Northeast Florida Medicine - Winter 2016 - Immunotherapy by Duval County Medical Society

WINTER CMEs: Immunotherapy for Metastatic Melanoma & Proton Beam Radiation

Northea st Florida

MedicinE

Published by the DCMS Foundation Marking 163 Years of Local Organized Medicine

Vo lu m e 67, N O 4

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In partnership with the Medical Societies of Duval, Clay and Nassau Counties

W in t e r 2 0 1 6

Immunotherapy ALSO IN THIS ISSUE: â&#x20AC;&#x201C; Ileitis: Keeping an Open Mind

VOLUME 67, NUMBER 4 Immunotherapy Winter 2016

Winter 2016

EDITOR IN CHIEF Ruple Galani, MD

Contents

MANAGING EDITOR Kristy Wolski ASSOCIATE EDITORS James Altomare, MD Megan Deacon-Casey, MD Mark Fleisher, MD Sunil Joshi, MD Ali Kasraeian, MD John Long, MD Amy Pollak, MD James St. George, MD John Stauffer, MD

CHIEF EXECUTIVE OFFICER Bryan Campbell DCMS FOUNDATION BOARD OF DIRECTORS President: Todd Sack, MD President Elect: Ashley Norse, MD Secretary/Treasurer: Ruple Galani, MD Douglas Baer Richard Brock Solomon G. Brotman, DDS Alan Harmon, MD Kelli Wells, MD

2016 FOUNDATION DONORS Molly and James Altomare, MD Raed Assar, MD Richard and Janice Brock William Parker Clarke, MD Lisa and Patrick DeMarco, MD Elizabeth DeVos, MD Jerry A. Dorsch, MD Robert E. Duncan, MD George H. Fink, MD Allan A. Girouard, MD Robert G. Harmon, MD Walter Alan Harmon, MD Kenneth A. Horn, MD Stephen Mandia, MD Russell D. Metz, MD Thomas Peters, MD Todd Sack, MD Guy T. Selander, MD Joseph B. Stokes, Jr., MD N.H. Tucker III, MD Jacksonville Jaguars Foundation

Winter CME An Update on Proton Beam Radiation

By Roi Dagan, MD, MS

In recent decades there have been many technological advances in cancer care. One has to look no further than the dissemination of proton therapy (PT) as a shining example of precision cancer care. In 2006, when the UF Health Proton Therapy Institute (UFHPTI) began treating patients, there were just five proton facilities in the United States. Currently, there are 14 centers in the U.S. with several others in planning and development.

Winter CME Current State of Immunotherapy for Metastatic Melanoma

By Richard W. Joseph, MD

Advancements in our understanding of how melanoma evades the immune system have led to major improvements in the treatment of patients with metastatic melanoma. Since 2011, the FDA has approved five novel immunotherapies for the treatment of metastatic melanoma resulting in a significant improvement in overall survival and quality of life. The success of these agents has provided excitement and hope for both patients and clinicians and, while these therapies have their limitations, they will provide excellent building blocks for the next generation of therapies.

Features An Introduction to the Abscopal Effect in Metastatic Cancers: Curing the Incurable?

By Tasneem Kaleem, MD and Nitesh N. Paryani, MD

The Emerging Role of Immunotherapy in Non-Small Cell Lung Cancer

By Troy H. Guthrie, Jr., MD

Immunotherapy for Genitourinary Cancers By Jason Starr, DO

Departments From the Editor’s Desk From the President’s Desk

From the Chief Executive Officer’s Desk

9 11 48

Residents’ Corner Guest Editorial Creative Corner

Also in this Issue Ileitis: Keeping an Open Mind By Mark Fleisher, MD

Please note: Editorial and contents of this magazine reflect the records of the Duval County Medical Society (DCMS). The DCMS has done their best to provide useful and accurate information, but please take into account that some information does change. E&M Consulting, Inc., publishers and the DCMS take no responsibility for the accuracy of the information printed, inadvertent omissions, printing errors, nor do they endorse products and services. We take no responsibility regarding representations or warranties concerning the content of advertisements of products/services for a particular use, including all information, graphics, copyrighted materials, and assertions included in the advertisements. The reader is advised to independently check all information before basing decisions on such information.

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Northeast Florida Medicine Vol. 67, No. 4 2016 5

From the Editor’s Desk

Field of My Dreams After 108 years, my beloved Chicago Cubs have won the

Every April, I would begin my annual ritual of reading up

World Series. I have been a diehard fan since the age of 5. I

on the Cubs roster and pitching staff. Spring training always

have watched the Cubs with hope, anguish, and despair year

brought about excitement that this would be THE YEAR

after year. Some my fondest

the Cubs would go all the way. Opening day and early spring

childhood memories were

was full of promise and hope. However, year after year, mid

played out on the baseball

summer would come and go and the Cubs would quickly

diamond as the Cubs’ first

fade into last place. Many near misses or what if ’s plagued the

baseman hitting the game

hearts of Cub fans. But year after year, October would come

winning World Series home

and go, and the Cubs are left hoping for more.

run. In the early hours of Nov 2, I watched that final out as the Cubs did the near Ruple Galani, MD Editor-in-Chief Northeast Florida Medicine

impossible, come back from a 3-1 deficit and win the World Series. I jumped for

joy, laughed and smiled with friends, and quietly shed a tear. My voice was hoarse, my heart was racing, and spirits were high. Life as a physician often parallels that of a diehard sports fan. At some point in the distant past, every physician gets the spark and excitement of wanting to become a doctor. At the age of 5, I picked up my first bat and ball and fell in love with the game. Also, on those long summer afternoons, I happened to stumble upon a team, in pin stripes, playing baseball at 1:20 in the afternoon on TV. Starting at the age of 7, I would accompany my father on Sunday morning rounds at our small community hospital. I would watch in awe as he would go room to room and put his mind and skills to the test. As time goes on, the drive to become a physician continues to strengthen and evolve. In my grade school and junior high years, I spent time with my father in his office seeing patients and going on evening hospital rounds. On weekends, once

High school came and went. The excitement and rigors of college in hopes of earning a spot in medical school consumed my life. Finally, one early March day, the letter of medical school acceptance came. The next four years my life was as turbulent as a Cubs fan. Excitement, hope and joy of the beginning of a life long dream was quickly mixed with anguish and despair as gross anatomy, microbiology, and embryology sucked the life out of me. Eternal hope was restored with Match Day four years later. Residency and fellowship proved to be much more daunting, mentally, physically, and emotionally, than the Cubs 1984 and 2003 heartbreak and agony. However, in 2009, I won my personal World Series. A lifetime of dedication and hard work culminated as a newly minted Cardiologist. Every day in practice, I celebrate the life and profession of being a physician. Though we will never have 5 million people cheer and rally for our hard work, it is the cheers, the hugs, and the thank yous from our patients that make each day our World Series victory. Fellow physicians, hold your head up high, be proud, and cheer our patients and our profession. Go, Cubs, Go. Go, Doctors, Go!! v

old enough, I spent time volunteering at the local hospital. With each passing day, I knew my love and passion in life was to become a physician.

6 Vol. 67, No. 4 2016 Northeast Florida Medicine

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From the President’s Desk

A Delegation of Leaders The 2016 Presidential campaign is thankfully over. It was

We come in all sizes and shapes. We are Republicans, Dem-

by far the most contentious and divisive 12 months that

ocrats, Libertarians, African, European, Indian, Hispanic,

I can remember in my life time. Many people around the

Baby Boomers, Gen-Xers and Millennials. But what binds us

world have tried to define

all together is that we are Americans. We have the freedom to

this election season as what

grow a business, raise a family, vote for our elected officials and

is “wrong with America,”

even disagree with their policies. It is indeed what makes us

while predicting our coun-

different that makes us great. No matter how much we argue

ty’s downfall. I could not

or disagree, there are many, many more things that unite us

disagree more.

and keep us strong.

The results are in and

We became independent from oppressors 240 years ago

we have a new President.

because of the solidarity of the great American people. Those

Regardless of how you feel

pioneers demanded freedom which eventually led to the

about the outcome, Amer-

world’s first true super power. It was the American people who

ica will survive. We have

developed the technology for the automobile, the airplane, the

been through a great deal in our 240 years of existence and

telephone, the computer, the internet and won two wars in

our country continues to move forward.

Europe. Americans rank number one internationally when it

Sunil Joshi, MD 2016 DCMS President

We are a great nation even though we are not always perfect. In both our recent and distant past, we have been devastated

comes to donating time and money to helping others locally, nationally and even globally.

by unprovoked attacks, economic collapse and crazy election

Yes, it was a divisive political season but that does not take

cycles. Each time, we rise from the ashes to become an even

anything away from who we are. We are the nation that has

greater republic. It is freedom that allows us to do this.

always had free elections, that transfers power peacefully and

When my parents left India in the 1960’s to come to the United States, they felt that Lady Liberty gave them the single best opportunity to have a successful life for themselves but most importantly for their children. Just like millions before and after them, they worked diligently to earn college degrees, obtain jobs and raise a family. Their sacrifice and its

sets an example for the world to follow. This will not change. Over 45 million people living here were born outside of the United States. Thus, for many folks around the world, America remains the perfect place to start a new life. Always remember that people die trying to get into this country, not trying to get out.

eventual success is, in essence, the American Dream. This is

My dad told me many years ago that he decided to come to

a story that is shared all over Northeast Florida. It’s a story

America because this is the place where “anything can happen

that will continue to occur for generations to come. This is

for anyone.” His words were as true then as they are now.

the story of America.

Despite what the outsiders say, I am proud to be an American and I hope that you are too. v

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Northeast Florida Medicine Vol. 67, No. 4 2016 7

From the CEO’s Desk

As Certain as Death and Taxes… It was a night 108 years in the making! On November 2, and into the wee hours of the next morning, I sat with my family in the living room watching history unfold as my beloved Chicago Cubs broke the longest futility streak in professional sports by winning the 2016 World Series title. I struggled and failed to hold back the tears as I thought about what the Cubs have meant to me and to so many throughout the years. I cried when I thought about Ron Santo. Santo was one of the most beloved Cubs of all-time, both as a player and later as a color man for WGN radio. SanBryan Campbell to was one of the biggest DCMS Chief Executive Officer Cubs fans there was. I was fortunate enough to meet Santo in 2006 when I was able to present him with an award for his efforts to raise money for the Juvenile Diabetes Research Foundation. Sadly, he passed away from complications due to his type 1 diabetes in 2008. He was not inducted into the Baseball Hall of Fame until a year after his death. He never got to see the Cubs win the World Series. I cried when they showed a Harry Caray Budweiser commercial. Caray was the television commentator for the Cubs on WGN during my formative years. He defined the spirit of the lovable losers. I knew that he was a Cub Fan and a Bud Man years before I knew what that particular beverage even tasted like. I wish he was here to see this. Less than a week later, I sat in the same room with the same family and watched another historic event unfold into the wee hours of the morning. Donald Trump was elected as the 45th President of the United States. Almost as surprising in the state of Florida was the mandate that more than 70% of the population vote to approve marijuana for medicinal use. I have two teenage children, including one that voted for the first time this year. Our house was divided on the Presidential race, and there were tears surrounding this outcome as well. While the Cubs victory meant very little in the grand scheme of things, these election results mean a great deal to your profession.

8 Vol. 67, No. 4 2016 Northeast Florida Medicine

The most immediate and obvious impact will be around Obamacare. President-elect Trump has stated repeatedly that he will repeal the six-year-old legislation. However, that may be easier said than done. There is the obvious answer that “Repeal and Replace” means that there must be a system to replace it with. It might be some time before we see that plan. Additionally, the Republicans do not have a filibuster-proof majority in the Senate, and therefore passing that legislation may prove difficult. The reasonable takeaway is this: President Obama made healthcare reform his top agenda item, and it still took him a few years to get it passed. Regardless of what the future holds for healthcare policy, don’t expect sudden change. A more immediate impact will be with the passage of Amendment 2: the legalization of marijuana for medicinal use in Florida. The reason for the immediate impact is that the majority of the regulation for implementation of this Amendment was actually passed in the past two legislative sessions when the Florida Legislature approved “Charlotte’s Web,” a version of low-THC cannabis used to treat intractable seizures, then this year expanded the use to terminally ill patients in the “Right to Try” act. Here’s what it means for you. If you do not want to prescribe marijuana to your patients, you do not have to. Some physicians in other states with similar laws have taken to posting signs in their waiting rooms that they will not prescribe it. If you are interested in learning more, there are several steps you need to complete. The first is to complete an eight-hour CME course offered exclusively through the FMA. You can find that course on our website at www.dcmsonline.org. Choose Medical Marijuana CME from the drop down menu under “Education.” Once the course is complete, you will need to add your name to the registry of providers in the state. Finally, you must have a patient relationship established for at least 90-days before you can prescribe “medical marijuana,” so you will want to have a system to communicate to patients you may choose to prescribe to about the process. There used to be just a few things you could rely on… death, taxes and Cubs fans saying “wait until next year.” I’m glad that we can take that last one off the list, but I think we can now safely replace it with “major changes are coming to the healthcare system.” v

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Residents’ Corner: St. Vincent’s Family Medicine St. Vincent’s Family Medicine Residency class of 2019

Focusing on Values: A Look at St. Vincent’s Family Medicine Residency By David El Hassan, MD and Jason Largen, MD About Our Program St. Vincent’s Family Medicine Residency Program was established in 1972 and has grown to accept ten residents per year for the three-year program. The residency is accredited by the Family Medicine Residency Review Committee and the Accreditation Council for Graduate Medical Education. The program has also been accredited by the American Osteopathic Association and the American College of Osteopathic Family Physicians since 2005. Since its inception, our program has focused on the core values of our hospital system: Service to the Poor, Reverence, Integrity, Wisdom, Creativity, and Dedication. The residency is part of St. Vincent’s Health Care System, which was founded by the Daughters of Charity in 1916, as well as Ascension Health, the nation’s largest Catholic and nonprofit health system. Today, St. Vincent’s Riverside is a 538 bed facility that serves more than 25,000 inpatients each year. An additional 50,000 patients visit for outpatient surgery and invasive procedures, and more than 60,000 people are cared for in the Emergency Room. The Family Medicine Center is responsible for more than 30,000 office visits per year, over 6,000 of which are pediatric visits. The program emphasizes continuity and full-spectrum care and is designed to develop critical clinical skills and decision making abilities. We are staffed by 15 full-time faculty physicians who are dedicated to resident education. This faculty includes family physicians with areas of special interest such

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as OMT, geriatrics, practice management, sports medicine, nutrition, medical informatics, hospital medicine and infertility, as well as specialists boarded in OB/GYN, pediatrics and dermatology. A clinical psychologist and two psychology fellows make up our behavioral health team. This unique blend allows for comprehensive training and development of the personal interests of residents. The St. Vincent’s Family Medicine Residency Program exists for two reasons - to provide superior education and training for family medicine residents and to give our patients the best possible medical care. We prepare our residents to succeed in the practice locations they will eventually choose, from urban to rural, and to be ready for leadership roles in their communities. Residents benefit from affiliations with Ascension Health, St. Vincent’s HealthCare, Wolfson Children’s Hospital, Florida State University College of Medicine, Nova Southeastern College of Osteopathic Medicine, and the University of Florida College of Medicine. In addition to Family Physician faculty, the program has full-time faculty in pediatrics, clinical psychology and OB/ GYN; all are committed to family physician education. This allows our residents to take advantage of superb educational opportunities not typically available to family medicine residents. St. Vincent’s has graduated skilled, successful, compassionate physicians since the program began in 1972, and our most recent class of graduates was no exception. Members of the

Northeast Florida Medicine Vol. 67, No. 4 2016 9

Residents’ Corner: St. Vincent’s Family Medicine

The St. Vincent’s Family Medicine Residency class of 2016 on graduation night

Jaguars tight end Julius Thomas with volunteers and children at the Reach Out and Read Book Drive

2016 graduating class have transitioned into local community clinics, military enlistment, and international medical endeavors.

A History of Service Our faculty and residents have a long tradition of being involved in both the Florida Academy of Family Physicians (FAFP) and the American Academy of Family Physicians (AAFP). Most recently one of our chief residents, Dr. Jason Largen, was voted to the position of Resident President of the FAFP. Our faculty physician, Dr. Robert Raspa, was recently voted to a three year term on the AAFP Board of Directors after previously serving as President and Chairman of the Board of the FAFP. Many of our other faculty members and residents also participate heavily in both FAFP and AAFP conferences, both in teaching and recruiting roles. Service to the poor has always been an instrumental part of our program’s mission, both locally and internationally. We annually send teams of our faculty physicians, residents, and support staff on international mission trips to Haiti, Jamaica, and most recently to rural Dominican Republic. Locally, our residents spent volunteer and elective time providing free medical care to thousands of poor uninsured patients via our mobile health outreach ministry and affiliations with The Way Clinic, Volunteers in Medicine, and the I.M. Sulzbacher Center. In March 2016, we had our inaugural Medical Mission at Home, which provided thousands of free medical care and social services to hundreds of our neighbors in need. We plan to continue that event annually and are expecting to more than double the number of patients next year with continued volunteer efforts from our residents, faculty physicians, and staff. The St. Vincent’s Mobile Health Outreach Ministry brings fully staffed doctors-offices-on-wheels to areas of the community where these services are needed the most. It is the only mobile provider of free acute and preventive medical care in Northeast Florida. This program, which began in 1991, successfully promotes prevention

10 Vol. 67, No. 4 2016 Northeast Florida Medicine

Dr. Diondra Burney provides volunteer medical care to a resident of rural Dominican Republic

through health screenings and education throughout our region. Our residents and faculty physicians are aboard the mobile units daily providing primary care services to adult and pediatric patients and school physicals at low income schools in Northeast Florida. In an effort to increase literacy in our pediatric population, Dr. Sonya Dominguez, our Associate Program Director, has grown our annual Read and Romp event which provides donated children’s books to families who may not have the means to acquire new reading material. Several thousand books are handed out at each event, and we are excited to host it again this December. The event has grown so large that our 2017 Read and Romp will be held at the Jacksonville Zoo! This event is paired with our Reach out and Read activity to promote literacy within our primary care offices. This year we were honored to have Jacksonville Jaguars tight end Julius Thomas participate in a book drive for Reach out and Read to provide children’s reading material at local primary care offices as an alternative to TV areas in waiting rooms and exam rooms. With a goal of 6,000, over 16,000 books were donated to go to primary care offices in Jacksonville and Orange Park, as well as Wolfson’s and Duval County Health Department offices.

Looking Ahead As we welcome a new class of interns this year, we do so with several exciting new additions. Dr. Danielle Carter, a former St. Vincent’s resident, returns as faculty following completion of a Maternal Child Health fellowship and work in private practice. We also welcome a new pediatrician to the faculty. Dr. Julie Kellogg has been a Navy pediatrician for the past 22 years. Our residents are excited for the completion of a new resident’s lounge that will be completed in 2016. We are excited to see where this year will take our residents as we continue to grow a culture focused not only on academics but on creating a healthier community! v

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Guest Editorial

Immunotherapy: Paradigm Shift in Cancer Therapy It is my great privilege and honor to serve as guest editor of this issue of Northeast Florida Medicine. As the guest editor, I selected the topic of cancer immunotherapy because this topic is what inspired me to become a clinical investigator in the world of cancer immunotherapy. My path towards becoming an oncologist with a focus on immunotherapy began during my second year of my Internal Medicine Residency. At the time, I was rotating on the leukemia service at Richard W. Joseph, MD Memorial Sloan Kettering Cancer Guest Editor Center. Anyone who has spent time on a leukemia service can appreciate the immense amount of suffering that patients endure, both from their disease and the treatment. While on this rotation, I was serendipitously exposed to my future mentor, Dr. Renier Brentjens, who was developing a novel cellular therapy using genetically modified T cells to target CD19 present on leukemic cells. In lay terms, he was using viruses to modify immune cells to fight cancer. To me, the thought of utilizing a patientâ&#x20AC;&#x2122;s own immune system to fight cancer, instead of giving high doses of extremely toxic chemotherapy, was riveting. This introduction into the world of tumor immunology and translational science directly inspired me to pursue a career in medical oncology and, more specifically, towards a career in translational research. Over the last 10 years, cancer immunotherapy has undergone a paradigm shift from a therapy that was seen as on the â&#x20AC;&#x153;fringeâ&#x20AC;? to what is now becoming the backbone of all cancer therapies. Recent and ongoing developments have greatly improved the therapeutic efficacy for patients with cancer by both boosting outcomes and decreasing toxicity compared to standard chemotherapy. For this issue, we have assembled a team of medical oncologists and radiation oncologists to address specific topics in cancer immunotherapy that will provide oncologists and non-oncologists an introduction to

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some of the major breakthroughs that are happening in our local area and across the country. Dr. Nitesh Paryani is a radiation oncologist at 21st Century Oncology and addresses the extremely fascinating phenomenon known as the abscopal effect of radiation therapy. The abscopal effect is a term used to define when a non-radiated tumor responds after a distant tumor is radiated. The exact mechanism of the abscopal effect remains unclear but is thought to be induced by the generation of an in-vivo vaccine created by the interface of the radiated tumor with the immune system. Dr. Roi Dagan, a radiation oncologist at the University of Florida Proton Center, provides an update on the use of proton beam radiation to fight cancer. His CME article has been approved for 1 AMA PRA Category 1 credit.TM Dr. Troy Guthrie, a medical oncologist at 21st Century Oncology, describes the impact of immunotherapy on nonsmall cell lung cancer. Until recently, metastatic lung cancer was thought to be incurable, however, with novel immunotherapies, many patients are experiencing durable remissions lasting years. My CME article describes the history, as well as the recent advances of immunotherapy, in fighting melanoma. Over the last six years, these advances in immunotherapy have improved the percentage of patients alive with Stage IV disease from an estimated five percent in 2010 and prior, to now an estimated 40-50 percent in 2016 and beyond. Dr. Jason Starr, a medical oncologist at the University of Florida, describes the advances of immunotherapy in genitourinary cancers including prostate, bladder, and renal cell carcinoma. The goal of this issue is to familiarize physicians across Northeast Florida on the exciting breakthrough of immunotherapy in cancer, as well as highlight some of the work that is being done in our area. I hope you enjoy it. v

Northeast Florida Medicine Vol. 67, No. 4 2016 11

Save the Date Join us in shaping the future of healthcare in Northeast Florida!

Fu tu re o f H e a lt h c a r e C onf e r e nce May 22-23, 2017 at University of North Floridaâ&#x20AC;&#x2122;s University Center For more information: tammy@dcmsonline.org

Immunotherapy

An Introduction to the Abscopal Effect in Metastatic Cancers: Curing the Incurable? By Tasneem Kaleem, MD1 and Nitesh N. Paryani, MD2 Resident, Radiation Oncology, Mayo Clinic, Jacksonville, FL

21st Century Oncology, Jacksonville, FL

Abstract: The abscopal effect is a rare phenomenon in which metastatic disease in sites distant from an irradiated field show regression. This response is hypothesized to be driven by systemic immunologic mechanisms catalyzed by radiation. Recent emergence of targeted immunomodulating drugs, such as ipilimumab, has ignited interest as a way to address biologically aggressive cancers through induction of the abscopal effect. The abscopal effect is observed in a spectrum of tumor histologies; however, it is more common in immunogenic type cancers. With the advent of new immunotherapies geared to a variety of cancers, the abscopal effect will likely become a more frequent observation. Although all aspects of the event are not completely understood, further research and understanding may prove the abscopal effect to become more clinically applicable.

Introduction Former President Jimmy Carter’s battle with melanoma gained widespread attention brought on by media coverage. “Former President Jimmy Carter Cured of Cancer” was an often repeated headline in early December of 2015 after surveillance imaging determined that he had no evidence of disease after undergoing aggressive radiation therapy to metastatic brain lesions. While somewhat hyperbolic, this headline offered a glimpse into a new and poorly understood field of cancer therapy: immunotherapy. With the possibility of curing the incurable, immunotherapy has burst upon the cancer treatment scene, bringing with it a lot of hope and promises. It is important to understand the scientific basis behind immunotherapy and to attempt to determine whether it is in fact the next big breakthrough in cancer care.

Background Radiation therapy remains a proven technique known to treat a variety of tumors. Clinical effects are often seen within a targeted, localized field. Rarely, tumor response beyond the scope of the radiation field occurs. This clinical phenomenon is known as the abscopal effect.

Address correspondence to: Nitesh N. Paryani, M.D. 21st Century Oncology 5742 Booth Road, Suite B Jacksonville Beach, FL 32207 Tel: 904-242-0166; Fax 904-242-0167 Email: nparyani@frogdocs.com DCMS online . org

The term “abscopal” was defined by Mole in 1953 as a tumor event occurring “at a distance from the irradiated volume but within the same organism.”1 It is derived from the Latin “ab” meaning away and “scopus” meaning target. Thus, the idea is that even a far-away target can respond to radiotherapy. This idea was heretical when first proposed – after all, radiation, like surgery, is thought to be a local treatment for cancer. Nevertheless, initial observational reports noted that when radiating a kidney for renal cell carcinoma, for example, distant lung metastasis would spontaneously regress. This response is hypothesized to be driven by systemic immunologic mechanisms catalyzed by radiation.2 Recent emergence of targeted immunomodulating drugs, such as ipilimumab, has ignited interest as a way to address biologically aggressive cancers through induction of the abscopal effect. This synergistic effect between immunomodulating agents and radiation in order to control and potentially eradicate advanced malignancies is very much in its infancy.

Role of the Immune System The immune system has long been known to play an important role in cancer treatment. Immunosuppressed patients often develop malignancies more readily, and their cancers tend to be more aggressive. Conversely, it is not unusual to see an immune response to cancer in healthy adults – i.e., a lung cancer patient with a mediastinal lymph node with no evidence of a primary lung tumor, which may have resolved due to an immune mediated response. The immune system plays a key role in the initiation abscopal effects after radiotherapy. Damage by radiation therapy induces a cascade leading to enhanced antigen expression, presentation and T cell activation. Radiation therapy induces an immunostimulatory form of cell death called immunogenic cell death (ICD). This type of cell death releases specific antigens called damage associated molecular patterns (DAMPS), which are engulfed and presented by dendritic cells. In turn, dendritic cells have improved presentation and enhanced activation of CD8+ T cells.3,4,5,6,7 Direct irradiation is also recognized to facilitate the presence of MHC I on tumor cell surfaces and boost recognition of the tumor itself.8 Furthermore, radiation therapy may elicit a cytokine response, which assists the Northeast Florida Medicine Vol. 67, No. 4 2016 13

Immunotherapy

function of CD8+ T cells.9,10,11,12 Thus, the hypothesis that direct radiation induces activation of CD8+ T cells through multiple pathways, thereby causing elimination of cancer cells, provides a possible explanation for the systemic and distant abscopal effects. Given the significant role of the immune system in generating the abscopal effect, combination of immunomodulation drugs and radiation may lead to an enhanced synergistic effect systemically. The combination of the immunotherapy drug and radiotherapy upregulates the immune response and enhances the body’s own ability to fight off and potentially eliminate the cancer.

Preclinical Studies and Biologic Basis Previous in-vivo studies have explored the effects of combination treatments of immunotherapy and irradiation in controlled settings. CTLA-4 blockade has been studied in several mouse models.13 CTLA-4 is a T cell marker with a significant role in down-regulation of T cell responses. Thus, CTLA-4 inhibition would improve anti-tumor T cell responses and presumably enhance or initiate the abscopal effect. Demaria et al demonstrated that metastatic breast cancer mouse models showed statistically significant survival advantage when treated with radiation and CTLA-4 blockade compared to controls.13 The increase in survival correlated with an inhibition of lung metastases formation. Furthermore, the study illustrated these effects were not present if CD8+T cells were depleted. This showed that systemic abscopal anti-tumor effects with combination radiotherapy and immunomodulating therapies require healthy, functioning CD8+ T cells.13 Synergism of irradiation with anti-PD-L1 immunotherapy was studied by Deng et al in metastatic mammary and colon cancer mice models.14 PD-L1, programmed death ligand, is a tumor cell marker responsible for inhibition of effector T cells, thus allowing tumors to evade immune destruction. When PD-L1 is up regulated, the immune response is decreased. The study demonstrated that treatment with radiation alone up regulated the expression of PD-L1. However, with the addition of anti-PD-L1 agents along with radiation, there was an overall reduction in tumor size at distant, non-irradiated sites as well. The authors hypothesized a synergistic effect of radiation and PD-L1 blockade provided an environment conducive for systemic tumor response by disinhibiting effector CD8+ T cells, allowing for a more robust immune response.14 In 1968, researchers hypothesized that radiation can cause the release of soluble factors into the blood that are capable of causing chromosomal damage even in cells that were not directly exposed 14 Vol. 67, No. 4 2016 Northeast Florida Medicine

to irradiation.15 These factors were labeled as “clastogenic,” or chromosome breaking. It is thought that these factors played a role in the carcinogenic effect of radiotherapy – that is, the potential for radiotherapy to actually cause a malignancy – by inducing chromosomal instability. This “messenger effect” of radiotherapy at distant organs may also play a role in the induction of the abscopal effect, via chromosomal damage that leads to tumor cell death.15 This effect may be enhanced by the immunomodulatory effects described above. In vivo studies reveal the occurrence of abscopal effects in the context of radiation and targeted immunomodulating therapies. 15,16,17 The presence of immune therapy in addition to radiation provides a systemic response possibly explaining the clinical relevance of the abscopal effect.

Clinical Overview Abscopal effects in response to radiotherapy alone have been reported since the early 1950’s, but only a few showed absolute results. Furthermore, because of the rarity and elusiveness of the effect, it is difficult to reproduce the response. However, several retrospective review articles found trends in available case reports. Case reports commenting on the abscopal effect after radiation alone have a wide range of primary histologies, including adenocarcinoma of the lung, lymphoma, leukemia, and Merkel cell carcinoma.16-29 Nevertheless, the abscopal effect is most prominently found in immunogenic tumor types, including renal cell carcinoma, hepatocellular carcinoma and melanoma. These tumors typically have a greater immunogenicity in phenotype and are thus likely more responsive based on the presumed underlying mechanism of the abscopal effect. Metastatic malignant melanoma has taken the spotlight as the most common malignancy investigated, partially because of the success of novel and available immunomodulating agents. Additionally, this is a disease that has unfortunately shown little response to traditional chemotherapy, leaving both patients and physicians desperate for a treatment that can improve survival from this aggressive disease. Ipilimumab, or Yervoy, is a CTLA-4 inhibitor that has steadily been gaining prominence as a treatment for melanoma. A recent review retrospectively investigated the efficacy of stereotactic radiosurgery (SRS) for 46 patients with melanoma brain metastasis who received ipilimumab from 2005 to 2011.29 SRS is a form of specialized radiation, similar to that which President Carter underwent, in which patients receive a very high dose of

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Immunotherapy

Figure 1: Axial, coronal and saggital images representing an intracranial radiosurgery plan.

radiation to a very small area, in the hopes of eradicating tumors (Figure 1). The authors of the study concluded concurrent delivery of ipilimumab and SRS was associated with improved locoregional control and longer overall survival.29 Although the primary purpose of the study was not designed to investigate whether brain SRS induces an abscopal effect in combination with ipilimumab, the authors noted one patient in their study who may have exhibited the abscopal effect. One patient who received treatment showed gradual response in the pelvis and lungs and remained alive at the time of analysis. The authors speculated that although it is difficult to prove the abscopal effect occurred in this or other cases within their study, their results do suggest a strong, beneficial interaction between radiation and immunomodulating drugs such as ipilimumab.29 Despite its rare occurrence, multiple case reports have highlighted and confirmed the presence of the abscopal effect in metastatic melanoma patients treated with combination therapy. A recent retrospective study reviewed 21 case reports of sequence ipilimumab and radiotherapy. Eleven out of the 21 patients showed an abscopal response after RT.28 Time to response ranged from 1-4 months and overall survival increased by 13 months.28 In 2012, 3 separate case reports noted the abscopal effect with ipilimumab combined with radiation. In these case reports, a variety of metastatic sites were radiated, including the liver, brain and paraspinal metastasis. Abscopal responses were found in the skin, lymph nodes and spleen. All three showed a four to six month time period for the abscopal effect, leading to a six month progression free survival after the abscopal effect was seen.31,32,33,34

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Conclusions The abscopal effect is a rare phenomenon in which metastatic disease in sites distant from the irradiated field show regression. It is observed in a spectrum of tumor histologies; however, it is more common in immunogenic type cancers. This is most likely a consequence of the significant role of underlying immunologic mechanisms initiated by radiation. In vivo studies evaluating combination therapies of radiation and immunomodulating therapies illustrate the synergistic effect leading to a systemic response. These results are translated clinically in multiple case reports describing the abscopal effects in patients with metastatic melanoma treated with combination therapies. With the advent of new immunotherapies geared to a variety of cancers, the abscopal effect will likely become a more frequent observation. Although all aspects of the event are not completely understood, further research and understanding may prove the abscopal event to become more clinically applicable. Unfortunately, given that many of these studies are retrospective in nature, it is difficult to isolate those factors that may induce an abscopal effect in patients. Currently, this creates a clinical quandary for physicians. Is it appropriate to approach all patients with metastatic immunogenic cancers like melanoma and renal cell carcinoma with a combination of aggressive immunotherapy and radiotherapy? Which patients are more likely to benefit? Can we justify the costs associated with these expensive drugs on the hopes of a rare response? These are some of the many questions with which physicians are faced and must find a way to address as immunotherapy becomes more widely utilized in the oncology community. Only then will physicians be able to determine if immunotherapy really is the next big breakthrough that may offer the hope of cure to those who were once considered incurable. v

References 1. Mole RH. Whole body irradiation; radiobiology or medicine? Br J Radiol. 1953 May;26(305):234–41. 2. Formenti SC, Demaria S. Systemic effects of local radiotherapy. Lancet Oncol. 2009 Jul;10(7):718–26. 3. Apetoh L, Ghiringhelli F, Tesniere A, et al. Toll-like receptor 4-dependent contribution of the immune system to anticancer chemotherapy and radiotherapy. Nat Med. 2007 Sep;13(9):1050–9. 4. Perez CA, Fu A, Onishko H, et al. Radiation induces an antitumor immune response to mouse melanoma. Int J Radiat Biol. 2009 Dec;85(12):1126–36.

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5. Krysko DV, Garg AD, Kaczmarek A, et al. Immunogenic cell death and DAMPs in cancer therapy. Nat Rev Cancer. 2012 Dec;12(12):860–75.

20. Nam SW, Han JY, Kim JI, et al. Spontaneous regression of a large hepatocellular carcinoma with skull metastasis. J Gastroenterol Hepatol. 2005 Mar;20(3):488–92.

6. Kroemer G, Galluzzi L, Kepp O, et al. Immunogenic cell death in cancer therapy. Annu Rev Immunol. 2013;31:51–72.

21. Okuma K, Yamashita H, Niibe Y, et al. Abscopal effect of radiation on lung metastases of hepatocellular carcinoma: a case report. J Med Case Rep. 2011 Mar 19;5:111.

7. Obeid M, Panaretakis T, Joza N, et al. Calreticulin exposure is required for the immunogenicity of gamma irradiation and UVC light-induced apoptosis. Cell Death Differ. 2007 Oct;14(10):1848–50. 8. Reits EA, Hodge JW, Herberts CA, et al. Radiation modulates the peptide repertoire, enhances MHC class I expression, and induces successful antitumor immunotherapy. J Exp Med. 2006 May 15;203(5):1259–71.

22. Rees GJ, Ross CM. Abscopal regression following radiotherapy for adenocarcinoma. Br J Radiol. 1983 Jan;56(661):63–6. 23. Fairlamb DJ. Spontaneous regression of metastases of renal cancer: a report of two cases including the first recorded regression following irradiation of a dominant metastasis and review of the world literature. Cancer. 1981 Apr 15;47(8):2102–6.

9. Golden EB, Pellicciotta I, Demaria S, et al. The convergence of radiation and immunogenic cell death signaling pathways. Front Oncol. 2012 Aug 7;2:88.

24. Takaya M, Niibe Y, Tsunoda S, et al. Abscopal effect of radiation on toruliform para-aortic lymph node metastases of advanced uterine cervical carcinoma – a case report. Anticancer Res. 2007 Jan-Feb;27(1B):499–503.

10. C hakraborty M, Abrams SI, Camphausen K, et al. Irradiation of tumor cells up-regulates Fas and enhances CTL lytic activity and CTL adoptive immunotherapy. J Immunol. 2003 Jun 15;170(12):6338–47.

25. Cotter SE, Dunn GP, Collins KM, Sahni D, Zukotynski KA, Hansen JL, et al. Abscopal effect in a patient with metastatic Merkel cell carcinoma following radiation therapy: potential role of induced antitumor immunity. Arch Dermatol. 2011 Jul;147(7):870–2.

11. L im JY, Gerber SA, Murphy SP, et al. Type I interferons induced by radiation therapy mediate recruitment and effector function of CD8(+) T cells. Cancer Immunol Immunother. 2014 Mar;63(3):259–71.

26. MacManus MP, Harte RJ, Stranex S. Spontaneous regression of metastatic renal cell carcinoma following palliative irradiation of the primary tumour. Ir J Med Sci. 1994 Oct;163(10):461–3.

12. Vacchelli E, Vitale I, Tartour E, et al. Trial Watch: anticancer radioimmunotherapy. Oncoimmunology. 2013 Sep 1;2(9):e25595. 13. Demaria S, Ng B, Devitt ML, et al. Ionizing radiation inhibition of distant untreated tumors (abscopal effect) is immune mediated. Int J Radiat Oncol Biol Phys. 2004 Mar 1;58(3):862–70. 14. Deng L, Liang H, Burnette B, et al. Irradiation and anti-PD-L1 treatment synergistically promote antitumor immunity in mice. J Clin Invest. 2014 Feb;124(2):687–95.

27. Wersall PJ, Blomgren H, Pisa P, et al. Regression of non-irradiated metastases after extracranial stereotactic radiotherapy in metastatic renal cell carcinoma. Acta Oncol. 2006;45(4):493–7. 28. Sham RL. The abscopal effect and chronic lymphocytic leukemia. Am J Med. 1995 Mar;98(3):307–8. 29. Kiess A, Wolchok JD, Barker CA, et al. Sterotactic radiosurgery for melanoma brain metastases in patients receiving Ipilimumab: Safety Profile and Efficacy of Combined Treatment. Int J Radiat Oncol Biol Phys. 2015 Jun 1;92(2):368-375.

15. Siva S, MacManus M, Martin R, et al. Abscopal effects of radiation therapy: A clinical review for the radiobiologist. Cancer Lett. 2015 Jan 1;356(1):82-90.

30. Grimaldi AM, Simeone E, Giannarelli D, et al. Abscopal effects of radiotherapy on advanced melanoma patients who progressed after ipilimumab immunotherapy. Oncoimmunology. 2014 May 14;3:e28780.

16. Siva S, Callahan J, MacManus MP, et al. Abscopal effects after conventional and stereotactic lung irradiation of non-small-cell lung cancer. J Thorac Oncol. 2013 Aug;8(8):e71–2.

31. Golden EB, Demaria S, Schiff PB, et al. An abscopal response to radiation and ipilimumab in a patient with metastatic non-small cell lung cancer. Cancer Immunol Res. 2013 Dec;1(6):365–72.

17. Ishiyama H, Teh BS, Ren H, et al. Spontaneous regression of thoracic metastases while progression of brain metastases after stereotactic radiosurgery and stereotactic body radiotherapy for metastatic renal cell carcinoma: abscopal effect prevented by the blood-brain barrier? Clin Genitourin Cancer. 2012 Sep;10(3):196–8.

32. Hiniker SM, Chen DS, Reddy S, et al. A systemic complete response of metastatic melanoma to local radiation and immunotherapy. Transl Oncol. 2012 Dec;5(6):404–7.

18. Tubin S, Casamassima F, Menichelli C, et al. A case report on metastatic thyroid carcinoma: radiation-induced bystander or abscopal effect? J Cancer Sci Ther. 2012 Nov 23;4:408–11. 19. Lakshmanagowda PB, Viswanath L, Thimmaiah N, et al. Abscopal effect in a patient with chronic lymphocytic leukemia during radiation therapy: a case report. Cases J. 2009;2:204.

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33. Postow MA, Callahan MK, Barker CA, et al. Immunologic correlates of the abscopal effect in a patient with melanoma. N Engl J Med. 2012 Mar 8;366(10):925–31. 34. Stamell EF, Wolchok JD, Gnjatic S, et al. The abscopal effect associated with a systemic anti-melanoma immune response. Int J Radiat Oncol Biol Phys. 2013 Feb 1;85(2):293–5.

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An Update on Proton Beam Radiation Background: The Duval County Medical Society (DCMS) is proud to provide its members with free continuing medical education (CME) opportunities in subject areas mandated and suggested by the State of Florida Board of Medicine to obtain and retain medical licensure. The DCMS would like to thank the St. Vincent’s Healthcare Committee on CME for reviewing and accrediting this activity in compliance with the Accreditation Council on Continuing Medical Education (ACCME). This issue of Northeast Florida Medicine includes an article, “An Update on Proton Beam Radiation,” authored by Roi Dagan, MD, MS, which has been approved for 1 AMA PRA Category 1 credit.TM For a full description of CME requirements for Florida physicians, please visit www.dcmsonline.org. Faculty/Credentials: Roi Dagan, MD, MS, Assistant Professor, Radiation Oncology, UFHealth Proton Therapy Institute, University of Florida, College of Medicine Objectives: 1. Demonstrate understanding and explain the rationale for proton radiation. 2. Understand the role of proton therapy in the management of established indication including pediatric cancer, prostate cancers, and ocular malignancies. 3. Be able to discuss the emerging role of proton therapy for lymphoma, breast cancer, head and neck cancers, and emerging technological advances in proton therapy. Date of release: Dec. 1, 2016

Date Credit Expires: Dec. 1, 2018 Estimated Completion Time: 1 hour

How to Earn this CME Credit: 1. Read the “An Update on Proton Beam Radiation” article. 2. Complete the posttest. Scan and email your test to Kristy Wolski at kristy@dcmsonline.org or mail it to 1301 Riverplace Blvd., Suite 1638, Jacksonville, FL 32207. 3. You can also go to www.dcmsonline.org/NEFMCME to read the article and take the CME test online. 4. All non-members must submit payment for their CME before their test can be graded. CME Credit Eligibility: A minimum passing grade of 70% must be achieved. Only one re-take opportunity will be granted. If you take your test online, a certificate of credit/completion will be automatically downloaded to your DCMS member profile. If you submit your test by mail, a certificate of credit/completion will be emailed within four to six weeks of submission. If you have any questions, please contact Kristy Wolski at 904.355.6561 or kristy@dcmsonline.org. Faculty Disclosure: Roi Dagan, MD, MS reports no significant relations to disclose, financial or otherwise, with any commercial supporter or product manufacturer associated with this activity. Disclosure of Conflicts of Interest: St. Vincent’s Healthcare (SVHC) requires speakers, faculty, CME Committee and other individuals who are in a position to control the content of this educations activity to disclose any real or apparent conflict of interest they may have as related to the content of this activity. All identified conflicts of interest are thoroughly evaluated by SVHC for fair balance, scientific objectivity of studies mentioned in the presentation and educational materials used as basis for content, and appropriateness of patient care recommendations. Joint Sponsorship Accreditation Statement This activity has been planned and implemented in accordance with the Essential Areas and policies of the Accreditation Council for Continuing Medical Education through the joint sponsorship of St. Vincent’s Healthcare and the Duval County Medical Society. St. Vincent’s Healthcare designates this educational activity for a maximum of 1 AMA PRA Category 1 credit. TM Physicians should only claim credit commensurate with the extent of their participation in the activity.

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An Update on Proton Beam Radiation By Roi Dagan, MD, MS

Introduction In recent decades there have been many technological advances in cancer care. One has to look no further than the dissemination of proton therapy (PT) as a shining example of precision cancer care. In 2006, when the UF Health Proton Therapy Institute (UFHPTI) began treating patients, there were just five proton facilities in the United States. Currently, there are 14 centers in the U.S. with several others in planning and development. The First Coast is lucky to have tremendous growth in the area of PT, with UFHPTI recently announcing an expansion of its facility and the Ackerman Cancer Center now offering PT. It is important to understand the rationale for PT and to be familiar with indications and supporting clinical data. Physicians should also understand the emerging role for PT in lymphoma, breast, and head and neck cancers and be knowledgeable about recent technological advances.

Figure 1: Depth-dose profile of proton beam versus x-ray radiotherapy.

Historic perspective and rationale for PT Ernest Lawrence won the Nobel Prize for inventing the cyclotron in 1929 while working at the University of California, Berkeley. This was the first of several devices capable of generating high energy, charged-particle radiation beams. In the 1940s, it was Robert Wilson who proposed the use of PT for treatment of cancers.1 An initial clinical experience of PT for pituitary adenoma was published in Sweden in 1957.1 Throughout most of the 20th century, PT was only available at a few clinical and research facilities in the U.S. However, the early 2000s saw an expansion of the technology with clinical centers opening in Jacksonville (UFHPTI), Houston, Texas (MD Anderson Cancer Center), and Philadelphia, Pennsylvania (University of Pennsylvania), to accompany existing centers. More recently, researchers have seen a new wave of expansion of PT with many single and multi-treatment room facilities opening across the U.S. The excitement behind this expansion is rooted in the fundamental differences in the way that PT is deposited when compared with conventional forms of radiation, which use photons or x-rays. Unlike x-rays, protons penetrate deeper and

Address correspondence to: Roi Dagan, MD, MS UF Health Proton Therapy Institute 2015 North Jefferson Street Jacksonville, FL 32206 904-588-1445 18 Vol. 67, No. 4 2016 Northeast Florida Medicine

have a finite range of dose deposition, described by the Bragg peak.1 This results in a significant reduction in the dose delivered outside of the target relative to the dose deposited within the target (Figure 1). Countless analyses have demonstrated the dosimetric benefits with PT over conventional radiation in prostate2, breast3, lung4, head and neck5, gastrointestinal6, and central nervous system7, pediatric cancers8, and lymphomas9 to name a few. Although corollary clinical data is still maturing, there is already a significant amount of evidence supporting a role for PT in pediatric cancers10, ocular tumors11, skull base/ spine tumors12, and prostate cancer.13

Disease sites with significant clinical experience with PT Prostate Cancer. The dosimetric rationale for PT for prostate cancer lies in reduced dose deposition to the bladder and rectal wall with PT versus x-ray-based techniques, such as Intensity Modulated Radiation Therapy (IMRT).2 Multiple prospective trials and large cohorts have demonstrated excellent results with PT for prostate cancer.13 Surprisingly, it was not toxicity reductions, but a benefit in biochemical disease control in intermediate and high-grade cancers that has emerged as one of the most compelling advantages of PT. In two prospective trials, the biochemical control with PT at five years for intermediate and high-risk prostate cancers was 99 percent and 76 percent, respectively. These figures compare favorably with 85 percent and 67 percent in intermediate and high-risk cancers with

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IMRT.14 While overall provider-reported toxicity is comparable, PT resulted in reduced patient-reported rectal urgency in an analysis using prospective patient-reported quality of life data.15 Skeptics of PT cite an analysis suggesting higher rates of rectal toxicity with PT using data collected from the SEER-Medicare database, and they continue to question the cost-effectiveness of PT given the increased cost compared with other treatments.16 Pediatric cancers. The developing tissues of children are particularly sensitive to the complications from cancer therapy, especially radiotherapy. Radiotherapy to the developing brain results in a range of late effects including reduced IQ, hearing loss, neuroendocrine disorders, and vasculopathy, to name a few.17 Analyses performed at St. Jude’s Children’s Research Hospital elegantly demonstrated these effects occurring in an age and dose/volume dependent fashion.18 Their models show that reductions in moderate and low dose radiation to significant volumes of the brain can significantly reduce the risk of these effects. Currently, there exists strong data supporting the role of PT in pediatric central nervous system (CNS) cancers demonstrating reduced second cancers19, improved cognitive outcomes20, and cost-effectiveness.21 Clinical outcomes support the role of PT in pediatric malignancies outside the CNS including Ewings sarcoma, rhabdomyosarcoma, and pediatric lymphomas. Skull base and spine chordoma and chondrosarcoma. The role for PT in the management of skull base and mobile spine neoplasms, such as chordoma and chondrosarcoma, has been well established.1 Aggressive treatment of tumors in the skull base is notoriously challenging because of the location of the target region relative to the eyes, visual pathways, brainstem, and brain. Harnessing the inherent dosimetric benefits of PT, several centers began treating these tumors years ago and a significant literature has demonstrated PT to yield superior disease control results compared with a series of patients treated with conventional radiation.12 Eye tumors. Ocular neoplastic disorders are exceedingly rare. Several treatment options exist for treating these tumors including enucleation, conventional external beam radiation, implanted radiation sources (brachytherapy), and PT. In a prospective randomized control trial comparing particle therapy to brachytherapy, particle therapy proved to be superior in terms of disease control and ocular preservation.11 To date, thousands of patients around the world have been treated with PT for uveal tumors with excellent results, and in very large tumors, PT often offers the only hope for ocular preservation.22 The UFHPTI is one of three centers in the U.S. that offers PT with a stereotactic eye-line. This technique delivers one of the most precise radiation beams commercially available. It is capable of delivering a therapeutic dose of radiation to tumor target in the eye, which can be localized for treatment with a 0.3 mm accuracy, and within 1 mm of the target, the dose falls off to a safe level (~20 percent of the maximum dose). DCMS online . org

Emerging role for proton beam therapy Lymphoma. In both Hodgkin’s and non-Hodgkin’s lymphoma, the role of radiotherapy has been decreasing as more effective chemotherapy regimens have emerged and a growing body of evidence has documented severe late effects from radiotherapy.23,24 Ng et al demonstrated that treatment related causes of deaths such as second malignancy and cardio-pulmonary disease far exceeded deaths from Hodgkin’s lymphoma or other causes 20-30 years after therapy.23 Consequently, radiotherapy has diminished from the era of total and sub-total lymphatic radiation and mantle radiation to reduced dose involved-field radiation, more recently involved-site radiation, and in some cases, omission of radiotherapy all together.23 Nevertheless, radiotherapy continues to have an important curative role in many cases of lymphoma, especially in patients with bulky-involvement of the mediastinal lymph nodes. The dosimetric rationale for PT in lymphoma has previously been demonstrated by reduced dose to the breasts, heart, and lungs with axillary or mediastinal disease and abdominal viscera with subdiaphragmatic involvement. Early clinical data reported by Hoppe et al demonstrated three-year relapse-free survival of 93 percent and no acute or late grade 3 nonhematologic toxicities.24 Imbedded within this study was a prospective dosimentric comparison of PT versus conventional radiotherapy and IMRT, which demonstrated that PT reduced the mean dose to the heart, lungs, and breasts for all patients compared with either conventional radiotherapy or IMRT (Figure 2).25 Currently, both the Children’s Oncology Group and National Comprehensive Cancer Network guidelines endorse the use of PT for lymphoma. Breast cancer. Treatment of left sided breast cancer can result in significant late effects from radiotherapy due to cardiac-pulmonary toxicity. Multiple studies have demonstrated increased

Figure 2: Example of heart, lung, and breast sparing PT (left) versus conventional RT (right) for Hodgkin lymphoma involving the neck, axilla, and mediastinum. Courtesy of BS Hoppe.

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risk of cardiac death in women treated for left versus right sided cancers, and a recent dose-response analysis demonstrated that ischemic heart disease increases in a linear fashion at ~7 percent per Gy mean dose to the heart.26 The issue is magnified in women who receive cardiotoxic drugs (adriamycin or Herceptin) or require irradiation of the left-sided internal mammary lymph nodes, which overly the heart. Two studies have recently been published highlighting the benefits of PT when targeting either the intact breast or post-mastectomy chest wall and lymphatics, including the internal mammary lymph nodes (Figure 3).27,28 In both analyses, PT nearly eliminated the cardiac dose, greatly reduced the lung dose, and afforded better dose coverage of the target volumes. Currently, Medicare, Medicaid, and many other insurance policies cover PT for left-sided breast cancer. Head and neck cancers. Compelling dosimetric and clinical data suggest that PT can significantly reduce toxicity in nasopharynx cancer and oropharynx cancer and improve disease

Figure 3: Dose distribution with conventional radiation (left) and cardio-pulmonary, sparing PT (right) targeting the postmastectomy chest wall and regional lymph nodes including internal mammary lymph nodes.

control in sinonasal cancer. In nasopharynx cancer, groups from the MD Anderson Cancer Center and Harvard have reported very favorable outcomes with PT. In one study, PT resulted in 100 percent local-regional disease control, no instances of high-grade xerostomia, and only one patient showed objective swallowing dysfunction at six months.29 In the other study, patients treated with PT were matched to patients treated in the same era with IMRT. This study reported a reduced rate of feeding tube dependence at three months from 58 percent with IMRT to 23 percent with PT, and objective swallowing dysfunction was reduced from 19 percent with IMRT to 8 percent with PT.30

only modestly improved local control to 65-75 percent, while reducing ocular toxicity.31 Extrapolating from advantages seen with PT for other skull base tumors, investigators at proton centers began treating sinonasal cancers many years ago. Early single institution reports were encouraging, and a recent systematic review and meta-analysis demonstrated a significant disease control and overall survival advantage with PT compared with IMRT.32 In one of the largest series published, investigators from UFHPTI reported an unprecedented 90 percent local control after gross-total resection and PT and a favorable 60 percent local control in patients with unresectable or incompletely resected disease.33 In oropharyngeal cancer, researchers have seen a significant change in the underlying biology of the disease over the last 20 years due to the human-papilloma virus (HPV) epidemic.34 These infections have resulted in an explosion of new cases of oropharynx cancer in the U.S. and worldwide. Fortunately, these cancers have a much more favorable prognosis than non-HPV oropharyngeal cancers, which occur more commonly in older patients with extensive exposure to tobacco.34 Consequently, there is a new emphasis on issues of survivorship and reducing treatment-related toxicity. Towards this end, current strategies have utilized reduced dose radiotherapy and chemotherapy and trans-oral robotic surgery. PT is an additional strategy for reducing treatment related toxicity in oropharynx cancer by reducing the irradiated volume, especially in organs involved in swallowing function, such as the pharyngeal musculature and larynx, and reducing xerostomia through decreased dose to the oral cavity and major salivary glands.35 PT may have the greatest advantages when treating patients with targets involving one side of the neck, such as early stage tonsil cancer, parotid cancers, and lateralized skin cancers that require radiotherapy. In this scenario, all exit radiation to the oral cavity, larynx, pharyngeal musculature, spinal cord, brainstem, and contralateral salivary glands can essentially be eliminated

Figure 4: Dose distribution with conventional radiation (left) and PT (right) for parotid cancer.

Delivery of aggressive local therapy for sinonasal cancers has been hampered by the location of the target in close proximity to the eyes, visual pathways, brainstem, and brain. Historically, local disease control rates hovered around 50-60 percent with surgery and radiotherapy and high rates of severe toxicity (15-30 percent) including blindness and CNS necrosis.31 IMRT has

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(Figure 4). A recent comparison of matched patients treated with PT compared with IMRT targeting a single neck demonstrated significant reduction in dose to organs at risk and acute mucosal toxicity.36 Data from UFHPTI demonstrated patients receiving PT to the parotid region only lost a negligible three percent of their baseline weight during therapy and showed no instances of high-grade acute toxicity.37

Recent technological advances in PT The PT field has been energized by significant advances in planning and delivery. New treatment planning systems are equipped with software that analyzes/minimizes uncertainties in dose delivery and patient set-up. Particle accelerators and gantry delivery systems are now available at significantly reduced cost and scale. Newer systems are equipped with advanced image-guided technologies, such as on-line cone-beam computed tomography. These systems allow providers to more clearly see the target position at the time of therapy and utilize computer-assisted registration algorithms and robotic 6-degree of freedom tables to precisely align patients for treatments. The advent of pencil-beam scanning or intensity modulated PT represents the next technological breakthrough. In these systems, high-precision scanning magnets are used to guide individual proton beam spots. Using computer optimization algorithms, spot placement and intensity weighting can be modulated to deliver radiation dose to complex 3D volumes with reductions in normal tissue doses. This technique also has the advantage of reducing treatment cost because it doesnâ&#x20AC;&#x2122;t require expensive beam shaping devices, called apertures and compensators, which are used with passively scattered beams. It is widely believed that as this form of PT gains further acceptance and dissemination, even more indications for PT will emerge.

Conclusion PT is gaining ever growing acceptance within the oncology community. A growing body of evidence supports its role in the management of prostate cancer, pediatric cancers, and skull base tumors. Emerging clinical and dosimetric evidence is also available in breast, head and neck cancers and lymphoma, to name a few, and technological advances should help further improve the therapeutic ratio in many clinical scenarios. While cost-effectiveness remains a legitimate concern, wider acceptance, increased market competition, and alternative re-imbursement strategies are likely to reduce the barriers to PT in the future. v

References 1. Doyen J, Falk AT, Floquet V, et al. Proton beams in cancer treatments: Clinical outcomes and dosimetric comparisons with photon therapy. Cancer Treat Rev. 2016 Feb;43:104-12. 2. Vargas C, Fryer A, Mahajan C et al. Dose-volume comparison of proton therapy and intensity-modulated radiotherapy for prostate cancer. Int J Radiat Oncol Biol Phys. 2008 Mar 1;70(3):744-51. 3. Xu N, Ho MW, Morris CG, et al. Can proton therapy improve the therapeutic ratio in breast cancer patients at risk for nodal disease? Am J Clin Oncol. 2014 Dec;37(6):568-74. 4. Kesarwala AH, Ko CJ, Ning H, et al. Intensity-modulated proton therapy for elective nodal irradiation and involved-field radiation in the definitive treatment of locally advanced non-small-cell lung cancer: a dosimetric study. Clin Lung Cancer. 2015 May;16(3):237-44. 5. Lukens JN, Lin A, Hahn SM. Proton therapy for head and neck cancer. Curr Opin Oncol. 2015 May;27(3):165-71. 6. Nichols RC, Huh SN, Prado KL, et al. Protons offer reduced normal-tissue exposure for patients receiving postoperative radiotherapy for resected pancreatic head cancer. Int J Radiat Oncol Biol Phys. 2012 May 1;83(1):158-63. 7. Dennis ER, Bussiere MR, Niemierko A, et al. A comparison of critical structure dose and toxicity risks in patients with low grade gliomas treated with IMRT versus proton radiation therapy. Technol Cancer Res Treat. 2013 Feb;12(1):1-9. 8. Ladra MM, Edgington SK, Mahajan A, et al. A dosimetric comparison of proton and intensity modulated radiation therapy in pediatric rhabdomyosarcoma patients enrolled on a prospective phase II proton study. Radiother Oncol. 2014 Oct;113(1):77-83. 9. Ho CK, Flampouri S, Hoppe BS. Proton therapy in the management of lymphoma. Cancer J. 2014 NovDec;20(6):387-92. 10. Ladra MM, Szymonifka JD, Mahajan A, et al. Preliminary results of a phase II trial of proton radiotherapy for pediatric rhabdomyosarcoma. J Clin Oncol. 2014 Oct 20; 32(33):3762-70. 11. Mishra KK, Quivey JM, Daftari IK, al. Long-term Results of the UCSF-LBNL Randomized Trial: Charged Particle with Helium Ion versus Iodine-125 Plaque Therapy for Choroidal and Ciliary Body Melanoma. Int J Radiat Oncol Biol Phys. 2015 Jun 1;92(2):376-83. 12. DeLaney TF, Liebsch NJ, Pedlow FX, et al. Long-term results of Phase II study of high dose photon/proton radiotherapy in the management of spine chordomas, chondrosarcomas, and other sarcomas. J Surg Oncol. 2014 Aug;110(2): 115-22.

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13. Mendenhall NP, Hoppe BS, Nichols RC, et al. Five-year outcomes from 3 prospective trials of image-guided proton therapy for prostate cancer. Int J Radiat Oncol Biol Phys. 2014 Mar 1;88(3):596-602.

25. Hoppe BS, Flampouri S, Su Z, et al. Effective dose reduction to cardiac structures using protons compared with 3DCRT and IMRT in mediastinal Hodgkin lymphoma. Int J Radiat Oncol Biol Phys. 2012 Oct 1;84(2):449-55.

14. Spratt DE, Pei X, Yamada J, et al. Long-term survival and toxicity in patients treated with high-dose intensity modulated radiation therapy for localized prostate cancer. Int J Radiat Oncol Biol Phys. 2013 Mar 1;85(3):686-92.

26. Darby SC, Ewertz M, McGale P, et al. Risk of ischemic heart disease in women after radiotherapy for breast cancer. NEJM. 2013 Mar 14;368(11):987-98.

15. Hoppe BS, Michalski JM, Mendenhall NP, et al. Comparative effectiveness study of patient-reported outcomes after proton therapy or intensity-modulated radiotherapy for prostate cancer. Cancer. 2014 Apr 1;120(7):1076-82. 16. Sheets NC, Goldin GH, Meyer AM, et al. Intensity-modulated radiation therapy, proton therapy, or conformal radiation therapy and morbidity and disease control in localized prostate cancer. JAMA. 2012 Apr 18;307(15):1611-20. 17. Merchant TE, Conklin HM, Wu S, et al. Late effects of conformal radiation therapy for pediatric patients with low-grade glioma: prospective evaluation of cognitive, endocrine, and hearing deficits. J Clin Oncol. 2009 Aug 1;27(22):3691-97.

27. Bradley JA, Dagan R, Ho MW, et al. Initial Report of a Prospective Dosimetric and Clinical Feasibility Trial Demonstrates the Potential of Protons to Increase the Therapeutic Ratio in Breast Cancer Compared With Photons. Int J Radiat Oncol Bio Phys. 2016 May 1;95(1):411-21. 28. MacDonald SM, Jimenez R, Paetzold P, et al. Proton radiotherapy for chest wall and regional lymphatic radiation; dose comparisons and treatment delivery. Radiat Oncol [Internet]. 2013 Mar 24;8(71). Available from: https://ro-journal.biomedcentral.com/articles/10.1186/1748-717X-8-71 29. Chan A, Adams JA, Weyman E. et al. A Phase II Trial of Proton Radiation Therapy With Chemotherapy for Nasopharyngeal Carcinoma. Int J Radiat Oncol Biol Phys. 2015; 84(3):S151-S152.

18. Merchant TE, Schreiber JE, Wu S, et al. Critical combinations of radiation dose and volume predict intelligence quotient and academic achievement scores after craniospinal irradiation in children with medulloblastoma. Int J Radiat Oncol Biol Phys. 2014 Nov 1;90(3):554-61.

30. Holliday EB, Garden AS, Rosenthal DI et al. Proton Therapy Reduces Treatment-Related Toxicities for Patients with Nasopharyngeal Cancer: A Case-Match Control Study of Intensity-Modulated Proton Therapy and Intensity-Modulated Photon Therapy. IJPT. 2015 Jul 20;2(1):19-28.

19. Geng C, Moteabbed M, Xie Y, et al. Assessing the radiation-induced second cancer risk in proton therapy for pediatric brain tumors: the impact of employing a patient-specific aperture in pencil beam scanning. Phys Med Biol. 2016 Jan 7;61(1):12-22.

31. Dagan R, Amdur RJ, Yeung AR, et al. Tumors of the nasal cavity. UpToDate [Internet]. 2015 Jan 6. Available from: http://www.uptodate.com/contents/tumors-of-the-nasal-cavity

20. Kahalley LS, Ris MD, Grosshans DR, et al. Comparing intelligence quotient change after treatment with proton versus photon radiation therapy for pediatric brain tumors. J Clin Oncol [Internet]. 2016 Jan 25. Available from: http://jco.ascopubs.org/content/early/2016/01/21/ JCO.2015.62.1383.abstract 21. Mailhot Vega RB, Kim J, BussiĂ¨re M, et al. Cost effectiveness of proton therapy compared with photon therapy in the management of pediatric medulloblastoma. Cancer. 2013 Dec 15;119(24):299-307. 22. Lane AM, Kim IK, Gragoudas ES. Long-term Risk of Melanoma-Related Mortality for Patients With Uveal Melanoma Treated With Proton Beam Therapy. JAMA Ophthalmol. 2015 Jul;133(7):792-6. 23. Ng AK, Bernardo MP, Weller E, et al. Long-term survival and competing causes of death in patients with early-stage Hodgkinâ&#x20AC;&#x2122;s disease treated at age 50 or younger. J Clin Oncol. 2002 Apr 15;20(8):2101-8. 24. Hoppe BS, Flamouri S, Zaiden R, et al. Involved-node proton therapy in combined modality therapy for Hodgkin lymphoma: results of a phase 2 study. Int J Radiat Oncol Biol Phys. 2014 Aug 1;89(5):1053-9. 22 Vol. 67, No. 4 2016 Northeast Florida Medicine

32. Patel SH, Wang Z, Wong WW, et al. Charged particle therapy versus photon therapy for paranasal sinus and nasal cavity malignant diseases: a systematic review and meta-analysis. Lancet Oncol. 2014;15:1027-38. 33. Dagan R, Bryant CB, Li Z, et al. Outcomes of sinonasal cancer treated with proton therapy. Int J Radiat Oncol Biol Phys. 2016 May 1;95(1):377-85. 34. Mehra R, Ang KK, Burtness B. Management of human papillomavirus-positive and human papillomavirus-negative head and neck cancer. Semin Radiat Oncol. 2012 Jul;22(3):194-7. 35. Holliday EB, Frank SJ. Proton radiation therapy for head and neck cancer: a review of the clinical experience to date. Int J Radiat Oncol Biol Phys. 2014 Jun 1;89(2):292-302. 36. Romesser PB, Cahlon O, Scher E, et al. Proton beam radiation therapy results in significantly reduced toxicity compared with intensity-modulated radiation therapy for head and neck tumors that require ipsilateral radiation. Radiother Oncol. 2016 Feb;118(2):286-92. 37. Dagan R, Bryant CM, Morris CG, et al. Proton Therapy Results in Low Rates of Acute GI Toxicity for Parotid Cancers. Oncol. 2015 Apr 30;29(S1):65.

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CME

An Update on Proton Beam Radiation CME Questions & Answers (circle one answer)/Free to DCMS Members/$55.00 charge non-members* (Return by December 1, 2018 by mail: 1301 Riverplace Blvd. Suite 1638, Jacksonville, FL 32207 or online: www.dcmsonline.org/NEFMCME) 1. Proton therapy differs from conventional radiotherapy, such as x-rays, because of differences in the physical dose deposition described the Bragg peak, which results in decreased __________. a. Entrance dose b. Biological effects on normal tissues in the target region c. Beam penumbra d. Exit dose

6. Radiotherapy for treatment of left sided breast cancers is associated with increased cardiac toxicity. Proton therapy nearly eliminates all heart radiation when treating left breast cancers. Dose/response models have estimated the risk for cardiac ischemic events increased ___% per Gy mean heart dose delivered. a. 1% b. 3% c. 5% d. 7%

2. In two prospective trials of proton therapy for prostate cancer, the 5-year biochemical disease control rates were ____ and ____for intermediate and high risk disease, respectively. a. 85% and 67% b. 50% and 33% c. 99% and 76% d. 80% and 62% 3. Which of the following is the most accurate statement regarding the use of particle therapy for ocular melanoma? a. In a prospective randomized control trial comparing particle therapy to brachytherapy, particle therapy proved improved disease control and ocular preservation b. In a prospective randomized control trial comparing particle therapy to brachytherapy, particle therapy proved improved disease control but not ocular preservation c. In a prospective randomized control trial comparing particle therapy to brachytherapy, particle therapy proved improved vision outcomes d. In a prospective randomized control trial comparing particle therapy to brachytherapy, particle therapy proved improved distant metastases rates

7. In the treatment of sinus and nasal cavity cancer, proton therapy results in the following improvements compared with conventional radiotherapy, including intensity modulated x-ray therapy (IMRT)? a. Improved local control b. Decreased visual pathway toxicity c. Decreased distant metastases d. Decreased CNS toxicity 8. In the treatment of HPV-related oropharyngeal cancer, proton therapy has the potential to ______? a. Improve local control b. Decrease distant metastases c. Decrease treatment related mucositis, xerostomia, and swallowing dysfunction d. Prevent second head and neck cancers

4. What is the target localization accuracy using the UFHealth Stereotactic Eyeline for treatment of ocular melanoma? a. 0.1 mm b. 0.3 mm c. 0.5 mm d. 1 mm

Emerging advances in proton radiotherapy include the following: a. 3D image-guidance using online cone-beam CT b. Robotic 6-degree of freedom tables to precisely align patients c. Pencil-beam scanning or intensity modulated PT d. All of the above

5. Which of the following national guidelines endorse the use of proton therapy for lymphoma? a. National Comprehensive Cancer Network (NCCN) b. Children’s Oncology Group (COG) c. A and B d. None of the above

10. There is prospective or retrospective evidence supporting the role of proton radiotherapy for all of the following indications except: a. Pediatric cancers b. Endometrial cancers c. Ocular cancers d. Head and neck cancers

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Northeast Florida Medicine Vol. 67, No. 4 2016 23

Immunotherapy

The Emerging Role of Immunotherapy in Non-Small Cell Lung Cancer By Troy H. Guthrie, Jr., MD Abstract: Non-small cell lung cancer (NSCLC) is the most commonly diagnosed primary malignancy of the lungs. Recent advances in the field of immunology have led to a better understanding of the role of immunesurveillance in this disease. Mechanisms of immune-surveillance evasion by NSLC have been recognized and novel therapeutic agents are being developed to block this immune evasion, setting the stage for the emerging role of immunotherapy in this population of patients.

Introduction Worldwide, as well as in the United States, lung cancer is the leading cause of cancer death. In 2014, approximately 225,000 new cases of lung cancer were diagnosed, estimated to result in 155,000 cancer related deaths over the subsequent five years.1 Ultimately about 80 percent of Americans diagnosed with lung cancer will succumb to their cancer.1 Despite efforts to improve screening for lung cancer with low dose computerized tomography (C-T) scans, serious problems with cost and specificity exist.2 Currently, and at least for the foreseeable future, these problems lead to the majority of patients with lung cancer being diagnosed at a later stage associated with more symptoms and less curable treatment options. The dismal outcome for most lung cancer patients has increased the urgency to introduce immunotherapy as an option to improve end results.

Staging and Past Treatment Strategies Biologically, lung cancer can be separated into two distinct entities, small cell lung cancer (12 percent of cases) and non-small cell lung cancer (88 percent of cases).3 These two entities are staged and treated with markedly different approaches. In general, NSCLC has been treated as two distinct groups, squamous and non-squamous cell carcinomas. Table 1 describes the differences in treating early versus more advanced recurrent stages.

Address correspondence to: Troy H. Guthrie, Jr., MD Medical Director of Clinical Research 21st Century Oncology of Jacksonville 425 North Lee Street, Suite 204 Jacksonville, FL 32204 Tel: (904) 427-1200 24 Vol. 67, No. 4 2016 Northeast Florida Medicine

Despite the employment of adjuvant therapy for some surgically resected patients, most patients will be immediately metastatic at presentation (40 percent). The remaining patients will have a recurrence with distant metastases after local and adjuvant therapy. Many patients will require palliative systemic therapy if physically fit. For the majority of patients, palliative systemic therapy includes chemotherapy, usually a platinum compound of either Cisplatinum or Carboplatinum, combined with a second drug. However, the response rates are low (30-50 percent) and duration of responses are short (6-9 months).4 Despite maintenance and salvage regimens, median survival for most patients is only 12-18 months after the diagnosis of metastatic NSCLC. Over the past decade, development and therapeutic use of oral targeted small molecule tyrosine kinase inhibitors (TKI) have resulted in prolonged survival compared to standard chemotherapy regiments, mostly in younger, non-smoking patients with nonsquamous malignancy with genetic driver mutations.5,6,7 The two most common mutations involve Epidermal Growth Factor Receptor (EGFR) and Anaplastic Lymphoma Kinase (ALK) and occur in 10-15 percent and 3-7 percent of American patients with adenocarcinoma of the lung respectively.8,9 For patients with EGFR mutations,

Table 1: Simplified Staging and Treatment of NSCLS Stage

Extent of Disease

Management

Primary Tumor < 7 cm No Node

Surgical Resection if medically operable; Radiation therapy if not

Tumor > 7 cm Âą Regional Nodes

Surgical resection if operable; Radiation therapy if not, Âą ChemotherapyAdjuvant Chemotherapy if resected

III

Locally Advanced Disease with no Malignant Plural Effusion

Surgical resection; if possible Radiation plus Chemotherapy; Adjuvant Chemotherapy if resectable

Distant Metastases Malignant Plural Effusion

Systemic Therapies; Chemotherapy; Targeted Therapies

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Immunotherapy

three drugs (Gefinitinib, Erlotinib and Afatinib) show significantly higher response rates (RR), progressive free survival (PFS) and, in some studies, overall survival (OS) compared to chemotherapy treatments.7,10,11

a brief discussion of the Checkpoint Blockade System13 provides a better understanding of the immunotherapy agents, their mechanisms of action and early results in lung cancer, particularly NSCLC.

Likewise, patients with ALK driver mutations have a higher response rate (60 percent) compared to chemotherapy with Crizotinib, the only FDA approved first line TKI for ALK positive patients.12 Ceritinib is now approved as second line therapy in ALK positive patients who have progressed on Crizotinib, and it has an impressive response rate of 70 percent.12

Two checkpoint receptor systems are now well defined, with multiple drugs being developed to assist tumor recognition and killing of different malignancies, including NSCLC. First, the Cytotoxic T-Lymphocyte Antigen 4 (CTLA-4) system is involved in the activation of T-Lymphocytes in the lymph nodes and their migration to the tumor site.14 Second, the Programmed Cell Death 1 (PD-1) receptor is involved in immune recognition and killing in both the tumor and normal micro-environments.15 Both the CTLA-4 and PD-1 checkpoint systems are important down regulators of the immune system to prevent uncontrolled autoimmunity and normal cell damage but can be hijacked by tumor cells to prevent immune destruction. In particular, the PD-1 receptors on activated T-cells can be used by tumor cells expressing the ligands PD-L1 and PD-L2 to downregulate activated T-cells in the tumor micro-environment and avoid tumor cell immune destruction.16 Pharmaceutical companies have focused on developing monoclonal antibodies to the PD-1 receptor on T-cells and the PD-L1 ligand on tumor cells to assist achieving clinical response in NSCLC patients.

Other less common driver mutations exist for which therapies are currently being defined. However, despite the initial response to TKI treatment, resistance ultimately develops leading to eventual disease progression.

Immunology as Applied to Lung Cancer A better understanding of the immune system and how tumor cells evade immune recognition and killing has been critical to identifying the therapeutic role of immunotherapy in managing lung cancer. A full discussion of immune regulation of tumor cells is beyond the scope of this article. However,

Table 2: Reported Efficacy of PD-1 and PD-L1 Inhibition Monotherapy in NSCLC PD-L1 Expression Required

Treatment Setting

Number of Patients, n

Overall Response Rate, %

Median Response Duration months

Advanced/metastatic, previously treated, squamous

272

NR*

3.5

9.2

Nivolumab

Advanced/metastatic, previously treated, previously treated,

582

19.2

17.1

2.3

12.2

Pembrolizumab

Yes

Advanced/metastatic, previously treated,

495

19.4

12.5

3.7

12.5

Yes

Advanced/metastatic, previously treated

287

ND#

2.8

11.4

Agent

Median PFS, Median OS, months months

PD-1 Nivolumab

PD-L1 Atezolizumab

*NR = Not Reached # ND = Not Documented

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Northeast Florida Medicine Vol. 67, No. 4 2016 25

Immunotherapy

Present Role of Immunotherapy

Toxicity of PD-1/PD-L1 Antibodies

Currently, two monoclonal antibodies to the PD-1 receptor on T-Lymphocytes (Nivolumab and Pembrolizomab) have FDA approval for second line therapy in NSCLC, and one PD-L1 ligand monoclonal antibody (Arezolizumab) appears close to FDA approval in previously treated NSCLC.17,18,19,20 There are multiple other monoclonal antibodies to either PD-1 or PD-L1 being developed but are earlier in development stages. The remainder of this article will be a brief discussion of the above three monoclonal antibodies including study trials, treatment results and common toxicities (Table 2).

Toxicities of the PD-1/PD-L1 monoclonal antibodies are similar and generally low grade and uncommonly cause discontinuation of therapy (Table 4). Unique for these drugs are Immune Related Adverse Events (IRAE) in which an inflammatory or autoimmune reaction triggered by the therapeutic agent is implicated. Most commonly IRAEs include

Nivolumab gained FDA approval as a second line therapy for squamous lung cancer in March 2015 and second line therapy for non-squamous NSCLC in October 2015, with both approvals based on improved overall survival in separate trials for each group (Table 3). Each trial tested for the expression of PD-L1 on tumor cells but did not require expression of the PD-L1 on tumor cells for patient entry. The FDA label for Nivolumab does not require testing for PD-L1 on the patientâ&#x20AC;&#x2122;s tumor cells for treatment, although more benefit is noted for those patients whose tumor expresses PD-L1 (Table 3). Both trials use Docetaxel as a control arm and both showed an improvement in median OS and survival at 12 months compared to Docetaxel chemotherapy in each histologic group. Toxicity of Nivolumab was generally manageable with 13 percent of patients stopping Nivolumab due to toxicity. Pembrolizomab, a PD-1 monoclonal antibody, was approved by the FDA for second line therapy of PD-L1-expressing NSCLC of either histology. This approval is based on a large single arm study done only in patients whose tumor expressed PD-L1 which demonstrated excellent response rates and improved overall survival compared to previous historical chemotherapy results (Table 3). Again, toxicity was relatively mild with less than 10 percent of patients stopping Pembrolizumab because of toxicity. Arezolizumab is a PD-L1 monoclonal antibody in which FDA approval is pending for treating NSCLC patients expressing PD-L1 on their tumor specimens. Improvement in median overall survival (11.4 vs 9.5 months) was noted among patients with previously treated PD-L1 expressing NSCLC compared to Docetaxel. Again, toxicity of Arezolizumab is relatively mild and generally manageable.21

Table 3: Most Common and Severe Adverse Events in PD-1/PD-L1 Trials in NSLC CheckMate 017 Phase 3, Nivolumab In squamous-cell NSCLC n=131

KEYNOTE-001

POPLAR

Phase 1, Pembrolizumab In NSCLC n=495

Phase 2, atezolizumab In NSCLC n=142

Fatigue Grade 3-5

16 1

19.4 0.8

NR* NR

Asthenia Grade 3-5

10 0

4.8 1

10 1

Pyrexia Grade 3-5

5 0

4.2 0.6

NR NR

Rash Grade 3-5

4 0

9.7 0.2

NR NR

Pruritus Grade 3-5

2 0

10.7 0

NR NR

Nausea Grade 3-5

9 0

7.5 0.8

22 1

Diarrhea Grade 3-5

8 0

8.1 0.6

17 1

Decreased appetite Grade 3-5

11 1

10.5 1

33 1

Pneumonitis Grade 3-5

5 1

3.6 1.8

2 NR

Hypothyroidism Grade 3-5

4 0

6.9 0.2

6 1

AST elevation ALT elevation Grade 3-5 AST Grade 3-5 ALT

2 2 0 0

3 2.2 0.6 0.4

4 4 NR NR

Infusion hypersensitivity reaction Grade 3-5

0.2

*NR = Not Reached

26 Vol. 67, No. 4 2016 Northeast Florida Medicine

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Immunotherapy

Table 4: Management of PD-1PD-L1 Antibody Toxicities Mild Grade I

Management

Treatment

Special Toxicities

Continue Drug Monitor for Toxicity

Moderate Grade II

High Grade III

Hold Drug Hold Drug Star Steroids Restart at Restart Drug at Grade 1 Grade I and after Steroid taper

Drug permanently discontinued for life threatening toxicities and all immune pneumonitis and neurological toxicities.

pneumonitis, colitis, endocrinopathies, hepatitis, dermatitis and neurologic toxicities.21,21,23 Criteria for recognition and management of toxicity for all agents are in place and minimize adverse effects. For all high grade toxicities, the drug is either temporarily or permanently stopped and immune suppressive therapy with steroids is employed.

Future Directions Intense research for the PD-1/PD-L1 antibodies is ongoing, exploring treatment settings other than second line after initial systemic therapy failure. These investigations include initial first line therapy and adjuvant therapy after surgery, combined with radiation and/or chemotherapy. Also, combined immunotherapy regimens, such as simultaneous CTLA-4 and PD-L1, or PD-L1 blockade, are being explored. Research is also looking into certain biomarkers and clinical scenarios that may help to identify those who are less likely to respond to this form of immunotherapy. To date, all studies indicate increasing expression of PD-L1 on tumor cells indicating increased benefit but most studies to date have some patients with no expression of PD-L1 on their tumor showing responses.

Summary Lung cancer therapy has markedly improved over the last three decades, with excellent results by employing surgical management of early stage cancers. However, despite advances in chemotherapy and development of TKIs to treat driver mutations, all patients with metastatic disease ultimately have disease progression leading to death. Advances in immunology have allowed development of monoclonal antibodies to the

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PD-1 receptor on activated T-lymphocytes or the PD-L1ligand on Tumor cells preventing NSCLC from evading immune destruction. Large studies have included patients who failed initial platinum based chemotherapy, as well as failed TKI therapy for those with defined driver mutations. These studies have shown equal to superior response rates, as well as increased median overall survival for the PD-1 monoclonol antibodies compared to Docetaxel. Even more encouraging is a significant proportion of patients have prolonged disease control. With all of these findings occurring in the last two years, much ongoing research remains to define the role of PD-1/PD-L1 therapies as initial therapy of metastatic disease, in the adjuvant setting, or in some combination with either radiation, chemotherapy or TKIs. Future understanding of these therapies will allow clinicians to predict which patients will respond and benefit from these forms of treatment. v

References 1. Siegel RL, Miller KD, Jemal A. Cancer statistics, 2015. CA Cancer J. Clin. 2015 Jan-Feb;65(1):5-29. 2. Moyer VA, US Preventive Services Task Force. Screening for lung cancer: U.S. Preventive Services Task Force recommendation statement. Ann Int Med. 2014 Mar 4;160(5): 330-8. 3. Chen Z, Filmore CM, Hammerman PS, et al. Non-small cell lung cancers; a heterogeneous set of diseases. Nat Rev Cancer. 2014 Aug;14(8):535-46. 4. Schiller JH, Harrington D, Belani CP, et al. Comparison of four chemotherapy regimens in advanced non-small-cell lung cancer. N Engl J Med. 2002 Jan 10;346(2):92-8. 5. Shepherd FA, Rodrigues Pereira J, Ciuleanu T, et al. Erlotinib in previously treated non-small-cell lung cancer. N Engl J Med. 2005 Jul 14;353(2):123-32. 6. Shaw AT, Kim DW, Nakagawa K, et al. Crizotinib versus chemotherapy in advanced ALK positive lung cancer. N Engl J Med. 2013 Jun 20;368(25):2385-94. 7. Kwak EL, Bang YJ, Camidge DR, et al. Anaplastic lymphoma kinase inhibition in non-small-cell lung cancer. N Engl J Med. 2010 Oct 28;363(18):1693-703. 8. Reguart N, Remon J. Emerging adenocarcinoma driver mutations. J Future Oncol. 2015;28:1-13. 9. Mok TS, Wu Y, Thongprasert S, et al. Gefitinib or carboplatinum- pactaxel in pulmonary adenocarcinoma. N Engl J Med. 2009 Sep 3;361:941-57.

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Immunotherapy

10. Rosell R, Carcereny E, Gervais R, et al. Erlotinib vs standard chemotherapy as first line treatment for European patients with advanced EGFR mutation-positive non-small-cell lung cancer (EURTAC): a multi-centre, open-label, randomized phase 3 trial. Lancet Oncol. 2012 Mar;13(3):239-46. 11. Yang JC, Wu YL, Schuler M, et al. Afatinib vs cisplatinum based chemotherapy for EGRF mutation positive lung adenocarcinoma (LUX-Lung 3 and LUX-Lung 6 ); analysis of overall survival for 2 randomized phase 3 trials. Lancet Oncol. 2015 Feb;16(2):141-51. 12. Shaw AT, Kim DW, Mehra R, et al. Ceritinib in ALK-rearranged non-small-cell lung cancer. N Engl J Med. 2014 Mar 27;370:1189-97. 13. Dunn GP, Bruce AT, Ikeda H, et al. Cancer immunoediting from immunosurveillance to tumor escape. Nat Immunol. 32002 Nov;3(11):991-8. 14. Pardell DM. The blockade of immune checkpoints in cancer immunotherapy. Nat Rev Cancer. 2012 Mar 22;12(4):252-64. 15. Francisco LM, Sage PT, Sharpe AH. The PD-1 pathway in tolerance and autoimmunity. Immunol Rev. 2010 Jul;236:219-42. 16. Nirschl CJ, Drake CG. Molecular Pathways: coexpression of immune checkpoint molecules: signaling pathways and implications for cancer immunotherapy. Clin Cancer Res. 2013 Sep 15;19(18):4917-24.

28 Vol. 67, No. 4 2016 Northeast Florida Medicine

17. Brahmer J, Reckamp KL, Baas P, et al. Nivolumib versus docetaxel in advanced squamous-cell non-small-cell lung cancer. N Engl J Med. 2015 Jul 9;373:123-35. 18. Borghaei H, Paz-Ares L, Horn L, et al. Nivolumab versus Docetaxel in advanced nonsquamous non-small-cell lung cancer. N Engl J Med. 2015 Oct 22;373(17):1627-39. 19. Herbst RS, Gurpide A, Surmont V, et al. A phase II/III randomized trial of two doses of MK3475 vs docetaxel in previously treated subjects with non-small cell lung cancer. 2014 ASCO Annual Meeting; 2014 May 30- Jun 3; Chicago, Illinois. 20. Spira AI, Park K, Mazieres J, et al. Efficiacy, safety and predictive biomarkers result from a phase II study comparing atezolizumab vs docetaxel in 2L/3L NSCLC (POPLAR). 2015 ASCO Annual Meeting; 2015; May 29- Jun 2; Chicago, Illinois. 21. Weber JS, Kahlar KC, Hauschild A. Management of immune-related adverse events and kinetics of response with ipilimumab. J Clin Oncol. 2012 Jul 20;30(21):2691-7. 22. Opdivo (Nivolumab) for injection [Package Insert] Princeton N.J., Bristol-Myers-Squibb, 2015. 23. Keytruda (Pembrolizumab) for injection [Package Insert], Whitehouse Station, N.J., Merk & Co. 2015.

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CME

Current State of Immunotherapy for Metastatic Melanoma Background: The Duval County Medical Society (DCMS) is proud to provide its members with free continuing medical education (CME) opportunities in subject areas mandated and suggested by the State of Florida Board of Medicine to obtain and retain medical licensure. The DCMS would like to thank the St. Vincent’s Healthcare Committee on CME for reviewing and accrediting this activity in compliance with the Accreditation Council on Continuing Medical Education (ACCME). This issue of Northeast Florida Medicine includes an article, “Current State of Immunotherapy for Metastatic Melanoma” authored by Richard W. Joseph, MD, which has been approved for 1 AMA PRA Category 1 credit.TM For a full description of CME requirements for Florida physicians, please visit www.dcmsonline.org. Faculty/Credentials: Richard W. Joseph, MD, Assistant Professor, Mayo Clinic Florida Objectives: 1. Explain the mechanism of immunotherapy in cancer. 2. Describe the clinical utility of anti-CTLA4 agents. 3. Describe the clinical utility of anti-PD1 agents. 4. Describe the clinical utility of TVEC. Date of release: Dec. 1, 2016

Date Credit Expires: Dec. 1, 2018

Estimated Completion Time: 1 hour

How to Earn this CME Credit: 1. Read the “Current State of Immunotherapy for Metastatic Melanoma” article. 2. Complete the posttest. Scan and email your test to Kristy Wolski at kristy@dcmsonline.org or mail it to 1301 Riverplace Blvd., Suite 1638, Jacksonville, FL 32207. 3. You can also go to www.dcmsonline.org/NEFMCME to read the article and take the CME test online. 4. All non-members must submit payment for their CME before their test can be graded. CME Credit Eligibility: A minimum passing grade of 70% must be achieved. Only one re-take opportunity will be granted. If you take your test online, a certificate of credit/completion will be automatically downloaded to your DCMS member profile. If you submit your test by mail, a certificate of credit/completion will be emailed within four to six weeks of submission. If you have any questions, please contact Kristy Wolski at 904.355.6561 or kristy@dcmsonline.org. Faculty Disclosure: Richard W. Joseph, MD reports that he is a consultant for Merck, BMS, Genoptix and Eisai, and that he has received grant/ research support from Merck, Roche, BMS, Amgen, and X4. Dr. Joseph also reports that his article will not include discussion of any investigational or unlabeled use of a product. Disclosure of Conflicts of Interest: St. Vincent’s Healthcare (SVHC) requires speakers, faculty, CME Committee and other individuals who are in a position to control the content of this educations activity to disclose any real or apparent conflict of interest they may have as related to the content of this activity. All identified conflicts of interest are thoroughly evaluated by SVHC for fair balance, scientific objectivity of studies mentioned in the presentation and educational materials used as basis for content, and appropriateness of patient care recommendations. Joint Sponsorship Accreditation Statement This activity has been planned and implemented in accordance with the Essential Areas and policies of the Accreditation Council for Continuing Medical Education through the joint sponsorship of St. Vincent’s Healthcare and the Duval County Medical Society. St. Vincent’s Healthcare designates this educational activity for a maximum of 1 AMA PRA Category 1 credit. TM Physicians should only claim credit commensurate with the extent of their participation in the activity..

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Northeast Florida Medicine Vol. 67, No. 4 2016 29

CME

Current State of Immunotherapy for Metastatic Melanoma By Richard W. Joseph, MD Abstract: Advancements in our understanding of how melanoma evades the immune system have led to major improvements in the treatment of patients with metastatic melanoma. Since 2011, the FDA has approved five novel immunotherapies for the treatment of metastatic melanoma resulting in a significant improvement in overall survival and quality of life. The success of these agents has provided excitement and hope for both patients and clinicians, and while these therapies have their limitations, they will provide excellent building blocks for the next generation of therapies.

Introduction For many years, physicians and scientists knew of the important role of the immune system in detecting and eliminating cancer. However, initial efforts to stimulate the immune system to fight cancer were limited by a low success rate as well as great toxicity. Recently, improved understanding of how cancer evades immune surveillance has led to significant breakthroughs in cancer therapy by generating durable responses in a large percentage of patients and with fewer side effects compared to older regimens. To understand the current state of immunotherapy, it is important to review the history of immunotherapy in melanoma, as well as the recent breakthroughs in immunotherapy resulting in much improved outcomes for patients with metastatic disease.

Incidence and prognosis of melanoma Over 90,000 patients are diagnosed in the United States annually with melanoma and of those approximately 13,000 patients annually develop metastatic disease.1 Up until five years ago, the median survival for patients with metastatic melanoma was six to nine months with only ~five percent of patients alive at five years, making melanoma one of the most deadly forms of skin cancer.1 Melanoma has long been known as a tumor that interacts and evades a patient’s immune system. Examples of these immunologic interactions include the presence of tumor infiltrating lymphocytes in resected melanoma,

Address correspondence to: Richard W. Joseph, MD Mayo Clinic Florida 4500 San Pablo Road Jacksonville, FL 32224 904-953-7291 E-mail: joseph.richard@mayo.edu 30 Vol. 67, No. 4 2016 Northeast Florida Medicine

occasional spontaneous remissions in patients with metastatic melanoma, and clinical responses to immune stimulation. The immunogenicity of melanoma has led investigators to study novel immune strategies to overcome tumor immune evasion.

High dose interleukin-2 High dose interleukin-2 (IL-2) was the first successful immunotherapy for the treatment of melanoma and was originally approved by the Food and Drug Administration in 1994.2,3 Interleukin-2 (IL-2) is a naturally occurring cytokine made by the cells of the immune system that functions to activate, stimulate, or “step on the gas” of the immune system. The first clinical trials to utilize IL-2 occurred in the 1980’s at the National Institutes of Health.2 In these studies, patients with cancer were given a high dose of IL-2 in an attempt to stimulate an immune response to cancer. Patients treated with high dose IL-2 developed intense flu-like symptoms including fevers, rigors, and hypotension and, unfortunately, a small minority of patients died as a result of the treatment.2,3 For the patients that were able to tolerate high dose IL-2, ~10-20 percent of those with melanoma and renal cell carcinoma responded with significant shrinkage of their tumors.3 Interestingly, the responses to high dose IL-2 in these patients were durable with the vast majority of patients who responded remaining alive and disease free 10 years after being treated.3,4 While treatment with high dose IL-2 did produce significant benefits for patients, the toxicity of the regimen limited its utility as unfortunately only a small minority of patients were able to undergo this rigorous therapy. Needless to say, high dose IL-2 helped a small minority of patients but, more importantly, served as a proof of principle that immunotherapy has a role in cancer therapeutics as a therapy that can generate long term remissions. The goal moving forward was to identify therapies with less toxicity and increased efficacy.

Identification of checkpoint inhibitors While high dose IL-2 activates the immune system by “stepping on the gas,” recent discoveries have led to keeping the immune system active by “removing the brakes.” Like most organ systems of the body, the immune system possesses multiple checks and balances or “off and on switches.” These “switches” provide the proper amount of stimulation, when necessary, to fight an infection, as well as a way to turn themselves off once an DCMS online . org

CME

infection is cleared. For example, when infected with a virus such as the common cold or the flu, the human immune system is activated in order to clear the virus, and once the virus is cleared, the immune system turns itself off so that it does not remain in a perpetual state of activation. The off switches of the immune system are also known as immune checkpoints. Immediately upon stimulation, the cells of the immune system express these checkpoints on their surface, and when bound by a ligand or receptor signal, this interaction results in a dampening or inactivation of the immune system. While immune checkpoints work well to dampen immune activation and prevent autoimmune interactions, unfortunately, tumors have also evolved to manipulate the immune checkpoints to their advantage, resulting in tumor growth through evasion of the immune system.5 Fortunately, a better understanding of these immune checkpoints has led to the identification of therapies that can prevent the negative regulation of the immune system resulting in a powerful anti-cancer treatment. These therapies work by inhibiting the â&#x20AC;&#x153;brakesâ&#x20AC;? of the immune system and are collectively referred to as immune checkpoint inhibitors. At present, there are over 50 different immune checkpoints that can be either antagonized or agonized. However, there are only two checkpoint inhibitors that are FDA approved so far.4

Ipilimumab (anti-CTLA4) In 2011, the FDA approved ipilimumab for the treatment of metastatic melanoma. Ipilimumab works by inhibiting the immune checkpoint cytotoxic T-lymphocyte-associated antigen 4 (CTLA-4). CTLA-4 functions as a negative co-stimulatory molecule for the T cell, and therefore blocking CTLA-4 removes the brakes of the T cell and results in immune stimulation and antitumor activity.5 Two separate phase 3 randomized clinical trials have evaluated ipilimumab in metastatic melanoma. In the first trial, previously treated patients with metastatic melanoma were randomized to ipilimumab, ipilimumab plus glycoprotein 100 peptide vaccine (gp100), or gp100.6 In this study, the median overall survival (OS) for patients who received ipilimumab was significantly longer than patients who received gp100 (10.1 vs 6.4 months, p<0.001). In the second study, previously untreated patients with metastatic melanoma were treated with ipilimumab plus dacarbazine versus single agent dacarbazine. The ipilimumab plus dacarbazine arm demonstrated improvement in OS (11.2 vs 9.2 months).7 In both phase 3 studies, only 10-15 percent of the patients had a decrease in tumor size (complete or partial response) with an additional DCMS online . org

~30 percent of patients with stabilization of their tumors. In addition to improving the median survival, ipilimumab also improved the percent of patients who were alive at five years to ~18 percent versus 8 percent who did not receive ipilimumab.8 In contrast to high dose IL-2, where only a small minority of patients are healthy enough to receive therapy, the side effects of ipilimumab are much more tolerable, allowing the majority of patients to be treated. The side effects of ipilimumab are a result of an over active immune system or autoimmunity and manifest as immune-related enterocolitis, hepatitis, hypophysitis, and dermatitis.7 All of these side effects, with the exception of hypophysitis, are reversible with a course of an immunosuppressant such as glucocorticoids.6 In summary, ipilimumab was the first drug to demonstrate an improvement in survival for patients with metastatic melanoma in a randomized controlled study. While the clinical activity was relatively modest, the toxicity was mild, moving the bar forward in terms of success of immunotherapy in melanoma.

Programmed death ligand one (PDL1) and programmed death one (PD1) While T cells express CTLA4 upon initial activation, they express programmed death one (PD1) after chronic stimulation. When PD1 binds its respective ligand, programmed death ligand 1 (PDL1), the net effect is immune suppression.9,10,11 Unfortunately, tumors have also evolved to express PDL1, allowing the tumor to evade the immune system. Inhibiting the interaction between PD1 and PDL1 results in a net stimulation of the immune system and a potent anti-cancer activity.7 Currently, two drugs that inhibit PD1 are now approved for the treatment of metastatic melanoma. These are pembrolizumab and nivolumab. In September 2014, pembrolizumab was the first anti-PD1 agent approved for patients with metastatic melanoma. In the initial study, pembrolizumab was given to previously treated and treatment naĂŻve patients resulting in a response rate of approximately 40 percent.12 Unlike with ipilimumab, responses to pembrolizumab tended to occur more quickly, even in patients with a high burden of disease.7 In a second study, pembrolizumab was tested only in patients who were refractory to ipilimumab, generating responses in 26 percent of patients.13 Following this, a phase 3 study tested the efficacy of two different doses of pembrolizumab versus ipilimumab in patients who had not received either therapy before.14 In this study, pembrolizumab had a higher response rate (33 percent versus 12

Northeast Florida Medicine Vol. 67, No. 4 2016 31

CME Table 1: Summary of efficacy of immune checkpoint inhibitors percent), as well as percent alive at one year (70 percent versus 58 percent). Based on the above studies, the FDA has approved the use of pembrolizumab to treat both treatment naïve and previously treated patients with metastatic melanoma.

Adapted from Larkin J, Hodi FS, Wolchok JD. Combined Nivolumab and Ipilimumab

Also in the fall of 2014, the FDA approved the second anti-PD1 agent, nivolumab, for patients with metastatic melanoma. In a large phase 3 study, nivolumab was compared to dacarbazine (chemotherapy) in patients with previously untreated metastatic melanoma.15 In this study, nivolumab was superior to dacarbazine, in terms of response (40 percent versus 14 percent) and percent alive at one year (73 percent versus 42 percent).8

Median PFS, months (95% CI)

Both pembrolizumab (Merck) and nivolumab (Bristol Myers Squibb) have very similar efficacy and toxicity. The only real difference between the drugs is that pembrolizumab is given every three weeks while nivolumab is given every two weeks. Pembrolizumab, also known as Keytruda, has recently been in the press as the drug that President Jimmy Carter received for his metastatic melanoma.

Combination of nivolumab and ipilimumab Given that both ipilimumab and nivolumab have improved outcomes in patients with metastatic melanoma, researchers sought to determine if the combination of ipilimumab and nivolumab could improve outcomes compared to each therapy alone. First the combination of ipilimumab and nivolumab was tested in a phase 1 study to assess both the safety and efficacy. In this study, the combination induced response rates of greater than 50 percent.16 The success of the phase 1 study led to a larger phase 2 study comparing ipilimumab to ipilimumab and nivolumab.17 In this study, the combination of ipilimumab and nivolumab resulted in a superior response rate to ipilimumab (61 percent versus 11 percent). The success of the phase 2 study led to a large phase 3, three arm study comparing the combination of ipilimumab and nivolumab or single agent nivolumab to

or Monotherapy in Untreated Melanoma. N Engl J Med. 2015 Sep 24;373(13):1270-1.

HR (99.5% CI) vs. IPI Overall Response Rate % (95% CI)

NIVO + IPI (N=314)

NIVO (N=316)

IPI (N=315)

11.5 (8.9– 16.7)

6.9 (4.3–9.5)

2.9 (2.8–3.4)

0.42 (0.31–0.57)*

0.57 (0.43–0.76)*

43.7 (38.149.3)

57.6 (52.0– 63.2)

19.0 (14.9–23.8)

<0.001

P-value vs. Ipilimumab

single agent ipilimumab.18 In this study, the combination of nivolumab and ipilimumab and single agent nivolumab were both superior to single agent ipilimumab (58 percent versus 44 percent versus 19 percent respectively, see Table 1). In addition, median progression free survival was also significantly improved in the combination ipilimumab and nivolumab arm, as well as the single agent nivolumab arm, when compared to single agent ipilimumab (11.5 vs 6.9 vs 2.9 months respectively, see Table 1).9 The study does not have long enough follow up to report on overall survival at present. While the combination of ipilimumab and nivolumab did demonstrate improved clinical efficacy when compared to single agent nivolumab and single agent ipilimumab, the benefits did come at a significant medical cost with a major increase in side effects. For example, grade 3-4 toxicities were much higher in the combination arm versus the single agent arms (Table 2). Given the greatly increased toxicity of the combination, physicians must be careful when choosing which patients to administer the combination versus the less toxic single agent. In the fall of 2015, the FDA approved the use of the combination of ipilimumab and nivolumab for patients with metastatic melanoma.

Table 2: Summary of toxicity of immune checkpoint inhibitors Adapted from Larkin J, Hodi FS, Wolchok JD. Combined Nivolumab and Ipilimumab or Monotherapy in Untreated Melanoma. N Engl J Med. 2015 Sep 24;373(13):1270-1.

Patients Reporting Event, %

NIVO + IPI (N=313)

NIVO (N=313)

IPI (N=311)

Any Grade

Grade 3–4

Any Grade

Grade 3–4

Any Grade

Grade 3–4

Treatment-related adverse event (AE)

95.5

55.0

82.1

16.3

86.2

27.3

Treatment-related AE leading to discontinuation

36.4

29.4

7.7

5.1

14.8

13.2

Treatment-related deaths

32 Vol. 67, No. 4 2016 Northeast Florida Medicine

0.3

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CME

Talimogene laherparepvec (TVEC) In addition to immune checkpoint inhibitors, oncolytic viruses have also demonstrated success in treating metastatic melanoma. Oncolytic viruses are novel cancer treatments that, once injected into a tumor, can induce an immune response to attack the tumor. In the fall of 2015, the FDA approved talimogene laherparepvec (TVEC) as the first oncolytic virus to treat patients with metastatic melanoma. TVEC is a genetically modified herpes simplex virus that is designed to replicate in lyse tumor cells, while at the same time secreting a growth factor for the immune system called granulocyte macrophage colony stimulating factor (GM-CSF). TVEC is injected as a liquid directly into tumors every two weeks until a response is achieved or until disease clearly progresses. The approval of TVEC was based on a large phase 3 study that compared TVEC to injectable GM-CSF in patients with cutaneous or injectable melanoma.19 In this study of 436 patients, two-thirds received TVEC while one-third received GM-CSF. The overall response rate was significantly higher in the TVEC group (26 percent versus 6 percent).10 In addition, the median overall survival was longer in the TVEC arm; however, it was not quite statistically significant (23.3 versus 18.9 months). TVEC is relatively well tolerated with few serious side effects. The most common side effect is fatigue (50 percent), chills (49 percent), and fever (43 percent), with the vast majority of these side effects being grade 1-2 and temporary.10

Conclusion Since 2011, five different immunotherapy regimens have been approved for the treatment of metastatic melanoma including ipilimumab, nivolumab, pembrolizumab, the combination of ipilimumab and nivolumab, and TVEC. Prior to 2011, the percent of patients with Stage IV melanoma that were alive at five years was ~five percent. As of 2016, an estimated 40 percent of patients with Stage IV disease are alive at three years. Given the ability of the immune system to evolve as the cancer evolves, researchers expect that the majority of patients who are alive at three years will also be alive at five years. While immunotherapy has come a long way in five years, there remains much area for improvement including identification of additional immunologic checkpoints, defining optimal duration of therapy, and identification of biomarkers that predict benefit to these agents. Despite these areas of improvement, the present and future of immunotherapy is extremely bright, providing patients with real hope in their battle versus cancer. v DCMS online . org

References 1. Siegel RL, Miller KD, Jemal A. Cancer statistics, 2016. CA Cancer J Clin. 2016 Jan-Feb;66(1):7-30. 2. Rosenberg SA, Mule JJ, Spiess PJ, et al. Regression of established pulmonary metastases and subcutaneous tumor mediated by the systemic administration of high-dose recombinant interleukin 2. J Exp Med. 1985 May 1;161(5):1169-88. 3. Rosenberg SA, Yang JC, Topalian SL, et al. Treatment of 283 consecutive patients with metastatic melanoma or renal cell cancer using highdose bolus interleukin 2. JAMA. 1994 Mar 23-30;271(12):907-13. 4. Pardoll DM. The blockade of immune checkpoints in cancer immunotherapy. Nat Rev Cancer. 2012 Mar 22;12(4):252-64. 5. Melero I, Hervas-Stubbs S, Glennie M, et al. Immunostimulatory monoclonal antibodies for cancer therapy. Nat Rev Cancer. 2007 Feb;7(2):95-106. 6. Hodi FS, Oâ&#x20AC;&#x2122;Day SJ, McDermott DF, et al. Improved survival with ipilimumab in patients with metastatic melanoma. N Engl J Med. 2010 Aug 19;363(8):711-23. 7. Robert C, Thomas L, Bondarenko I, et al. Ipilimumab plus dacarbazine for previously untreated metastatic melanoma. N Engl J Med. 2011 Jun 30;364(26):2517-26. 8. Maio M, Grob JJ, Aamdal S, et al. Five-year survival rates for treatment-naive patients with advanced melanoma who received ipilimumab plus dacarbazine in a phase III trial. J Clin Oncol. 2015 Apr 1;33(10):1191-6. 9. Keir ME, Butte MJ, Freeman GJ, et al. PD-1 and its ligands in tolerance and immunity. Annu Rev Immunol. 2008;26:677-704. 10. Riley JL. PD-1 signaling in primary T cells. Immunol Rev. 2009 May;229(1):114-25. 11. Okazaki T, Honjo T. The PD-1-PD-L pathway in immunological tolerance. Trends Immunol. 2006 Apr;27(4):195-201. 12. Hamid O, Robert C, Daud A, et al. Safety and tumor responses with lambrolizumab (anti-PD-1) in melanoma. N Engl J Med. 2013 Jul 11;369(2):134-44. 13. Robert C, Ribas A, Wolchok JD, et al. Anti-programmed-death-receptor-1 treatment with pembrolizumab in ipilimumab-refractory advanced melanoma: a randomised dose-comparison cohort of a phase 1 trial. Lancet. 2014 Sep 20;384(9948):1109-17. 14. Robert C, Schachter J, Long GV, et al. Pembrolizumab versus Ipilimumab in Advanced Melanoma. N Engl J Med. 2015 Jun 25;372(26):2521-32. 15. Robert C, Long GV, Brady B, et al. Nivolumab in previously untreated melanoma without BRAF mutation. N Engl J Med. 2015 Jan 22;372(4):320-30. 16. Wolchok JD, Kluger H, Callahan MK, et al. Nivolumab plus ipilimumab in advanced melanoma. N Engl J Med. 2013 Oct 31;369(2):122-33. 17. Postow MA, Chesney J, Pavlick AC, et al. Nivolumab and ipilimumab versus ipilimumab in untreated melanoma. N Engl J Med. 2015 May 21;372(21):2006-17. 18. Larkin J, Hodi FS, Wolchok JD. Combined Nivolumab and Ipilimumab or Monotherapy in Untreated Melanoma. N Engl J Med. 2015 Sep 24;373(13):1270-1. 19. Andtbacka RH, Kaufman HL, Collichio F, et al. Talimogene Laherparepvec Improves Durable Response Rate in Patients With Advanced Melanoma. J Clin Oncol. 2015;33(25):2780-88.

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CME

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Current State of Immunotherapy for Metastatic Melanoma CME Questions & Answers (circle one answer)/Free to DCMS Members/$55.00 charge non-members* (Return by December 1, 2018 by mail: 1301 Riverplace Blvd. Suite 1638, Jacksonville, FL 32207 or online: www.dcmsonline.org/NEFMCME)

1. Clinical trials showed that high dose interleukin-2 generates complete and durable remissions in approximately what percent of patients with metastatic melanoma? a. 10-20% b. 15-25% c. 20-30% d. 25-35% 2. The first drug to demonstrate an improvement in survival for patients with metastatic melanoma in a randomized controlled study was: a. Nivolumab b. TVEC c. Ipilimumab d. Pembrolizumab 3. Approximately what percent of patients with stage IV melanoma who receive ipilimumab remain alive at five years? a. 8% b. 18% c. 28% d. 38%

4. Studies show the anti-PD1 agents, pembrolizumab and nivolumab, induce response in approximately what percent of treatment naïve metastatic melanoma patients? a. 50% b. 40% c. 30% d. 20% 5. A phase 3 study on the combination of ipilimumab and nivolumab showed an induced response in what percent of treatment naïve metastatic melanoma patients? a. 28% b. 38% c. 48% d. 58% 6. TVEC is a genetically modified herpes virus that has been shown to induce durable remissions in what % of patients? a. 26% b. 20% c. 14% d. 8%

7. Immune checkpoints are naturally occurring “brakes” or “off switches” of the immune system. a. True b. False 8. Approximately how many patients are diagnosed with melanoma every year in the United States? a. 90,000 b. 80,000 c. 70,000 d. 60,000 9. Approximately how many patients develop metastatic melanoma every year in the United States? a. 3,000 b. 13,000 c. 23,000 d. 33,000 10. Immune checkpoint inhibitors increase the body’s ability to fight cancer. a. True b. False

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Immunotherapy

Immunotherapy for Genitourinary Cancers By Jason Starr, DO Abstract: Advanced genitourinary cancers, specifically of the

prostate and bladder, continue to challenge oncologists and remain incurable diseases. Immunotherapy has officially made it into the armamentarium for the treatment of genitourinary cancers and has offered the hope of improving survival. Castrate resistant prostate cancer (CRPC) was the first on the scene with the introduction of sipuleucel-T (Provenge) which offers a modest improvement in median overall survival. Atezolizumab (Tecentriq) was just recently approved for refractory urothelial cancer after showing unprecedented survival improvements. The sequencing and combinations of different immunotherapy agents are actively being studied and undoubtedly will continue to advance the field.

Introduction As illustrated throughout this issue, we have entered the era of immunotherapy in oncology. Certainly melanoma and lung cancer have received the most publicity in regards to these new treatments; however, patients with genitourinary cancer have also benefited. Advances have been made in prostate and bladder cancer as it pertains to immunotherapy.

Immunotherapy in Prostate Cancer

(docetaxel) from later lines (i.e. castrate resistant) to earlier lines (i.e. hormone- naĂŻve) of treatment has demonstrated an overall survival benefit.4,5 After patients develop castrate resistance the only meaningful option prior to 2010 was docetaxel. Since 2010, five treatments have been approved in this setting, all shown to improve overall survival. These treatments include: sipuleucel-T (Provenge), cabazitaxel (Jevtana), abiraterone (Zytiga), enzalutamide (Xtandi) and radium-223 (Xofigo). The sequencing of these treatments has been a topic of debate, and there is certainly no consensus. Focusing on immunotherapy, it is crucial to take a close look at sipuleucel-T. This is a first-of-its-kind active cellular immunotherapy. Patients first have their peripheral-blood mononuclear cells (i.e. antigen presenting cells) harvested via a central catheter. These cells are then sent to a central laboratory where they are exposed to a recombinant fusion protein (PA2024). PA2024 consists of a prostate antigen, prostatic acid phosphatase, which is fused to granulocyte-macrophage colony-stimulating factor (GM-CSF), an immune-cell activator.6

Prostate cancer is the most common cancer in men in the United States with an estimated incidence of 180,890 cases in 2016.1 It is also the second leading cause of cancer-related death in men with an estimated 26,120 deaths in 2016. The five-year survival for local/regional stage disease approaches 100 percent; however, for metastatic (i.e. stage IV) disease, that number is a sobering 28 percent.1 Traditionally, newly diagnosed (hormone-naĂŻve) metastatic prostate cancer has been treated with androgen deprivation therapy (ADT). The median duration of response to initial ADT is approximately 20 months.2 After progression of disease while on ADT, therapy patients are considered to be castrate resistant. The median survival for castrate resistant prostate cancer (CRPC) is approaching three years.3 Recently, moving chemotherapy

This treatment was studied in a phase 3 double-blind, placebo-controlled trial that randomly assigned 512 patients to either sipuleucel-T or placebo.4 Of note, only patients with asymptomatic disease were enrolled. Results revealed a 4.1 month improvement in median overall survival for the sipuleucel-T arm (25.8 months vs 21.7 months). The 36-month survival probability was 31.7 percent in the sipuleucel-T group versus 23 percent in the placebo group. Based on these results, the FDA approved sipuleucel-T in 2010 for the treatment of asymptomatic or minimally symptomatic castrate resistant prostate cancer.4 It should be noted that with this therapy there are typically not responses radiographically or reductions in PSA. There is an ongoing debate on the sequencing and/or combination of this treatment in the setting of the other recently approved therapies.

Address correspondence to: Jason Starr, DO Hematologist/Oncologist University of Florida 2000 SW Archer Road Gainesville, FL 32610 jason.starr@medicine.ufl.edu

Other exciting immunotherapy strategies are on the horizon. One worth mentioning is rilimogene galvacirepvec/rilimogene glafolivec (Prostvac). This is an engineered poxvirus containing PSA and T-cell costimulatory molecules. This, in effect, activates anti-PSA T-cells to then attack prostate cancer cells. Two phase II trials have shown promising data in CRPC with median overall survival benefit.7,8 Another agent that is being investigated in this space is ipilimumab (Yervoy). Ipilimumab

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Immunotherapy

is a monoclonal antibody that blocks CTLA-4, a “brake” on the immune system. This allows for T-cell activation and proliferation. A phase III trial comparing ipilimumab and radiation versus radiation alone in the metastatic CRPC setting showed no improvement in overall survival.9 There was, however, an unplanned subset analysis showing an overall survival benefit of ipilimumab in patients with low burden of disease.9 A very exciting phase I trial looked at ipilimumab and Prostvac in patients with mCRPC. The median overall survival was 31.3 months, and 20 percent of patients in the 10mg/kg ipilmumab arm were alive at the 80-month mark.10 A myriad of other immunotherapy trials are ongoing in prostate cancer in an effort to improve overall survival.

Immunotherapy in Bladder Cancer Bladder cancer is not a highly publicized or discussed cancer; however, it is the fourth most common cancer in men and ninth most common cancer worldwide.1,11 There are different histologies that can be seen with bladder cancer, but transitional cell carcinoma is the most common in the United States.12 Cigarette smoking is most often implicated in the carcinogenesis of bladder cancer in western countries.13 Patients commonly present with asymptomatic hematuria to their primary care physician. Approximately 50 percent of patients present with non-muscle invasive (i.e. in situ) bladder cancer, and the cure rate approaches 96 percent for those patients.14 On the other end of the spectrum, metastatic (stage IV) bladder cancer treated with chemotherapy is associated with a median survival of about 15 months with five-year survival of about 15 percent.15 Progress for bladder cancer has been stagnant for the last 15 years after the pivotal trial comparing gemcitabine and cisplatin (GC) versus methotrexate, vinblastine, doxorubicin, and cisplatin (MVAC).15 This trial established that GC was non-inferior and less toxic than MVAC and led to the widespread adoption of GC as first-line treatment for metastatic bladder cancer.15 Second line therapies for this disease are unimpressive and ineffective. Interestingly, bladder cancer was one of the first cancers to show a benefit from immunotherapy 40 years ago.16 The bacillus Calmette-Guérin (BCG) vaccine was administered intravesically and was found to be effective for superficial (i.e. non-invasive) bladder cancer.16 The BCG vaccine continues to be used for superficial bladder cancer treatment. Now research has moved to testing this hypothesis for systemic disease. The most promise has been seen from monoclonal antibodies directed against programmed death receptor 1 (PD-1) on the T-cell and

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programmed death receptor ligand 1 (PD-L1) on the tumor cell. Similar to the mechanism of ipilimumab, PD-1 (or PD-L1) blockade takes the “brakes” off the immune system and allows the T-cells to be activated against the tumor cells. It should be mentioned that the immune system is activated non-discriminately with these agents, and there can be “auto-immune” type reactions such as rash, colitis, and endocrine dysfunction.17,18 At this juncture the most compelling data for immunotherapy comes from atezolizumab, a PD-L1 antibody. In a phase 1 trial of second line atezolizumab in metastatic transitional cell carcinoma, the overall response rate (ORR) was 52 percent for patients with tumors expressing high levels PD-L1 compared to 14 percent in patients with tumors having low expression.19 Historically, response rates in the second line setting with chemotherapy is only 10 percent.20 Atezolizumab was then tested in a phase II study of 310 patients in the second line setting. In patients with high PD-L1 expression there was a response rate of 26 percent. With a median follow up of 11.7 months there were ongoing responses in 84 percent of the responders.21 Based on this study, the FDA approved atezolizumab (Tecentriq) in May 2016 for patients with locally advanced or metastatic urothelial carcinoma after progression on platinum chemotherapy. This drug is the biggest advancement in bladder cancer in over 25 years. Another agent being tested in this setting is pembrolizumab (Keytruda). Notable findings from a phase 1b study showed an ORR of 25 percent (38 percent in patients with PD-L1 expression) and a 12-month progression free survival (PFS) of 19 percent.22 As seen with prostate cancer, combinations of immunotherapy are also being investigated. These agents represent the biggest advances in the treatment of metastatic bladder cancer in the last 30 years.

Conclusion It is undoubtedly a time for optimism and excitement in the field of oncology, as physicians usher in the era of immunotherapy. Further research and clinical trials are going to be aimed at optimizing these treatments and defining which patients benefit most from these therapies. The field of oncology hinges on this research. Patients should be encouraged to participate in clinical trials to benefit themselves and advance the field.v

Northeast Florida Medicine Vol. 67, No. 4 2016 37

Immunotherapy

References 1. American Cancer Society. Cancer Facts & Figures 2016. Atlanta (GA): American Cancer Society; 2016. 2. James ND, Spears MR, Clarke NW, et al. Survival with Newly Diagnosed Metastatic Prostate Cancer in the “Docetaxel Era”: Data from 917 Patients in the Control Arm of the STAMPEDE Trial. Eur Urol. 2015 Jun;67(6):1028-38. 3. Beer TM, Armstrong AJ, Rathkopf DE, et al. Enzalutamide in metastatic prostate cancer before chemotherapy. N Engl J Med. 2014 Jul 31;371(5):424-33. 4. James ND, Sydes MR, Mason MD, et al. Docetaxel and/ or zoledronic acid for hormone-naïve prostate cancer: First overall survival results from STAMPEDE. J Clin Oncol 33, 2015 (suppl; abstr 5001) 5. Sweeney CJ, Chen YH, Carducci M, et al. Chemohormonal Therapy in Metastatic Hormone-Sensitive Prostate Cancer. N Engl J Med. 2015 Aug;373(8):737-46. 6. Kantoff PW, Higano CS, Shore ND, et al. Sipuleucel-T immunotherapy for castration-resistant prostate cancer. N Engl J Med. 2010 Jul 29;363(5):411-22. 7. Kantoff PW, Schuetz TJ, Blumenstein BA, et al. Overall analysis of a phase II randomized controlled trial of a Poxviral-based PSA-targeted immunotherapy in metastatic castration-resistant prostate cancer. J Clin Oncol. 2010 Mar 1;28(7):1099-105. 8. Gulley JL, Arlen PM, Madan RA, et al. Immunologic and prognostic factors associated with overall survival employing a poxviral-based PSA vaccine in metastatic castrate-resistant prostate cancer. Cancer Immunol Immunother. 2010 May;59(5):663-74. 9. Gerritsen WR, Kwon ED, Fizazi K, et al. CA184-043: A randomized, multicenter, double-blind phase 3 trial comparing OS in patients with post-docetaxel castration-resistant prostate cancer and bone metastases treated with ipilimumab vs placebo, each following single-dose radiotherapy [abstract 2850]. 17th European Cancer Conference; 2013 Sep 27– Oct 1; Amsterdam, The Netherlands. 10. Singh H, Madan RA, Dahut WL, et al. Combining active immunotherapy and immune checkpoint inhibitors in prostate cancer. 2015 Genitourinary Cancers Symposium; 2015 Feb 26; Orlando, Florida.

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11. Torre LA, Bray F, Siegel RL, et al. Global cancer statistics, 2012. Cancer J Clin. 2015;65(2):87-108. 12. National Comprehensive Cancer Network. Bladder Cancer (Version 2.2016) [Internet]. Cited Aug 8. Available from: https://www.nccn.org/professionals/physician_gls/pdf/ bladder.pdf. 13. Freedman ND, Silverman DT, Hollenbeck AR, et al. Association between smoking and risk of bladder cancer among men and women. JAMA. 2011 Aug 17;306(7):737-45. 14. SEER Database [Internet]. National Cancer Institute, Surveillance, Epidemiology, and End Results Program; 2005-2011. Available from: http://seer.cancer.gov/ 15. Von der Masse H, Sengelov L, Roberts JT. Long-term survival results of a randomized trial comparing gemcitabine plus cisplatin, with methotrexate, vinblastine, doxorubicin, plus cisplatin in patients with bladder cancer. J Clin Oncol. 2005 Jul 20;23(21):4602-8. 16. Morales A, Eidinger D, Bruce AW. Intracavitary Bacillus Calmette-Guerin in the treatment of superficial bladder tumors. J Urol. 1976 Aug;116(2):180-3. 17. Topalian SL, Sznol M, McDermott DF, et al. Survival, durable tumor remission, and long-term safety in patients with advanced melanoma receiving nivolumab. J Clin Oncol. 2014;32(10):1020. 18. Weber JS, Dummer R, de Pril V, et al. Patterns of onset and resolution of immune-related adverse events of special interest with ipilimumab: detailed safety analysis from a phase 3 trial in patients with advanced melanoma. Cancer. 2013;119(9):1675-82. 19. Powles T, Eder JP, Fine GD, et al. MPDL3280A (anti-PD-L1) treatment leads to clinical activity in metastatic bladder cancer. Nature. 2014 Nov 27;515(7528):558-62. 20. Bellmunt J, Theodore C, Demkov T, et al. Phase III trial of vinflunine plus best supportive care compared with best supportive care after a platinum-containing regimen in patients with advanced transitional cell carcinoma of the urothelial tract. J Clin Onc. 2009;27(27):4454-4461 21. Rosenberg J, Hoffman-Centis J, Powles T, et al. Atezolizumab in patients with locally-advanced and metastatic urothelial carcinoma who have progressed following treatment with platinum-based chemotherapy: a single-arm, multicentre, phase 2 trial. Lancet. 2016 Mar 4; 387(10031):1909-20.

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GI Corner

Ileitis: Keeping an Open Mind By Mark Fleisher, MD

Introduction After a long night on call, it was the responsibility of the admitting team to present the cases that were admitted overnight. Never mind that one was expected to know every physical finding and lab result. More daunting was the generation of the differential diagnosis. No patient presents with an illness. Rather, each patient presents with a mystery to be unraveled. Upon accumulating data, the core of our profession is confronted. The physician must generate a differential diagnosis. As we proceed in practice, we have to approach each patient as if it is our own private morning report. I can remember one senior resident who when queried “what could this be?” would always reply “well, it could be Henoch Schonlein!” Forget the fact that 90 percent of Henoch Schonlein presents in children and our patients were adults. In her mind, it was a possibility. She displayed what is often lost: an open mind. As a gastroenterologist who has a particular interest in inflammatory bowel disease, I make sure to hear that whisper in my head every day. “It could be Henoch Schonlein!” is merely an example of the need to always keep an open mind. Even when it seems a patient could have Crohn’s Disease, it is imperative to generate the full differential diagnosis. The following cases are presented to illustrate that despite my predilection, it is not always Crohn’s Disease. Here is a sample of my morning report.

Patient 1 Patient 1 is a 25 year old male who presents with right lower quadrant pain. The pain is constant and radiates to his back. It has been going on for weeks and it is new. He has joint pains for which he is using Goody Powder. The patient has recently noted that his stools have become softer and darker. He has come to the ER because he now has blood with his bowel movements.

Discussion: CT scan reveals thickening of the terminal ileum. Colon exam reveals some scattered erosions throughout the colon and intense ulceration of the ileum. Biopsies reveal ileitis but no granulomas.

Address correspondence to: Mark R. Fleisher, MD Borland-Groover Clinic Jacksonville, FL mfleisher@bgclinic.com DCMS online . org

This could be Crohn’s disease, based on the ileitis, joint pains, and bloody stools. However, before diagnosing for Inflammatory Bowel Disease (IBD), perhaps a differential diagnosis is in order. Biopsies of ileitis, in general, are not specific.1 A physician should never make a diagnosis of IBD based on a biopsy. In order to diagnose IBD, one needs to meet a few parameters: history and physical consistent with IBD, labs and pathology consistent with IBD and, most importantly, the test of time. It is a truism that everybody is allowed to get enteritis once in their life. They just can’t get it repetitively. The diagnosis of IBD is perhaps the most difficult in all of medicine. In this case, the patient had a good outcome. The nonsteroidal anti-inflammatory was the cause of the ileitis. Upon stopping this seemingly innocuous drug, the signs and symptoms resolved completely and expediently. A recent study discussed the interplay in IBD between a defective mucosal barrier, a dysregulated immune response and an excessive reactivity against the gut microbiota.2 These are assumed to cause a breakdown of the intestinal homeostasis and lead to chronic inflammation. Piroxicam treatment is a method for induction of colitis in IL-10 knock out mice, which integrates a dysfunction of both the intestinal barrier and the immune system. In essence, this non-steroidal is given to mice to help create IBD.2 Although, in the first patient, Crohn’s Disease is near the top of the differential diagnosis, readers should understand that the culprit is often hidden in the list of medications.

Patient 2 A merchant marine lands on Jacksonville Beach and makes his way to our ER. He has a few months of right lower quadrant pain that radiates to his back. The patient has profound weight loss and bloody stools. He has fevers daily and is diaphoretic. In the ER, a CT scan reveals thickening of the terminal ileum and the appendix.

Discussion: There have been cases of Crohn’s disease of the appendix. In fact, IBD of the appendix can lead to neoplasms of this vestigial organ.3 A colleague notes that he has seen this before, but it was tuberculosis. And so it was. After appropriate serologies and ileoscopy with biopsy, the patient rapidly improved upon initiation of treatment for tuberculosis. A simple axiom in all of medicine, tissue is the issue, was confirmed once again. Although tests pointed to Crohn’s disease, the biopsy report confirmed what my colleague suspected all along. After two decades of progress toward tuberculosis (TB) elimination with annual decreases of ≥0.2 cases per 100,000 persons, TB incidence in the United States remained leveled off with approximately 3.0 cases per 100,000 persons Northeast Florida Medicine Vol. 67, No. 4 2016 45

GI Corner

during 2013–2015.6 Although the ileum looked ulcerative as it would in IBD, tissue was the issue. Biologic therapy recipients have been known to reactivate their latent TB.6

Patient 3 52 year old female presents with right lower quadrant pain. The pain has been worsening over the past few months. She has significant weight loss and is anemic. Her stools have become softer and at the time of presentation are dark and bloody. She notes nightly fevers and comes to the ER quite frightened.

Discussion: CT scan reveals intense thickening of the terminal ileum. Endoscopy with terminal ileal intubation revealed intense ulceration and nodular erythema of the region. Biopsies revealed that the patient had B-cell lymphoma. Lymphomas of the terminal ileum may be T-cell, B-cell, Hodgkin’s and non-Hodgkin’s.7,8,9,10 Considering that biologic and/or immunotherapy recipients are at an increased risk of developing lymphoma, the assumption of IBD in this setting could have been catastrophic.11,12

Patient 4 A 42-year-old female presents with loose stools, weight loss and diffuse abdominal pain. She has been seeing her primary care physician regularly for hypertension for the past year. Despite appropriate lifestyle modifications, her blood pressure warranted pharmacologic therapy and an angiotensin converting enzyme inhibitor was started three months ago. Ever since starting this medication, the patient began to notice diffuse abdominal pain associated with looser and sometimes bloody stools. She presented to the ER because this episode was unrelenting.

Discussion: CT scan revealed diffuse thickening of the jejunum and terminal ileum and a scant amount of ascites. Although this has all the hallmarks of Crohn’s disease, the patient’s symptoms resolved and have not recurred since stopping the ACE-inhibitor. The recognition of intestinal angioedema as a consequence of this medication is not an easy diagnosis. However, angioedema occurs in 0.1 to 0.7 percent of patients treated with ACE inhibitors and ACE inhibitors account for 20 to 30 percent of all angioedema cases presenting to emergency departments.

Conclusion You will notice that despite my best efforts, I still have not encountered one case of Henoch Schonlein in my career. Nevertheless, keeping an open mind and always generating a differential diagnosis will help me avoid missing it. Despite thinking that everyone may have Crohn’s disease, the previous cases demonstrate this is not the case. v

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References 1. Woodman I, Schofield JB, Haboubi N. The histopathological mimics of inflammatory bowel disease: a critical appraisal. Tech Coloproctol. 2015 Dec;19(12):717-27. 2. Holgersen K, Kvist PH, Markholst H, et al. Characterisation of enterocolitis in the piroxicam-accelerated interleukin-10 knock out mouse--a model mimicking inflammatory bowel disease. J Crohns Colitis. 2014 Feb;8(2):147-60. 3. Orta L, Trindade AJ, Luo J, et al. Appendiceal mucinous cystadenoma is a neoplastic complication of IBD: case-control study of primary appendiceal neoplasms. Inflamm Bowel Dis. 2009 Mar;15(3):415-21. 4. Gurzu S, Molnar C, Contac AO, et al. Tuberculosis terminal ileitis: A forgotten entity mimicking Crohn’s disease. World J Clin Cases. 2016 Sep 16;4(9):273-80. 5. Wijewantha HS, de Silva AP, Niriella MA, et al. Usefulness of Routine Terminal Ileoscopy and Biopsy during Colonoscopy in a Tropical Setting: A Retrospective Record-Based Study. Gastroenterol Res Pract. 2014 Jan 16;2014:343849. 6. Salinas JL, Mindra G, Haddad MB, et al. Leveling of Tuberculosis Incidence - United States, 2013–2015. MMWR Morb Mortal Wkly Rep. 2016 Mar 25;65(11):273–278. 7. Bayol Ü, Cumurcu S, Karaman K, et al. Natural Killer-Like T-Cell Lymphoma Localized to the Terminal Ileum: Case Report. Turk Patoloji Derg. 2016;32(1):40-3. 8. Saka R, Sasaki T, Matsuda I, et al. Chronic ileocolic intussusception due to transmural infiltration of diffuse large B cell lymphoma in a 14-year-old boy: a case report. Springerplus. 2015 Jul 22;4:366. 9. Gibson B, Podoll MB, Baumgartner EM, et al. Syncytial Variant of Nodular Sclerosis Classical Hodgkin Lymphoma of the Terminal Ileum in a Patient with Longstanding Crohn’s Disease. Ann Clin Lab Sci. 2016 Spring;46(2):219-21. 10. Joo YW, Koh DH, Lee KN, et al. A case of natural killer like T cell lymphoma misdiagnosed as Behcet’s Enteritis of the terminal ileum. Korean J Gastroenterol. 2011 Jun;57(6):365-9. 11. Dulai PS, Siegel CA. The risk of malignancy associated with the use of biological agents in patients with inflammatory bowel disease. Gastroenterol Clin North Am. 2014 Sep;43(3):525-41. 12. Warman JI, Korelitz BI, Fleisher MR, et al. Cumulative experience with short- and long-term toxicity to 6-mercaptopurine in the treatment of Crohn’s disease and ulcerative colitis. J Clin Gastroenterol. 2003 Sep;37(3):220-5. 13. Benson BC, Smith C, Laczek JT. Angiotensin converting enzyme inhibitor-induced gastrointestinal angioedema: a case series and literature review. J Clin Gastroenterol. 2013 Nov-Dec;47(10):844-9.

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Creative Corner

Good Care By Mark R. Fleisher, MD Vacations are supposed to be about relaxation and rejuvenation. Sometimes they’re even about education. I knew it was time for a vacation. I could use an euphemism, but in all candor, I was just becoming plain old crabby. It was time to take a trip. I contacted my friends at touringisrael.com and off we went. As a graduate of the Sackler School of Medicine of Tel Aviv University, I can say I lived in Israel. However, in all candor, it was twenty years ago, and even when I lived there, I basically saw nothing. Immersed in school, I Mark Fleisher, MD learned my subjects but only years later did I learn my lessons. Real lessons. Not whether this muscle inserts here or this muscle inserts there. Not what is a Golgi apparatus? Real lessons that come with the most important aspect of medicine: observation. We see a patient at one locus in time, and we have no idea what their fate may be. But when we watch them and observe them, we start to plot a course. It is akin to sitting in the chair at the optometrist: better, worse or the same. My internal barometer told me to go on vacation so that I could get better. The first five days were amazing. Ibex in the desert. Eating caper shrubs. Walking through dry wadis. Lunching on hummus stuffed in pita with Bedouins. I certainly never did this in medical school, and yet this was quite an education. As Friday night cooled the region, our tour guide, Joe, took us to his home for Shabbat dinner. We met his wife and three children. Hosted by his in-laws, Sarah and Felix, we were the honored guests. From Tunisia, they spoke French and Hebrew. Being from Brooklyn, I barely speak English. Despite having gone to school in Tel Aviv, I never learned Hebrew. An opportunity lost. I may know an endoplasmic reticulum, but I can’t communicate with an entire nation despite having spent four years amongst them. Perhaps I never lived in Israel; I merely sojourned there, like the Jews in Egypt in Exodus. As Felix doled out heaping portions of Sarah’s creations, I was able to learn about him. Came here penniless. Given the name, Willie, of the Nazi soldier who spared his father’s life. The Nazi who said he was sorry. Awarded the highest honor from the president of France for helping French and Tunisian expatriates to resettle in Israel. Just a seemingly simple elderly man ladling out Sarah’s couscous. More importantly, he was teaching us important lessons. Humility. Charity. Memory. That was quite a dinner.

The next day around two miles south of Nazareth, I fell off my mountain bike. With a fractured clavicle and a few broken ribs, I was brought to the nearest hospital. Afula. A speck on the map. My arm dangling, my legs bleeding and my head covered in thorns, the triage woman said “from Nazareth?” I sure looked the part. I was whisked right in. So there I was, a Manhattan trained gastroenterologist in the middle of nowhere doing my best humpty dumpty imitation. One thing I knew. I knew I would get good care. I live in Jacksonville, and whenever someone from New York or LA or Chicago gets admitted, I can read their xenophobic fear: will I get good care? As if only traffic jams and smog will allow good care to be rendered. I had no such fear. I know wherever I go, doctors and nurses and technicians and transporters are universally going to strive to give good care. Maybe the equipment is not the newest, maybe the floors aren’t the shiniest, but the people always do their best. Worldwide, people in medicine always do the best they can. By my definition, that’s good care. The waiting room was half Arab, half Jewish. So was the staff. All in the same boat. Each tacitly agreeing to who should go first based upon how bad the other looked. As I lay quietly, the nurse wheeled the entire bed over to the nurses’ station. She handed me the phone. “For me? I don’t know anyone,” I thought. The head of the hospital wanted to know if I was OK. He wanted to know if I was getting good care. He wanted me to know that he was available if I needed anything. He told me that he was a friend of Felix. I had to be wheeled for three more phone calls. An orthopedist came in to look at my films. On the Sabbath. During a doctors strike. I got good care. But I have a feeling that the orthopedist would come in because that’s what they do. I know that everyone else was getting the best care available. They just didn’t get wheeled to the nurses’ station to speak on the phone with people whose names tend to be on letterheads. After I was discharged, I spent the next few days in our hotel while our boys did more hiking and swimming and rappelling. With me out of the way, they probably had a better time. But you could see the concern in their eyes. Fear and relief is a strange brew. Little did I know that Joe, our tour guide, my friend, was calling every hour to check on me. So did his wife. So did Felix. My wife doted on me but that’s nothing new. She always does. As I got better, I learned a great lesson. The best part of life are the relationships you form. One thing I didn’t need to learn. I knew I got good care. v Creative Corner articles do not necessarily reflect the views of the Duval County Medical Society or DCMS Foundation.

Want to contribute to the Creative Corner? Email your submission to kristy@dcmsonline.org

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