVSI, ER+(>95%), PR+(50%), Her2-, Ki67 5%. Discussion . How do you recommend monitoring response during neoadjuvant treatment? ‐ Modality? • PET/CT • Multiple foci in the left breast (SUV 3.67). ‐ Frequency of imaging? • Axillary lymph nodes in axilla (SUV 12.09) • Internal mammary node (SUV 7.17). • No distant metastases. ‐ Quantification?

• Stage: cT3N3bM0, grade 2, ER/PR+Her2- (Stage IIIB)

• Received neoadjuvant AC-T

9 | [footer text here] If radiographic CR, can biopsy identify those with pCR to avoid surgery? Mastectomy . Left breast mastectomy and axillary lymph node dissection . MICRA TRIAL ‐ Multi-center observational prospective cohort ‐ 6.6 cm residual invasive carcinoma with neuroendocrine differentiation study [N=167] ‐ Extensive lymphovascular invasion ‐ After neoadjuvant systemic therapy with ‐ Residual intermediate grade DCIS radiographic CR or PR (൒30% size reduction) on MRI [79% rCR, 21%rPR] ‐ All margins were negative ‐ 4/17 nodes involved (3 macromets, 1 micromet, 1 ITC), up to 1.6 cm ‐ US-guided core biopsies near prior clip: 4 central (<0.5 cm) and 4 peripheral biopsies (0.5-1.5cm). ‐ ypT3N2a

‐ False negative rate of biopsy: 45% in rCR, 13% in ‐ IHC: ER+(>98%), PR+(10%), Her2-, Ki67 5%. rPR

‐ Radiographic CR plus biopsy does not accurately assess for pCR.

San Antonio Breast Conference 2019

60 yo woman with IDC of the left breast, cT3N3bM0, grade 2, SACME3: When delivering intensity modulated post-mastectomy ER+PR+Her2-, s/p neoadjuvant AC-T, mastectomy and ALND, radiotherapy with regional nodal irradiation (axillary, ypT3N2M0. supraclavicular, and internal mammary), what do you cite as the risk of grade 3 radiation pneumonitis? Discussion . How would you deliver PMRT? A. 1% ‐ 3-field or IMRT/VMAT? B. 5% ‐ Which nodal regions would you cover? C. 10% Boost to involved undissected nodes? ‐ D. 20% ‐ Traditionally fractionated or hypofractionated? E. 33%

10 | [footer text here] SACME3: When delivering intensity modulated post-mastectomy radiotherapy with regional nodal irradiation (axillary, VMAT PMRT Simulation supraclavicular, and internal mammary), what do you cite as the risk of grade 3 radiation pneumonitis? . Supine, arms above head, head turned right A. 1% B. 5% . Breast board at 5 degree incline C. 10% D. 20% . 3-5 mm custom wax bolus E. 33% . Wire breast borders and scars

Structure35Gy Parameter Limit Lung, Ipsilateral V20Gy <30% Breast V10Gy <65% IMRT/VMAT Mean <18Gy OAR Lung, contralateral V20Gy <5% Heart V25Gy <3% (left), <0.5% (right) Constraints DMax <4-8Gy LAD DMax <25Gy Thyroid Mean <20Gy Esophagus Dmax <35Gy Brachial plexus DMax <55Gy Contralateral breast/implant Mean <6Gy Liver Mean <8Gy Stomach Mean <8Gy Spinal cord DMax <20Gy

11 | [footer text here] IMN MSKCC Prospective Breast IMRT Experience PTV . N=113 . Respiratory Toxicity . Median follow-up 53.4 months ‐ Grade 1: 6.7% . Technique ‐ Grade 2: 2.9% ‐ 50 Gy in 25 fracions Stomach ‐ Grade 3: 1% ‐ 8-12 coplanar beams, 6 MV ‐ Grade 4/5: 0% ‐ 3-5 mm bolus

Lung, L . 5-year Clinical Outcomes Cord . Dosimetry ‐ LRRF: 93.2% Heart Lung, R Esophagus ‐ Median lung V20Gy=29% ‐ DFS: 63.6% ‐ Median lung V5Gy=100% ‐ OS: 80.3%

Ho et al. Long-Term Pulmonary Outcomes of a Feasibility Study of Inverse-Planned, Multibeam Intensity Modulated Radiation Therapy in Node- Positive Breast Cancer Patients Receiving Regional Nodal Irradiation. Int J Radiat Oncol Biol Phys. 2019 Apr 1;103(5):1100-1108. PMID: 30508620.

SACME4: As compared to conventional post-mastectomy SACME4: As compared to conventional post-mastectomy radiotherapy (50 Gy in 25 fractions), hypofractionated PMRT (43.5 radiotherapy (50 Gy in 25 fractions), hypofractionated PMRT (43.5 Gy in 15 fractions) to the chest wall and supraclavicular region Gy in 15 fractions) to the chest wall and supraclavicular region results in: results in:

A. Inferior locoregional control and similar acute skin toxicity A. Inferior locoregional control and similar acute skin toxicity B. Inferior locoregional control and less acute skin toxicity B. Inferior locoregional control and less acute skin toxicity C. Non-inferior locoregional control and similar acute skin toxicity C. Non-inferior locoregional control and similar acute skin toxicity D. Non-inferior locoregional control and more acute skin toxicity D. Non-inferior locoregional control and more acute skin toxicity E. Non-inferior locoregional control and less acute skin toxicity E. Non-inferior locoregional control and less acute skin toxicity

12 | [footer text here] Hypofractionated PMRT – Chinese trial FABREC trial – hypofractionated PMRT after reconstruction

. Randomized, non-inferiority trial . T1-3N+ s/p mastectomy with immediate expander/implant . Post-mastectomy, T3-4N2-3 (N=820) reconstruction . 6-9 MeV, 5 mm bolus . Arms . Arms; Post-mastectomy RT +/- IMNs ‐ Conventional (50 Gy / 25 fx) ‐ Conventional: 50 Gy / 25 fx ‐ Hypofx (43.5 Gy / 15 fx) ‐ Hypofx: 42.56 Gy / 16 fx (39.9 Gy / 15 fx to SCV) . Median follow-up 58.5 months . 5-year local recurrence (8.3 vs 8.1%) . Outcome measures . No difference in overall toxicity ‐ Except less acute grade 3 skin toxicity (8 vs 3%) ‐ Primary: patient reported, 6 month physical well being ‐ Secondary: Oncologic, clinical, and cosmetic

60 yo woman with IDC of the left breast, cT3N3bM0, grade 2, ER+PR+Her2-, s/p neoadjuvant AC-T, mastectomy and ALND, SACME: NSABP B-51 includes all of the following EXCEPT: ypT0N0M0. Discussion A. T1-3 B. N1 . How can radiographic and Medomics be used to predict who will have a pCR? C. Adjuvant chemotherapy D. Post-mastectomy RT to the chest wall only (without regional nodal irradiation) . What adjuvant treatment do you recommend if our patient E. Sentinel node biopsy or axillary dissection achieved a complete pathologic response with neoadjuvant systemic therapy?

13 | [footer text here] SACME: NSABP B-51 includes all of the following EXCEPT: Mamounas et al (2012) A. T1-3 Combined analysis of B. N1 NSABP-B18 and –B27 C. Adjuvant chemotherapy D. Post-mastectomy RT to the chest wall only (without regional nodal irradiation) E. Sentinel node biopsy or axillary dissection

ASTRO Consensus guidelines NSABP B-51

. ypN+ → PMRT

. ypN0 → pre-chemo decision making

Recht et al. Postmastectomy Radiotherapy: An American Society of Clinical Oncology, American Society for Radiation Oncology, and Society of Surgical Oncology Focused Guideline Update. J Clin Oncol. 2016 Dec 20;34(36):4431-4442. PMID: 27646947.

14 | [footer text here] Questions?

15 | [footer text here] Proton beam therapy at The Christie, Manchester with a focus on head and neck cancers

Dr David Thomson UCSF Continuing Medical Education Consultant Clinical Oncologist The Christie NHS Foundation Trust, Manchester

24 April 2021

Disclosure Proton beam therapy at The Christie, Manchester with a focus on head and neck cancers

Merck Sharp & Dohme Advisory Pecuniary, unrelated to talk International landscape and high level challenges

Practical considerations and uncertainties

NHS commissioned indications and avenues of clinical investigation

Future translational, pre-clinical research

1 | [footer text here] 10 27 19 15 36 40

2015 2020

PBT barriers to routine implementation Lack of level I evidence

Challenges Cost - reimbursement/commissioning Plan comparisons and models usually insufficient justification Willingness to randomise Practical considerations Technology Realising potential IMPT more recently implemented Robust optimisation 3D-verification imaging Planning uncertainties Proton range sensitivity

2 | [footer text here] Practical Considerations and Uncertainties

Proton range uncertainties

Set-up and immobilisation

Weight loss and tumour regression

Dental amalgam and metal work

Courtesy: Dr Mat Lowe Data derived from: Hurley et al. (2012) Med. Phys. 39 (5)

Depth /mm Courtesy: Dr Mat Lowe

3 | [footer text here] Weight gain / fluid from chemotherapy Weight loss Affecting coverage Hot spot in lumen Increased dose to spinal cord CTV2 under-coverage

Ant: trt below chin, LAO: ipsilateral side Tumour response Llat, RPO: ipsilateral side to shoulders, CTV1 119% under uncertainty, Post: L side to shoulder to help, spare parotid, OC spinal cord 2Gy over tolerance 5 beams, MFO with 5cm RS, split target, 3mm, 3.5% Avoid shoulder, amalgam, posterior and chin Spare central structures, SMG, parotid, OC Parotids: 7Gy, 17.5Gy / OC: 19Gy / SMG: 23, 27Gy / Larynx: 25Gy

NHS Commissioned Indications

Curative intent WHO PS 0/1 Where indicated, optimal surgery/clearance from dose limiting structure

Adults Base of skull tumours (radio-resistant). Spinal and para-spinal tumours (radio-resistant). Teenagers and Young Adults (TYA) - age 16–24 Avoid where possible Adult indications. Beam arrangement Paediatric tumours – as per paediatric indications. Discuss with dentists and surgeons Paediatric Tumours in adult indication list. Know what material is used Most paediatric tumours, malignant and benign. Some materials are preferred over others e.g, PEEK / Carbon > Titanium > Cobalt Chrome

4 | [footer text here] UK Proton Clinical Trials – Current, In Set-up, Future

Oropharynx - TORPEdO CTCAE/PROMs High cure rate Integral dose Breast - PARABLE Instrumental measurement high late toxicities OAR dose-function CNS – APPROACH Biomarkers Mediastinal lymphoma

Oesophagus/Pancreas/Liver Dose-volume coverage Survival Low cure rate Sinonasal Integral dose CTCAE, PROMs high toxicities Lung, mesothelioma OAR dose-function Instrumental measurement Re-irradiation

1. Adult chordorma 73.8 Gy(RBE=1.1) in 41 fractions of 1.8 Gy(RBE=1.1)/fraction, SFO, 2 phases 4/2 fields Integral dose Overall survival Patient factors High acute toxicities RT-drug delivery 2. Paediatric grade I/II astrocytoma: 50.4 Gy(RBE=1.1) in 28 fractions of 1.8 Gy(RBE=1.1)/fraction, SFO 2 fields. VMAT plan also shown for comparison

TOxicity Reduction using Proton bEam therapy for Oropharyngeal cancer TOxicity Reduction using Proton bEam therapy for Oropharyngeal cancer

Acute toxicities reduced (24% vs 47% required a feeding tube) A phase III trial of intensity-modulated proton beam therapy versus intensity-modulated radiotherapy for multi-toxicity reduction in oropharyngeal cancer IMPT late toxicities - late grade 2 dryness 25% and 12-month gastrostomy dependence 2%

CRUK/18/010 150 patients 1:2 IMPT:IMRT grade 3 weight loss or gastrostomy-tube dependence 12-months OR=0.23 CI: David Thomson Lower mandibular doses reduced rates of osteoradionecrosis (2% vs 8%)

Reduction in the ‘top 5’ MDASI symptoms scores up to 3 months

Observational Studies

5 | [footer text here] TOxicity Reduction using Proton bEam therapy for Oropharyngeal cancer TOxicity Reduction using Proton bEam therapy for Oropharyngeal cancer Validating a NTCP model to help identify who might benefit most from protons vs photons Translational Physics, Imaging, Biology

Dose-volume parameters for organs-at-risk Comparative planning of protons vs photons Dutch composite model for different toxicities (xerostomia ≥grade 2, dysphagia ≥grade 2, tube feeding dependence) at 6 months Method approved by the Netherlands whilst recognising the need for prospective biomarker validation and to inform selection thresholds Hypothesise that for an enriched subgroup of patients (~50%) with a predicted difference in SUM-NTCP (IMRT vs IMPT) of 15% at 6 months, UW-QoL physical composite scale at 12 months would increase by ≥15 points

Pre-clinical, biological and physical science Radiation Oncology Physics ENT Surgery Patient Representatives Dr Lip Lee Prof Ran Mackay Prof Terry Jones Dr Helen Bulbeck Dr Andrew McPartlin Dr Mat Lowe Mr Jason Fleming Dr Tim Humphrey Dr James Price Dr Matt Clarke Prof Jarrod Homer Emma Kinloch Prof Mererid Evans Dr Frances Charlwood Mr Navin Mani Prof Chris Nutting Dr William Beasley RTTQA Dr Anna Thompson Dr Callum Gilles ICR CTSU Elizabeth Miles Dr Dawn Carnell Prof Emma Hall Dr Helen Baines Dr Matt Beasley Translational Science Clare Cruickshank Dr Romaana Mir Dr Olly Donnelly Prof Catharine West Natasha Iles Dr Bernie Foran Courtesy: Dr Mike Merchant Prof Marcel Van Herk MCRC Dr Nachi Palaniappan Prof Karen Kirkby Liverpool CTU Prof Rob Bristow Dr Robin Prestwich DNA damage and molecular and cellular responses, genomic markers Dr Mike Merchant Charlotte Rawcliffe Prof David Wedge Dr Russell Banner RBE heterogeneity Dr Alan McWilliam Richard Jackson Combination with chemotherapy and immune response modifiers Prof Hans Langendijk NHS England FLASH effect Prof Adrian Crellin CBE

6 | [footer text here] 7 | [footer text here] 4/24/2021

Disclosures The Proton Therapy Landscape in the U.S. and • None What Comes Next William F. Hartsell, MD Medical Director Northwestern Medicine Proton Center

The Proton Therapy Landscape in the U.S.: Proton Therapy Centers in the US ‐ 2001 Current status

• Number and location of proton therapy centers WA ME MT ND 2001 • Equipment and treatment rooms OR MN VT NH ID SD WI MI NY MA RI • Tumor types treated WY CT IA PA NE NJ NV OH • Efficiency of centers 1994 IL MD DE UT IN CA CO WV KS MO VA • Reimbursement KY NC TN AZ OK 1990 AR SC NM AL GA MS

TX LA

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Proton Therapy Centers in the US ‐ 2006 Proton Therapy Centers in the US ‐ 2011

WA WA ME ME MT MT ND 2001 ND 2001 OR MN VT OR MN VT NH NH ID SD WI MI NY MA ID SD WI MI NY MA WY CT RI WY CT RI IA PA IA PA NE NJ NE NJ NV OH NV 2010 OH 1994 IL MD DE 1994 IL MD DE UT IN UT IN CA CO WV CA CO WV 2010 KS MO VA KS MO VA KY KY NC NC TN TN AZ OK AZ OK 1990 AR SC 1990 AR SC NM 2004‐14 NM 2009 2004‐14 2010 AL GA AL GA MS MS

TX LA TX LA

FL FL 2006 2006

2006 2006

Proton Therapy Centers in the US ‐ 2016 Proton Therapy Centers in the US ‐ 2021 2017

2016 2016 2016 2019 2016 2001 2001 2019 WA WA 2013 ME 2013 ME MT ND MT ND OR MN VT OR MN VT NH NH 2015 2015 ID SD WI MI NY MA ID SD WI MI NY MA RI RI WY 2015 CT WY 2015 CT IA PA 2012 IA PA 2012 NE NJ NE NJ NV 2010 OH NV 2010 OH 1994 IL MD DE 1994 IL MD DE UT IN 2010 UT IN 2010 CA CO WV CA CO WV KS MO VA KS MO VA KY 2014 KY 2014 2004‐14 2016 2016 2013 NC 2013 NC 2016 TN 2016 TN AZ OK 2010 AZ OK 1990 2016AR 1990 2016AR 2010 2009 SC 2009 SC 2018 NM NM 2018 2018 AL GA 2020 AL GA 2019 MS 2019 MS 2015 2015 2020 TX LA TX LA 2015 2006 2015 2006 2014 2014 2019 FL FL 2014 2014 2020 2016 2016 2006 2006 2017

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New centers? Trends in Proton Therapy 1990‐2020: Type of treatment room

100 Under construction 90 80 70 60 rooms Gantry of 50 Fixed 40 Incline Number In planning stages 30 20 10 0 1990 1995 2000 2005 2010 2015 2020 Year

9 From PTCOG website April 2021

How many operational proton treatment rooms do you have? How many operational proton treatment rooms do you have?

Mark Pankuch & Deborah Godes, NAPT 2019 Mark Pankuch & Deborah Godes, NAPT 2019

3 4/24/2021

What are the average hours per treatment day? The Proton Therapy Landscape in the U.S.: Current status • Number and location of proton therapy centers • Equipment and treatment rooms • Tumor types treated • Efficiency of centers • Reimbursement

Mark Pankuch & Deborah Godes, NAPT 2019

Conditions Treated (CY 2012 –CY 2019)

CONDITIONS TREATED 2012 2013 2014 2015 2016 2017 2018 2019 Conditions Treated (CY 2012 –CY 2019)

Central Nervous System 598 639 714 1,014 1,169 1,201 1,620 1,432 Changes in % of Intraocular Neoplasms 250 250 276 296 390 328 247 251 total conditions -19.8% Pituitary Neoplasms 50 64 71 44 35 28 50 68 treated: Base of Skull or Axial . Intraocular 179 239 270 232 249 259 259 359 Skeleton neoplasms Head and Neck 316 387 576 808 973 1,389 1,536 1,640 . Head and neck Lung 437 490 595 596 612 818 788 740 . Prostate Soft Tissue Sarcoma 16 22 16 209 242 234 215 284 . Breast Pediatric 685 749 940 1,090 1,110 1,536 1,311 1,542 Gastrointestinal Tract 170 308 427 520 664 721 684 835 Urinary Tract 1313243537213419 +8.4% Female Pelvic Organs 24 29 42 38 59 96 65 86 +7.2% Prostate 2,336 2,094 2,355 2,311 2,606 2,909 2,981 2,729 Breast 93 183 319 425 666 787 970 1,030 -2.5% Lymphoma 164 158 208 185 Other 210 367 459 273 200 415 553 324 Total 5,377 5,834 7,084 7,891 9,176 10,900 11,522 11,524 N 11 13 16 20* 24* 26* 28* 28* * Number of patients treated were estimated based on publicly available data (1 in 2015, 2 in 2016, 1 in 2017, 1 in 2018, 1 in 2019)

Deborah Godes, NAPT presentation, December 2020 -15- Deborah Godes, NAPT presentation, December 2020 -16-

4 4/24/2021

The Proton Therapy Landscape in the U.S.: Hypofractionation Current status USE OF HYPOFRACTIONATION (N=25) No (4) • Number and location of proton therapy centers Yes (21) • Equipment and treatment rooms

Breast (9, 42.9%) Prostate (18, 85.7%) • Tumor types treated • Efficiency of centers PERCENT OF PATIENTS TREATED (N=9) PERCENT OF PATIENTS TREATED (N=17) . 1 – 10%: 44.4% . 1 – 10%: 29.4% • Reimbursement . 11 – 25%: 0.0% . 11 – 25%: 41.2% . 26 – 50%: 33.3% . 26 – 50%: 17.6% . >50%: 22.2% . >50%: 11.8%

Variability in the most commonly used Ultrafractionate? Yes (35.3%) (N=17) hypofractionation treatment schedule (6 Variability in the percent of patients responses) treated with hypofractionation (N=4)

Deborah Godes, NAPT presentation, December 2020 -17-

What is the Annual number of proton patients treated? How many dedicated proton Radiation Oncologists FTE’s?

Mark Pankuch & Deborah Godes, NAPT 2019 Mark Pankuch & Deborah Godes, NAPT 2019

5 4/24/2021

How many dedicated proton Medical Physicist FTE’s? How many dedicated proton Medical Physicist FTE’s?

Mark Pankuch & Deborah Godes, NAPT 2019

How many dedicated proton Dosimetrist FTE’s? How many dedicated proton Intake FTE do you have?

6 4/24/2021

Proton center efficiency The Proton Therapy Landscape in the U.S.: • The current staffing models (ACR, ACRO, ASTRO) that are commonly used for photon clinics under‐estimate the staff currently in place at 28 active Current status proton therapy centers. • Number and location of proton therapy centers • Equipment and treatment rooms • The data from the 2018 survey demonstrates that Proton therapy centers require more professional resources than those typically observed in a • Tumor types treated photon clinic. • Efficiency of centers • Reimbursement • Modifications to the standard staffing models are necessary to accurately predict the staff required to run a proton center in the current state of technological development of proton therapy

Payor Mix: All Sites (2017 – 2019) Prior / Pre‐Authorization

Percent from Medicare and MA Required to get PA Percent of Claims Requiring Prior Average Wait Time for PA plans grew from 2015 through from ROBMs (N=23) or Pre-Authorization (N=22) (N=24) 2017 (38.8% to 46.4%), held 95.7% 36.4% 45.8% 27.3% 31.8% steady for 2018 (45.6%), and 29.2% grew again in 2019 12.5% 12.5% 4.3% 4.5% Percent from Medicaid and Yes No 1-10% 11-25% 26-50% >50% 3 days 4-5 6-10 More than Medicaid MC has remained or less days days 10 days relatively constant. The Blues plans dropped slightly, back to Number of FTEs spent on PA Process Care Delays due to PA Process (N=23) (N=24) 17.4% in 2019 compared to 45.8% 54.2%

19.4% in 2018. 25.0% 25.0% Note: Payor mix (N = 25) is self-reported, based 20.8% 20.8% on distribution provided by member centers. 4.2% 4.2%

% of Rev. from Direct-to-Employer Arrangements: 1.3% (n=16) 21-30 31-40 41-50 51-60 60+ Rarely / Sometimes Often / % of Rev. from SPAs: 3.2% (n=16) hours hours hours hours hours Never Always

-27- -28-

7 4/24/2021

Percentage of patients approved, appealed and denied for proton therapy Percentage of patients approved, appealed and denied for proton therapy

Gupta et al, Int J Radiat Oncol Biol Phys 2019, 104:714-23. Gupta et al, Int J Radiat Oncol Biol Phys 2019, 104:714-23.

Percentage of patients approved, appealed and denied for proton therapy

Ning et al, Int J Radiat Oncol Biol Phys 2019, 104:724-33. Gupta et al, Int J Radiat Oncol Biol Phys 2019, 104:714-23.

8 4/24/2021

The Proton Therapy Landscape in the U.S. Reimbursement issues What Comes Next • RO APM • Number and location of proton therapy centers • Growth is continuing but slowing • Case rate –may help to eliminate prior authorization, but rates are • Equipment and treatment rooms lower • Trend toward fewer rooms per center • Strong trend toward gantry PBS • Hypofractionation may help • Tumor types treated • Medicare Advantage • Breast, head & neck, lung increasing • More plans refusing protons • CNS, pediatrics increasing as well • Prostate stable • May change trend back toward • Reimbursement private payors • More data / trials needed – but this is difficult • RO‐APM may change practice as well

Proton therapy is effective, but not efficient

• Until we get to flash therapy!

9 Disclosures

. None

Contouring and Treatment Planning Consensus Guidelines for Head and Neck and Skin Cancers

Jason Chan, MD UCSF Radiation Oncology Assistant Professor

Objectives Objectives Become familiar with recent consensus guidelines on the following topics Become familiar with recent consensus guidelines on the following topics

. Dose prioritization . Dose prioritization

. OARs . OARs

. Targets . Targets ‐ Primary tumor (CTVp) for OC, OPX, LX, HPX; NPC ‐ Primary tumor (CTVp) for OC, OPX, LX, HPX; NPC ‐ Post-op and flaps ‐ Post-op and flaps ‐ Perineural ‐ Perineural ‐ Elective nodes ‐ Elective nodes

3 4

1 | [footer text here] Dose Prioritization NPC Dose Prioritization Generally prioritize tumor coverage over most OARs

Three PTV levels all priority 2

AW Lee, WT Ng, JJ Pan, CL Chiang, SS Poh, HC Choi… - International Journal of …, 2019 5 K Jensen, J Friborg, CR Hansen, E Samsøe… - Radiotherapy and Oncology, 2020 6 AW Lee, WT Ng, JJ Pan, CL Chiang, SS Poh, HC Choi… - International Journal of …, 2019

PTV1 Objectives PTV2 and 3 Objectives Not meeting these parameters are considered major deviations Much fewer QA parameters

PTV1 Dose Ref. PTV1 Dose Ref. No hot spot constraints PTV2/3 Dose Ref. 0.03 cc 117% HN004 D100% 90% DAHANCA D95% 95% HN004/5 0.03 cc 115% HN005 D99% 90% HN005 CTV2/3 Dose (Gy) Ref. 1.8 cc 110% DAHANCA D95% 95% DAHANCA D95% 95% DAHANCA 10% 107% NPC GTV Dose (Gy) Ref. 20% 105% NPC D100% 95% (66.5) NPC Overlapping PTVs are optimized as the higher dose level

AW Lee, WT Ng, JJ Pan, CL Chiang, SS Poh, HC Choi… - International Journal of …, 2019 AW Lee, WT Ng, JJ Pan, CL Chiang, SS Poh, HC Choi… - International Journal of …, 2019 7 K Jensen, J Friborg, CR Hansen, E Samsøe… - Radiotherapy and Oncology, 2020 8 K Jensen, J Friborg, CR Hansen, E Samsøe… - Radiotherapy and Oncology, 2020 W De Neve, Y Wu, G Ezzell - Image-guided IMRT, 2006

2 | [footer text here] DAHANCA Dose Prioritization Objectives Different priorities for PTV1 and elective targets PTV2 and PTV3 Become familiar with recent consensus guidelines on the following topics

1. Critical OARS, 4. Targets . Dose prioritization potentially lethal PTV1 complication CTV2 and CTV3 . OARs SpinalCord PTV2 and PTV3 BrainStem . Targets 5. Remaining OARs Which other OARs should be 2. Targets …LarynxSG higher priority than PTV2 and ‐ Primary tumor (CTVp) for OC, OPX, LX, HPX; NPC GTV Larynx G CTV1 OralCavity PTV3? ‐ Post-op and flaps BuccalMuc ‐ Perineural 3. Critical serial PCM… OARs ‐ Elective nodes EyeFront and 6. Avoid overdosage EyeBack of PTV2 and PTV3 Chiasm

9 K Jensen, J Friborg, CR Hansen, E Samsøe… - Radiotherapy and Oncology, 2020 10

OARs OARs Involved in Swallowing Accurate OAR contouring is just as important as target delineation

. Superior and middle PCM should be contoured separately

11 R Mir, SM Kelly, Y Xiao, A Moore, CH Clark… - Radiotherapy and Oncology, 2020 12 MEMC Christianen, JA Langendijk, HE Westerlaan… - Radiotherapy and Oncology, 2011 CL Brouwer, RJHM Steenbakkers, J Bourhis… - Radiotherapy and Oncology, 2015

3 | [footer text here] OARS involved in Swallowing CRUK/14/014 (DARS) Phase III IMRT ± Dysphagia Optimization Pterygoid plates 1st slice caudal to hyoid bone

Hyoid bone Arytenoids Superior/Middle (SMPCM) Inferior (IPCM) . Dmean < 50 Gy SMPCM outside CTV_6500 1st slice caudal 1st slice caudal to to arytenoids cricoid cartilage . Dmean < 20 Gy (OP) or < 40 Gy (HPX) IPCM outside CTV_6500 . Do not spare overlap within PTV_6500 margin Cricoid cartilage Thoracic inlet . Dose prioritization: critical OARS (spinal cord and brainstem); Cricopharyngeus muscle EIM (first 1 cm) and cervical esophagus PTV_6500; constrictors; PTV_5400; other OARs

13 econtour.org 14 I Petkar, K Rooney, JWG Roe, JM Patterson… - BMC cancer, 2016

CRUK/14/014 (DARS) Objectives Phase III IMRT ± Dysphagia Optimization Become familiar with recent consensus guidelines on the following topics

. Dose prioritization

. OARs

. Targets ‐ Primary tumor (CTVp) for OC, OPX, LX, HPX; NPC . 112 patients. T1-4 N0-3 M0 OP (97%)/HPX cancer. 84% CCRT ‐ Post-op and flaps . Standard vs. Dysphagia-optimized IMRT ‐ Perineural . Median mean S/MPC 57 vs. 50 Gy; IPC 50 vs. 28 Gy ‐ Elective nodes . Median mean 1y MDADI 70 vs. 78

15 C Nutting, K Rooney, B Foran, L Pettit, M Beasley… - ASCO 2020 16

4 | [footer text here] Primary tumor (CTVp) Glottic Larynx T1b Larynx, Hypopharyx, Oropharynx, Oral Cavity; Nasopharynx Exception to “5+5” rule: CTV2 is not recommended for T1 glottic SCC

5 mm (70 Gy) + 5 mm (60 Gy) Exclude thyroid cartilage

V Grégoire, M Evans, QT Le, J Bourhis, V Budach… - Radiotherapy and Oncology, 2018 17 AW Lee, WT Ng, JJ Pan, SS Poh, YC Ahn, H AlHussain… - Radiotherapy and Oncology, 2018 18 V Grégoire, M Evans, QT Le, J Bourhis, V Budach… - Radiotherapy and Oncology, 2018 K Jensen, J Friborg, CR Hansen, E Samsøe… - Radiotherapy and Oncology, 2020

Glottic Larynx T2 Supraglottic Larynx T3

Include: Include: Supraglottis Anterior commissure ± Oropharynx (e.g. lingual Include post-cricoid but not Subglottis Thyroid cartilage surface epiglottis and vallecula) posterior pharyngeal wall Vocal process of arytenoid

19 V Grégoire, M Evans, QT Le, J Bourhis, V Budach… - Radiotherapy and Oncology, 2018 20 V Grégoire, M Evans, QT Le, J Bourhis, V Budach… - Radiotherapy and Oncology, 2018

5 | [footer text here] Supraglottic Larynx T4a Hypopharynx T2

Extend beyond strap muscles if macroscopically invaded Extensive submucosal extension with HPX: consider 5+10 instead of 5+5 Posteriorly include part of PCM but not pre-vertebral fascia Caudally may extend to cervical esophagus Superiorly may extend into oropharynx

21 V Grégoire, M Evans, QT Le, J Bourhis, V Budach… - Radiotherapy and Oncology, 2018 22 V Grégoire, M Evans, QT Le, J Bourhis, V Budach… - Radiotherapy and Oncology, 2018

Hypopharynx T4b Tonsil T2

Posteriorly extend into part of PCM Extensive submucosal extension with HPX: consider 5+10 instead of 5+5 Laterally include parapharyngeal space but not medial pterygoid muscle Posteriorly include pre-vertebral fascia if invaded Caudally extend to cervical esophagus Superiorly extend into oropharynx

23 V Grégoire, M Evans, QT Le, J Bourhis, V Budach… - Radiotherapy and Oncology, 2018 24 V Grégoire, M Evans, QT Le, J Bourhis, V Budach… - Radiotherapy and Oncology, 2018

6 | [footer text here] Soft Palate T1 Soft Palate T3

Should not extend into non-contiguous mucosa Extend into hard palate, parapharyngeal space e.g. posterior pharyngeal wall

25 V Grégoire, M Evans, QT Le, J Bourhis, V Budach… - Radiotherapy and Oncology, 2018 26 V Grégoire, M Evans, QT Le, J Bourhis, V Budach… - Radiotherapy and Oncology, 2018

Base of Tongue T2 Vallecula T3

Laterally extend through hyoglossus muscle Extend inferiorly into pre-epiglottic fat Anteriorly may extend into the mobile tongue and genioglossus

27 V Grégoire, M Evans, QT Le, J Bourhis, V Budach… - Radiotherapy and Oncology, 2018 28 V Grégoire, M Evans, QT Le, J Bourhis, V Budach… - Radiotherapy and Oncology, 2018

7 | [footer text here] Posterior Pharyngeal Wall T4b Oral Tongue T4

Extend through pre-vertebral fascia into longus colli and longus capitis muscles Include deep extrinsic muscles of tongue

29 V Grégoire, M Evans, QT Le, J Bourhis, V Budach… - Radiotherapy and Oncology, 2018 30 V Grégoire, M Evans, QT Le, J Bourhis, V Budach… - Radiotherapy and Oncology, 2018

Nasopharynx T1 Objectives Become familiar with recent consensus guidelines on the following topics

. Dose prioritization

. OARs

. Targets ‐ Primary tumor (CTVp) for OC, OPX, LX, HPX; NPC ‐ Post-op and flaps Sphenoid 1/2 Pterygoid fossa Inferior limit of nasopharynx is at ‐ Perineural Petrous apex Parapharyngeal caudal edge of C1 Max sinus ≥ 5 mm Clivus 1/3 ‐ Elective nodes Ovale, rotundum, lacerum

31 AW Lee, WT Ng, JJ Pan, SS Poh, YC Ahn, H AlHussain… - Radiotherapy and Oncology, 2018 32

8 | [footer text here] Post-op and Flaps Free Flaps Standard delineation needed to refine post-op CTV definition

J Le Guevelou, V Bastit, PY Marcy, A Lasne-Cardon… - Radiotherapy and Oncology, 2020 33 SV Porceddu, C Daniels, SS Yom, H Liu, J Waldron… - International Journal of …, 2020 34 J Le Guevelou, V Bastit, PY Marcy, A Lasne-Cardon… - Radiotherapy and Oncology, 2020

Radial Forearm Free Flap Anterolateral Thigh Free Flap

35 J Le Guevelou, V Bastit, PY Marcy, A Lasne-Cardon… - Radiotherapy and Oncology, 2020 36 J Le Guevelou, V Bastit, PY Marcy, A Lasne-Cardon… - Radiotherapy and Oncology, 2020

9 | [footer text here] Fibula Free Flap Post-op with Free Flap

CTVp_HR CTVp_LR HRTV

CTVn_LR

. CTVp_HR (60 Gy): HRTV + minimum 5 mm, may include most of post-op bed/flap

. CTVp_LR (54-56 Gy): Remaining post-op bed/flap

. CTVn_LR (54-56 Gy): Undissected ipsilateral Ib, II, III, XIII (parotid), IX (bucco-facial)

37 J Le Guevelou, V Bastit, PY Marcy, A Lasne-Cardon… - Radiotherapy and Oncology, 2020 38 SV Porceddu, C Daniels, SS Yom, H Liu, J Waldron… - International Journal of …, 2020

Post-op Neck (DAHANCA) Objectives Become familiar with recent consensus guidelines on the following topics

. Dose prioritization

. OARs

. Targets ‐ Primary tumor (CTVp) for OC, OPX, LX, HPX; NPC ‐ Post-op and flaps ‐ Perineural ‐ Elective nodes

39 K Jensen, J Friborg, CR Hansen, E Samsøe… - Radiotherapy and Oncology, 2020 40

10 | [footer text here] Perineural Invasion and Spread PNI/PNTS Recommendations

RL Bakst, CM Glastonbury, U Parvathaneni, N Katabi… - International Journal of …, 2019 41 J Biau, V Dunet, M Lapeyre, C Simon, M Ozsahin… - Radiotherapy and Oncology, 2019 42 RL Bakst, CM Glastonbury, U Parvathaneni, N Katabi… - International Journal of …, 2019

Extensive PNI PNI/PNTS Recommendations Elective V3 coverage to foramen ovale

43 RL Bakst, CM Glastonbury, U Parvathaneni, N Katabi… - International Journal of …, 2019 44 RL Bakst, CM Glastonbury, U Parvathaneni, N Katabi… - International Journal of …, 2019

11 | [footer text here] PNTS along V3 ATN and VII PNI/PNTS Recommendations Tympanic segment

ATN Posterior genu

CN VII Canalicular segment

70 Gy Elective

45 RL Bakst, CM Glastonbury, U Parvathaneni, N Katabi… - International Journal of …, 2019 46 RL Bakst, CM Glastonbury, U Parvathaneni, N Katabi… - International Journal of …, 2019

PNTS along V2 with Anterograde Objectives Become familiar with recent consensus guidelines on the following topics

Rotundum . Dose prioritization PPF Ovale . OARs GSPN Meckel’s . Targets Cochlea Cave ‐ Primary tumor (CTVp) for OC, OPX, LX, HPX; NPC ‐ Post-op and flaps ‐ Perineural ‐ Elective nodes

RL Bakst, CM Glastonbury, U Parvathaneni, N Katabi… - International Journal of …, 2019 47 J Biau, V Dunet, M Lapeyre, C Simon, M Ozsahin… - Radiotherapy and Oncology, 2019 48

12 | [footer text here] Level Group Elective Nodes Ia Submental Elective Nodes Ib Submandibular II Upper Jugular III Middle Jugular IVa Lower Jugular Oral Cavity Oropharynx Va and Vb Upper and Lower Posterior Triangle Vc Lateral SCV VIa Anterior Jugular VIb Pre-laryngeal, pre-tracheal, paratracheal VIIa Retropharyngeal VIIb Retro-styloid VIII Parotid IX Bucco-facial Contralateral neck may be omitted as per Tsai et al. Xa Retroauricular and subauricular Xb Occipital

J Biau, M Lapeyre, I Troussier, W Budach, J Giralt… - Radiotherapy and Oncology, 2019 49 J Biau, M Lapeyre, I Troussier, W Budach, J Giralt… - Radiotherapy and Oncology, 2019 50 CJ Tsai, TJ Galloway, DN Margalit, RL Bakst… - Head & neck, 2021

Elective Nodes Elective Nodes

Hypopharynx Larynx Nasopharynx Paranasal Sinus

51 J Biau, M Lapeyre, I Troussier, W Budach, J Giralt… - Radiotherapy and Oncology, 2019 52 J Biau, M Lapeyre, I Troussier, W Budach, J Giralt… - Radiotherapy and Oncology, 2019

13 | [footer text here] Elective Nodes (DAHANCA) Summary Much more selective than Biau et al. Recent consensus guidelines

VIIa VIIb I II III IV Va Vb VI Other (RP) (Retrostyloid)

Extend elective regions ≥ 2 cm CC of GTV-N . Dose prioritization: NPC, DAHANCA prioritize PTV1 over most OARs All N+ If ENE to muscle, include entire muscle ≥ 2 cm CC of GTV-N Oral Cavity N0 X X X . OARs: contour individual swallowing OARs (SMPCM and IPCM per DARS) Oral Cavity N+ X X X

Nasopharynx N0 X X X X X . Targets Nasopharynx N+ X* X X X X X X X *Ib included if invasion of SMG, OC, anterior NC ‐ Primary tumor (CTVp) for OC, OPX, LX, HPX; NPC: “5+5” rule, consider larger for HPX *Ib included if OC involvement Oropharynx N0 X* X X X* *RP included if posterior pharyngeal wall involvement ‐ Post-op and flaps: entire flap should be part of post-op target; follow free flap atlas Oropharynx N+ X* X X X* *The cranial part of level II can be excluded after individual ‐ Perineural: coverage for elective nerve pathway, interconnections, anterograde spread Hypopharynx N0 X* X X X* consideration *Level VI if subglottic/esophageal involvement ‐ Elective nodes: Biau et al. and DAHANCA for recommendations by primary tumor Hypopharynx N+ X X X X* *Level VI if subglottic/esophageal involvement

*Level IV on side of nodal involvement or bilateral if Supraglottic / X* XXX* hypopharynx involved Glottic (≥ T3) *Level VI if subglottic/esophageal involvement

53 K Jensen, J Friborg, CR Hansen, E Samsøe… - Radiotherapy and Oncology, 2020 54

Questions? [email protected]

14 | [footer text here] Disclosures

Systemic therapy update 2021 • Scientific Advisory Board – Bayer and Achilles therapeutics SCCHN • Consultant – PIN therapeutics and MitoImmune

2021 UCSF Radiation Oncology Update • Research funds (clinical trials) – Kura Oncology, Elevar Therapeutics, Exelisis, Eli Lilly, PDS Biotechnology, Hyunseok Kang, MD, MPH NeoImmune Tech, and Prelude therapeutics Associate Professor of Clinical Medicine • Off-label use of medications: None

4/24/2021

Educational Objectives Outline

. Summarize recent advances in systemic therapy including . Updates in previously untreated locally advanced SCCHN chemotherapy, targeted therapy and immune therapy of head and neck squamous cell carcinomas . Updates in recurrent/metastatic SCCHN

. Summarize advances and emerging systemic therapy for head and neck squamous cell carcinomas . Emerging therapy in SCCHN

3 Presentation Title

1 | [footer text here] Current treatment approach

Previously untreated Recurrent/Metastatic Recurrent/Metastatic Premalignancy locally advanced SCCHN – 2nd line SCCHN – 1st line SCCHN and beyond Previously untreated locally advanced No approved Multimodality Systemic Systemic therapy therapy Immunotherapy Chemotherapy and/or +/- targeted therapy SCCHN • Surgery  chemotherapy RT or CRT • Chemotherapy • PD-L1 positive: • Concurrent Pembrolizumab • Cetuximab chemoRT • PD-L1 negative: Pembrolizumab • Clinical trial + platinum based chemo

IAP inhibitor and chemoradiation – Debio 1143 IAP inhibitor and chemoradiation – Debio 1143

• Members of the Inhibitor of Apoptosis Protein (IAP) family are key negative regulators of programmed cell death

• IAPs are overexpressed in SCCHN

• The oral monovalent SMAC mimetic Debio 1143 functions as an antagonist of multiple IAPs thus facilitating cell death

2 | [footer text here] IAP inhibitor and chemoradiation – Debio 1143 Concurrent cisplatin: weekly versus high dose

PFS In 2017, a study from Tata Memorial in India suggested high dose cisplatin (100 mg/m2) might be superior in Locoregional control LRC compared to weekly (30 mg/m2)

Sun XS et al. Lancet Oncol 2020;21:1173-1187 Noronha V et al. J Clin Oncol 2017;36:1064-1072

Immune checkpoint inhibitor and (chemo)radiation Pembrolizumab and RT in SCCHN HPV positive HPV negative

Overall Survival: OS (ITT)

Powell SF et al. J Clin Oncol 2020; 38:2427-2437 Presented By Naomi Kiyota at ASCO 2020 annual meeting

3 | [footer text here] Immune checkpoint inhibitor and (chemo)radiation Immune checkpoint inhibitor and (chemo)radiation Javelin head and neck 100 Javelin head and neck 100

Cohen EW et al. ESMO 2020 Annual Meeting Cohen EW et al. ESMO 2020 Annual Meeting

Summary – PULA SCCHN

. IAP inhibitor + chemoradiation (high risk patients) ‐ Looks promising, a randomized phase 3 study is ongoing

. Weekly versus high dose cisplatin Recurrent/metastatic SCCHN ‐ Still confusing, NRG Oncology plans to launch a large randomized phase 3 study in definitive treatment setting

. Immune checkpoint inhibitor + CRT ‐ Javelin head and neck 100 came back negative ‐ Keynote-412 and IMvoke010 studies completed accrual

4 | [footer text here] Tipifarnib for HRAS mutated SCCHN Immune checkpoint inhibitor and cetuximab

. Tipifarnib is a farnesyl transferase inhibitor . Pembrolizumab and cetuximab ORR 55% (11 out of 20) in VAF ≧ 20% ‐ 33 patients with IO naïve, platinum-refractory or ineligible RM-SCCHN patients ‐ Single arm, open-label, phase 2 study ‐ Results

. 1 CR and 14 PR out of 33 patients (ORR 45%)

. Median duration of response = 14.9 months

. Median overall survival = 18.4 months

Ho AL et al. J Clin Oncol 2021;doi:10.1200/JCO.20.02903 Sscco AG et al. 2020 Multidisciplinary Head and Neck Cancer meeting

Immune checkpoint inhibitor and cetuximab Summary – RM SCCHN

. Nivolumab and cetuximab . Tipifarnib for HRAS mutated SCCHN ‐ 47 patients with RM-SCCHN patients who had at least 1 line of therapy ‐ Looks promising, a pivotal phase 2 study is ongoing ‐ Single arm, open-label, phase 2 study ‐ Results . Immune checkpoint inhibitor + cetuximab . 23 (51%) had ICI and 22 (49%) were IO-naïve

. 1 CR and 9 PR out of 47 patients (ORR 22.2%) – ORR 23% (5/22) in IO naïve pts, 18% (4/22) in prior ICI ‐ Limited efficacy, mainly seen in IO naïve patients

. Median overall survival = 11.5 months (9.7 months in prior ICI, 13.3 months in IO naïve)

. Disappointing results from multiple ICI combination studies

Chung CH et al. ASCO 2020 annual meeting

5 | [footer text here] PAMP (pathogen associated molecular pattern)

. TLR9 agonist: SD-101 + pembrolizumab (phase 1/2) . TLR3 agonist: poly-ICLC + tremelimumab and durvalumab Emerging therapy (phase 1/2) . TLR7/8 agonist: CV8102 + anti- PD1 Ab . STING agonist: MIW815 + pembrolizumab, MK-1454 + pembrolizumab

Agrawal S and Kandimalla ER. IOTECH 2019;3:15-23

TLR9 agonist (SD-101) STING agonist

. Phase 1b/2 study with SD-101 + pembrolizumab (1st line) . Phase 1 study of MK-1454 +/- pembrolizumab ‐ Preliminary results from 45 patients with various tumor types (3 HNSCC pts) Total ORR: 24%

No response with monotherapy ORR in 2mg cohort: 22.2% ORR in 8mg cohort: 26.1% 24% ORR with combination (3 out of 6 responders HNSCC)

These patients were anti-PD1 naive

Cohen EE et al. ASCO Annual Meeting 2019 Harrington KJ et al. ESMO Annual Meeting 2018

6 | [footer text here] Combination immune checkpoint inhibitors Cell therapy - TIL TIL + pembrolizumab in IO naïve patients . Immunoglobulin-like transcript 4 (ILT4) is an inhibitory receptor highly expressed by myeloid cells (APCs, MDSCs, macrophages, granulocytes) and targeting ILT4 may relieve myeloid suppressive activity in the tumor microenvironment

. MK-4830 is a monoclonal Ab targeting ILT4

. In a phase 1 study, ORR = 24% in pembrolizumab combination (8 out of 34 pts)

. 5 responses were seen in patients with prior disease progression on ICI

Siu LL et al. ESMO Annual Meeting 2020 Jimeno A et al. STIC Annual Meeting 2020

Other novel approaches Opportunities in targeted approach in SCCHN

HER pathway . Adoptive T cell therapy (targeting viral or common cancer antigens) PI3K pathway

RAS/RAF pathway . Cytokine based agents + ICI combinations CDK4/6 HPV targeting . Therapeutic HPV vaccine + ICI combinations therapy

Synthetic lethal . Synthetic lethal approach for TP53 mutated SCCHN approach

MS Lawrence et al. Nature 517, 576-582 (2015) doi:10.1038/nature14129

7 | [footer text here] Summary

. No major practice changing study in 2020

. Promising activity seen in PULA and RM SCCHN ‐ IAP inhibitor + chemoRT ‐ Tipifarnib in HRAS mutated SCCHN

. Future developments ‐ Many promising studies are ongoing and will result in near-future ‐ Many active clinical trials are underway – please consider referring patients for clinical trials!

8 | [footer text here] 4/5/2021

Disclosures

. Advisory board: Bristol-Myers Squibb, Loxo Oncology, Principles of Oral Cavity Surgery and Rakuten Medical Morbidity Reduction . Educational funding: Stryker, Johnson and Johnson, Medtronic, Axogen Patrick Ha, MD FACS Irwin Mark Jacobs and Joan Klein Jacobs Distinguished Professor Chief, Division of Head and Neck Surgical Oncology . Not relevant to this talk Medical Director, Mission Bay Adult Services University of California San Francisco UCSF Radiation Oncology Update, April 24, 2021

Objectives Oral Cavity

. Better understand the anatomy of the oral cavity • Anterior – lips . Understand AJCC 8th edition staging • Posterior – circumvallate papillae, anterior tonsil pillars, . Consider the subsites of the oral cavity and how we address junction of hard/soft palate them surgically • Oral competence, mastication, . Neck management digestion, speech, social interaction

1 4/5/2021

Oral Cancer T-staging, AJCC 8th Edition Early stage treatment

AJCC 8th ed Cancer Staging Manual, 2016, Chicago, USA

Advanced stage oral cancer Surgery vs radiation for early-stage cancer

. NCDB analysis, 2004-13 . Stage I-II Oral cancer . 19,823 had surgery . 956 had radiation . univariate = 3-fold increased risk of dying with radiation . Multivariable = 2-fold risk

Ellis MA et al, Otolaryngol Head Neck Surg 2017

2 4/5/2021

Surgical principles Anatomic structures of the neck

. Must assess resectability . Muscles – sternocleidomastoid, digastric, omohyoid, midline . En bloc resection of primary when possible strap muscles . Try to clear perineural invasion when possible . Nerves – marginal mandibular, spinal accessory, lingual, . Segmental resection when mandible eroded, tumor fixed to hypoglossal, vagus, phrenic, mandible, medullary space invasion brachial plexus, cutaneous . Margins – 1.5-2cm of visible normal. Pathologically 5mm is sensory clear margin . Structures – internal jugular vein, carotid artery, thoracic duct . Reconstruction when needed (left), submandibular gland

Elective neck dissection Sentinel lymph node biopsy

. SENT (Sentinel European Node Trial) – oral SCC patients . Prospective, randomized study of 596 patients with T1- . 415 patients T1-T2 oral SCC T2 oral cavity cancer . If SN positive, then went for neck dissection . 85% of patients had tongue . SN identified in 99.5% of cases, positive SN = 23% cancer . 3.2 SN per patient . <3mm of invasion was a relative cutoff (p=0.12) . Lateral tumors had contralateral nodes in 10% . Nodal positivity: . Midline lesions had 60% contralateral nodes ‐ 3mm = 5.6% ‐ 4mm = 16.9% . 85% of pts with positive sentinel node had no further metastatic nodes on neck dissection

D’Cruz A et al, NEJM 2015 Schilling C et al, Eur J Cancer, 2015

3 4/5/2021

Sentinel node biopsy Buccal/retromolar cancers

. Relatively rare in US . Failed to detect occult neck metastasis in 15/109 patients . May be exposure related . Of those, 8/15 were amenable to salvage – ie chewing tobacco, pan/betel . 71% of patients spared neck dissection . Higher rate of occult . Reduction in bilateral neck dissection nodal disease (up to 25%) . Function: ‐ Mouth opening ‐ Gingivobuccal sulcus

Schilling C et al, Eur J Cancer, 2015

Surgical considerations

. How deep does it go? ‐ will it go through the cheek skin ‐ Buccal branch of facial nerve . What about the teeth/gingiva? . What about the mandible? . Is it oropharyngeal? . Neck management? . Reconstruction – trismus prevention

4 4/5/2021

Floor of mouth

. More common of a subsite . Present in smoker/drinkers . High rate of nodal metastasis . Anatomy is tricky! . Function: ‐ Salivary flow (Wharton’s duct) ‐ Tongue movement

Floor of mouth cancer Surgical considerations

. 222 oral tongue vs 121 . Anatomy: FOM cancers ‐ Wharton’s ducts – obstruction of submandibular glands, dry mouth . For FOM 2.1 – 4mm, ‐ Lingual nerve – tongue sensation nodal metastasis 41.7% ‐ Hypoglossal nerve – tongue movement . Statistical modeling . Depth of invasion suggests 1.1 – 2mm = . Tongue movement/tethering – reconstruction 20% risk of N+ disease . Mandible . Neck management – often consider bilateral

Balasubramanian D et al, Oral Oncology 2014

5 4/5/2021

Palate/maxilla/upper gingiva

. Palate cancers often can be salivary in origin . Function to separate mouth from nose – swallowing and speech intelligibility . Holds in dentition . Occult nodal metastasis 10-15% for T1-T2 tumors

Surgical considerations

. Anatomy ‐ Hard/soft palate junction ‐ Greater palatine artery ‐ Hard palate – take it or not. Imaging and aggressiveness ‐ Gingiva ‐ Lip position . Reconstruction vs obturator

6 4/5/2021

Tongue

. Function: move food bolus around, speech, cleans teeth . Most common site of involvement . Subset of patients are young nonsmokers with lateral tongue cancer . Depth of invasion studies most relevant for neck involvement

Surgical considerations Advanced approaches to oral cavity . Anatomy ‐ Tongue musculature – try to preserve. Must be able to touch roof of mouth for speech. ‐ Hypoglossal nerve ‐ Floor of mouth involvement – prefer flap reconstruction . Boundaries are muscle – not very oncologically isolated . Access – transoral, transcervical, midline mandibulotomy, visor . Neck dissection for >3mm depth . Reconstructive ladder ‐ Secondary intention -> close primarily -> skin graft -> local flap/rotation -> free flap

7 4/5/2021

Mandible Surgical considerations

. Can be superficial on . Bony surgery is not tactile – margins can be tough to assess gingiva . Consider dental condition and mastication . Often not only site . Requires complex bony reconstruction, or none at all (swing) involved . Healing time to get to radiation . Function: hold teeth, chewing, speech, mouth opening, cosmetic

8 4/5/2021

Team Approach

. Surgery, Medical, Radiation oncology . Radiology, pathology - diagnostics . Reconstructive surgery – put things back together . Speech language pathology – swallowing & voice rehab . Dental oncology/oral surgery – dental rehab, assessment, reconstruction . Dietician – help during treatment and afterwards . Nursing – education, integration . Social work – resources, support . Symptom management service – pain management, psychological concerns, palliative care

Conclusions

. Complex set of tumors and risks . Each subsite has its own anatomic and functional considerations – surgery is a mainstay of treatment of the primary and neck . Requires multidisciplinary care and management

9 Disclosure

Nothing to disclose Comprehensive Management of Thyroid Cancer

Jonathan George, MD, MPH Associate Professor Head & Neck Surgical Oncology UCSF Medical Center

4/24/2021

Comprehensive Management of Thyroid Cancer

Objective Overview Management of Thyroid Cancer

• To inform & update radiation oncology and other advanced health . Anatomy & Epidemiology care providers on management options for advanced thyroid cancer . Clinical Evaluation, Imaging & FNA . Treatment • Advanced Thyroid Cancer . Surgery . Radioiodine Ablation . External Beam RT . Systemic Therapy

Comprehensive Management of Thyroid Cancer Comprehensive Management of Thyroid Cancer

1 4/24/2021 [ADD PRESENTATION TITLE: INSERT TAB > HEADER & FOOTER > NOTES AND HANDOUTS] Thyroid Anatomy Thyroid Anatomy

– 10-20 g butterfly-shaped gland • Important nearby structures • 2 lobes + isthmus – Trachea • Pyramidal lobe above isthmus (50%) – Recurrent laryngeal nerve – Fibrous capsule – Vessels (carotid, jugular) – Anterior to 2nd and 3rd tracheal rings – Esophagus – Parathyroid glands • Lymph node drainage – Level VI (central compartment) – Level II-IV (anterior deep cervical) – Level V (posterior cervical) – Superior mediastinum

Comprehensive Management of Thyroid Cancer Comprehensive Management of Thyroid Cancer

Thyroid Cancer Groupings Misperceptions of Thyroid Cancer

. Histological Subtypes • Differentiated • A ‘benign’ malignancy ‒ Papillary ‒ Follicular • Seldom recurs ‒ Hürthle cell • Recurrences easily managed with • Poorly differentiated surgery or I-131 ‒ Insular, Columnar, etc • Minimal survival impact ‒ Medullary • Undifferentiated ‒ Anaplastic

Comprehensive Management of Thyroid Cancer Comprehensive Management of Thyroid Cancer

2 4/24/2021 [ADD PRESENTATION TITLE: INSERT TAB > HEADER & FOOTER > NOTES AND HANDOUTS] 6 7 Differentiated Thyroid Cancer Differentiated Thyroid Cancer

.Papillary thyroid cancer (PTC) • Follicular thyroid cancer (FTC) ‒ Excellent prognosis ~ 95% 10y DSS • Risk of metastasis at diagnosis: 2-5% ‒ ~5% have distant metastasis at diagnosis – 10-year DSS: 85% • Poor prognosis variants – . Tall Cell Hürthle cell carcinoma (3%) • Less favorable prognosis . Diffuse sclerosing • Large size, invasive, early nodal and distant . Columnar cell metastasis ‒ Associated with early invasion, large • 10 yr DSS ~75% tumor size, distant metastsis

Comprehensive Management of Thyroid Cancer Comprehensive Management of Thyroid Cancer

DTC Epidemiology DTC Epidemiology

Increasing incidence, mortality unchanged… Increased incidence likely due to early capture & treatment

Ahn HS et al. Korea’s Thyroid Cancer “Epidemic” – Screening and Overdiagnosis. NEJM 371(19), Nov 6 2014.

Comprehensive Management of Thyroid Cancer Comprehensive Management of Thyroid Cancer

3 4/24/2021 [ADD PRESENTATION TITLE: INSERT TAB > HEADER & FOOTER > NOTES AND HANDOUTS] Thyroid Cancer Thyroid Cancer DTC Epidemiology Differentiated Thyroid Cancer

Excellent survival Locally recurrent disease is bad… but recurrence remains a problem • Mortality: 11-17% • Recurrence  higher mortality • 36-80% of deaths secondary to uncontrolled local disease Grogan et al, 2013: 30 year FU (N=2883): • Recurrence ~30%

Djalilian et al, 1974 Grogan RH, et al. AAES 34th Annual Meeting, 2013.

Comprehensive Management of Thyroid Cancer Comprehensive Management of Thyroid Cancer

Poorer Outcomes Poorer Outcomes

Larger Tumors Multifocal disease

• ~20-60% of DTC • 2x increased risk of nodal mets, 3x distant mets

. \

Bilimoria KY et al. Annals of Surgery 246(3), 375-384; 2007 Tsang 1998; Kebebew 2005

Comprehensive Management of Thyroid Cancer

4 4/24/2021 [ADD PRESENTATION TITLE: INSERT TAB > HEADER & FOOTER > NOTES AND HANDOUTS] Poorer Outcomes Poorer Outcomes

Extrathyroidal Extension Nodal Metastasis •36% local recurrence rate . Higher recurrence •18% death from disease . Clinical N+ Samaan et al Head Neck 1994 . ~22% recurrence Sites of Invasion • Strap muscle 53% . vs 4-6% for clinical N0 • RLN 47% 20-year Survival (DSS) • Trachea 37% . Age N0 N1 • Esophagus 21% Worse Survival • Larynx 12% <45 yrs 94% 100% • Other sites 30% >45 yrs 90% 79% McCaffery et al Head and Neck 1994, N=264, 1940-1999 p = 0.04

Comprehensive Management of Thyroid Cancer Comprehensive Management of Thyroid Cancer Cranshaw, Surg Oncol 2008; Bardet, Eur J Endo 2008; So, Surgery 2010; Wada, Ann Surg 2003.

Prognostic Factors Prognostic Factors

BRAF V600E Oncogene (PTC) BRAF V600E Oncogene (PTC) • Most common genetic alteration in PTC Present in ~20-80% • Worse outcomes in several retrospective studies of PTC ‒ Xing et al. JAMA 2013 (N=1849) • May indicate more aggressive phenotype . Overall mortality higher in patients with BRAF mutation • Associated with ETE, LN metastasis, and advanced stage (5.3% vs. 1.1%) • Worse outcomes in several retrospective studies • But not significant after accounting for other pathologic features • Unclear if this is truly an independent risk factor • BRAF inhibition: Vemurafenib, dabrafenib

Comprehensive Management of Thyroid Cancer Comprehensive Management of Thyroid Cancer

5 4/24/2021 [ADD PRESENTATION TITLE: INSERT TAB > HEADER & FOOTER > NOTES AND HANDOUTS] Clinical Evaluation Clinical Evaluation Voice Assessment

Most thyroid nodules detected by either palpation or imaging (incidental) • Preop voice assessment is officially recommended ■ All patients undergoing thyroid surgery should have preoperative voice • History assessment • Compressive symptoms, dysphagia, dyspnea, voice ■ Voice is part of the physical exam for thyroid cancer changes/hoarseness ■ Preoperative laryngeal exam should be performed in all patients with: • Symptoms of hypo- or hyperthyroidism ‐ Preoperative voice abnormalities • History of ionizing radiation ‐ Known thyroid cancer with posterior ETE or extensive CNM • Family history of thyroid cancer ‐ History of cervical or upper chest surgery ‐ Postop voice & laryngeal assessment ■ Patients should have their voice assessed in the postoperative period. ■ Formal laryngeal exam should be performed if the voice is abnormal.

Comprehensive Management of Thyroid Cancer Comprehensive Management of Thyroid Cancer

Clinical Evaluation Diagnostic Imaging Voice Assessment Ultrasound • In-clinic Nasolaryngoscopy

Initial Imaging: Diagnostic US ‐ Recommendation 6: Thyroid US ■ Thyroid/neck US for all patients with known or suspected thyroid nodules ‐ Sonographic pattern & size guide need for FNA

Comprehensive Management of Thyroid Cancer

6 4/24/2021 [ADD PRESENTATION TITLE: INSERT TAB > HEADER & FOOTER > NOTES AND HANDOUTS] Diagnostic Imaging Diagnostic Imaging Ultrasound Ultrasound

Published in Thyroid. January 2016, 26(1): 1-133. DOI: 10.1089/thy.2015.0020

© Mary Ann Liebert, Inc. FIG. 1. Algorithm for evaluation and management of patients with thyroid nodules based on FIG. 2. ATA nodule sonographic patterns and risk of malignancy. US pattern and FNA cytology. R, recommendation in text.

Comprehensive Management of Thyroid Cancer Comprehensive Management of Thyroid Cancer

Diagnostic Biopsy Diagnostic Imaging Fine Needle Aspiration Cross-sectional Imaging • CT or MRI Pattern of nodule sonographic features confers risk of malignancy which, when combined with nodule size, guides decision-making ‒ if concerning US or physical exam . Bulky thyroid mass . Lymph node metastasis US + CT have improved sensitivity and comparable . Recurrent disease . FNA cutoffs modified specificity for nodal disease in if… . Vocal cord paralysis thyroid cancer patients than either exam alone. • Presence of . Dysphagia suspicious LNs Kim E. Thyroid 2008. • Patient risk . Fixation of mass factors . Substernal extension

Comprehensive Management of Thyroid Cancer Comprehensive Management of Thyroid Cancer

7 4/24/2021 [ADD PRESENTATION TITLE: INSERT TAB > HEADER & FOOTER > NOTES AND HANDOUTS] Multidisciplinary Management Diagnostic Imaging Thyroid Cancer Conference Cross-sectional Imaging .Surgery • PET/CT ‒No role in initial diagnosis of DTC .Endocrinology . Inverse relationship between FDG avidity and .Radiology differentiation, iodine uptake • Neuroradiology & Nuclear Medicine . Poorly or De-Differentiated >FDG uptake .Pathology ‒Indications: .Radiation Oncology . Negative whole body I131 scans, Rising TG .Medical Oncology ‒Survival Correlation if high-volume FDG-avid disease Comprehensive Management of Thyroid Cancer

Management Goals “Thyroid surgery is horrid butchery; no honest and sensible .Surgery: Gross total resection surgeon would ever engage in .Post-operative RAI thyroid surgery” .TSH Suppression Samuel D. Gross – 1866 .EBRT in select cases .Systemic therapy for high-risk DM pts .Long-term surveillance with US & TG

8 4/24/2021 [ADD PRESENTATION TITLE: INSERT TAB > HEADER & FOOTER > NOTES AND HANDOUTS] “The extirpation of the thyroid gland typifies perhaps better than any operation the supreme triumph of the Theodore Kocher surgeon’s art.” - William Halsted (1841-1917)

First surgeon to win Nobel prize (1909)

Surgery Surgery Goals of Surgery Goals of Surgery

‐ Remove primary tumor, disease extending beyond thyroid capsule, • ATA Guidelines clinically evident lymph node metastases ‐ 2009 ATA ‐ Minimize risk of recurrence ■ Total thyroidectomy for any tumor >1cm with or without evidence ‐ Facilitate treatment with RAI of locoregional or distant metastasis ‐ Permit accurate staging and risk stratification ‐ 2015 ATA ‐ Permit accurate surveillance ■ New studies  Clinical outcomes are similar following unilateral ‐ Minimize treatment-related morbidity and bilateral thyroid surgery

Comprehensive Management of Thyroid Cancer Comprehensive Management of Thyroid Cancer

9 4/24/2021 [ADD PRESENTATION TITLE: INSERT TAB > HEADER & FOOTER > NOTES AND HANDOUTS] Surgery Goals of Surgery Surgery Importance of Thyroid Lymphatics

ATA 2015: Three categories ‐ Thyroid cancer <1cm without extrathyroidal extension and cN0 .Cross-communication of intraglandular lymphatics ‐ Thyroid cancer >1cm and <4cm without extrathyroidal extension .Extensive bilateral drainage and without clinical evidence of any lymph node metastasis (cN0) .High incidence of regional metastasis ‐ Thyroid cancer >4cm, or with gross ETE (cT4), or clinically .Multiple nodal groups at risk apparent metastatic disease to nodes (cN1) or distant sites (cM1) .Lymphatic channels parallel venous drainage

Comprehensive Management of Thyroid Cancer Comprehensive Management of Thyroid Cancer

Neck Lymph Node Metastasis Central Neck Surgical Management When to do a central neck dissection?

.Advanced thyroid primary: T3 or T4a .Advanced thyroid primary: T3 or T4a .Advanced age .Older age .Node positivity .Node positivity • cN+, US+, USGFNA+ • cN+, US+, USGFNA+ .Advanced histologies .Advanced histologies • Hurthle cell, Insular, cytopath “features c/w poorly differentiated carcinoma” (“spindle cells”) • Poorly differentiated • Anaplastic (IVA) • Medullary carcinoma

Comprehensive Management of Thyroid Cancer Comprehensive Management of Thyroid Cancer

10 4/24/2021 [ADD PRESENTATION TITLE: INSERT TAB > HEADER & FOOTER > NOTES AND HANDOUTS] Lateral Neck Dissection Parapharyngeal Metastasis • Be aware on imaging • Significantly less controversial • Parapharyngeal node ‒ Therapeutic only excision • Compartment-oriented en- ‒ Important to do bloc neck dissection . Open vs TORS ‒ May reduce the risk of • recurrence and possibly no comparative data mortality Cooper et al 2009 ‒ Levels IIA-VB Farrag et al 2009, Lee et al 2007; ATA Surgery Working Group

Comprehensive Management of Thyroid Cancer Comprehensive Management of Thyroid Cancer

Locally Invasive Thyroid Cancer Revision surgery Trachea, Larynx, Esophagus Significantly higher risk

• Significantly higher risk due to more variable anatomy Radical resection may be necessary to remove all • Full-compartment surgery if minimal prior dissection gross disease • Focused surgery may be relevant Incomplete resection  High rates of local relapse ‒ Preop imaging shows a localized target and decreased survival . Targeted dissection Central premise: clear disease to protect vital functions of breathing, speaking, and swallowing.

Comprehensive Management of Thyroid Cancer Comprehensive Management of Thyroid Cancer

11 4/24/2021 [ADD PRESENTATION TITLE: INSERT TAB > HEADER & FOOTER > NOTES AND HANDOUTS] Locally Invasive Thyroid Cancer Locally Invasive Thyroid Cancer RLN Invasion Management of the Functional RLN

• Always reduce down to microscopic residual disease whenever feasible • Exception: Both functioning RLNs grossly involved • Do not leave “gross disease” • For tracheal margins, seek microscopic free margins if feasible (without laryngectomy)

Comprehensive Management of Thyroid Cancer Comprehensive Management of Thyroid Cancer

Local Invasion Locally Invasive Thyroid Cancer Trachea – Sleeve Resection Management of the Functional RLN

RLN RLN Tumor

Tumor

Nerve Preservation Nerve Resection

Comprehensive Management of Thyroid Cancer Comprehensive Management of Thyroid Cancer

12 4/24/2021 [ADD PRESENTATION TITLE: INSERT TAB > HEADER & FOOTER > NOTES AND HANDOUTS] Local Invasion Invasion of Trachea Trachea – Sleeve Resection Sleeve Resection

Comprehensive Management of Thyroid Cancer Comprehensive Management of Thyroid Cancer

Invasion of Trachea Invasion of Trachea Sleeve Resection Sleeve Resection

Comprehensive Management of Thyroid Cancer Comprehensive Management of Thyroid Cancer

13 4/24/2021 [ADD PRESENTATION TITLE: INSERT TAB > HEADER & FOOTER > NOTES AND HANDOUTS] Invasion of Trachea Invasion of Trachea Sleeve Resection Sleeve Resection

Comprehensive Management of Thyroid Cancer Comprehensive Management of Thyroid Cancer

Local Invasion Local Invasion Esophagus Larynx

.Independent survival predictor .Mucosal invasion is rare (6%) .Often associated with concomitant tracheal invasion, RLN compromise .May need to consider laryngopharyngectomy • Need to be ready for reconstruction

McCaffrey et al, Nakao et al 2009

Comprehensive Management of Thyroid Cancer Comprehensive Management of Thyroid Cancer

14 4/24/2021 [ADD PRESENTATION TITLE: INSERT TAB > HEADER & FOOTER > NOTES AND HANDOUTS] Local Invasion Local Invasion Larynx When to do a laryngectomy? .Insufficient data .Follow axiom of local control .Most often seen in recurrence of patient noncompliant with surveillance, rather than primary treatment .Laryngectomy for local control and functional optimization

Comprehensive Management of Thyroid Cancer Comprehensive Management of Thyroid Cancer

Invasion of Larynx Local Invasion Larynx Anterolateral vertical hemilaryngectomy

Comprehensive Management of Thyroid Cancer Comprehensive Management of Thyroid Cancer

15 4/24/2021 [ADD PRESENTATION TITLE: INSERT TAB > HEADER & FOOTER > NOTES AND HANDOUTS] Postoperative Management in WDTC Adjuvant Treatment for DTC

2015 ATA Guidelines: Modified Initial Risk Stratification System (MIRS) • Thyroxine suppression of TSH • Risk Stratification for recurrence after initial surgery and remnant • Radioactive iodine (RAI) therapy ablation • External beam radiotherapy (EBRT) • 2015 Guidelines use ~same system as 2009 • Systemic therapy

Comprehensive Management of Thyroid Cancer 4/24/2021 Comprehensive Management of Thyroid Cancer

Adjuvant Treatment for DTC Adjuvant Treatment for DTC TSH Suppression Radioiodine ablation

• Thyroid Hormone for TSH Suppression Goals of RIA • Restores normal endocrine function .Ablate thyroid remnant to achieve undetectable TG • Suppresses TSH secretion .Eliminate suspected micrometastases • Reduces recurrence rates .Ablate known persistent disease to decrease recurrence risk ‒ Eliminates trophic effect of TSH on residual thyroid cells .Integral to surveillance with total body iodine scans and thyroglobulin measurements

Comprehensive Management of Thyroid Cancer Comprehensive Management of Thyroid Cancer

16 4/24/2021 [ADD PRESENTATION TITLE: INSERT TAB > HEADER & FOOTER > NOTES AND HANDOUTS] Adjuvant Treatment for DTC Adjuvant Treatment for DTC RAI: NCCN Guidelines RIA: NCCN Guidelines Recommended for ALL patients with I-131 Dosing .Gross extrathyroidal extension .Thyroid remnant ablation: 30 mCi .Primary tumor size > 4 cm .Adjuvant therapy: 30-100 mCi .Distant metastases .Treatment of metastatic foci: 100-200 mCi

n Post-operative unstimulated Tg > 5-10 ng/mL

NCCN Clinical Practice Guidelines Version 2.2012. 12/19/2011 Schlumberger et al. and Mallick et al. NEJM 2012

Comprehensive Management of Thyroid Cancer Comprehensive Management of Thyroid Cancer

Adjuvant Treatment for DTC Adjuvant Treatment for DTC RIA: Update External Beam Radiotherapy Schlumberger, et al. NEJM May 2012 • Role not well-defined • No prospective studies • Adjuvant & palliative treatment in high-risk pts • Multiple retrospective studies Mallick, et al. NEJM May 2012 • Improvement in LRC & DFS in high-risk patients

Comprehensive Management of Thyroid Cancer

17 4/24/2021 [ADD PRESENTATION TITLE: INSERT TAB > HEADER & FOOTER > NOTES AND HANDOUTS] Adjuvant Treatment for DTC Adjuvant Treatment for DTC External Beam Radiotherapy Postop EBRT: Retrospective Data Indications Authors N % EBRT Benefit Subset benefitting None are consistent, mutually exclusive • Older age (45 or 60 years-old) Farahati et al. 169 59 LRC pT4, >40 yo, and LN+ • Massive primary disease • Extensive extrathyroidal extension • Macroscopic iodine-negative components Brierley et al. 729 44 LRC, DSS pT4, >60 yo, • Recurrent locoregional disease, particularly if not iodine-avid Chow et al. 842 12 LRC Gross residual • Resection of all gross recurrence Kim et al. 91 25 LRC pT4 or N+ • Morbidity of additional surgery Philips et al. 91 25 LC ETE or +margin

Comprehensive Management of Thyroid Cancer

Adjuvant Treatment for DTC Adjuvant Treatment for DTC Postop EBRT: Acute Side Effects Postop EBRT: Late Side Effects Acute Side Effects Late Side Effects • Mucositis of larynx, trachea and esophagus • Dry mouth (depends on radiation technique and • Skin erythema and desquamation prior RAI) • Dry mouth • Fibrosis of the soft tissues of the neck • Airway edema • Possible esophageal stenosis • Possible vascular injury

18 4/24/2021 [ADD PRESENTATION TITLE: INSERT TAB > HEADER & FOOTER > NOTES AND HANDOUTS] Treatment of Metastatic DTC Treatment of Metastatic DTC Systemic TKI Treatment Options • First targets: VEGF, VEGF • I-131 • Other targets identified • Systemic therapy (TKI) • BRAF, NRAS, HRAS, RET/PTC, FGFR, PDGFR • Surgery for focal DM • Multitargeted TKIs developed • Sorafenib (Nexavar) • TKI targeting VEGFR-1, -2, and -3, -PDGFR β, Raf- 1, RET, and BRAF

B Salajegheh A et al. Eur J Surg Oncol 2011; Ferrara N et al. Nat Med 2003; Yu XM et al. Ann Surg 2008

Treatment of Metastatic DTC Treatment of Metastatic DTC Systemic TKI Systemic TKI • Multitargeted TKIs developed • Multitargeted TKIs developed Lenvantinib Lenvantinib Schlumberger M et al. NEJM 2015. Phase 3 Schlumberger M et al. NEJM 2015. Phase 3 • Phase 3 multicenter study • Lenvantinib vs placebo • RAI-refractory thyroid cancer • HR (progression/death): 0.21 (0.14-0.31, p<0.001) • PFS benefit observed in all subgroups

Bergers G et al. Nat Rev Cancer 2008. Ebos JM et al. Clin Cancer Res 2009. Boelaert K et al. J Bergers G et al. Nat Rev Cancer 2008. Ebos JM et al. Clin Cancer Res 2009. Boelaert K et al. J Clin Endocrinol Metab 2003. He G et al. Oncol Lett 2014. Volante M et al. J Clin Endocrinol Clin Endocrinol Metab 2003. He G et al. Oncol Lett 2014. Volante M et al. J Clin Endocrinol Metab 2009. Metab 2009.

19 4/24/2021 [ADD PRESENTATION TITLE: INSERT TAB > HEADER & FOOTER > NOTES AND HANDOUTS] Treatment of Metastatic DTC Medullary Thyroid Carcinoma Systemic TKI – Neuroendocrine parafollicular C-cell origin • Multitargeted TKIs developed • Do not have TSH receptors Carbozantinib  Metastatic MTC • Do not take up iodine Vandetanib  Unresectable or metastatic MTC Doxorubicin  All metastatic TC – Lymph nodes frequently involved (~50%) Sorafenib  Recurrent, RAI-nonavid TC – Calcitonin staining is specific – 80% are sporadic, but some can result from • Side effects MEN 2 syndrome. • Hand and foot skin rxn, diarrhea, alopecia, rash, • Hereditary cases/syndromes myelosuppresion, cardiotoxicity – Germline RET mutation – MEN2A & 2B

Bergers G et al. Nat Rev Cancer 2008. Ebos JM et al. Clin Cancer Res 2009. Boelaert K et al. J Comprehensive Management of Thyroid Cancer Clin Endocrinol Metab 2003. He G et al. Oncol Lett 2014. Volante M et al. J Clin Endocrinol Metab 2009.

Medullary Thyroid Carcinoma (MTC) Undifferentiated/Anaplastic Synopsis – <5% of thyroid cancers – .Surgery 15-40% of thyroid cancer deaths – Mean age of diagnosis is 65 .No RAI or TSH suppression – Rapidly growing, widely invasive, may see regions .Role for EBRT  Enhance locoregional control of necrosis and hemorrhage .Systemic TKI therapy  Role in metastatic disease – Undifferentiated histology – Thought to be a de-differentiation of a previously differentiated thyroid cancer. • 20-30% have concurrent papillary thyroid CA • p53 loss thought to be a major step in de- differentiation.

Comprehensive Management of Thyroid Cancer

20 4/24/2021 [ADD PRESENTATION TITLE: INSERT TAB > HEADER & FOOTER > NOTES AND HANDOUTS] Anaplastic Thyroid Cancer ATC Management

Synopsis Synopsis • <5% of thyroid cancers .No effective therapy exists • 14-40% thyroid cancer deaths • BRAF–targeted therapy may delay mortality • Mean age of diagnosis is 65 .Disease is nearly universally fatal • Rapidly growing, widely invasive, may see regions • Median survival ~3-7 months of necrosis and hemorrhage .Extensive local invasion is common • Undifferentiated histology .DM at diagnosis ~50% – Spindle Cell .RAI not useful for treatment or imaging – Giant Cell – Squamoid

Untch et al, 2006

ATC Management ATC Management

Surgery Chemoradiotherapy • Indicated only If complete .Clinical trials preferred resection is possible .Improves short-term survival, • Debulking  no benefit local control, and palliation • Higher RT doses associated with improved survival • CRT following complete resection may provide prolonged survival

De Crevoisier R et al. Int J Radiat Oncol Biol Phys 2004.

Comprehensive Management of Thyroid Cancer Comprehensive Management of Thyroid Cancer Wang 2006

21 4/24/2021 [ADD PRESENTATION TITLE: INSERT TAB > HEADER & FOOTER > NOTES AND HANDOUTS] Summary Summary Comprehensive Management of Thyroid Cancer Comprehensive Management of Thyroid Cancer

• Thyroid cancer can be aggressive • Beware of clinical presentation • Surgery front-line to remove all possible gross disease • RAI and EBRT for residual disease • Systemic therapy for distant metastasis • Managing aggressive thyroid cancer is a team effort

Comprehensive Management of Thyroid Cancer Comprehensive Management of Thyroid Cancer

22 4/24/2021 [ADD PRESENTATION TITLE: INSERT TAB > HEADER & FOOTER > NOTES AND HANDOUTS] 4/20/2021

Panelists

• Sue Yom, MD, PhD, MAS –Radiation Oncology HN Case‐Based Learning: • Hyunseok Kang, MD –Medical Oncology Self‐Assessment Session • Patrick Ha, MD –Head and Neck Surgery • Jonathan George, MD –Head and Neck Surgery UCSF Radiation Oncology Annual Course 2021 • Jason Chan, MD –Radiation Oncology (Moderator)

Learning Objectives Case 1

• Understand ongoing de‐escalation strategies on protocol for HPV‐ • 71 y.o. never smoker with AJCC8 associated oropharyngeal squamous cell carcinoma T1N1 (AJCC7 N2b) SCC of the left tonsil • Define the current consensus recommendations for post‐operative • Physical exam noted nodule in left neck management in oral tongue squamous cell carcinoma inferior pole, no BOT involvement • Define the current recommendations for head and neck re‐irradiation • PET/CT • Hypermetabolic level 2A lymph • Updates in systemic therapy for recurrent and metastatic squamous nodes measuring up to 2.5 cm in cell carcinoma largest dimension. • Soft tissue effacement of the left vallecula and left glossal tonsilar sulcus, but without hypermetabolic activity.

1 4/20/2021

TORS ORATOR1 • Resect with 1 cm margins ORATOR • Circumferential margins taken • Primary RT (68% chemo) had • Surgeons required to have statistically superior experience of ≥ 10 TORS cases swallowing scores, less pain • Tracheostomy strongly recommended but not mandatory and trend toward less shoulder dysfunction at 1 year Adjuvant RT alone compared to primary surgery • pT3‐4, N+, LVI, SM < 2 mm (71% PORT)

Adjuvant CRT • Primary RT with more hearing • SM+, ENE loss (38% vs. 15%), tinnitus

Nichols, Lancet Oncol 2019 (35% vs. 6%) Nichols, Lancet Oncol 2019

SA‐CME: The ORATOR study was a phase 2 study that randomized patients with T1–T2, N0–2 (≤4 cm) squamous cell ECOG 3311 Low Risk: carcinoma of the oropharynx to radiotherapy (70 Gy, with T1‐T2, N0‐N1 AND clear (> 3mm) chemotherapy if N1–2) or TORS plus neck dissection (with or margins, AND no ECE or PNI/LVI without adjuvant chemoradiotherapy, based on pathology). Intermediate Risk: Which of the following were true? “Close" (< 3mm) margin(s), OR "Minimal" (< 1mm) ECE, OR N2a (1 or more lymph node >3cm in diameter), A. Swallowing‐related QOL scores were higher in the RT arm 5 years OR N2b (2‐4 lymph nodes positive, any after treatment diameter < 6cm), OR PNI/LVI

B. Swallowing‐related QOL scores were higher in the RT arm 1 year High Risk: after treatment Positive margin(s), OR “Extensive” (> 1mm) ECE, OR ≥ 5 metastatic lymph C. There were more cases of trismus in the RT arm nodes (regardless of primary tumor D. There were less cases of hearing loss in the RT arm margin status)

2 4/20/2021

ECOG 3311 (ASCO 2020) NRG HN‐002

N2‐year PFS Deaths Recurrences LRF DM (without recurrence) Arm A (0 Gy) 37 93.9% 0 2 1 1 Arm B (50 Gy) 102 95.0% 1 4 2 2 Arm C (60 Gy) 104 95.9% 0 4 0 4 Arm D (66 Gy + 110 90.5% 3 7 4 3 • Higher acute but not late grade 3‐ CDDP 40 mg/m2 4 toxicities with IMRT + C weekly) • 1‐year MDADI mean scores were high and not different between IMRT + C vs. IMRT (85.30 vs. 81.76)

Ferris, ASCO 2020 Yom, J Clin Oncol 2021

NRG HN‐005 60 Gy in 5 weeks on NRG HN‐002 PI: Dr. Sue Yom

8th ed. stage I-II excluding T0, T1-2N0, or any N2

3 4/20/2021

Which of the following patients with Case 2 squamous cell carcinoma of the oropharynx • 58 y.o. male h/o Hodgkin’s Lymphoma and R neck radiotherapy 10 years ago with new would NOT be eligible for NRG HN‐005? left lateral tongue SCC cT1N0. • L partial glossectomy and L selective ND levels I‐III, primary closure • Unifocal 1.8 x 1.4 x 0.7 cm A. T2N1 (AJCC 8th edition) and 10 pack‐year smoking history • Depth of invasion 7 mm th • Poorly‐differentiated B. T2N1 (AJCC 8 edition) and 5 pack‐year smoking history • Negative margins, closest 12 mm from deep C. T2N0 (AJCC 8th edition) and 5 pack‐year smoking history • Unifocal intratumoral PNI 0.2 mm • Worst Pattern of Invasion present (tumor D. T3N0 (AJCC 8th edition) and 10 pack‐year smoking history satellites) • 0 of 38 nodes • pT2N0

Depth of Invasion is not tumor thickness Oral Tongue T Stage by Size and DOI

• The horizon is at the level of T Category Size DOI the basement membrane T1 ≤ 2 cm ≤ 5 mm relative to the closest intact squamous mucosa T2 ≤ 2 cm > 5 mm • The greatest DOI is measured > 2 cm and ≤ 4 cm ≤ 10 mm by dropping a “plumb line” from the horizon T3 > 2 cm and ≤ 4 cm > 10 mm > 4 cm ≤ 10 mm T4a >4 cm > 10 mm

AJCC 8th Edition AJCC 8th Edition (Refer to 3rd Print)

4 4/20/2021

58 M with poorly‐differentiated SCC of the left lateral oral tongue, pT2 (DOI 7 mm) N0 Stage II, negative Omission of RT in pN0 neck margins, unifocal intratumoral PNI 0.2 mm, WPOI‐5 • Discussion: what would you recommend for adjuvant • Exclusion: prior HN cancer, radiotherapy prior HN surgery • No radiation • No contralateral neck PORT • Radiation to primary alone • 24% tumor bed PORT only • Radiation to primary and ipsilateral neck • 47% concurrent chemo • Radiation to primary and bilateral neck • Unirradiated neck control 97%

Contreras, J Clin Oncol 2019

SA‐CME: A recent phase II study evaluated 58 M with poorly‐differentiated outcomes after omission of postoperative SCC of the left lateral oral tongue, radiotherapy to the pN0 neck. What was the pT2 (DOI 7 mm) N0 Stage II, unirradiated neck control on this study? negative margins, PNI, WPOI‐5

A. 97% • 60 Gy in 30 fractions B. 74% to tumor bed • 54 Gy in 30 fractions C. 46% to ipsilateral neck D. 24%

5 4/20/2021

70 M ECOG 1 with neck recurrence 4 years from prior Case 3 RT, encasing carotid, PD‐L1 CPS 50% • 70 y.o. male with • Discussion: what would you recommend history of p16+ SCC R tonsil, T4N2b • Clinical trial (AJCC7) treated with • Salvage neck dissection chemoradiation to 6996 cGy in 33 • Anti PD‐1 ± Chemotherapy fractions • SBRT • 4 yrs later with L • Chemoradiation neck recurrence encasing carotid, p16+ SCC PD‐L1 CPS 50%; ECOG 1

MIRI Collaborative: retrospective cohort of > 400 HN patients No benefit with hyperfractionation or elective treated with conformal re‐irradiation at 9 institutions nodal treatment with re‐irradiation in IMRT era

Caudell, Int J Radiat Oncol Biol Phys. 2018

6 4/20/2021

SA‐CME: A multi‐institutional retrospective cohort study on Re‐irradiation target reirradiation of recurrent or second primary squamous carcinoma of the head and neck found that elective nodal treatment had what impact on locoregional control (LRC) and overall survival (OS)?

A. Improved LRC, no improvement on OS B. Improved LRC and OS C. No improvement on LRC or OS D. No improvement on LRC, improved OS • 66 patients re‐irradiated with 3D‐CRT/ IMRT to rGTV + 5 mm • 47 LRFs (71%), of which 96% occurred within the re‐irradiated rGTVs • Support small re‐RT targets to reduce re‐irradiated tissue volumes

Popovtzer et al. Int J Radiat Oncol Biol Phys. 2009

SBRT Re‐Irradiation Case 4

• 70 M h/o T4N2 p16+ OPC CRT in 2013, 4 yrs later with L neck recurrence • 61 year‐old 60 py smoker with p16 • SBRT with Cetuximab, 40 Gy in 5 fx QOD negative squamous cell carcinoma of the right neck T0N3bM0 AJCC8 Stage IVB • PET/CT • Large nodal conglomerate centered in the right lateral neck • Local invasion of the carotid sheath resulting in right IJ compression and CN XI and XII denervation • Next step?

7 4/20/2021

Total population: Pembro vs. Chemo TPF x 2 KEYNOTE‐048

• Decrease sized of right • Randomized (1:1:1) to pembro alone neck mass but new lung vs. pembro + chemo vs. cetuximab + nodules, concerning for chemo metastasis • Pembro with a platinum and 5- fluorouracil improved OS in total Total population: Pembro with Chemo vs. Chemo • Molecular profiling population • TP53, ARID1A and PIK3CA • Pembro alone improved OS in CPS ≥ 1 with low tumor mutation and ≥ 20 subgroups burden • Establishes anti-PD-1-based therapy • More consistent with as a first-line treatment option for mucosal HN SCC than patients with locally incurable recurrent cutaneous or metastatic HNSCC • Next step?

Burtness, The Lancet 2019

SA‐CME: What were the treatment arms on KEYNOTE‐048, Pembrolizumab x 10 cycles which supports the use of Pembrolizumab in the first‐line treatment of recurrent or metastatic HNSCC? • Complete response of presumed lung metastases but progression of neck disease A. Pembrolizumab vs. Placebo • Cetuximab added to Pembro for 3 additional cycles but B. Pembrolizumab vs. Pembrolizumab + chemotherapy continued progression of neck disease • C. Pembrolizumab vs. cetuximab + chemotherapy Next step? D. Pembrolizumab vs. Pembrolizumab + chemotherapy vs. cetuximab + chemotherapy

Pembro x 10 Cetux/Pembro x 3

8 4/20/2021

61 year‐old 60 py smoker with p16 negative squamous cell carcinoma of the right neck Case 5 T0N3bM0 AJCC8 Stage IVB • 63 year‐old • VMAT 6 MV immunocompetent male with cSCC of the right 6996 / 5940 / posterior scalp s/p Mohs 5412 cGy in 33 • Tumor extended to fractions periosteum. No residual • Weekly cisplatin tumor after 2 stages. No 40 mg/m2 PNI or LVI. • CT simulation suspicious for early recurrence, FNA confirmed cSCC • Next step?

63 M cSCC of posterior scalp Cemiplimab in Metastatic cSCC

• He undergoes right posterolateral • Immunocompromised selective neck dissection (1/2 nodes patients excluded involved with ENE) and left selective neck dissection (4/4 nodes involved, • IV Cemiplimab (PD‐1) 3 with ENE) mg per kg Q2 weeks • Starts adjuvant radiotherapy 66 Gy in • ORR 50% 33 fractions • In‐field progression during radiation • Next step?

Migden, NEJM 2018

9 4/20/2021

Cemiplimab in Metastatic cSCC Pembrolizumab in Recurrent/Metastatic cSCC

• Immunocompromised patients excluded • IV Cemiplimab (PD‐1) 3 mg per kg Q2 weeks • ORR 44%

Migden, Lancet Oncol 2020 Grob, J Clin Oncol 2020 (KEYNOTE‐629)

63 M cSCC of posterior scalp, in‐field recurrence during adjuvant radiotherapy • Re‐planned with 70 Gy to gross disease • Two cycles of cemiplimab added during radiation • PET/CT 4 months post‐RT NED • Continuing adjuvant cemiplimab

Mary Feng, MD

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4/23/2021

Outline

• Overview Organ Preservation in • Treatment Paradigm • Evaluation of Response Rectal Cancer • Surveillance UCSF Annual Radiation Oncology Course, April 24, 2021 • Outcomes Mekhail Anwar • Local recurrence Associate Professor, Radiation Oncology, UCSF • Salvage • Distant Recurrence [email protected] • Critical Questions • Dose escalation • Patient Selection

Anatomy Drives Treatment Do Patients With a pCR Need Surgery? • Upper, middle, RT ? lower segments govern new paradigms in management TNT

NOM

Rodel, J Clin Oncol;2005

1 4/23/2021

Do patient with a pCR need surgery? Rationale for Non‐Operative Management Radical rectal resection associated with • Significant toxicity • Surgical complications in ~30% • Peri‐op mortality up to 3% • Permanent or temporary stoma • Impaired bowel function • Late complications: • Bowel obstruction • Incisional hernias • Urinary incontinence • Sexual dysfunction

Rodel, J Clin Oncol;2005 Adapted from Dr. Karen Goodman

Rationale for Non‐Operative Management Rationale for Non‐Operative Management Clinical Complete Response Incomplete Response

Adapted from Dr. Karen Goodman World J Gastrointest Surg. 2015 Nov 27; 7(11): 306–312.

2 4/23/2021

Treatment Paradigm Evaluation of Response

Assessment Criteria DRE No palpable tumor Endoscopy Flat white scar with or without telangiectasia; no ulcer; no nodularity Imaging ‐ Significant regression with fibrosis and with no residual tumor ‐ Low signal intensity (dark) on T2 images ‐ No evidence of extra rectal residual disease Diffusion: ‐ Low signal on high (800‐1000) B‐ value; lack of, or low signal, on ADC map ‐ No suspicious/visible lymph nodes. Biopsy* Negative Courtesy of, and adapted from, Dr. K. Goodman

Near Complete Response When to Assess cCR Assessment Near complete response Time from completion of neoadjuvant treatment to assessment of response versus DRE Absence of ulceration; smooth induration or minor mucosal abnormalities local regrowth Endoscopy Small mucosal nodules or minor irregular mucosal abnormality Superficial ulceration Mild persisting erythema of the scar Imaging Obvious downsizing with fibrosis but heterogeneous or irregular aspect or signal; Mostly dark T2; some remaining intermediate signal Nodes: Obvious downsizing but nodes >5 mm without malignant enhancement Diffusion: Significant regression with small focal area of high signal on high b‐value; Minimal or low residual signal on ADC map Biopsy (rare) Dysplastic changes Dossa et al, Lancet Gastroenterol Hepatol 2017; 2: 501–13

3 4/23/2021

Response Rates Timing of Recurrence • CRT with 45 Gy • 126 patients •  • 54 Gy  6 cycles of 5FU‐based CTX 333 pts 259 to surgery • 31 to Watch and Wait (10%) • 80 had initial cCR (63%) • + 98 pts from OnCoRe registry • 9 underwent LE out of abundance of caution (pCR for all) • LR in 44 of 129 pts • 22 had LR (@ median 1 yr) • 7 of 44 with DM • 27‐40% LR • 88% salvaged • 49 had no LR (60%) • Median interval to cCR: 19 weeks (2/3’s > • OS and DFS 16 weeks) reduced for those • 22% > 6 months who recur, • 6 (12%) developed DM @ 10.3 ±8.7 despite salvage months

Renehan et al, Lancet Oncol 2015

Timing of Recurrence International Watch and Wait Database • 11 studies 602 patients, med f/u of 37.6 months • Outcomes InterCoRe consortium IWWD • LR (2 yr): 21.4% • OS (5 yr): 87% N 602 880 • DFS [non regrowth*] (5 yr): 81% • DM (3 yr): 9% LR (2 yr) 25.2 21.4 • 50% had local regrowth OS (5 yr) 84.7 87 • cT stage vs LR @ 2‐year • 19% for cT1 and cT2 DM (3 yr) 8 9 • 31% for cT3 • 37% for cT4 Salvage 89 69 • Factors not associated with LR • N +/‐; CEA; RT Dose (>60?) ‐ R0 97 88 • Salvage ‐ OS post salvage (3 yr) 80.1 • 83% salvaged (50% with colostomies) • OS (3 yrs after salvage): 80% ‐ DFS post salvage (5 yr) 81.3 • 50% in those not undergroing salvage with LR (mets/cormodbidities) Chadi et al, Lancet Gastroenterol Hepatol 2018; 3: 825–36

*non-regrowth disease-free survival: length of time after treatment until death (any cause), local pelvic recurrence, and distant metastasis—not including local regrowths van der Valk, Lancet 2018; 391: 2537–45

4 4/23/2021

OPRA OPRA: Patient Characteristics

• 324 patients MRI Stage 2 or 3, requiring APR or coloanal anastomosis • 4 months of oxaliplatin‐based chemotherapy + CRT (50 Gy + 4‐6 Gy boost) • Restage 8‐12 weeks after TNT with DRE, flex sig, and MRI • cCR or nCR  WW • Incomplete response  TME

OPRA: Treatment Course Disease Free Survival

5 4/23/2021

Distant Metastases Free Survival TME‐Free Survival by Treatment Group

Path Stage at Surgery Surveillance Assessment OPRA DRE, Sigmoidoscopy, q4m x 2 yrs q6m x 3 yrs Colonoscopy 1 yr after diagnosis; per guidelines thereafter Imaging (MRI) q6m x 2 yrs q12m x 3 yrs Imaging (CT CAP) q12m x 5 years CEA q4m x 2 yrs q6m x 3 yrs

6 4/23/2021

OPRA Controversies Summary

• CRT prior to CTX biases response • NOM can be safely. Implemented in favor of CRT • • We do not see a sudden jump in Strict adherence to follow up is needed TME at evaluation period • Responses can take up to 6 months • These have responded and then recurred early versus not responding • CRT  CTX may be advantageous • Dose intensification • Higher CRT dose in (chemo) consolidation • Median difference 2 Gy (5% dose) • More use of 5FU with RT in consolidation arm • Only 6% difference • Induction arm received more systemic therapy

7 3/16/2021

Rectal Cancer Response Disclosure Assessment Using MRI • Stockholder, Nextrast, Inc Zhen Jane Wang, MD Professor in Residence UCSF Department of Radiology

Why rectal cancer imaging Rectal MRI • Select patients for MRI • Advantages • Sphincter preserving • Excellent visualization of surgery anatomy, can see high nodal disease and past • Neoadjuvant therapy stenoses • MRI for local staging PET • CT+/-PET for distant • High resolution MRI disease staging predicts curative resection vs potential failure

1 3/16/2021

Rectal MRI Technique Rectal MRI Interpretation • Key: High resolution (small • Mnemonic “DISTANCE” field of view) T2 weighted • DIS: Distance from inferior tumor to anal images verge • ~3mm slice thickness • T: T staging • 0.6-0.8mm in plane • A: Anal complex resolution • N: nodal staging • Axial /coronal planes • C: Circumferential resection margin orthogonal to the rectal wall • E: Extramural vascular invasion • To improve local staging

Nougaret et al. Radiology. 2013; 268: 330-344

Rectal Cancer Staging-DISTANCE Rectal Cancer Staging-DISTANCE Distance from anal verge T1/2: tumor confined to muscularis propria >10cm, High rectal cancer <5cm, Low rectal cancer

T2 w sequence

2 3/16/2021

Rectal Cancer Staging-DISTANCE Rectal Cancer Staging-DISTANCE T3: tumor invades mesorectum Advanced T3 disease Early T3 disease (> 5mm invasion) (< 5mm invasion)

T2 w sequence

Rectal Cancer Staging-DISTANCE Rectal Cancer Staging-DISTANCE

Advanced T3 disease • MR excellent for T4: tumor invades bladder (> 5mm invasion) predicting depth of invasion into the mesorectum • >5mm invasion associated with worse prognosis

Axial T2 image Sagittal T2 image MERCURY Study group, Radiology 2007, BMJ 2006

3 3/16/2021

Rectal Cancer Staging-DISTANCE Rectal Cancer Staging-DISTANCE

Tumor involves levator ani and internal • Anterior peritoneal reflection sphincter For low rectal cancer • Must be assessed in high  Assess relationship to the rectal tumor sphincter complex to • Invasion through the determine feasibility of peritoneal reflection is T4 sphincter preserving Increase recurrence surgery

Coronal T2 image

Rectal Cancer Staging-DISTANCE Rectal Cancer Staging-DISTANCE

• Suspicious nodes • >5mm • Mesorectal fascia • Irregular border represents the surgical • Heterogenous signal excision plane (CRM) • Note any suspicious pelvic side- CRM wall lymph nodes • CRM involvement • adjust radiation field predicts recurrence and • additional node dissection during surgery poor survival within 1mm of mesorectal fascia Coronal T2 image

4 3/16/2021

Restaging of Rectal Cancer After Rectal Cancer Staging-DISTANCE Neoadjuvant therapy • Accurate assessment of treatment • Extramural vascular response can influence patient invasion management and quality of life • Independent risk factor Tumor with complete or near for recurrence complete response  Non-operative management may be appropriate • Expanded vessel Accurate MRI assessment in T4 • Tumor signal in the tumor following treatment is useful to vessel avoid unnecessary exenterative surgery

Restaging of Rectal Cancer After Restaging of Rectal Cancer After Neoadjuvant therapy Neoadjuvant therapy • Difficulty in reliably distinguishing fibrosis • MRI is most commonly used vs. residual tumor • MR accuracy in re-staging • Dark T2 signal favors fibrosis Less accurate than baseline • Diffusion weighted MRI may be helpful Meta-analysis of 33 studies with  Improves sensitivity of detecting 1556 patients: sensitivity of 50% residual disease (helps to exclude and specificity of 91% for patients from non-operative detecting residual tumor using management) T2-weighted MRI  Low PPV (cannot confidently identify complete responders)  Limited by artifact Chen et al. Dis Colon Rectum 2005;48(4):722–728. Kuo et al. Dis Colon Rectum 2005;48(1):23–28. Chen et al. Dis Colon Rectum 2005;48(4):722–728. Kuo et al. Dis Colon Rectum 2005;48(1):23–28. Kim et al. Radiology 2009;253(1):116–125. van der Paardt MP et al. Radiology 2013; (1):101-12 Kim et al. Radiology 2009;253(1):116–125. van der Paardt MP et al. Radiology 2013; (1):101-12

5 3/16/2021

Restaging of Rectal Cancer After Restaging of Rectal Cancer After Neoadjuvant therapy Neoadjuvant therapy

• 48 year old man with T3 low rectal tumor • Post-treatment MRI shows good response with decreased tumor volume and low T2 signal consistent with fibrosis

Baseline Post-neoadjuvant

Restaging of Rectal Cancer After Restaging of Rectal Cancer After Neoadjuvant therapy Neoadjuvant therapy

• 43 year old man with T3 rectal tumor • Post-treatment diffusion weighted MRI shows residual tumor with diffusion restriction.

Baseline Post-neoadjuvant

6 3/16/2021

Restaging of Rectal Cancer After How to further improve staging post- Neoadjuvant therapy CRT? • Recent study (50 patients) suggests improved staging using combination of clinical assessment (digital rectal exam, endoscopy with or without biopsy) and MRI Identified 98% of complete responders Needs further validation • Greater standardization in MRI performance • Multidisciplinary TB discussion of discordant, unusual or challenging cases to reach consensus on best treatment approach

Maas et al. Ann Surg Oncol 2015;22(12):3873-3880 Blazic et al. Br J Radiol 2016;89(1064):20150964

PET/MRI for one-stop staging? PET/MRI for one-stop staging?

T2 N1 rectal cancer Metastatic rectal cancer

7 3/16/2021

Take home message Thank you!

[email protected]

8 4/16/2021

Panel Disclosure GI Oncology • Mary Feng, MD • Mary Feng, MD – Research (Varian,UpToDate Breast Sarcoma • Mekhail Anwar, MD, PhD Chapter, Zenith Epigenetics), Consultant (Myovant Sciences, Case‐Based • Jane Wang, MD Riovant Sciences, Astellas Pharma), Stock (SerImmune) • Sorbarikor Piawah, MD • Mekhail Anwar, MD, PhD ‐ None Review • Jane Wang, MD ‐ None Moderator: Horatio Thomas, MD • Sorbarikor Piawah, MD ‐ None

1. Understand staging studies for rectal cancer Case 1

2. Discuss the rationale for total • 56‐year‐old man with hematochezia. neoadjuvant therapy for rectal cancer PCP notes a mass on DRE • Colonoscopy shows an ulcerated 5cm Learning 3. Discuss the pros and cons of organ mass 4‐5 cm from the anal verge. preservation strategies for rectal cancer Biopsy shows moderately differentiated Objectives adenocarcinoma, MMR intact. 4. Understand imaging and staging for • CEA is not elevated. CT ‐ no mets pancreatic cancer • Flexible sigmoidoscopy shows a distal rectal tumor just proximal to the 5. Discuss management options for anorectal ring hepatocellular cancer

1 4/16/2021

Rectal Cancer Staging: MRI & Prognosis What is your preferred method for local staging of rectal cancer? Mercury Trial • MRI assessment of Circumferential Resection Margin predicts LR, DFS, & OS 1. Endorectal ultrasound QUESTION 1 • 2. MRI Involvement of CRM is significantly associated with risk of metastasis 3. CT CRM involved on CRM clear on MRI P value 4. PET CT MRI 5 yr OS 30.2 % 63.3 %P < 0.001 63.3 %34 % 63.3 % P < 0.001 5yr LR 26.4% 6.5 %P < 0.001

Taylor, et al. JCO 2014

MRI Results What would you recommend for this patient (with a low‐lying T3N1 • MRI shows a 4.7 cm low‐ tumor)? lying rectal mass located 5 A. ChemoRT followed by APR and adjuvant cm from the anal verge. chemotherapy • T3N1 (3 suspicious QUESTION 2 B. Short course radiation followed by APR mesorectal nodes with and adjuvant chemotherapy mixed signal intensity) C. Combination of chemotherapy and chemoRT followed by APR • CRM is not threatened D. Combination of chemotherapy and chemoRT followed watchful waiting if complete response

2 4/16/2021

Why total neoadjuvant therapy? Treatment Options

• Neoadjuvant chemotherapy is better tolerated and more likely completed than adjuvant chemo Patient was offered: • 1. Total neoadjuvant therapy followed by definitive Earlier chemo starts eradicating micromets sooner resection (most likely APR) • Patients don’t have to wait until completion of adjuvant 2. Total neoadjuvant therapy with potential for non‐ operative therapy on the OPRA (Organ Preservation chemo for ostomy takedown in Rectal Adenocarcinoma) protocol • Allows for potential nonoperative management approach The patient elected to enroll on study and was randomized to receive chemo followed by chemoRT

Chemoradiation Plan IMRT

• 50 Gy to tumor, 45 Gy to Protocol Schema elective nodes over 25 fractions • 6 Gy (3 fraction) boost to primary tumor Concurrent Capecitabine

Presented By Julio Garcia-Aguilar

3 4/16/2021

What are the potential risks of NOM?

Have patients asked you to treat • Patients lost to follow‐up them with non‐operative management (NOM) for rectal cancer off protocol? • Local recurrence or residual disease leads to QUESTION 3 metastases A. Yes B. No • Salvage surgery more difficult/complicated

Post-treatment evaluation Post-treatment evaluation

Endoscopy at Diagnosis Endoscopy after chemo Endoscopy after chemo‐RT T2 MRI at Diagnosis T2 MRI after chemo T2 MRI after chemo‐RT

4 4/16/2021

What constitutes a clinical CR? Watchful Waiting

•No luminal tumor seen on endoscopic exam • Pooled analysis of 17 studies, 692 patients •Resolution of tumor on MRI •Tumor no longer palpable by digital rectal exam • 22.4% incidence of clinical complete responders (out of 2973 pts)

Dattani, et al. Annals of Surgery 2018

What is the risk of local recurrence? Patient embarks on surveillance

• 21.6% 3‐year local regrowth • Physical exam, endoscopic exam, labs, MRI every 3‐6 months until year 2, • Timing then every 6 months. Annual CT CAP • 61.8% of recurrences in year 1 • MRI @ 18 months shows an area of • 3.8% after year 3 restricted diffusion w/o mass • Endoscopy  prominent scar • Majority of recurrences were detected endoluminally • Biopsy shows tubular adenoma

Dattani, et al. Annals of Surgery 2018

5 4/16/2021

24 months post treatment 24 months post treatment

• MRI shows focal thickening Patient undergoes APR along the left distal rectum with restricted diffusion Final pathology • PET CT shows focal area of • 2.6 cm low grade uptake along left rectum adenocarcinoma • Widely negative margins • 0/5 lymph nodes • Repeat endoscopy ‐ biopsy • ypT2N0 shows invasive carcinoma

• Staging: MRI assessment of circumferential Pooled Analysis Surgical Salvage resection margin predicts LR, DFS, & OS.

• Treatment: Total neoadjuvant therapy is well‐ • 88% of patients with local tolerated, allows for earlier ostomy takedown, and recurrence underwent may allow non‐operative management. surgical salvage • Treatment: Non‐operative management (NOM) Summary should be offered to carefully selected patients who • 93% of these surgeries agree to close surveillance. yielded R0 resections • NOM Surveillance: ~21% of patients will recur locally in 3 years and most of the recurrence happen in the first year

Dattani, et al. Annals of Surgery 2018 • Salvage: Salvage surgery often safe and feasible.

6 4/16/2021

Case 2 What is the preferred imaging study to • 64F presents to PCP with dull LLQ pain and evaluate the resectability of a pancreatic fatigue x 1 month mass? • Pain refractory to Metamucil and proton pump inhibitor • PMH: HTN , diabetes, GERD QUESTION 4 A. CT Abdomen with single phase contrast • FH: maternal aunts x 2, breast cancer B. CT Abdomen with multiple phases of contrast maternal cousin, breast cancer 64 y/o • ECOG PS 1 C. MRI Abdomen with single phase contrast • Her PCP orders a CT abdomen which shows an ill‐ D. MRI abdomen with multiple phase contrast defined mass in the head of the pancreas, looks E. PET CT with single phase contrast like it is encasing multiple vessels

Baseline CT scan pancreas protocol NCCN Resectability

SMA >1800 encasement

SMV <1800 involvement

7 4/16/2021

Sequencing of chemotherapy and RT The patient has locally advanced tumor with SMA encasement. What is your preferred first treatment regimen?

QUESTION 5 a. Conventionally fractioned RT with concurrent chemotherapy b. SBRT c. Chemotherapy

Palta M et al Practical Rad Oncol 2019 ASTRO guidelines

Evaluation on Chemotherapy What type of radiation therapy would you recommend for this patient?

A. Conventionally fractionated radiation QUESTION 6 with concurrent chemotherapy B. Stereotactic body radiation therapy C. Proton radiation D. No radiation therapy

Post 2 months of mFOLFIRINOX Post 4 months of mFOLFIRINOX

8 4/16/2021

After SBRT • Grade 1 well differentiated ductal adenocarcinoma Multi‐Disciplinary • Ill‐defined mass 5.5 cm with chronic Tumor Board evaluation pancreatitis; few small foci of residual tumor shrank adenocarcinoma largest <0.1cm; cancer comprises <5% of mass Pathology • 16 lymph nodes negative for metastatic carcinoma • No lympho‐vascular invasion • Margins negative Whipple 3 weeks after SBRT

• Patient recovered with no post‐ • Diagnostic: Pancreatic Protocol CT op complications consists of multiple contrast phases and thin slices to evaluate mass size and vascular involvement. • 4 weeks post surgery, started 4 cycles (2 months) of Follow‐up mFOLFIRINOX to complete a Summary • Treatment: Treatment paradigm depends total 12 cycles (6 months) on resectability.

• Alive with no evidence of • Treatment: Locally advanced tumors disease 2 ½ years after surgery benefits from chemotherapy followed by definitive radiation therapy and may become resectable.

9 4/16/2021

Case 3 Would you obtain a biopsy for this lesion? • 51‐year‐old male with alcoholic cirrhosis (Child‐Pugh A) went to ED for abdominal and back pain. QUESTION 7 • CT abdomen revealed 2 lesions: A. Yes • 1.6cm lesion at the dome B. No • 2.4cm posterior segment 7 • Liver protocol CT was performed for further characterization

How do we diagnose HCC without a biopsy? What treatment would you offer this • LI‐RADS criteria: arterial hyperenhancement, PV washout, capsule, threshold patient? growth (double in 6 months). • LR4= Probable HCC. Sensitivity 95%, Specificity 75% • LR5= Definite HCC. Sensitivity 75%, Specificity 95% A. Arterial Directed Therapy QUESTION 7 (TACE or TARE) B. Radiofrequency ablation *MUST check quality of arterial contrast timing prior to C. Stereotactic Body Radiation Therapy evaluating enhancement D. Systemic Therapy ‐Contrast in aorta AND PVs ‐Spleen looks splotchy

Arterial, too early Arterial, perfect Portal Venous

10 4/16/2021

Treatment options Post-TACE Follow-up

Yu and Feng, Sem in Rad Onc 2018 Treatment Modality Pro Con Liver resection Effective Invasive, inadequate liver remnant • Dome: Unchanged Liver transplant Cures both HCC and cirrhosis High risk, long wait time, drinking Radiofrequency ablation Single treatment, effective for Difficult to visualize tumors at • Post Seg 7: Complete response small tumors dome Stereotactic body radiotherapy Non‐invasive, effective Multiple treatments, difficult for patients who live far away • AFP 10 Transarterial chemoembolization/ Can be single treatment High local recurrence, regional radioembolization therapy with regional toxicity • He joined AA and was listed for Systemic therapy Treats disease outside of liver For liver‐confined disease, systemic (Sorafenib/Nivolumab/Pembrolizumab) therapy is unnecessary transplant Post 2 months of mFOLFIRINOX

6 Months Later What treatment would you offer this patient?

A. Arterial Directed Therapy QUESTION 8 (TACE or TARE) B. Radiofrequency ablation C. Stereotactic Body Radiation Therapy D. Systemic Therapy

• Dome lesion growth (2.5cm) • CP A5  B7 • AFP 111

11 4/16/2021

Discussed at tumor board SBRT for HCC

Treatment Modality Pro Con Liver resection Effective Invasive, inadequate liver remnant Liver transplant (Listed!) Cures both HCC and cirrhosis High risk, long wait time Radiofrequency ablation Single treatment, effective for Difficult to visualize tumors at Safe small tumors dome Transarterial chemoembolization Can be single treatments Decompensated after previous TACE Stereotactic body radiotherapy Non‐invasive, effective Multiple treatments, difficult for patients who live far away Systemic therapy Treats disease outside of liver For liver‐confined disease, systemic Effective (Sorafenib/Nivolumab/Pembrolizumab) therapy is unnecessary

Yu and Feng, Semin in Rad Onc 2018

When is SBRT preferred over RFA? How does SBRT compare with RFA?

• Unresectable tumor or medically • No prospective trials have inoperable patient successfully been completed. • RFA cannot be safely performed • Near bowel or gall bladder (perforation) • Retrospective data suggest • Not visualizable with ultrasound (dome) SBRT has similar results for • Anesthesia risk Ramkaransingh and Johnson, Endovascular Today 2015 tumors <2cm but higher • RFA would not completely local control for larger control tumor tumors • Close to large vessel • No difference in (low) (heat sink) • Too large toxicity rates

Yu and Feng, Semin in Rad Onc 2018 Wahl, et al. JCO 2016

12 4/16/2021

How does SBRT compare with TACE? Where does SBRT fit into BCLC?

• SBRT can be safe and effective • Ongoing comparative trial • We need to continue to broaden • Retrospective data expertise and suggest that local generate control is much comparative data better after SBRT

Sapir, et al. IJROBP, 2018 Yu and Feng, Semin in Rad Onc 2018

Where does SBRT fit into BCLC? Treatment Plan • SBRT can be safe and effective 36 Gy in 3 fractions

• We need to 2 years later, still on continue to broaden transplant list, also expertise and generate received SBRT to TACE site comparative data

Yu and Feng, Semin in Rad Onc 2018

13 4/16/2021

• Diagnostic: Hepatocellular carcinoma can be diagnosed using high quality imaging.

• Treatment: Liver‐confined disease can be treated with targeting based on the size, Summary location, and distribution of disease.

• Treatment: SBRT is a safe and effective targeted local therapy that may be used even with unfavorable tumor location and decreased liver function.