TON Nov/Dec 2014 | Vol 7 | No 6 by The Oncology Nurse

november/december 2014

www.TheOncologyNurse.com

Vol 7, No 6

Empowering Patients and Survivors

Cancer Center Profile

Cancer and Fertility Program, Memorial Sloan Kettering Cancer Center

Cancer Survivor Tech Angela Long

“Necessity…the mother of invention.”

ow can I help? It’s a question cancer patients commonly get from family, friends, and supporters during their treatment. Recently, technology developers have begun asking the same question and are increasingly addressing the concerns of cancer patients. A cancer diagnosis brings challenges for patients above and beyond undertaking a medical treatment regimen while managing their already demanding lives. It is a tidal wave that sucks away their time, energy, and money in its wake. Their supporters seek to ease these burdens for them, but these supporters are

often at a loss as to just how or where to fill in. The modern world in “the cloud” is responding to these issues by developing websites, programs, and applications (apps) that cancer patients can use to help themselves in some very big ways.

Communicating With Family and Friends

One of the first and most difficult challenges a cancer patient faces after diagnosis is informing family and friends. I dreaded this so much that I had my husband inform everyone. One by one, he made the calls, buffering me from the “how” and “why” questions of shock. He made those same phone calls Continued on page 5

Best Practices Joanne Frankel Kelvin, MSN, RN, AOCN, leads the Cancer and Fertility Program, part of the Survivorship Program at Memorial Sloan Kettering Cancer Center.

t a time when many of their peers are planning families, each year more than 126,000 men and women between the ages of 20 and 45 years learn that they have cancer. Because the focus in the past was on treating the cancer, the question of fertility may not have been explored. But as more patients survive cancer, preserving fertility options has become a growing concern. To address this issue, the Survivorship Program at Memorial Sloan Kettering (MSK) Cancer Center launched the Cancer and Fertility Program in 2009.

Continued on page 6

Conference News

Highlights From the American Society for Radiation Oncology 2014 Annual Meeting Alice Goodman

he annual meeting of the American Society for Radiation Oncology (ASTRO) took place in San Francisco, California, on September 14-17, 2014. The meeting draws more than 11,000 attendees, bringing together clinicians, scientists, and researchers from all oncology disciplines. ASTRO highlights how technology and biology advance the field of radiation oncology and improve outcomes

and quality of life for patients. As ASTRO’s needs statement for the annual meeting points out, nearly twothirds of the estimated 1.6 million people who will be diagnosed with cancer this year will receive radiation therapy—this makes it imperative that all members of the multidisciplinary team be aware of best practices. Below are summaries of some highlights from the meeting.

Infection Prophylaxis Update Alice Goodman

ith Ebola virus in the news, infection is a hot topic. At the recent National Comprehensive Cancer Network (NCCN) 9th Annual Congress: Hematologic Malignancies, Laura Zitella, MS, RN, ACNPBC, AOCN, updated attendees on how to prevent and treat cancer-related infections.1 Zitella is with the Stanford Cancer Institute in Stanford, California. “We can increase overall survival by risk-stratified prophylaxis. Assessment of risk is key. Prevention of infections is controversial and warrants additional

inside 10 Leukemia Managing Patients Receiving Ibrutinib 1 Nutrition in Focus 1 Help Improve Quality of Life for Oncology Patients 12 Perspectives A Pair of Shoes 14 Best Practices Room for Improvement in Symptom Management

Continued on page 8

research. Consider antimicrobial and antifungal prophylaxis for high-risk patients. Antiviral prophylaxis is recommended for patients at high risk of reactivation,” she stated. “Hand washing is still the most effective strategy to prevent infection,” she reminded listeners. There are also myths and old wives’ tales related to infection control. Restricting fruits and vegetables has not been proven to decrease infection, she continued. Risk factors for infection include severity and duration of neutropenia because Continued on page 13

15 Genetic Counseling Expanding Phenotypes of Inherited Colorectal Cancer Syndromes 16 The Patient’s Voice The Transition From “Why Me?” to “Why Her?”

Complimentary CE Faculty Perspectives—Latest Treatment Advances for Individualized Care of Melanoma See page 20

Evasion of apoptosis may be a question of balance Increased BCL-2 expression helps cancer cells to survive1 BCL-2

Displacement of pro-apoptotic proteins may trigger apoptosis1

Pro-apoptotic proteins sequestered by BCL-2

Free pro-apoptotic proteins

Increased expression of BCL-2 impairs the pathway to programmed cell death Like normal cells, cancer cells will often induce expression of pro-apoptotic proteins in response to stressors like limited metabolic resources, rapid cell division, or exposure to cytotoxic agents1. Cancer cells may increase expression of the anti-apoptotic protein, BCL-21. Pro-apoptotic proteins are bound and sequestered by BCL-2, helping the cancer cell to avoid programmed cell death2. Pro-apoptotic proteins—if displaced from BCL-2—have the potential to trigger apoptosis1. Mitochondria

To learn more about the BCL-2 pathway,

BOOTH #1343

visit and at the ASH annual meeting

#1909

References: 1. Letai, A.G., Diagnosing and exploiting cancer’s addiction to blocks in apoptosis. Nat Rev Cancer, 2008. 8(2): p. 121-32. 2. Garcia-Saez, A.J., The secrets of the Bcl-2 family. Cell Death Differ, 2012. 19(11): p. 1733-40.

A3469581

From The Editor This issue of The Oncology Nurse-APN/PA (TON) is our final issue for 2014. We look forward to wrapping up the year on a high note and plan on pertinent and insightful coverage for 2015. In this issue, we finalize our coverage of the news from this year’s Oncology Nursing Society (ONS) 39th Annual Congress. Susan C. McMillan, Beth Faiman, PhD(c), MSN, who received the ONS DisAPRN-BC, AOCN tinguished Nurse Researcher Editor-in-Chief Award, discussed how we can improve cancer-related and treatment-related symptoms for our patients, noting that “We need to do better. It is the oncology nurse’s job to address symptom management.” Gretchen McNally presented information about ibrutinib, which has been approved by the FDA to treat patients with chronic lymphocytic leukemia and mantle cell lymphoma. A show of

hands of her audience at ONS showed that the majority of oncology nurses have not yet had any experience with ibrutinib. Both presentations provide information that will help us all in our daily practice. We also present coverage from the recent annual meeting of the American Society for Radiation Oncology. Approximately two-thirds of the estimated 1.6 million people who will be diagnosed with cancer this year will receive radiation therapy. This is a topic we all need to be familiar with. Be sure to read Sue Bond’s Perspectives column. In A Pair of Shoes, she discusses the connections, intended or not, that nurses may make with those who need care. She reflects on a statement a colleague made: “You go in, you go in deep, and then you’re out.” Sue talks about some healthy ways we can all use when these connections are made. New technology that potentially can help patients is the topic of our reader poll. Read Angela Long’s Empowering Patients and Survivors column and then see below for information about going to our website, www.The OncologyNurse.com, to answer the question and provide your comments. All of us at TON wish you the best for 2015. n

Reader Poll Do you talk to your patients about websites and apps that might help them and their caregivers? o Yes In her Cancer Survivor Tech article, Angela Long discusses websites, programs, and applications (apps) that “cancer patients can use to help themselves in some very big ways.” Angela notes that some of this recent technology would have made things easier for her and her family as she

o No

dealt with her cancer diagnosis and treatment 10 years ago. Do you talk to your patients about how technology resources might help them? Are you knowledgeable about the resources that are available? Tell us if your patients ask you for information about these resources.

Go to www.TheOncologyNurse.com to answer the question and add your comments.

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The Oncology Nurse-APN/PA®, ISSN 1944-9798 (print); ISSN 1944-9801 (online) is published 6 times a year by Green Hill Healthcare Communications, LLC, 1249 South River Road, Suite 202A, Cranbury, NJ 08512. Telephone: 732.656.7935. Fax: 732.656.7938. Copyright ©2014 by Green Hill Healthcare Communications, LLC. All rights reserved. The Oncology Nurse-APN/PA® logo is a registered trademark of Green Hill Healthcare Communications, LLC. No part of this publication may be reproduced or transmitted in any form or by any means now or hereafter known, electronic or mechanical, including photocopy, recording, or any informational storage and retrieval system, without written permission from the Publisher. Printed in the United States of America. EDITORIAL CORRESPONDENCE should be addressed to EDITORIAL DIRECTOR, The Oncology Nurse-APN/PA®, 1249 South River Road, Suite 202A, Cranbury, NJ 08512. E-mail: editorial@greenhillhc.com. YEARLY SUBSCRIPTION RATES: United States and possessions: individuals, $105.00; institutions, $135.00; single issues, $17.00. Orders will be billed at individual rate until proof of status is confirmed. Prices are subject to change without notice. Correspondence regarding permission to reprint all or part of any article published in this journal should be addressed to REPRINT PERMISSIONS DEPARTMENT, Green Hill Healthcare Communications, LLC, 1249 South River Road, Suite 202A, Cranbury, NJ 08512. The ideas and opinions expressed in The Oncology Nurse-APN/PA® do not necessarily reflect those of the Editorial Board, the Editorial Director, or the Publisher. Publication of an advertisement or other product mentioned in The Oncology Nurse-APN/PA® should not be construed as an endorsement of the product or the manufacturer’s claims. Readers are encouraged to contact the manufacturer with questions about the features or limitations of the products mentioned. Neither the Editorial Board nor the Publisher assumes any responsibility for any injury and/or damage to persons or property arising out of or related to any use of the material contained in this periodical. The reader is advised to check the appropriate medical literature and the product information currently provided by the manufacturer of each drug to be administered to verify the dosage, the method and duration of administration, or contraindications. It is the responsibility of the treating physician or other healthcare professional, relying on independent experience and knowledge of the patient, to determine drug dosages and the best treatment for the patient. Every effort has been made to check generic and trade names, and to verify dosages. The ultimate responsibility, however, lies with the prescribing physician. Please convey any errors to the Editorial Director.

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november/december 2014 I VOL 7, NO 6

Editorial Board EDITOR-IN-CHIEF

Beth Faiman,

PhD(c), MSN, APRNBC, AOCN Cleveland Clinic Taussig Cancer Institute Cleveland, OH

Cassandra J. Hammond, RN, MSN, CRNP

Avid Education Partners, LLC Sharpsburg, MD

Catherine Bishop,

Shannon Hazen,

Johns Hopkins Kimmel Cancer Center/Sibley Infusion Washington, DC

Charlotte, NC

DNP, NP, AOCNP

Deena Damsky Dell, RN-BC, MSN,

RN, BSN, OCN

Taline Khoukaz, MSN, ACNP-C

Keck Hospital of University of Southern California Norris Cancer Center Los Angeles, CA

Wendye DiSalvo,

Sandra E. Kurtin,

DNP, APRN, AOCN Genentech New London, NH

RN, MS, AOCN, ANP-C

Jayshree Shah, RN, APN-C, AOCNP, MSN

Pharmacy John F. Aforismo,

College of Nursing and Allied Health Professions University of Louisiana Lafayette, LA

Gary Shelton,

DNP(c), MSN, NP, ANP-BC, AOCNP

City of Hope National Medical Center Duarte, CA

John Theurer Cancer Center Hackensack University Medical Center Hackensack, NJ

Constance Engelking, RN,

Kena C. Miller,

Jacqueline Marie Toia, RN, MS,

The CHE Consulting Group, Inc. Mt. Kisco, NY

Millennium Pharmaceuticals, Inc Boston, MA

Northwestern University Myeloma Program Chicago, IL

Patricia Molinelli,

Pamela Hallquist Viale, RN, MS,

Amy Ford, RN, Quintiles Dallas, TX

MS, RN, APN-C, AOCNS

Somerset Medical Center Somerville, NJ

RD, CSO

Patient Advocacy Peg Ford

BSN

Joseph D. Tariman,

BSN, OCN

Nutrition Karen Connelly,

Lori Stover, RN,

Ann McNeill,

MS, CNS, OCN

RJ Health Systems International, LLC Wethersfield, CT

Somerset Medical Center Somerville, NJ

Denice Economou,

RN, MSN, ARNP-BC

BSc Pharm, RPh, FASCP

NYU Clinical Cancer Center New York, NY

Western Pennsylvania Cancer Institute Pittsburgh, PA

RN, MSN, APN

PhD, RN, AOCN

Northern Michigan University Independent Oncology & Palliative Care Consultant Marquette, MI

Arizona Cancer Center Tucson, AZ

RN, MN, CNS, AOCN

Rita Wickham,

RN, DNS

John Theurer Cancer Center Hackensack University Medical Center Hackensack, NJ

Fox Chase Cancer Center Philadelphia, PA

AOCN, LNC

Melinda G. Oberleitner,

PhD, ANP-BC DePaul University Chicago, IL

Ovarian Cancer Alliance of San Diego San Diego, CA

Social Work Carolyn Messner, DSW, LCSW-R, BCD, OSW-C CancerCare New York, NY

DNP

CS, ANP, AOCN Saratoga, CA

Genetic Counseling Cristi Radford, MS, CGC

Invitae Atlanta, GA

Managed Care and Pharmaceutical Management Burt Zweigenhaft, BS

Onco360/OncoMed New York, NY

Sharon S. Gentry, RN, MSN, AOCN, CBCN

Novant Health: Derrick L. Davis Cancer Center Winston-Salem, NC

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Ellen A. Neylon, MSN, FNP-BC, CCRP, OCN

Columbia University Medical Center Center for Lymphoid Malignancies New York, NY

Connie Visovsky,

PhD, RN, ACNP-BC University of South Florida College of Nursing Tampa, FL

Isabell Castellano, RN

Bristol-Myers Squibb Childrenâ&#x20AC;&#x2122;s Hospital Robert Wood Johnson University Hospital New Brunswick, NJ

Jeanne Westphal, RN Meeker Memorial Hospital Litchfield, MN

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Empowering Patients and Survivors

Cancer Survivor Tech to update friends and loved ones after every treatment and surgery. While I was beyond grateful to him for doing this, it certainly wasn’t easy for him. How things have changed! Thanks to technology, cancer patients today are able to communicate with others in ways that keep them connected, but not exposed. With popular social media sites (like Facebook), one can set the privacy settings or create groups so that select information goes out to only those individuals chosen by the user. Today’s cancer patients have access to websites created specifically for the purpose of opening up communication channels for them. Websites like CaringBridge.org enable cancer patients to write and share blogs of any length or share photos and videos to help friends and loved ones feel connected and aware of the patient’s progress. Messages go out all at once and only to those who have permission to receive such information, saving the author the time and energy that would be required to reach out to each person individually.

Calendar for Chores, Meals, and Errands

Scheduling busy lives is challenging enough when people are well. Accepting assistance with busy schedules requires planning ahead, a task that can be overwhelming when juggling surgeries or cancer treatment with everything else. Technology can help here too. Some communication websites have wonderful features to help with scheduling meals, babysitting, and running errands for the patient and family. I know I could have used this! A dear friend took on the task of organizing these tasks for me and my family. She set us up with 3 to 5 meals after every treatment or surgery. She enlisted friends and neighbors who volunteered to help. She made sure the helpers knew when and where each meal was to be delivered and notified them of my children’s food likes and dislikes. Other friends stepped up to help with carpools and taking the kids for me to give me a break. Some would call and ask if I needed anything when they were at the grocery store. My supporters eased the burden on my husband by taking care of these everyday duties. They also made me feel loved and cared for. The websites available to help with coordinating these supportive efforts are amazing. Not only do they make it much easier for the organizer, they make it easier for the volunteers to sign on and feel engaged. Almost all supporters can and will find some way to help if the “what, where, and how” are clearly defined for them.

www.TheOncologyNurse.com

Continued from cover

Doctor/Patient Communication

Trying to absorb and comprehend the diagnosis, treatment, and medical instructions in the brief allotted time with the

ease patient anxiety, some doctors utilize graphic computer technology to show patients (in the most pleasant way) procedures and follow-up care that they will undergo.

Prescription Tracking

Many apps have been developed to track medications, vitamins, and supplements. This can be extremely helpful for patients and their caregivers. Most allow patients to input their dosage information and set up reminders to

Peer Support

Currently in development is a mobile app for cancer peer support called Instapeer. It is an app that “brings 1-to-1 peer connection into the 21st century” for those affected by cancer. Stupid Cancer, an organization specializing in young adult cancer, is the mastermind behind this technology that will match cancer patients around the world via SMS text. Instapeer will enable cancer patients to converse, support, and help one another through living with cancer.

Patients are responding positively to institutions that have created online systems for retrieving records, reports, doctors’ notes, treatment schedules, and account information. Angela Long

medical team can be a challenge even for those versed on the topic of cancer. Those entirely new to the subject and gripped by fear don’t hear much after those words “You have cancer.” People used to suggest carrying a notepad with prewritten questions and for taking notes, as well as a folder to store all of a patient’s info, receipts, test results, records, etc. These days, technology frees patients from the burden of having to remember it all and enables them to make the most of their doctors’ visits. Smartphones can be used to record conversations with doctors so that patients can review them later, keep track of upcoming appointments, and snap photos of documents to have on file. There are apps developed for this too.

One of the first and most difficult challenges a cancer patient faces after diagnosis is informing family and friends. The LIVESTRONG Cancer Guide and Tracker iPad app was developed to provide easy access to information and tools needed to make informed decisions throughout the cancer journey. The app lets patients store and access information relevant to their treatment and survivorship electronically. In addition, patients learn what to expect, what questions to ask, and where to connect to resources. Patients are responding positively to institutions that have created online systems for retrieving records, reports, doctors’ notes, treatment schedules, and account information. In an attempt to

keep track of when to take the medications. The apps provide information about medications, how they work, how they interact with other medications, and how they may affect a person.

Nutrition

Cancer patients and survivors frequently have questions about nutrition. Dana-Farber Cancer Institute created the Ask the Nutritionist: Recipes for Fighting Cancer app to help those interested in eating healthy to find recipes right for them. The app, developed by registered and board-certified dietitians, also offers users the ability to search by common symptoms (such as nausea or mouth sores), helping to customize dietary needs while patients are going through treatment. Not only does the app offer recipes for fighting cancer, it also has an “Ask the Nutritionist” questions-and-answers feature.

Emotional Support

According to my private online focus group for “Empowering Patients and Survivors,” technology’s greatest impact is in connecting patients and survivors with a 24/7 network of support. Many find comfort through social media groups formed on Facebook, Twitter, and cancer website forums, but many apps are also being developed with emotional support for cancer patients and caregivers in mind. My Cancer Manager, created by the Cancer Support Community, provides cancer patients and caregivers with a unique set of tools for addressing physical, social, and emotional concerns related to living with cancer and its treatment. Patients can monitor their common concerns such as fatigue, difficulty sleeping, sadness, anxiety, and pain. Over time they can track progress with their healthcare team. They can also track potential life worries, such as family, work, money, and nutrition.

The organization believes this technology will especially appeal to the adolescent and young adults that account for 72,000 new cancer diagnoses each year.

Fund-raising

Dealing with a cancer diagnosis is hard enough, but often the financial burden prevents patients from focusing on the real priority, their health. There are few existing financial assistance programs. Sometimes basic needs are met purely through the support of family and friends. To make it easier for those seeking such help from supporters, crowdfunding websites have been developed to help raise funds with relatively little effort or expense. Crowdfunding websites create a win/win situation for friends and family looking for a way to support their loved one while giving an indirect way for the patient to ask for help.

The Role of Oncology Nurses

Technology has come a long way in the past 10 years since my own diagnosis, and this is likely just the beginning of technology’s rapidly expanding role in facilitating support for and easing some of the burdens faced by cancer patients and survivors. The next step is to ensure that information about these resources reaches those that need it, when they need it. As the first point of contact for most of these patients, this is where oncology nurses come in. For a list of websites and apps developed to assist cancer patients and caregivers, go to www.BreastInvestigators.com/con tent/cancer-support-technology. n

Angela Long is the founder and creator of Breast Investigators. Breast Investigators serves as a comprehensive resource guide to help those affected by breast cancer readily gain access to quality information, care, assistance, and support. Visit www.BreastInvestigators.com.

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Cancer Center profile

Cancer and Fertility Program, Memorial Sloan Kettering Joanne Frankel Kelvin, MSN, RN, AOCN, a fertility clinical nurse specialist who leads MSK’s program, spoke with The Oncology Nurse-APN/PA about the steps needed to develop the program, how she became involved and educated herself about the issue, and her experience with patients, as well as some of the challenges and hopes—now and in the future.

How did you become interested in leading a fertility preservation program?

Joanne Frankel Kelvin (JFK): It was a confluence of events. I’ve been a nurse since 1976 and at MSK since 1987. I had been working as a manager for a number of years and wanted to return to patient care for the last phase of my career; however, I also wanted a role with leadership responsibilities, so I was exploring various possibilities. In 2003, MSK had started a cancer survivorship program and learned from surveys of survivors that many felt their fertility issues had not been adequately addressed at diagnosis. As part of the Survivorship Program strategic plan, I was hired as a clinical nurse specialist to lead the development of a program to address this problem. It was a good match between my desire for a new career focus and their need to improve care in this area. I didn’t know much about fertility at the time.

How did you get yourself up to speed on fertility issues?

JFK: I took 6 months to begin to educate myself, although this is an ongoing process. I read everything I could find on the topic, and I met with experts in the field of reproductive medicine to learn what they could offer our patients. I also reached out to patient advocates, particularly Lindsay Beck, the founder of Fertile Hope, the first nonprofit advocacy program to address fertility in can-

cer patients. This community of experts was very generous in sharing their knowledge and helping me network with others in the field. To learn more about practice at MSK, I gathered baseline data to identify barriers for our clinicians in discussing fertility with their patients. Although there was a wide range of responses, barriers for many included not being aware of all the options to preserve fertility or of where they could refer patients, lack of time for in-depth patient discussions, and discomfort about opening a discussion of fertility. I also gathered baseline data from patients about their satisfaction with information received related to fertil ity, which confirmed the need to improve how we address fertility risk and preservation options.

What else did you need to do to launch the fertility program?

JFK: I formalized the relationships with certain reproductive specialists and centers to ensure we had a systematic process for referrals, and I wrote patient education materials for clinicians to give to patients to facilitate discussing fertility. I also provided education in-service programs for physicians and nurses, and provide these on an ongoing basis. In addition, I created an intranet site that clinicians could access as needed, with numerous resources to help them discuss fertility with their patients.

What is the bulk of your practice at MSK?

JFK: I provide education and counseling to patients referred to me by MSK clinicians. About two-thirds of the patients I counsel are at diagnosis and one-third are posttreatment. With the first group, I focus on describing options for fertility preservation before treatment, particularly freezing eggs, embryos, or sperm. There are more females

than males in this group, because sperm banking is more widely understood than embryo and egg freezing, and the process is more matter of fact, so it’s easier for clinicians to discuss with their patients. The second group is a bit more complicated, and is usually evenly divided between females and males. These people may have been rendered infertile by treatment and want to know all their options for building a family. This can include donor sperm or eggs, adoptions, and surrogacy.

How many patients use your services?

JFK: The number has grown exponentially. The first year I saw 71 patients. Last year, the fifth year of the program, I saw 376 patients.

Are there new options for fertility preservation?

JFK: Egg freezing is no longer considered experimental and is now accepted as a standard option for fertility preservation, according to the American Society for Reproductive Medicine and the American Society of Clinical Oncology. This is a new and exciting option for young women, and they need to know about it. Not only should it be offered for fertility preservation before treatment, but egg freezing should also be discussed as an option after treatment in teens and young adults who are at risk for premature menopause but not yet ready to start a family.

Continued from cover

itive for procedures such as egg or embryo freezing and surrogacy.

Have you followed your patients to quantify pregnancy and live birth outcomes?

JFK: That is also a challenge. Because patients receive their reproductive healthcare outside of our cancer center, I have no way to access the ultimate outcomes of the referrals I make. In addition, there is no national database or registry tracking reproductive health outcomes of cancer survivors in the United States.

What would you like to accomplish in the future?

JFK: I am trying to incorporate the lessons learned from our experience at MSK to identify strategies other organizations can use to improve practice in the area of cancer and fertility. There is no one right way to set up a program. Institutions have different cultures and different resources. Many are smaller than MSK, and they may vary in how centralized they are. I am hoping to determine how best to implement the core elements of a cancer and fertility program that ensures widespread improvement in clinical practice, sustained over time. n

Website: www.mskcc.org/ cancer-care/survivorship/ services-survivors#fertility

What is challenging about your job?

JFK: One of the biggest challenges is the financial constraints. Most fertility preservation options are not covered by health insurance. I can provide information about options and make referrals, but many patients cannot afford to pay for these services out of pocket. Even with discounts, the cost is prohib-

Take action: get YOUR cancer center profiled!

We are looking to interview oncology nurses from cancer centers around the country. It’s an easy process—a short phone interview and you need to submit some photos.

Contact editorial@greenhillhc.com for information. 6

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conference news: ASTRO Continued from cover

ASTRO’s Choosing Wisely List Continuing its participation in the American Board of Internal Medicine’s Choosing Wisely campaign, ASTRO released its second list of 5 radiation treatments that should be questioned and not used routinely in clinical practice. The 2014 list follows: • Don’t recommend radiation following hysterectomy for endometrial cancer patients with low-risk disease. • Don’t routinely offer radiation therapy for patients who have resected non–small cell lung cancer (NSCLC), negative margins, N0-1 disease. • Don’t initiate noncurative radiation therapy without defining the goals of treatment with the patient and con-

sidering palliative care. • Don’t routinely recommend follow-up mammograms more often than annually for women who have had radiotherapy following breast conserving surgery. • Don’t routinely add adjuvant whole brain radiation to stereotactic radiosurgery for limited brain metastases. Along with ASTRO’s 2013 list, this totals 10 radiation treatments that should not be used routinely without thorough discussion between patients and physicians. ASTRO’s 2013 Choosing Wisely list included these recommendations: • Don’t initiate whole breast radio-

therapy as a part of breast conservation therapy in women age ≥50 with early stage invasive breast cancer without considering shorter treatment schedules. • Don’t initiate management of lowrisk prostate cancer without discussing active surveillance. • Don’t routinely use extended fractionation schemes (>10 fractions) for palliation of bone metastases. • Don’t routinely recommend proton beam therapy for prostate cancer outside of a prospective clinical trial or registry. • Don’t routinely use intensity-modulated radiotherapy (IMRT) to deliver

whole breast radiotherapy as part of breast conservation therapy. 2014 ASTRO President Bruce Haffty, MD, was quick to note that there are specific circumstances where these treatments are warranted but said that they should not be prescribed routinely. He also noted that there is some evidence that clinical practice has shifted as a result of the campaign. Choosing Wisely is aimed at reducing unnecessary healthcare expenditures while at the same time providing appropriate high-quality care. To see all the recommendations from medical societies in the United States, go to www. choosingwisely.org. n

Preserving Sexual Function in Patients With Prostate Cancer It may be possible to preserve sexual function in men with prostate cancer undergoing curative radiation therapy (RT) by using a vessel-sparing Patrick McLaughlin, MD radiation technique, according to a 5-year follow-up of a group of men who underwent vessel-sparing radiation therapy in this setting.1 The study included 90 men diagnosed with prostate cancer; about 50% underwent external beam RT alone and 50% had the external beam RT plus brachytherapy. No patient received androgen deprivation therapy. “Using MRI to define the patient’s anatomy, the vessels involved in main-

taining an erection can be spared in some patients,” explained author Patrick McLaughlin, MD, of the Univer sity of Michigan Providence Cancer Institute in Novi. “This is not possible in all patients, for example, those with prostate cancer at the apex of the prostate,” he said. All forms of cancer therapy affect sexual function, McLaughlin continued. A 2009 study found that among patients with good baseline erectile capacity, after 36 months erectile capacity was present in only one-third of those treated with prostatectomy, 50% of those who got external beam RT, and 80% of those who received brachytherapy.2 In 2005, McLaughlin and his colleagues defined the vessel-sparing technique. At the 2014 ASTRO annual meeting, he presented a 5-year follow-up on patients treated with it.

Two patient-reported metrics were used to assess sexual function: Metric A, which measured erections sufficient for sexual intercourse; and Metric B, which was more general about any form of sexual activity. Using Metric A, which looked only at erectile function sufficient for sexual intercourse, at 2 years, erectile capacity was achieved in 16.5% of those in the RT-alone group and 20.8% of the group receiving RT plus brachytherapy. At 5 years, 15.4% and 16.9%, respectively, were able to maintain an erection. Using Metric B, erectile function sufficient for sexual activity with or without aids was preserved in 78.6% of RT-alone patients and 91.8% of those who received RT plus brachytherapy at 5 years. McLaughlin said that as people age, sexuality changes and many couples

engage in types of sexual activity other than sexual intercourse, which can be painful to women after menopause. That’s why he thinks Metric B is more reflective of sexuality in older people. Cure rates were excellent. At 5 years, cure rates were 98% among low-risk men (55% of the 90 patients), 96% among intermediate-risk men (30% of the patients), and 87% in the high-risk patients (5% of the sample). n

References

1. Liss AL, Evans C, Narayana V, et al. Comparison of external beam and combination therapy for prostate cancer: patient reported outcomes of sexual function with 5-year follow-up. Int J Radiat Oncol Biol Phys. 2014;90(1)(suppl):S54. Presented at: 56th Annual Meeting of the American Society for Radiation Oncology; September 14-17, 2014; San Francisco, CA. Abstract 111. 2. Chen RC, Clark JA, Talcott JA. Individualizing quality-of-life outcomes reporting: how localized prostate cancer treatments affect patients with different levels of baseline urinary, bowel, and sexual function. J Clin Oncol. 2009;27(24):3916-3922.

Single Fraction Radiation for Bone Metastases A study based on patient-reported outcomes in a broad sample of cancer patients with bone metastases showed that single fraction radiation therapy (SFRT) was as effective as multiple fraction radiation therapy (MFRT) for alleviating pain and improving function and quality of life (QOL). This study has cost implications as well as implications for patient convenience, noted senior author Robert Olson, MD, a radiation oncologist at the British Columbia (BC) Cancer Agency Centre for the North, Canada. “We see variations in patterns of use of MFRT. No doubt some of the use of MFRT [in the United States] is driven by cost considerations,” he noted.

“Previous studies have shown that SFRT is equally effective as the more costly and inconvenient MFRT for patients with painful bone metastases.

This study has cost implications as well as implications for patient convenience. Many patients typically seen in clinical practice—those with fractures, neurologic damage—are excluded from these trials, though. There is a low utilization of SFRT worldwide, partly because oncologists are often reluctant to treat

november/december 2014 I VOL 7, NO 6

patients who do not mirror those in clinical trials,” he said. The study is ongoing. Results presented at ASTRO were based on self-reports from 648 patients treated with RT for bone metastasis. Patients were asked about pain levels, physical function, and symptom frustration. No major differences were seen between SFRT and MFRT for these parameters. Partial pain response was achieved in 73% of those treated with SFRT or MFRT; complete pain response was achieved in 19% and 22%, respectively. Improvement by 1 point or more was similar in both groups: improvement in functional complaints by at least 1 point was

observed in 71% and 77%, respectively; and at least a 1-point improvement in symptom frustration was reported by 77% and 80%, respectively. “These findings indicate that SFRT should be the standard management policy for uncomplicated bone metastases. Although the study is limited by a small sample size thus far, there is no evidence of inferiority for SF versus MF in complicated bone metastases,” Olson stated. n Reference

Olson RA, Olivotto L, Tiwana M, et al. Impact of program-wide dissemination of the inconsistent utilization of single fraction radiation therapy for bone metastases across a provincial program. Int J Radiat Oncol Biol Phys. 2014;90(1)(suppl):S691. Presented at: 56th Annual Meeting of the American Society for Radiation Oncology; September 14-17, 2014; San Francisco, CA. Abstract 3222.

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conference news: ASTRO

Radiation Does Not Increase Lymphedema Risk Radiation therapy (RT) does not increase the risk of lymphedema in patients with node-negative breast cancer beyond that of surgery, according to a secondary analysis of the NSABP (National Surgical Adjuvant Breast and Bowel Project) B-32 trial. “These results should reassure breast cancer patients that radiation therapy to the level 1 axilla when radiating the whole breast does not contribute to lymphedema risk beyond surgery,” stated lead author Susan McCloskey, MD, of the David Geffen School of Medicine at the University of California Los Angeles. McCloskey added, “This analysis suggests that lymphedema should not be an impediment to women choosing breast-conservation surgery and radiation therapy.”

The original study compared sentinel node biopsy (SNB) plus axillary node dissection (ALND) with SNB alone in 5611 women with no involved nodes.

The original study compared sentinel node biopsy (SNB) plus axillary node dissection with SNB alone in 5611 women with no involved nodes. Data from that trial were used to evaluate the impact of RT on the risk of lymphedema in those who underwent SNB or ALND. Ninety-three

percent of the women underwent breast-conserving surgery and 97% received breast or chest wall–only radiation (nonregional node radiation). Objective measurements (relative arm volume difference [RAVD]) were available for 3894 women (80% received RT), and subjective metrics were available for 730 women (80% had RT). No impact of radiation was observed on physician-reported lymphedema based on RAVD or on patient-reported lymphedema in either SNB+ALND patients or SNB patients. At 36 months, lymphedema (RAVD >10%) was detected in 13% of the SNB+ ALND group and 8% of the SNB group, with no difference between those treated with RT and those who did not have RT.

Interestingly, a lack of agreement was observed between patient-reported bothersome lymphedema and physician-measured lymphedema according to RAVD. At 36 months, 12.4% of the SNB+ALND and 7.4% of the SNB patients had measurable lymphedema on RAVD. Among these women, 7.4% and 3.2%, respectively, said their lymphedema was bothersome. “We still have a lot to learn,” McCloskey stated. n

Reference

McCloskey SA, Bandos H, Julian T, et al. The impact of radiation therapy on lymphedema risk and the agreement between subjective and objective lymphedema measures: NSABP B-32 secondary data analysis. Int J Radiat Oncol Biol Phys. 2014;90(1)(suppl):S4-S5. Presented at: 56th Annual Meeting of the American Society for Radiation Oncology; September 14-17, 2014; San Francisco, CA. Abstract CT-06.

Simple Blood Test to Predict Outcome Researchers reported that results of a simple blood test measuring VEGF-A and TGF-β1 can be used as predictive markers for response to treatment in patients with squamous cell esophageal cancer undergoing concurrent chemotherapy and radiation therapy (CCRT) followed by esophagectomy, or removal of part of the esophagus. “The blood levels of these two proteins can be used as biomarkers to predict tumor response to therapy. This simple test can help tailor treatment decisions in patients with esophageal cancer,” stated lead author Yun Chiang, MD, National Taiwan University Hospital, Taipei. From 2004 to 2013, blood samples were collected from 103 patients with esophageal squamous cell carcinoma

before and after CCRT. Serum samples were measured for 15 potential markers to correlate the levels of these markers

“This simple test can help tailor treatment decisions in patients with esophageal cancer.” —Yun Chiang, MD with pathologic response and survival. The assay used to screen tiny blood samples was developed at Stanford University and is called proximity ligation assay (PLA), said Chiang. The biomarkers significantly associat-

ed with pathologic response and survival rates were further analyzed by enzymelinked immunoabsorbent assay (ELISA) to confirm findings using PLA. Only 2 of the markers were significantly associated with disease-free survival (DFS; P = .009) and these were of borderline significance for overall survival (OS; P = .07). Patients with low levels of VEGF-A pre-CCRT were more likely to achieve a pathologic complete response to CCRT than those with higher levels: 57.1% versus 26.5%, respectively (P = .002). Patients with high pre-CCRT serum VEGF-A/TGF-β1 levels had significantly worse median DFS versus those with lower levels, and worse median OS (19.2 months vs 46.2 months, respectively; P = .07).

“Low serum levels of VEGF-A increased the chance of pathological complete tumor regression, and high serum levels of VEGF-A and TGF-β1 were associated with significantly worse disease control and borderline worse survival,” Chiang told listeners. The clinical implication of high serum levels of both proteins suggests that more intensive therapy is needed, he said. n

Reference

Chiang Y, Cheng J, Graber M, et al. Serum vascular endothelial growth factor-A and transforming growth factor-β1 can predict pathological response and disease-free survival of esophageal cancer patients treated with neoadjuvant chemoradiotherapy followed by esophagectomy. Int J Radiat Oncol Biol Phys. 2014;90(1)(suppl):S9-S10. Presented at: 56th Annual Meeting of the American Society for Radiation Oncology; September 14-17, 2014; San Francisco, CA. Abstract 10.

Risk of Second Primary Lung Cancer Remains High in Smokers Patients who are diagnosed with lung cancer but continue to smoke are at much higher risk of developing a secondary primary lung canJohn Michael Boyle, MD cer (SPLC) compared with never smokers as well as those who have quit smoking, according to the largest analysis of its kind. “This study, which looked at the relationship between smoking history and developing a second lung cancer, adds to the evidence of the harmfulness of

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cigarette smoking. We presumed that never smokers would have a lower risk than current smokers, but we were encouraged to find that quitting smoking lowered the risk of SPLC and quitters had similar overall survival rates as never smokers,” said John Michael Boyle, MD, lead author, a radiation oncology resident at Duke Cancer Institute in Durham, North Carolina. “These findings confirm that smoking cessation is crucial and should be an integral part of patient care for all patients as well as cancer survivors.” The study included 1484 patients who underwent surgery for stage I-IIIA non–small cell lung cancer between 1995 and 2008; this included 372 current smokers, 1014 former smokers,

and 98 never smokers. The 5-year incidence of SPLC was 13%, 7%, and 0%, respectively, which was statistically significant when both current and former smokers were compared with never smokers (P = .03). During follow-up, only 1 never smoker developed a second lung cancer 7 years later. The risk of SPLC increased with the number of years of tobacco exposure, equaling an 8% increased risk with every 10 pack-years. The risk of developing SPLC was driven by cumulative smoking history, never smokers having zero risk at 5 years, and those who quit (whether <5 years ago or >5 years ago) having a similar 5-year risk of 7%; current smokers had a 12.8% risk.

Results for overall survival (OS) were quite different, Boyle explained. “OS was the worst for current smokers. Quitting smoking mitigated increased risk of mortality,” he noted. The rate of 5-year OS was 54.1% in never smokers, 46.1% in those who quit >5 years ago, 47.1% in those who quit <5 years ago, and 39% in current smokers. No difference in rates of local control or distant metastasis was evident based on smoking status. n

Reference

Boyle JM, Chino JP, Tandberg D, et al. Tobacco use and secondary lung malignancies after surgery for non-small cell lung cancer. Int J Radiat Oncol Biol Phys. 2014;90(1)(suppl):S79-S80. Presented at: 56th Annual Meeting of the American Society for Radiation Oncology; September 14-17, 2014; San Francisco, CA. Abstract 170.

November/December 2014 I VOL 7, NO 6

Leukemia

Managing Patients Receiving Ibrutinib Alice Goodman

brutinib represents a major advance in the treatment of previously treated chronic lymphocytic leukemia (CLL) and mantle cell lymphoma (MCL), having achieved dramatic and sometimes durable responses in both diseases. Although ibrutinib is approved by the US Food and Drug Administration for both CLL and MCL, judging by the show of hands at the Oncology Nursing Society 39th Annual Congress, the majority of oncology nurses have not yet had experience with it. “Research suggests that this highly active oral therapy changes the rates of remission, and the drug is life-saving for many patients,” said Gretchen McNally, PhD, ANP-BC in hematology/ oncology, at James Cancer Center in Columbus, Ohio. The effect on survival is not yet known. Ibrutinib is a first-in-class small-molecule inhibitor of Bruton’s tyrosine kinase (BTK), which is part of the B-cell signaling pathway, and inhibition of this pathway leads to cell death. The drug is administered orally once a day and has a half-life of 4 to 6 hours.

CLL Experience

In a phase 1b/2 trial of 48 previously treated patients, ibrutinib achieved dramatic shrinkage of lymph nodes and spleen. However, the lymphocytes migrate from the tumor into the peripheral blood, causing lymphocytosis. “At first the white blood cell counts skyrocket,” McNally told listeners.

Ibrutinib is also associated with diarrhea in more than 60% of CLL patients, which usually is manageable with antidiarrheal medication. If severe diarrhea occurs, perform lab tests for electrolyte abnormalities and instruct patients to stay hydrated. Other potential adverse events include infections, fatigue, and musculoskeletal complaints, she said.

“For once-daily dosing of ibrutinib, patients should be encouraged to take the drug at the same time each day and swallow the capsules whole. If they forget a dose, they can take it later the same day and return to the normal schedule the next day.” —Gretchen McNally, PhD, ANP-BC “It is important to educate patients that lymphocytosis is expected and does not signal disease progression. Not all CLL patients experience lymphocytosis; it tends to occur in patients with nonbulky disease,” she told listeners.

The majority of adverse events reported in CLL were grades 1 and 2. The most common grade 3 or 4 nonhematologic adverse events were pneumonia, hypertension, and atrial fibrillation. Hematologic adverse events were

Noteworthy Numbers

In 1994, the National Family Caregiver Association sponsored a 1-week program in recognition of the role of family caregivers. The program grew, and since 1997, each US president has designated November as National Family Caregivers Month. Below are a few facts about this major aspect of patient care in the United States. Caregiving in the U.S., published in 2009, was a collaboration between the National Alliance for Caregiving and AARP. The study included telephone interviews with 1480 caregivers and was similar to surveys conducted in 2004 and 1997. For the first time, however, caregivers of special needs children were interviewed. Key findings of the 2009 study include1: n 65.7 million people had served as unpaid family caregivers to an adult or a child in the previous 12 months, representing 29% of the adult population and 31% of all households n Family caregivers provide an average of 20 hours of care per week n 66% of American caregivers are female n 86% care for a relative, most often a parent (36%)

n 70% of caregivers care for

someone over age 50 n 14% of caregivers provide care, over and above regular parenting, to a child with special needs n Caregiving lasts an average of 4.6 years In 2009, at any given time, about 42.1 million family caregivers provided care to an adult. The economic value of the care provided by all unpaid caregivers in 2009 was estimated to be $450 billion, nearly 4 times the $119 billion spent by Medicaid on longterm services and support.2 One of the many internet resources available to caregivers, the Caregiver Community Action Network is a dedicated group of over 100 volunteers in more than 40 states who provide education and support to family caregivers.3

november/december 2014 I VOL 7, NO 6

More than 15 million adults in the United States currently provide care to relatives with cancer.4 Oncology nurses may be able to provide needed guidance to family caregivers. In a study of 667 caregivers of patients newly diagnosed with cancer, almost 50% of the caregivers reported needing, but not receiving, training for administering medications, managing nausea and pain, changing dressings, and managing other symptoms, including patients’ emotional concerns.5 Sources

1. http://www.caregiving.org/research/ general-caregiving. 2. http://www.aarp.org/relationships/ caregiving/info-07-2011/valuing-fs. html. 3. http://www.caregiveraction.org/ resources/ccan/. 4. Glajchen M. J Support Oncol. 2004;2: 145-155. 5. http://www.medscape.com/viewarticle/ 773157.

mostly grades 1 and 2; about 34% of patients had grade 3 neutropenia. Hyperuricemia occurred in 40% of patients, which led to use of allopurinol for the first 4-week cycle. If patients develop rash on allopurinol, stop the allopurinol and determine whether the rash was due to ibrutinib or allopurinol, she continued.

MCL Experience

In an open-label, multicenter, single-arm phase 2 trial of 111 heavily pretreated patients, about one-third of the patients developed lymphocytosis. Unlike in CLL, the onset of lymphocytosis occurred during the first few weeks of treatment and typically resolved by a median of 8 weeks, although some patients developed severe lymphocytosis. Adverse events were similar to those reported in the CLL study and were mostly grades 1 and 2. The most common grades 3 and 4 nonhematologic events (≥5%) were pneumonia, abdominal pain, atrial fibrillation, diarrhea, fatigue, and skin infections. Hyperuricemia can also develop. Myelosuppression is similar to what is seen in CLL.

Nurse’s Role

“Nurses are on the front lines for adverse events. We see patients weekly for the first cycle when they are most vulnerable to side effects. Then we see them monthly [during] cycles 2 to 6; after that, we see them every 3 months,” McNally explained. Bleeding events can occur, and patients on anticoagulants are at increased risk of hemorrhage. This effect is not well understood, she said. “Use your clinical judgment. At Ohio State, we don’t allow patients on anticoagulants to take ibrutinib. For minor surgical procedures such as tooth extraction, we hold ibrutinib for 3 days before and 3 days after. For major surgery, we hold the drug for a week before and a week after,” McNally continued. “Patients are understandably nervous about withholding ibrutinib for 2 weeks, but they need to understand that the risk of bleeding outweighs the benefit,” she said. “When they withhold ibrutinib, the lymph nodes may swell, but they should be told that this will resolve when they restart the medication.” Grade 3 or higher infections occurred in 35% of CLL and 25% of MCL patients. Monitor patients and treat them appropriately, she advised. At Ohio State, antiviral prophylaxis is used in most patients, and antibiotic and antifungal prophylaxis is instituted

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Nutrition in Focus

Help Improve Quality of Life for Oncology Patients: Changing From Reactive Nutrition Support to Proactive Nutrition Intervention in Clinical Practice

he diagnosis of cancer and the following treatment both have a profound impact on all aspects of a patient’s life. Quality of life is impacted in many aspects, including physical functioning, psychological well-being, and social life. Even at diagnosis, up to 50% of cancer patients present with some nutritional deficit that may be impacting physical functioning.1 Most of the anticancer treatments (ie, surgery, chemotherapy, and radiation) will jeopardize food intake and therefore nutrition status at some point during treatment. This disruption contributes further to declining quality of life throughout care and into survivorship. In order to help improve or minimize the impact of treatment on quality of life, it is important to identify patients at risk of malnutrition at diagnosis or early during care.2 In 2007, a group of researchers published a review of the literature that highlighted the relationship between quality of life and nutrition intervention in patients with cancer.2 The researchers made practice recommendations based on findings from the literature linking weight loss and other nutrition-related symptoms to low quality of life and reduced response to antitumor treatment.2 The group concluded: • Early nutrition intervention can reduce

or reverse poor nutrition status, improve performance, and improve quality of life. • There should be a prescription for patient-tailored nutrition intervention (ie, counseling, oral nutrition supplementation, tube feeding, or parenteral nutrition). • The role of nutrition intervention in curative care is to increase treatment tolerance and response, decrease complications, and reduce mortality. • The role of nutrition in palliative care is to improve quality of life by improving clinical symptom management (vomiting, nausea, etc). A review published in February 2014 by a group of experts continues to highlight the importance of early identification of malnutrition and cachexia in oncology patients.3 The group emphasized the importance of completing a clinical assessment of all patients for malnutrition and cachexia in order to prescribe the appropriate intervention. Cancer-related weight loss, or cachexia, is different from simple starvation due to the tumor-associated metabolic abnormalities that prevent normal nutrition refeeding to restore nutrition status. When patients reach the stage of cancer cachexia, conventional nutrition support alone is not sufficient to reverse this state.4 Unfortunately, malnutrition and cachexia are common during cancer care and are related to low quality of life.2 Cancer cachexia represents 10% to 22% of all cancer deaths.5 Inadequate intake may be the primary reason for weight loss in some patients. In such cases, conventional nutrition support may be given in the form of counseling, oral nutrition supplements, or tube feeding. Cancer

on an individual basis. During flu season patients are given intravenous immunoglobulin. Myelosuppression occurred in at least one-third of patients. Blood counts should be monitored monthly, and at each visit patients should undergo lab tests for CBC, LFT, LDH, and uric acid. Fatal and severe cases of renal toxicity have been reported in patients taking ibrutinib. Nurses should measure serum creatinine and encourage their patients to maintain adequate hydration. Do not give ibrutinib to patients with baseline hepatic impairment.

Ibrutinib increases the risk of developing second primary malignancies (mainly skin cancers), which have been reported in 10% of CLL patients and 5% of MCL patients. Patients taking ibrutinib should not become pregnant, and breastfeeding is unwise, she said. With the shift from intravenous to oral chemotherapy, patients have the extra burden of making sure to take their medications. “There is no way to double-check whether patients are adherent, but drugs don’t work in patients who don’t take them,” she said. “For once-daily dosing of ibrutinib,

Tiffany DeWitt, MS, MBA, RD, LD Abbott Nutrition

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cachexia has the additional clinical challenges of altered metabolism and systemic inflammation. In patients with cachexia, multimodal therapy—including oral nutrition supplements with or without omega-3 fatty acids, nonsteroidal anti-inflammatory drugs, and exercise—should all be considered.3 The authors conclude that, regardless of tumor type, each patient should have access to individualized nutrition care throughout the course of treatment and into survivorship.3

Most of the anticancer treatments (ie, surgery, chemotherapy, and radiation) will jeopardize food intake and therefore nutrition status at some point during treatment. Proactive and continuous nutrition care can be integrated into treatment pathways to significantly impact quality of life. Associations and accrediting organizations support comprehensive cancer care that includes nutrition services.6,7 Although nutrition services are generally available to all patients, access may be difficult. Therefore, each member of the multidisciplinary team has responsibility to identify areas of patient need, including nutrition. Creating an automatic or required nutrition screen such as the Malnutrition Screening Tool (MST) at each visit will help identify early signs of nutri-

patients should be encouraged to take the drug at the same time each day and swallow the capsules whole. If they forget a dose, they can take it later the same day and return to the normal schedule the next day,” she continued. Interrupt therapy for any grade 3 or 4 toxicity. Once toxicity resolves to grade 1 or baseline, restart ibrutinib at the initial dose; if the toxicity recurs, reduce the dose by 1 capsule. If toxicities persist following 2 dose reductions, the drug needs to be discontinued. Ibrutinib is metabolized by CYP3A. Therefore, avoid use of strong or moderate CYP3A inhibitors if possible. If

tion risk and allow for early intervention. It is also helpful to have simple and readily available nutrition interventions, such as education or oral nutrition supplements, to encourage clinicians to start intervention as soon as a patient is identified as being at risk for malnutrition. Nutrition intervention has been shown to reduce the number of complications patients may experience during the acute phase of curative oncology treatment.2 Expert reviews have demonstrated that improvement in patient outcome can be achieved with early and proactive nutrition intervention.2,3 Providing nutrition as an integrated part of the oncology patient’s treatment plan is one way you can make a significant contribution to a patient’s quality of life. n Tiffany DeWitt works for Abbott Nutrition Research & Development.

References

1. Halpern-Silveira D, Susin LR, Borges LR, et al. Body weight and fat-free mass changes in a cohort of patients receiving chemotherapy. Support Care Cancer. 2010;18(5):617-625. 2. Marin Caro MM, Laviano A, Pichard C. Nutritional intervention and quality of life in adult oncology patients. Clin Nutr. 2007;26(3):289-301. 3. Aapro M, Arends J, Bozzetti F, et al. Early recognition of malnutrition and cachexia in the cancer patient: a position paper of a European School of Oncology Task Force. Ann Oncol. 2014;25(8):1492-1499. 4. Fearon K, Strasser F, Anker SD, et al. Definition and classification of cancer cachexia: an international consensus. Lancet Oncol. 2011;12(5):489-495. 5. Tisdale MJ. Cachexia in cancer patients. Nat Rev Cancer. 2002;2(11):862-871. 6. Marino MJ, Patton A, eds. Cancer Nutrition Services: A Practical Guide for Cancer Programs. Association of Community Cancer Centers; 2012. http://www.accccancer.org/resources/NutritionPrograms-Overview.asp. 7. Commission on Cancer, American College of Surgeons. Cancer Program Standards 2012, Version 1.2.1: Ensuring Patient-Centered Care. Chicago, IL: American College of Surgeons; 2012. https://www.facs. org/quality%20programs/cancer/coc/standards.

the patient must use a strong CYP3A inhibitor, it should be used short term with close monitoring. With strong or moderate CYP3A inhibitors, closely monitor the patient for signs of ibrutinib toxicity. CYP3A inducers decrease ibrutinib concentration 10-fold, and these drugs should be avoided while on therapy. Consider alternatives and use only over the short term with close monitoring. n

Reference

McNally G. A new treatment option in previously treated chronic lymphocytic leukemia and mantle cell lymphoma. Presented at: Oncology Nursing Society 39th Annual Congress; May 1-4, 2014; Anaheim, CA.

November/December 2014 I VOL 7, NO 6

Perspectives

A Pair of Shoes Sue Bond

few years ago my son talked me into buying him a pair of Reeboks. It’s not that they were all that expensive, but they were purple and orange and, well, sorta ugly. I caved and bought him the shoes after he promised he would “wear them every day.” He wore them for a while, but then they just ended up in the back of his closet. I mean, how long can you wear purple and orange shoes? His feet grew, as boys’ feet do, and I took the shoes (still with plenty of wear left) to Goodwill. I saw those shoes today. I was volunteering at a free cancer screening clinic when a man walked in with those ugly purple and orange shoes. He was there with many issues: he had untreated high blood pressure, he had not been to a dentist in years, he was unable to use one of his hands (he just woke up that way one day), and he had blisters on his feet because the shoes were 2 sizes too small. He really wasn’t all that interested in the cancer screening. Most important for him was finding some Lysol for the shoes. He wanted to disinfect them. It was obvious within the first few minutes that he had some serious issues. He was a recovering addict, and it was apparent that he had lost use of some gray matter during his addiction, but those shoes made me connect with him. It was that simple…for me. He, on the other hand, could not understand why I was trying to solve all of his problems, when all he really wanted was some Lysol.

Sometimes you meet a patient and you find that you share the same interests in books, movies, etc, and you know that if you met outside of this clinical world you would be besties. That happens to me a lot as a caregiver. I see a young patient wearing the same kind of T-shirt that my own son has, and I become overly involved. I meet a patient with a German accent (like my mother’s), and instantly I am ready to jump over the boundaries that would keep me more professional. Sometimes you meet a patient and you find that you share the same interests in books, movies, etc, and you know that if you met outside of this clinical world you would be besties. And therein lies the rub. We are in

the clinical world, and these are our patients, not our children, parents, or even friends. It is hard to maintain professional boundaries when you are with

Sue Bond

people who are going through such a difficult time and who need so much. I once heard another oncology nurse say that with our patients, “You go in, you go in deep, and then you’re out.” We create a true therapeutic relationship, in

I once heard another oncology nurse say that with our patients, “You go in, you go in deep, and then you’re out.” which we allow ourselves to be whatever that particular patient needs at that time. Sometimes it’s a cheerleader and encourager, sometimes it’s a confidant for secrets and/or fears, other times it’s the stern maternal figure that helps rein in some acting out, but most of the time we are ears and shoulders. Listening and compassion are what most patients need, but providing these can be difficult and draining for the caregiver. All this investment of care and emotional support, and then it’s over, either for the best or the inevitable. So how do we avoid becoming an emotional wreck? Sometimes it is impossible. Most oncology nurses, NPs, and PAs I know have a big box of tissues in their car, and that drive home can be very cathartic. I have had people ask me at stop signs if I am OK, and on rare occasions I have had to pull over for the safety of all—the wipers are, after all, on the outside of the windshield. Having your own strong support system is also a necessity. Good friends are an absolute must, especially those that can bear your venting—again, and always have a cold pinot grigio for you. A good dog that likes to go on hikes is

november/december 2014 I VOL 7, NO 6

priceless, especially since you can’t violate HIPAA with him. Family too can be a great balm; nothing beats a good hug from someone you love when you get home after a long day. Even in oncology, laughter can be the best medicine, and as in any specialty we have our own twisted sense of humor. For instance, I never shave a young man’s head without showing him what he could look like in 30 years, sometimes even including a comb-over. Sometimes for (the patient’s) kicks, I make visiting friends gown up, complete with ugly shower caps, before they enter the patient’s room. Looking for laughter in the little things seems almost normal, even if the little things are anything but normal for these patients. I once had a patient tell me about a time when she reached up for a can of peaches in a grocery store, and her prosthetic breast fell out. We had tears in our eyes when we discussed the benefit of it being a prosthetic breast for a woman over 50 years rather than for a younger woman—less bounce, easier to catch. Sometimes we can make a tangible target in the personification of cancer

because then we can beat it, kick its butt, tell it that it sucks—and that helps. Cancer becomes beatable; we can fight; we can wear our ribbons of many different colors, boasting of our

Even in oncology, laughter can be the best medicine, and as in any specialty we have our own twisted sense of humor. intended defeat of a particular cancer. Making cancer a target can motivate us to raise money, run races, and find other ways to beat it once and for all. We feel stronger and empowered, and we need that because otherwise cancer is something that we can’t really get our mind around—this insidious disease that can walk into anyone’s life at any time, quietly, stealthily, and ugly, sort of like a pair of purple and orange Reeboks that you thought, hoped, you would never see again. n

have you ever wanted to write an article for TON ?

We’re interested in articles about the everyday issues that affect nurses—everything from chemotherapy safe handling to supportive care for patients to challenging cases.

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Best Practices

Infection Prophylaxis Update of disease and chemotherapy, status of malignancy, and breakdown of normal skin and mucosal barriers due to indwelling catheters or mucositis, and tumor-related obstruction. Infection can also develop due to defects in humoral and cellular immunity resulting from cancer or its treat-

Continued from cover

Strategies for Prophylaxis

ments. Such reactions may include altered B- and T-cell function in patients with lymphoid malignancies; those caused by treatment with steroids, anti-CD20 monoclonal antibodies, and purine analogs; or such defects caused by hypogammaglobulinemia or splenectomy.

Potential strategies for prevention of infection include pharmacologic prophylaxis with antimicrobials, colony-stimulating growth factors, and vaccination. Nonpharmacologic approaches include neutropenic precautions and environmental interventions.

3RD ANNUAL

s V Th erie iew eO s o th nc nli e olo ne gy at Nu rse .

NCCN guidelines for prevention and treatment of cancer-related infections (version 2.2014) list key factors for low, intermediate, and high risk of infection.2 Prior to 2005, no survival benefit was found for antibiotic prophylaxis, but that changed in 2005 when a large meta-analysis of 95 randomized controlled trials found that antibiotic prophylaxis in afebrile neutropenic cancer patients reduced overall mortality by

“Hand washing is still the most effective strategy to prevent infection.” — Laura Zitella, MS, RN, ACNP-BC, AOCN

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A 5-part series The publishers of The Oncology Nurse-APN/PA are proud to present our 3rd annual Conquering the Cancer Care Continuum™ series.

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33% and infection-related mortality by 42% versus placebo or no treatment.3 In the same study, fluoroquinolone prophylaxis reduced overall mortality by 48% and infection-related mortality by 62% versus placebo or no treatment. More recently, a 2012 Cochrane review by the same author examining 109 trials that included 13,579 patients also showed a reduction in mortality for antibiotic prophylaxis, as well as a preference for quinolones over trimethoprim/sulfamethoxazole (TMP/SMX).4 “At present, consider antibiotic prophylaxis for all high-risk neutropenic patients, but not for low-risk patients. The drugs of choice are levofloxacin or ciprofloxacin,” Zitella said. “Continue to monitor patients on antibiotics for resistance.” Colony-stimulating factors are recommended for patients with a 20% or greater risk of febrile neutropenia.5 “The caveat is that they are not routinely recommended for patients undergoing radiation therapy or treated for acute myeloid leukemia or Hodgkin’s disease patients,” Zitella stated.

Antifungal Prophylaxis

Antifungal prophylaxis is indicated for herpes simplex virus (HSV)-positive patients, such as those undergoing transplant, those with acute leukemia, or those undergoing treatment with proteasome inhibitors, alemtuzumab, or purine analogs; those with graft-versus-host disease being treated with steroids; or patients with prior HSV reactivation during treatment. Drugs of choice include valacyclovir, acyclovir, and famciclovir. Cytomegalovirus (CMV) prophylaxis should be considered for high-risk patients who are CMV positive, such as those undergoing allogeneic transplant Continued on page 14

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November/December 2014 I VOL 7, NO 6

Best Practices

Room for Improvement in Symptom Management Alice Goodman

ven though oncology nurses are charged with improving patients’ cancer-related and treatment-related symptoms, there is much room for improvement, according to Susan C. McMillan, PhD, ARNP, FAAN. McMillan received the Distinguished Nurse Researcher Award at the Oncology Nursing Society 39th Annual Congress and gave a presentation about symptom management in oncology nursing.1 McMillan is Thompson Professor of Oncology Quality of Life Nursing at the University of South Florida in Tampa as well as the Director of the Oncology Nursing Program. She has conducted numerous studies in the field of symptom management, with a concentration on pain management and, more recently, constipation. The main focus of her efforts has been to improve symptom management and quality of life for cancer patients.

Appropriate pain assessment is important and, when pain is properly assessed, patients have less need for sedation and their pain intensity is reduced. In her talk, she mentioned that the trajectory of cancer care is changing, and it is now recognized that palliative care should be given much earlier in the course of therapy to address patients’ symptoms.

McMillan’s studies of pain management in cancer patients show that appropriate pain assessment is important and that, when pain is properly assessed, patients have less need for sedation and their pain intensity is reduced. A study she conducted in 2006 found that cancer pain was significantly undertreated, and RNs were giving only about one-third of the prescribed doses of pain medications. “Many patients had daily unrelieved pain, and 18% of the patients with moderate pain got no analgesic,” she said. Patients’ charts revealed inadequate pain assessment. Only 4% of the patients in the study had been rated for pain, and the site of pain was documented in only 53%. A study done in the hospice setting in the year 2000 (N=85) about nurses’ knowledge and attitudes about pain management in cancer patients showed that not only did nurses have inadequate knowledge about pain, but their attitudes toward pain treatment were based on false assumptions. This study also showed that patients’ pain was being undertreated.2 Nurses knew the least about physiology of pain, pharmacology of analgesics, treatment goals, and nonpharmacologic methods. Furthermore, 84% did not know that around-the-clock dosing is preferable, and 82% falsely believed that around-the-clock dosing increased the risk of sedation and respiratory depression. One might assume that because this study was conducted 14 years ago there has been some improvement. Sadly, not much has changed. McMillan

Infection Prophylaxis Update or treatment with alemtuzumab. If CMV viremia is detected, treatment should include valganciclovir, ganciclovir, foscarnet, or cidofovir. “Hepatitis B virus [HBV] reactivation is emerging as an important pathogen in patients with hematologic malignancies,” Zitella continued. “HBV reactivation can lead to fulminant hepatitis and death,” she cautioned. Patients undergoing stem cell transplant or immunosuppressive therapy may lose immune control of HBV. Testing for HBV is recommended for all patients undergoing immunosuppressive therapy, allogeneic stem cell transplant, treatment with anti-CD20 monoclonal antibodies and alemtuz umab, and any patient with obvious risk factors for HBV. For patients who

reported on a repeat of the same study on nurses’ attitudes conducted in 2014 (N=41, to be published) showing that, in some domains, nurses’ scores were even more disappointing. The scores

“We need to do better. It is the oncology nurse’s job to address symptom management. Become involved in evidence-based projects to study these problems.” — Susan C. McMillan, PhD, ARNP, FAAN on knowledge about pain ranged from 39% to 81%, with a mean score of 63%. Only 17% of nurses scored higher than 70%, which would be equivalent to an “F” if they were graded on test results. Looking at attitudes in that study, 95% disagreed that around-the-clock pain care is better, and 95% agreed that around-the-clock dosing increases the risk of sedation and respiratory depression. Only 15% agreed that patients in pain can tolerate higher doses of opioids without worrying about respiratory depression. McMillan emphasized that pain is not the only symptom cancer patients experience and certainly not the only distressing symptom they have. A recent study using the Cancer Symptom

References

1. McMillan SC. Distinguished Nurse Researcher Award: are we there yet? Symptom management in oncology nursing. Presented at: Oncology Nursing Society 39th Annual Congress; May 1-4, 2014; Anaheim, CA. 2. McMillan SC, Tittle M, Hagan S, et al. Knowledge and attitudes of nurses in veterans hospitals about pain management in patients with cancer. Oncol Nurs Forum. 2000;27(9):1415-1423.

Continued from page 13

are hepatitis B surface antigen positive, antiviral prophylaxis is recommended with entecavir, tenofovir, adefovir, or telbivudine.

Alternatives are atovaquone, dapsone, and inhaled pentamidine. Regarding vaccines, Zitella said the recommendations have changed recent-

Risk factors for infection include severity and duration of neutropenia because of disease and chemotherapy, status of malignancy, and breakdown of normal skin and mucosal barriers due to indwelling catheters or mucositis, and tumor-related obstruction. Patients with T-cell deficiency should be considered for Pneumocystis carinii pneumonia (PCP) prophylaxis, for which the drug of choice is TMP/SMX.

november/december 2014 I VOL 7, NO 6

Scale reported the following symptoms in cancer patients treated in hospice: fatigue (83%), pain (73%), dry mouth (71%), drowsiness (60%), loss of appetite (56%), and shortness of breath (55%). Patients cited fatigue, loss of appetite, constipation, difficulty sleeping, and cough as the most distressing. The oncology nurse should find out from individual patients which symptoms are the most distressing, she continued. “We can’t help them if we don’t know what they are experiencing and how distressing the symptoms are. I encourage all oncology nurses to use a multisystem assessment,” she said. McMillan currently has a grant from the National Cancer Institute to study constipation with a multidisciplinary team. She noted that constipation is the major side effect of opiates, and that patients report distress and pain related to constipation. Yet constipation is undertreated and often ignored, even though it is very treatable. In rare cases, constipation, if left untreated, can cause bowel perforation and death. Regarding the current state of symptom management, McMillan said: “We need to do better. It is the oncology nurse’s job to address symptom management. Become involved in evidence-based projects to study these problems.” n

ly. “Do not give live attenuated vaccines to cancer patients.” Specific vaccine recommendations are available at the Centers for Disease Control and

Prevention website and the NCCN website. n

References

1. Zitella L. Updates on the prevention and treatment of cancer-related infections. Presented at: National Comprehensive Cancer Network 9th Annual Congress: Hematologic Malignancies; September 19-20, 2014; New York, NY. 2. National Comprehensive Cancer Network (NCCN). NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines): Prevention and Treatment of Cancer-Related Infections. Version 2.2014. http://www.nccn.org/pro fessionals/physician_gls/pdf/infections.pdf. Accessed October 4, 2014. 3. Gafter-Gvili A, Fraser A, Paul M, et al. Meta-analysis: antibiotic prophylaxis reduces mortality in neutropenic patients. Ann Intern Med. 2005;142(12 pt 1):979-995. 4. Gafter-Gvili A, Fraser A, Paul M, et al. Antibiotic prophylaxis for bacterial infections in afebrile neutropenic patients following chemotherapy. Cochrane Database Syst Rev. 2012;1:CD004386. 5. National Comprehensive Cancer Network (NCCN). NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines): Myeloid Growth Factors. Version 2.2014. http://www.nccn.org/professionals/physician_gls/pdf/ myeloid_growth.pdf. Accessed October 4, 2014.

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Genetic Counseling

Expanding Phenotypes of Inherited Colorectal Cancer Syndromes Cristi Radford, MS, CGC Invitae

he first multigene panels for colorectal cancer became clinically available in 2012.1 Prior to that date, clinical testing for inherited colorectal cancer syndromes typically proceeded in a sequential fashion. A clinician would develop a differential diagnosis and test corresponding genes in order of those most likely to have a causative mutation. Thus, analyzing multiple genes for inherited colorectal cancer risk was both time intensive and costly. Additionally, the genes selected for analysis were based on established diagnostic criteria. As more individuals tested positive for a particular cancer syndrome, the phenotypic criteria evolved. However, a bias still existed as patients used to modify syndrome characteristics were typically detected because they met defined clinical criteria. The true phenotype associated with gene mutations is challenging to determine without population-based prospective studies, and such studies rarely exist. However, with the advent of multigene panels for inherited colorectal cancer, clinicians are able to cast the net wider and examine many genes associated with colorectal cancer risk. As a result, patients are being identified who do not closely resemble established clinical criteria, and the phenotypes of inherited colo rectal cancer syndromes are evolving.

As more individuals tested positive for a particular cancer syndrome, the phenotypic criteria evolved. Cragun and colleagues1 described clinical laboratory data for results reported for an inherited colorectal cancer panel between March 2012 and March 2013. In this data set, 1 in 4 individuals did not meet established syndrome-based testing guidelines. Of these individuals, there were patients

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with clinical histories that were suggestive of the condition diagnosed via genetic testing and also several atypical cases. Among the atypical cases were 2 individuals with SMAD4 mutations and no juvenile polyps, 1 individual with a PTEN mutation and greater than 100 adenomatous colonic polyps, and 1 individual with a CDH1 mutation who did not have breast or gastric cancer and whose family history did not report gastric cancer. Without multigene panels, it is likely these families would not have been genetically diagnosed. As the number of individuals undergoing gene panels for inherited colon cancer increases, so do the data surrounding atypical cases and expanding phenotypes. This was recently seen at the 2014 Collaborative Group of the Americas on Inherited Colorectal Cancer (CGA-ICC) meeting. Data from both academic institutions and commercial laboratories were reported. Several authors suggested that an association between colorectal cancer and Li-Fraumeni syndrome exists and that TP53 analysis should be included in young colorectal cancer patients.2-4 Of interest, of the 42 patients with clinically actionable mutations described by Cragun and colleagues,1 only 1 patient was identified with a TP53 mutation, and this patient met Chompret criteria. However, as this paper was focused on results obtained from an inherited colo rectal cancer panel, it is possible other colorectal cancer survivors could have been identified with a TP53 mutation via a multigene panel that covered colo rectal cancer and other cancers, such as breast or gynecologic malignancies, which was not reported in this study. Data presented at the CGA-ICC meeting also suggested overlapping phenotypes between hereditary breast and ovarian cancer syndrome and Lynch syndrome, two of the most well-described hereditary cancer syndromes. In a laboratory cohort described by Myriad Genetics in which a multigene panel was performed on samples previously submitted for Lynch syndrome testing, approximately 11% of the non–Lynch syndrome highly penetrant mutations (defined as BRCA1/2, APC, biallelic MUTYH, or STK11/ BMPR1A mutation carriers) identified were in BRCA1/2. The majority of these individuals (93%) met National Comprehensive Cancer Network (NCCN) criteria for Lynch syndrome testing while only 33% met NCCN criteria for BRCA1/2 testing.5 Similar findings were demonstrated in a cohort described by GeneDx. In this laboratory

cohort, results for any multigene panel ordered on an individual with colorectal cancer and/or polyps were analyzed. As such, the exact genes analyzed varied depending on the panel performed. However, approximately 20% of individuals testing positive for a non–Lynch syndrome highly penetrant gene (defined as BRCA1/2, APC, biallelic MUTYH, or STK11/BMPR1A mutation carriers) were found to carry a mutation in BRCA1.6 An association of breast cancer with PMS2 and MSH6 mutations was also suggested.7,8

Data from both academic institutions and commercial laboratories were reported at the CGA-ICC meeting. Similar to those in the Cragun and colleagues paper, cases were also presented at CGA-ICC that did not meet the defined clinical criteria and would have likely been missed if testing strategies relied on single-syndrome approaches.9 Ambry Genetics presented several cases in which individuals with PTEN mutations met criteria for attenuated or classic familial adenomatous polyposis,10 as well as individuals who carried CDH1 mutations but did not have a personal and/or family history of gastric cancer.11 Additionally, many authors reported individuals testing positive for mutations in moderately penetrant genes,5,6,12,13 further emphasizing the need for better risk estimates and management guidelines surrounding these mutations.

Take-Home Messages

• The phenotypes surrounding inherited colorectal cancer syndromes continue to evolve and new descriptions and risk estimates may be needed. • More data are needed to determine the association of colorectal cancer with Li-Fraumeni syndrome and breast cancer with Lynch syndrome. • Multigene panels increase mutation detection in individuals at risk for inherited colorectal cancer syndromes. n

References

1. Cragun D, Radford C, Dolinsky JS, et al. Panel-based testing for inherited colorectal cancer: a descriptive study of clinical testing performed by a US laboratory. Clin Genet. 2014;86(6):510-520. 2. Yurgelun M, Masciari S, Joshi V, et al. Germline TP53 mutations in patients with early onset colorectal

cancer. Presented at: 18th Annual Meeting of the Collaborative Group of the Americas on Inherited Colorectal Cancer; September 15-16, 2014; New Orleans, LA. Abstract 1. 3. Kohlmann W, Samadder J, Jasperson K, et al. Evaluation of the risk for Li-Fraumeni syndrome associated cancers in individuals presenting with early onset gastrointestinal cancers. Poster presented at: 18th Annual Meeting of the Collaborative Group of the Americas on Inherited Colorectal Cancer; September 15-16, 2014; New Orleans, LA. Abstract 16. 4. Mork M, You N, Ying J, et al. Elucidating the impact of hereditary colorectal cancer syndromes in adolescents and young adults ages 35 and under diagnosed with colorectal cancer. Presented at: 18th Annual Meeting of the Collaborative Group of the Americas on Inherited Colorectal Cancer; September 15-16, 2014; New Orleans, LA. Abstract 18. 5. Yurgelun MB, Allen B, Kaldate RR, et al. Multigene panel testing in patients suspected to have Lynch syndrome. Presented at: 18th Annual Meeting of the Collaborative Group of the Americas on Inherited Colorectal Cancer; September 15-16, 2014; New Orleans, LA. Abstract 7. 6. Weissman S, Booker J, Farengo-Clark D, et al. GeneDx’s first 6 months of NGS panel testing in individuals with a personal history of colorectal cancer and/ or colorectal polyps: a descriptive report. Presented at: 18th Annual Meeting of the Collaborative Group of the Americas on Inherited Colorectal Cancer; September 15-16, 2014; New Orleans, LA. Abstract 25. 7. Roberts M, Marshall M, Farengo-Clark D, et al. Breast cancer and Lynch syndrome: a possible association with low penetrance genes, specifically PMS2. Presented at: 18th Annual Meeting of the Collaborative Group of the Americas on Inherited Colorectal Cancer; September 15-16, 2014; New Orleans, LA. Abstract 13. 8. Kaushik P, Evans B, Moyes K, et al. Clinical presentations of MMR mutation positive patients with no personal or family history of colon or endometrial cancer. Presented at: 18th Annual Meeting of the Collaborative Group of the Americas on Inherited Colorectal Cancer; September 15-16, 2014; New Orleans, LA. Abstract 19. 9. Williams C, Raymond V, Stoffel E, et al. Utilization of next generation panel genetic testing diagnoses a patient with atypical colon polyp presentation. Presented at: 18th Annual Meeting of the Collaborative Group of the Americas on Inherited Colorectal Cancer; September 15-16, 2014; New Orleans, LA. Abstract 76. 10. Panos L, Chen Weltmer E, LaDuca H, et al. Further defining the polyposis phenotype associated with PTEN mutations. Presented at: 18th Annual Meeting of the Collaborative Group of the Americas on Inherited Colorectal Cancer; September 15-16, 2014; New Orleans, LA. Abstract 60. 11. Sturgeon D, Espenschied C, Lowstuter K, et al. Unexpected CDH1 mutations identified on multigene panels. Presented at: 18th Annual Meeting of the Collaborative Group of the Americas on Inherited Colorectal Cancer; September 15-16, 2014; New Orleans, LA. Abstract 4. 12. Lowstuter K, Sturgeon D, Ricker C, et al. Unexpected findings with multiplex panel testing: is it time to re-define syndromic classification in differential diagnosis. Presented at: 18th Annual Meeting of the Collaborative Group of the Americas on Inherited Colorectal Cancer; September 15-16, 2014; New Orleans, LA. Abstract 23. 13. Parker M, Ali-Khan Catts Z, Milewski B, et al. CHEK2 mutations: should we rethink about testing hereditary nonpolyposis colorectal cancer families? Presented at: 18th Annual Meeting of the Collaborative Group of the Americas on Inherited Colorectal Cancer; September 15-16, 2014; New Orleans, LA. Abstract 29.

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November/December 2014 I VOL 7, NO 6

The Patient’s Voice

The Transition From “Why Me?” to “Why Her?” Carolyn Comeau

or a cancer survivor, it’s enough to lay you flat. There’s a day when you learn that someone who has been in your survivor universe is no longer a part of that universe. And this news not only shakes you to the core, it roils the pot of emotions resting on your internal stovetop to a vigorous boil. I’m a seven-and-a-half-year breast cancer survivor, and when I got diagnosed, I was certain I’d never awaken on another morning of my life without my first thought being of cancer. There are really so many worries to have: Is this all some horrible mistake? How will I get through chemo—and is there a good chance that I will be the historic exception and not lose my hair? How do I tell my children, loved ones, and friends? Will I or will I not opt for reconstruction? Why did I get this freaking disease and not the woman I’m spying from the bank drive-thru who is smoking, obese, and sashaying into McDonald’s without a care in the world? (Note: one of my particular and not-too-healthy coping mechanisms during my illness was being crazily judgmental and idealizing everyone else’s life.) I remember being at the playground with my kids and feeling absolutely furious about the fact that other moms and their kids were running around, swinging, and laughing in a most carefree way—indicative again that they had no real concerns about life weighing on their minds! Looking back, I think I needed to compartmentalize and reduce things to their most “blackand-white” state to make it through sometimes. And then the unimaginable happened: Somewhere along the way I had a day when my first thought was of breakfast, eagerly anticipated time with a friend, or a walk with my kids and our new puppy. And that day was followed by another…and another. This is not likely true of all cancer patients, but in the black-and-white thinking realm, I wanted to believe that if I did everything I was supposed to do (have my mastectomy, chemo, radiation, and Herceptin), then I would deserve to live. Hell, anyone who went through any of this stuff should at least be given a pass in the form of an assured future, I thought. Denial, as they say, is not just a river in Egypt. I still get mad and ask why cancer can’t be more like school—if you work hard, you’ll get an “A.” So much for simple and wishful thinking. The first loss I experienced of someone with breast cancer was a woman a bit older than I who had been super healthy before her diagnosis. She was a respected professional, an avid golfer, long and happily coupled, a loving

mother to an adult daughter, and an allround wonderful person. She was diagnosed perhaps 2 or 3 years after I was. I tried as best I could to talk to her about my experience in a helpful way, participated with her in various pink events, had her over for lunch, and checked in with a phone call periodically. But something happened we didn’t expect. She didn’t get better, didn’t thrive, went downhill. I watched her lose her strength, and as a tangential friend, there came a point where I didn’t see her at all anymore. The communication about her condition started to be shared via social media and mutual friends I’d run into on the street. And then, all of a sudden, I heard that Sarah had passed away. See, I even have trouble writing the word “died.” I felt nauseated upon hearing the news. My next concern was for her partner’s and daughter’s pain. What were they going through? At the same time, it didn’t seem real, and I was loath to accept it.

This is when I switched from the “Why me?” question so familiar to those diagnosed with cancer to the “Why her?” question. I needed to steel myself for attending the funeral. And then I felt guilty for needing to steel myself because I was still on this earth—eating, laughing, writing, gardening, enjoying my family. The stunning and raw reality of it all seemed incomprehensibly cruel. It made me hate cancer even more. Not to be outdone, cancer (she is such a bitch!) provided another chilling moment when my phone rang as I was getting out of my car to attend Sarah’s funeral. As soon as my feet hit the pavement, I answered and heard the shaky voice of a friend in my support group, anxious about a “weird” blood test result and other symptoms she was having. Thankfully everything she was experiencing turned out to be a different, solvable problem entirely, but it’s times like these that can make a survivor feel like she’s drowning in cancer worry. The “what if’s” that linger after treatment is done can pull at us like so many maliciously pinching fingers. The next two losses came in fairly quick succession. An acquaintance I’d known through our kids’ school was diagnosed with triple negative breast

november/december 2014 I VOL 7, NO 6

cancer, the triple crown (and not in a good way) of breast cancers, the kind that people still whisper about because it is so hard to treat. She had an incredible neighborhood mom posse who took care of her and her family, but they too had lots of grief to process as they watched her endure robotic brain surgery, extensive treatment, and trips from North Carolina to Philadelphia to see a specialist. As she neared death, social media again blew up, with a Facebook-framed plethora of photographs from better, healthier times and tributes from the heartbroken who loved her desperately. Angie was an incredible mom to two teens, a highly respected high school teacher, and, from all accounts at her beautiful memorial service, the kind of person people sought to emulate—for her unique joy, for her loving ways and pronounced lack of snarkiness, for her humor. She had the ability to make everyone she encountered feel special. She also had the kind of marriage people talk about with envy—love filled and lengthy. I took my kids with me to her memorial service because I thought it was important, but they chose to focus on anything and everything other than the service and the matter at hand, which I understand. Parents often second-guess their decisions, but this was one of those times that showing up was more than important, if for no one else than Angie’s own children. They needed to see her legacy of love that day, in the form of a sea of faces—no matter that they were twisted in grief. This is when I switched from the “Why me?” question so familiar to those diagnosed with cancer to the “Why her?” question. Winter brought the most recent loss of a friend from my support group. She had traveled for years from her home in the mountains of western North Carolina to Duke and to MD Anderson in Texas for treatment. She was funky and sassy, laughing uproariously the day I met her after I complimented her on her beautiful, long hair. I was envious because I had not one hair on my head; in her inimitable Southern style, she pulled off her “hair” and handed it to me, exclaiming “You want it?!” There was never a time that I knew her when she didn’t have cancer, and yet during these years she learned to paint from another breast cancer survivor and professional artist (and was very gifted), traveled to Italy, and went to more days-long music festivals than I could count. She had a sweet mutt who was her constant companion until his

death, which preceded hers by a couple of years. I remember wishing fervently that she could have been spared that loss, what with everything else she was dealing with. I’ve heard the elderly speak about how hard it is to lose your friends, one by one, to various maladies and old age. But it’s another frightening and enraging thing to be losing them when they’re in their thirties, forties, and fifties. I don’t know that I’ll ever let go of my desire for more justice in all this. I have no profound suggestions for coping strategies, no miracle healing outlets. These losses have made me, simultaneously, a million times more grateful for my survival, intensely conscious of what I want my life to stand for and how I want to be remembered—loving mother and wife, compassionate friend, and change-maker for the things I care about (which include children and schools, historic preservation, a handful of political causes) would be just fine, thank you— and afraid of death. Yes, the kicking and screaming kind of afraid. Since I was diagnosed when my kids were 3 and 6, I’ve never been able to identify with folks who talk about being at peace with whatever yet-tobe-revealed plan is in place for them. I don’t disrespect their outlook—in fact, I’d give anything for their seeming “at peace-ness.” I still remember, very clearly, feeling more desperate and helpless than I’ve ever felt. I’d picture my memorial service (morbid, I know, but your mind wanders to all sorts of never-before-visited places when you’re in the chemo chair) and then hear, internally, a Warner Brothers cartoon-like screeching-brake sound. Goddammit, I’d think. I AM NOT READY! I know cancer didn’t care, but I wasn’t. I worried, didn’t sleep, imagined horrifying things. I continue NOT to be OK with the idea of my death. There are too many people I love, two very special ones who are now 13 and nearly 11 who need me, and myriad things I want to do, places I want to visit, beauty I want to see, art I want to make, magical moments I want to slide under my belt. I’ve decided that since I am still here and despite the fact that I cannot make practical sense out of the last 7 years, I want to honor, via my life, in small and hopefully sometimes bigger ways, the women I’ve lost who inarguably had exemplary, limitless courage. And who mattered beyond all measure. Lemonade out of lemons indeed. n

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Over the past decade, significant progress has been made in the management of multiple myeloma, including new standards of care and the development and approval of several novel, effective agents. Despite this progress, more work needs to be done and numerous questions remain regarding the application and interpretation of recent clinical advances. In this sixth annual “Considerations in Multiple Myeloma” newsletter series, we continue to explore unresolved issues related to the management of the disease and new directions in treatment. To ensure an interprofessional perspective, our faculty is comprised of physicians, nurses, and pharmacists from leading cancer institutions, who provide their insight, knowledge, and clinical experience related to the topic at hand. In this second issue, experts from Dana-Farber Cancer Institute answer questions related to the management of patients in the maintenance setting.

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Breast Cancer

Relation Between Stomatitis and Clinical Outcomes of Everolimus Treatment Examined by Trial Investigators Caroline Helwick

these patients, with the episodes tending to be less severe. The incidence was highest (71%) in the breast cancer trials. Most stomatitis was grade 1/2, with grade 3/4 observed in only 8.6%. Only

25 patients (1.7%) discontinued treatment as the result of stomatitis. “Stomatitis occurred rapidly,” Rugo noted. More than 60% of the 973 patients reporting this toxicity devel-

R E G I S T E R

oped it by 2 months; median time to the first episode was 0.82 months and 89% of all first episodes were observed within 8 weeks. “Sixty percent of patients who experi-

T O D A Y I

n patients receiving everolimus in clinical trials, stomatitis frequently occurred in the initial weeks of treatment, but this did not compromise clinical outcomes, according to Hope S. Rugo, MD, Professor of Medicine and Director of Breast Oncology and Clinical Trials at the University of California San Francisco Helen Diller Family Comprehensive Cancer Center. In fact, there was some indication that the occurrence of stomatitis was actually predictive of greater treatment benefit, she noted at the American Society of Clinical Oncology’s 2014 Breast Cancer Symposium. “In this retrospective analysis, stomatitis appeared to be associated with longer progression-free survival [PFS]” in most of the trials, Rugo indicated, though she cautioned that this was an unplanned analysis. “In many patients with stomatitis, we reduced or held doses. We can’t say the outcome is better in patients who got stomatitis, but it’s certainly not worse. It tells us that patients who get stomatitis, even though we hold or reduce doses, have at least the same PFS, and in some patients, stomatitis may be a marker [of prognosis],” Rugo said.

Hope S. Rugo, MD

Meta-Analysis of Key Trials

The relationship between stomatitis and clinical outcomes in patients treated with mTOR inhibitors had not been evaluated prior to this meta-analysis. The study also aimed to assess the incidence, time to occurrence, and severity of stomatitis in patients treated with everolimus. The researchers examined data from 7 randomized, double-blind, phase 3 clinical trials of everolimus in patients with advanced breast cancer (BOLERO-2 and -3), neuroendocrine tumors (RADIANT-2 and -3), renal cell carcinoma (RECORD-1), and tuberous sclerosis complex (EXIST-1 and -2). Altogether, of the 1455 cancer patients treated with everolimus, 67% experienced stomatitis of any grade. A second episode was reported in 40% of

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Through the eyes of an advocate

Global Commitment to Impact Evidence-Based Healthcare Peg Ford

vidence-based healthcare, considered to be the best healthcare in the world, is a premise that many believe has become the norm in the United States. However, there are several reasons why this is not always the case. For example, one traditional standard is the empirical approach of teaching in the medical profession, “see one, do one, teach one,” which is not necessarily based on current best evidence. This method may have been the best available in the past, but as research and medicine are moving more quickly than ever before, healthcare providers need additional tools to keep abreast of advances founded on evidence-based research. Because I am a believer in the importance of evidence-based care, one of my goals was to assist in any way possible as a layperson in effecting change not only in support of evidence-based practice but also toward advancing shared decision making in our healthcare system. Originally, I had no idea striving toward this goal would lead to a global journey. I began by traveling on a fellowship to Salzburg, Austria, in December 2010 to attend the Salzburg Global Seminar Session 477, “The Greatest Untapped Resource in Healthcare: Informing and Involving Patients in Decisions about Their Medical Care.” This effort resulted in an important step toward patients partnering with physicians: “The Salzburg Statement on Shared Decision Making.” What has amazed and delighted me is to see how far and wide this initiative has reached since its publication on February 7, 2011, as shown by ‘googling’ the statement title! My search continued when I became a consumer reviewer for the Cochrane Gynaecological Cancer Group in the United Kingdom. The Cochrane Collaboration (www.cochrane.org) is an inde-

pendent network of healthcare providers, researchers, and patient advocates from over 120 countries working together to produce trustworthy, accessible healthcare information free of industry sponsorship and other conflicts of interest. In addition, after attending the Cochrane Colloquium in Keystone, Colorado, in 2010 as an advocate, I became a member of Consumers United for Evidence-Based Healthcare (CUE) (www.uscochrane.org/CUE). CUE is a national alliance of health and consumer advocacy organizations established in 2003 by the United States Cochrane Center and dedicated to advancing consumers’ ability to engage in and mandate high-quality healthcare. In 2013, I was nominated and elected as CUE’s representative to the Steering Committee for Guidelines International Network/North America (G-I-N/ NA). G-I-N/NA is a regional community representing various stakeholders from Canada, Mexico, and the United States in the Guidelines International Network (www.g-i-n.net). G-I-N/NA is committed to improving the effectiveness, thoroughness, and efficacy of guideline development, adaptation, dissemination, implementation, and performance measurement. As part of this commitment, G-I-N/ NA offers a series of educational webinars, regional training conferences, social media, and special events. The webinars are monthly, except December, and cover vital aspects of guideline development from all facets. In September 2014, I was moderator for the webinar “Involving Consumers in Guideline Development: A Case Study,” which focused on how a G-I-N/NA member organization successfully involved consumer representatives in its development of clinical practice guidelines. The panel represented not only the

member organization’s viewpoint but also the consumers’ perspective and personal experience. In addition, Richard Rosenfeld, MD, MPH, discussed why it is critical to involve consumers in guideline development and how to orient and integrate consumers into the process. Dr Rosenfeld is professor, chairman, and program director of otolaryngology at SUNY Downstate Medical Center; former editor-in-chief of Otolaryngology—Head and Neck Surgery, the official journal of the American Academy of Otolaryngology—Head and Neck Surgery; and chair emeritus of G-I-N/NA. He has also chaired numerous national committees and is the author, coauthor, or editor of 5 books and more than 280 scientific publications and textbook chapters. Dr Rosenfeld has given over 650 scientific presentations and is an international authority on guideline development and evidence-based medicine. I had the pleasure of hearing Dr Rosenfeld’s presentation several years ago in which he encouraged the vital participation of consumers on guideline development. This was long before the current paradigm shift to involve consumers as important stakeholders in medicine and research. I acknowledge Dr Rosenfeld as a visionary and thank him for his efforts! October’s webinar topic was also one of importance to advocates: “Enhancing Shared Decision-Making at the Point of Care: The SHARE-IT Project & MAGICapp.” The focus of this webinar was to provide information on how to overcome challenges by using decision aids that can facilitate shared decision making, particularly when designed to be used in the clinical encounter. The webinar presented the initial success of the SHARE-IT project in applying a new approach for the generic produc-

tion of multilayered and interactive decision aids, directly Peg Ford linked to recommendations in clinical practice guidelines. Additional information can be found by visiting G-I-N/NA at www.g-i-n.net/ regional-communities/g-i-n-na. Topics for January and February 2015 webinars will lead up to the G-I-N/NA conference in March 2015, “Evidence-Based Guidelines Affecting Policy, Practice and Stakeholders (E-GAPPS II): The Challenges of Implementation.” This will be the second such conference cosponsored by G-I-N/NA and the Section on Evidence Based Health Care (SEBHC) of the New York Academy of Medicine. The first was held in December 2012. E-GAPPS II, which is also funded in part by Doctor Evidence, LLC, will be held at the New York Academy of Medicine, New York City, on March 2-3, 2015, and will focus on promoting constructive dialogue in guideline development, dissemination, and implementation. It will be an exciting, timely, and important conference to attend, as all stakeholders, including a strong contingent of consumers and advocates, will participate throughout in keynotes, plenaries, and breakout sessions. Further information and details can be found at http://www.nyam.org/events/2015/evi dence-based-guidelines-conference.html or by contacting ebmny@nyam.org. There is no doubt that an escalation of commitment and emphasis is occurring to overcome any and all challenges to the successful achievement of evidence-based healthcare and participation of consumers in guideline development not only in this country but worldwide. n

enced stomatitis experienced only 1 episode. Regardless of whether a patient experienced 1 or 2 episodes, most were of grade 1 or 2 severity,” Rugo indicated. Dose reductions and interruptions were necessary for approximately one-quarter of patients, usually those with grade 3 or 4 stomatitis. Adjustments were most likely during the breast cancer trials.

patients without this toxicity, was associated with longer PFS in the BOLERO-2 (hazard ratio [HR] = 0.78) and RADIANT-3 (HR = 0.70) trials. A similar trend was observed for the RECORD-1 (HR = 0.90) and RADIANT-2 (HR = 0.87), but not for BOLERO-3, the analysis showed. In BOLERO-2, median PFS was 8.48 months in everolimus-treated patients who developed stomatitis, 6.90 months for patients without stomatitis, and 3.17 months for the control arms. In RADIANT-3, median PFS was 13.86 months, 8.31 months, and 4.60 months, respectively.

Recommendations

She treats stomatitis with steroid mouthwash and is studying the mouthwash as prophylaxis as well. “My personal experience is that you have to stop the drug for grade 2 stomatitis, use the steroids, then restart everolimus with the patient on the mouthwash. Many patients can escalate back up to the same dose. Patient education is also critical,” Rugo said. n

Progression-Free Survival Improved?

Development of stomatitis within 8 weeks of everolimus treatment initiation, compared with everolimus-treated

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“A big issue with everolimus is toxicity. Grade 2 stomatitis is actually very unpleasant. Altogether, about 30% of our breast cancer patients are bothered by this, the majority within the first 6 weeks, but it doesn’t impact efficacy,” Rugo said. “These findings support continuing everolimus with dose adjustments and management according to the approved prescribing information in patients who experience stomatitis,” she said. Rugo recommended checking on patients 2 weeks after the start of treatment, and managing grade 2 or higher toxicity with dose delays or reductions.

Reference

Rugo HS, Yao JC, Pavel M, et al. Stomatitis incidence and its relationship with efficacy: a meta-analysis of everolimus clinical studies. J Clin Oncol. 2014;32(suppl 26):abstract 151. Poster presented at: American Society of Clinical Oncology 2014 Breast Cancer Symposium; September 4-6, 2014; San Francisco, CA.

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NOVEMBER 2014 • VOLUME 5 • NUMBER 2

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OVERVIEW Every day, exciting advances are being made in the field of cancer research and treatment, due to a better understanding of cancer initiation, progression, and response to treatment. In addition, significant technical achievements continue to be made in bioinformatics and genome/proteome analysis, markedly expanding available treatment options and the ability to tailor therapy to individual patients. This trend toward personalized cancer care was reflected in numerous posters and presentations at 2 recent international oncology meetings—the 50th Annual Meeting of the American Society of Clinical Oncology (ASCO) and the 39th European Society for Medical Oncology (ESMO) Congress. This 4-part Faculty Perspectives™ series will provide readers with summaries of pivotal emerging data from ASCO and ESMO 2014 as well as expert perspectives on the application of the data to daily patient care. The first issue in this series discussed recent advances in the management of breast cancer. This issue focuses on the latest advances in the treatment of melanoma, with subsequent supplements covering the topics of non–small-cell lung cancer and colorectal cancer.

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Nursing Continuing Education Global Education Group is accredited as a provider of continuing nursing education by the American Nurses Credentialing Center’s COA. This educational activity for 1 contact hour is provided by Global Education Group. Nurses should claim only the credit commensurate with the extent of their participation in the activity.

Statement of Need/Program Overview The purpose of this activity is to enhance competence of physicians, nurses, and pharmacists concerning the management of patients with solid tumors.

Pharmacist Accreditation Statement Global Education Group is accredited by the Accreditation Council for Pharmacy Education as a provider of continuing pharmacy education.

Educational Objectives After completing this activity, the participant should be better able to: • Assess emerging data from ASCO 2014 and ESMO 2014 on the discovery of molecular biomarkers and their impact on the management of patients with solid tumors • Discuss the advances from ASCO 2014 and ESMO 2014 on the personalized therapy for patients with solid tumors • Outline the practical aspects of integrating molecular biomarkers and emerging targeted agents into everyday clinical practice in the personalized treatment of cancer patients

Credit Designation Global Education Group designates this continuing education activity for 1 contact hour(s) (0.1 CEU) of the Accreditation Council for Pharmacy Education. (Universal Activity Number 0530-9999-14-197-H01-P)

Faculty Sanjiv S. Agarwala, MD Chief of Medical Oncology and Hematology St Luke’s Cancer Center, Bethlehem, PA Professor of Medicine Temple University, Philadelphia, PA

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Amy Schippers, PA-C Physician Assistant, St Luke’s Cancer Center Bethlehem, PA Atheer A. Kaddis, PharmD Senior Vice President, Sales and Business Development Diplomat Specialty Pharmacy, Flint, MI Term of Offering Estimated time to complete activity: 1.0 hour Date of initial release: November 21, 2014 Valid for CME/CPE/CE credit through: November 21, 2015 Physician 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 (ACCME) through the joint providership of Global Education Group (Global) and Center of Excellence Media, LLC. Global is accredited by the ACCME to provide continuing medical education for physicians. Physician Credit Designation Global Education Group designates this enduring material for a maximum of 1.0 AMA PRA Category 1 Credit™. Physicians should claim only the credit commensurate with the extent of their participation in the activity.

This is a knowledge-based activity. For information about the accreditation of this program, please contact Global at 303-395-1782 or inquire@globaleducationgroup.com

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Fee Information & Refund/Cancellation Policy There is no fee for this educational activity. Disclosure of Conflicts of Interest Global Education Group (Global) requires instructors, planners, managers, and other individuals and their spouse/life partner who are in a position to control the content of this 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 vetted by Global for fair balance, scientific objectivity of studies mentioned in the materials or used as the basis for content, and appropriateness of patient care recommendations. The faculty reported the following financial relationships or relationships to products or devices they or their spouse/life partner have with commercial interests related to the content of this CME/CPE/CE activity: Name of Faculty or Presenter Sanjiv S. Agarwala, MD Amy Schippers, PA-C Atheer A. Kaddis, PharmD

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tionships or relationships to products or devices they or their spouse/ life partner have with commercial interests related to the content of this CME/CPE/CE activity: Name of Planner or Manager Reported Financial Relationship Susan Berry Nothing to disclose Andrea Funk Nothing to disclose Sy Schlager Nothing to disclose Amanda Glazar, PhD Nothing to disclose Ashley Marostica, RN, MSN Nothing to disclose Disclosure of Unlabeled Use This educational activity may contain discussion of published and/or investigational uses of agents that are not indicated by the FDA. Global Education Group and Center of Excellence Media, LLC, do not recommend the use of any agent outside of the labeled indications. The opinions expressed in the educational activity are those of the faculty and do not necessarily represent the views of any organization associated with this activity. Please refer to the official prescribing information for each product for discussion of approved indications, contraindications, and warnings. Disclaimer Participants have an implied responsibility to use the newly acquired information to enhance patient outcomes and their own professional development. The information presented in this activity is not meant to serve as a guideline for patient management. Any procedures, medications, or other courses of diagnosis or treatment discussed in this activity should not be used by clinicians without evaluation of patient conditions and possible contraindications on dangers in use, review of any applicable manufacturer’s product information, and comparison with recommendations of other authorities. To obtain a digital version, download a free QR code app on your SmartPhone and then scan this code.

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Updates from ASCO 2014 and ESMO 2014 INTRODUCTION The 50th Annual Meeting of the American Society of Clinical Oncology (ASCO) was held in Chicago, Illinois, May 30–June 3, 2014, and the 39th European Society for Medical Oncology (ESMO) Congress was held in Madrid, Spain, September 26–30, 2014. Both meetings brought together thousands of oncology professionals from a wide range of specialties. This supplement will address important topics in melanoma treatment presented at these meetings. Sanjiv S. Agarwala, MD, of St Luke’s Cancer Center and Temple University; Amy Schippers, PA-C, of St Luke’s Cancer Center; and Atheer A. Kaddis, PharmD, of Diplomat Specialty Pharmacy, after reviewing the presented data, provide their key takehome messages for community oncology practices.

CHECKPOINT INHIBITORS IN MELANOMA

With the advent of targeted agents and immunotherapies, the treatment landscape for patients with melanoma is rapidly evolving. In particular, immune checkpoint inhibitors are demonstrating potent antitumor immune responses, resulting in significant and unprecedented improvements in overall survival (OS) for patients with advanced disease.1 Cytotoxic T-lymphocyte antigen-4 (CTLA-4) and programmed death-1 (PD-1) are nonredundant immune checkpoints in T-cell activation and function that have emerged as promising targets in the treatment of melanoma. Blockade of CTLA-4 and PD-1 pathways appears to augment antitumor T-cell immune responses, providing the rationale for clinical evaluation of novel targeted therapies.2,3 Based on proven efficacy from clinical trials, ipilimumab, a first-in-class attenuator of the inhibitory immune checkpoint CTLA-4, has been approved by the US Food and Drug Administration (FDA) for the treatment of metastatic melanoma.4,5 Ipilimumab showed a

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survival benefit when administered with or without the glycoprotein 100 peptide vaccine compared with vaccine alone (median OS, 10 months and 10.1 months vs 6.4 months, respectively) in patients with previously treated, unresectable, stage III or IV melanoma.5 However, given the incidence of serious immune-related adverse events (AEs) that occurred in the ipilimumab groups, management of toxicities is of concern.5 Several novel immunotherapeutic agents, including those targeting the PD-1/PD-ligand 1 (PD-L1) pathway, are currently under development. Predominant among these are pembrolizumab, a humanized high-affinity antibody that exerts dual PD-L1 blockade, and nivolumab, a fully human anti–PD-1 antibody.6-8 Pembrolizumab in Advanced Melanoma At ASCO 2014, Ribas and colleagues presented results from a pooled analysis of a phase 1 expansion trial (KEYNOTE-001) of 411 patients with advanced melanoma who received pembrolizumab.8 In this nonrandomized

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CONTINUING EDUCATION

Table 1. Efficacy Analyses in the Phase 1 KEYNOTE-001 Trial of Pembrolizumab8-10 Population

ORR, %

Pooled analysis (Ribas et al)

Total cohort, N=411 IPI-N IPI-T

365

168

197

Dose comparison (Hamid et al)

Total cohort, N=276

IPI-N 2 mg/kg q3w

10 mg/kg q3w

2 mg/kg q3w

10 mg/kg q3w

224

IPI-R

Dose comparison (Robert et al)10 Total cohort, N=244 10 mg/kg q3w

107

10 mg/kg q2w

117

10 mg/kg q3w

10 mg/kg q2w

10 mg/kg q3w

10 mg/kg q2w

IPI-N

IPI-T

IPI-N indicates ipilimumab-na誰ve; IPI-R, ipilimumab-refractory; IPI-T, ipilimumab-treated; ORR, overall response rate.

dose-escalation trial, 135 ipilimumab-naive (IPI-N) and IPI-treated (IPI-T) patients received 10 mg/kg q2w, 10 mg/kg q3w, or 2 mg/kg q3w of pembrolizumab to determine the optimal dose and schedule. Based on the results of the KEYNOTE-001 trial, on September 4, 2014, pembrolizumab received accelerated approval from the FDA, at a dose of 2 mg/kg q3w, for the treatment of patients with unresectable or metastatic melanoma and disease progression following other therapies. In the total study population, the incidence of treatment-related grade 3/4 AEs was 12%, with no treatment-related deaths reported. Of interest in this class of agents, immune-mediated AEs were hypothyroidism, hyperthyroidism, pneumonitis, colitis, and hepatitis, which were mostly grade 1/2 in severity. The safety profiles were similar in both the IPI-N and IPI-T patient cohorts.8 In the 365 patients with measurable disease at baseline who were assessed for response, an overall response rate (ORR) by Response Evaluation Criteria in Solid Tumors (RECIST) criteria of 34% was achieved (Table 1).8 The study noted a higher response rate among IPI-N patients compared with IPI-T patients (40% and 28%, respectively). Regarding pembrolizumab dose/schedule, there did not appear to be superiority of any one dose regimen, with doses of 2 mg/kg or 10 mg/kg q3w being equally effective. Most importantly, prolonged durability of responses with this agent has been observed, with 88% of responses ongoing at analysis and median duration of response (DOR) not reached (range, 6+ to 76+ weeks). In the overall population, the median progression-free survival (PFS) was 5.5 months (with a 6-month PFS rate of 45%), whereas the median OS was not reached (with a 1-year OS rate of 69%).8 In addition, Hamid and colleagues presented a more in-depth analysis of the expansion cohort (n=276), in which IPI-N (n=103) and ipilumumab-refractory (IPI-R) (n=173) patients were randomized to the 2 pembrolizumab dose cohorts of 2 mg/kg or 10 mg/kg q3w.9 The median follow-up was 12 months for IPI-N and 8 months for IPI-R patient cohorts. Their findings were consistent with the conclusions of the pooled analysis: there were no significant differences in ORR by RECIST criteria between pembrolizumab 2 mg/kg and 10 mg/kg q3w in the IPI-N group (33% vs 40%,

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respectively) or the IPI-R group (26% vs 26%; Table 1). Furthermore, the responses achieved were long-lasting in both dose cohorts: median DOR was not reached for either cohort by study cutoff, and the DORs ranged from 6+ weeks to 39+ weeks. There were no differences noted in 24-week PFS rates (by RECIST criteria) between the 2 doses in the IPI-N (48% vs 50%) and IPI-R (37% vs 44%) patient groups. The 1-year OS rates were 68% and 60% in the IPI-N and IPI-R patient cohorts, respectively. The safety analysis showed that grade 3/5 treatment-related AEs were higher in the 2-mg/kg dose cohort compared with the 10-mg/kg dose cohort in both IPI-N (22% vs 2%) and IPI-R (15% vs 8%) patients. However, treatment-related AEs leading to discontinuation were nonexistent or minimal in the 2 patient groups. The immune-mediated AEs observed were similar to those reported in the pooled analysis. Perspectives The impressive results from this large phase 1 effort led to FDA approval of a drug that is, by all parameters, a breakthrough in the treatment of melanoma. While results from randomized trials are still awaited, the consistent and high response rate and minimal toxicity associated with pembrolizumab convinced the regulators to proceed with approval. Although response rates are higher in IPI-N patients, robust efficacy is seen in IPI-R patients as well. When data from randomized frontline trials become available, it is likely that pembrolizumab will be indicated in this setting as well. Until then, clinicians will need to use ipilimumab first when prescribing immunotherapy. -Sanjiv S. Agarwala, MD The results of this study are impressive and encouraging for the melanoma community as it will allow providers more options for treatment. Hopefully, pembrolizumab will eventually be available as a frontline therapy, offering patients less toxicity and promising results. From a mid-level perspective, I feel that the PD-1 pathway inhibitors will make a great impact on how we treat patients in the future. Ipilimumab has also been an effective drug, although many patients have difficulty tolerating it, leading to diminished quality of life. -Amy Schippers, PA-C It is exciting to see such positive results in the management of advanced melanoma, which is typically very difficult to treat. Focusing on a new approach to treat this disease, the PD-1 pathway inhibitors may offer a more effective option compared with the standard of care being used today. It is also encouraging to see that the lowest dose of pembrolizumab used in the dose-ranging study was equally effective compared with higher doses and that there were minimal or nonexistent discontinuations due to treatment-related AEs. -Atheer A. Kaddis, PharmD

At ESMO 2014, Robert and colleagues presented efficacy and safety data on pembrolizumab from 2 additional dose-expansion cohorts (N=244), specifically, 10 mg/kg q3w (n=121) and 10 mg/kg q2w (n=123).10 A safety analysis showed that treatment-related AEs were similar between the 2 dose cohorts and were consistent with previous reports. In terms of efficacy, at a median follow-up of 42.3 weeks, a higher percentage of evaluable patients in the q3w cohort versus the q2w cohort achieved a decrease in target lesion size compared with baseline (70% vs 57%). In the total population, ORR by RECIST criteria was 33%; there were no significant differences in ORR between the 2 dose schedules or based on prior ipilimumab use (Table 1).10 Moreover, there were no between-schedule differences in PFS reported; median PFS was 13.1 weeks and 22.6 weeks in the q3w and q2w cohorts, respectively. Taken together, the findings from the KEYNOTE-001 trial support the use of the recently approved dose and schedule of pembrolizumab 2 mg/kg q3w in patients with advanced melanoma. Perspective Importantly, this analysis also indicates the similarity of benefit of pem-

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FACULTY PERSPECTIVES brolizumab in these 2 dose-expansion cohorts. It appears that the efficacy of this agent does not vary significantly among the doses and schedules tested. Currently, the approved dose of pembrolizumab is 2 mg/kg q3w for up to 2 years or until disease progression. -Sanjiv S. Agarwala, MD

Table 2. Survival End Points for Patients Treated with Nivolumab in the Phase 1 CA209-003 Trial11,12 Nivolumab Dose All doses

Pilot Study of Nivolumab in Advanced Melanoma A large phase 1 study (CA209-003) evaluated the safety, antitumor activity, and immune correlates of the fully human anti–PD-1 antibody nivolumab in patients with solid tumors.6 In this dose-escalation trial, 107 previously treated patients (1-5 prior therapies) with advanced melanoma but with no prior ipilimumab therapy were assigned to 5 dose levels of nivolumab ranging from 0.1 mg/kg to 10 mg/kg q2w.11 The study was amended to collect OS data, conduct subgroup analyses of response based on patient prognostic features, and perform exploratory PD-L1 analyses.11 At both ASCO and ESMO 2014, updated data were presented on the long-term survival, clinical activity, DOR off-therapy, and correlative studies with tumor PD-L1 ligand expression in IPI-N patients with advanced melanoma who were treated with nivolumab.11,12 At a median follow-up of 22 months, there were no new safety signals reported; predominant AEs were the same as previously described, and included those relating to skin, gastrointestinal, endocrine, and hepatic toxicities. Across all 5 dosing cohorts, the ORR by RECIST criteria was 32%, median PFS was 3.7 months, and median OS was 17.3 months. In particular, the clinical outcomes were significantly better in patients who received the 3-mg/kg q2w dose (ORR: 41%; median PFS: 9.7 months; median OS: 20.3 months) (Table 2), which was consequently selected for phase 3 studies. In the 34 responders, the median DOR was 99.4 weeks; 19 responses (56%) were ongoing at the time of analysis. In addition, 52% of responding patients who discontinued therapy for reasons other than progressive disease continued to show a response for ≥24 weeks. The 1-, 2-, and 3-year OS rates associated with nivolumab therapy were 63%, 48%, and 41%, respectively.11,12 Moreover, survival outcomes were correlated with the type of responses achieved and by PD-L1 expression status. Preliminary analyses indicated that patients who achieved immune-related–type responses can have similar outcomes as those with conventional RECIST responses. Although the responses were higher in patients with positive PD-L1 expression, based on 1% and 5% staining cutoff for PD-L1 tumor membrane staining, it was remarkable that responses were still noted even in patients with negative PD-L1 expression. In a subset of 41 patients with available tumor samples, median OS was not reached and 12.5 months for the patients who had PD-L1–positive (n=18) and PD-L1–negative (n=23) tumors; median PFS was 9.1 and 1.9 months, respectively.12 Perspectives Nivolumab is another anti–PD-1 antibody with impressive activity in melanoma, as shown by this analysis. Response rates appear to be similar to those obtained with pembrolizumab and there is a similar (low) toxicity profile. According to these results, the appropriate dose of this agent is 3 mg/kg q2w, which is different from the approved schedule and dose of pembrolizumab. Other important findings from this analysis are the similarity of benefit whether RECIST or immune criteria are used for response and outcome, and the lack of definitive correlation between PD-L1 expression and clinical benefit. -Sanjiv S. Agarwala, MD

Again, we see that the use of nivolumab has led to better responses in patients with melanoma. This drug has shown to be effective in decreasing the patient’s disease burden while maintaining a good side effect profile. It would be interesting to compare nivolumab with pembrolizumab in a head-to-head trial to determine whether one agent is more effective than the other. Both of these drugs are having a positive impact on how we treat advanced melanoma. -Amy Schippers, PA-C

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ORR, %

Median PFS, months

Median OS, months

3.7

17.3

0.1 mg/kg

3.6

16.2

0.3 mg/kg

1.9

12.5

1 mg/kg

9.1

43.1

3 mg/kg

9.7

20.3

10 mg/kg

3.7

11.7

PFS indicates progression-free survival; ORR, overall response rate; OS, overall survival.

Nivolumab Versus Investigator’s Choice of Chemotherapy in Advanced Melanoma Based on the encouraging activity of nivolumab monotherapy in advanced melanoma, the randomized, open-label, phase 3 CA209-037 trial evaluated nivolumab versus investigator’s choice of chemotherapy (ICC) in 405 patients with advanced melanoma who had progressed despite prior therapies directed against CTLA-4 or BRAF.13 Patients meeting eligibility criteria were randomized to receive nivolumab 3 mg/kg q2w (n=268) or ICC (dacarbazine 1000 mg/m2 q3w, or carboplatin AUC 6 + paclitaxel 175 mg/m2 q3w; n=102) until disease progression or unacceptable toxicity. For the BRAF wild-type patients to be eligible, they must have progressed following treatment with ipilimumab, whereas those with BRAF V600 mutations must have progressed on both ipilimumab and a BRAF inhibitor. For the coprimary end point of ORR by central review using RECIST criteria, 120 nivolumab-treated patients and 47 ICC-treated patients were included in the interim analysis. Results showed that a higher ORR was achieved in patients receiving nivolumab compared with those who received ICC (32% vs 11%). The median time to response in the nivolumab and ICC groups was 2.1 months and 3.5 months, respectively. The median DOR was not reached in the nivolumab group (range, 1.4+, 10+ months); in the group receiving ICC, the median DOR was 3.6 months (range, 1.3+, 3.5+ months). Notably, 36 of the 38 responses (95%) achieved with nivolumab therapy are still ongoing; ≥50% reduction in target lesion burden occurred in 82% (31/38) of nivolumab responders and 60% (3/5) of ICC responders. Immune-related response patterns and a ≥30% reduction in target lesion tumor burden were reported in an additional 10 (8.3%) of 120 nivolumab-treated patients.13 The safety profile of nivolumab was consistent with that previously described and included all treated patients. Grade 3/4 treatment-related AEs were reported in 9% of nivolumab patients compared with 31% of patients treated with ICC. Discontinuations due to any grade treatment-related AEs occurred in 2.2% of nivolumab patients and 7.8% of patients treated with ICC. Perspectives Not surprisingly, results from this phase 3 randomized trial showed superiority of nivolumab monotherapy compared with chemotherapy in patients who were refractory to anti–CTLA-4 or anti-BRAF therapy. FDA approval of nivolumab in this setting is expected soon, which will provide clinicians with a choice between pembrolizumab and nivolumab in this setting. -Sanjiv S. Agarwala, MD Persistence on therapy is an important factor related to ORRs for patients with advanced melanoma. Therefore, in addition to the impressive efficacy associated with the use of nivolumab in this study was the fact that patients treated with this drug experienced significantly fewer grade 3/4 AEs and were less likely to discontinue therapy compared with those who were treated with chemotherapy. -Atheer A. Kaddis, PharmD

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CONTINUING EDUCATION

Figure. Treatment response with nivolumab plus ipilimumab15

40%

Total concurrent cohorts (1-3) 21%

Cohort 1 (0.3 + 3 mg/kg)

47%

Cohort 2 (1 + 3 mg/kg)

50%

Cohort 2a (3 + 1 mg/kg) 33%

Cohort 3 (3 + 3 mg/kg)

43%

Cohort 8 (1 + 3 mg/kg)

41%

Sequenced Cohort

Overall Response Rate (%)

Combination Immunotherapies in Advanced Melanoma Results of a phase 1 study that evaluated concurrent and sequential treatment of nivolumab and ipilimumab were presented at ASCO and ESMO 2014.14,15 There were 5 concurrent cohorts; patients in cohort 1, 2, 2a, and 3 (n=53) received concurrent nivolumab (0.3, 1.0, or 3.0 mg/kg) q3w for 8 cycles plus ipilimumab (1.0 or 3.0 mg/kg) q3w for 4 cycles as induction, followed by maintenance therapy with both agents every 12 weeks for 8 doses, if patients had no progression by immune-related criteria and no dose-limiting toxicities. Patients in cohort 8 (n=41) received nivolumab 1 mg/kg plus ipilimumab 3 mg/kg at the same induction schedule as cohorts 1 to 3, and nivolumab 3 mg/kg q2w for up to 48 doses as maintenance treatment. In addition, there were 2 sequenced cohorts (n=33) where patients received nivolumab (1 or 3 mg/kg q2w) for up to 48 doses following failure of ipilimumab induction therapy (4-12 weeks after last ipilimumab dose). At ESMO 2014, Kluger and colleagues reported that patients in the initial concurrent cohorts 1 to 3 achieved an ORR of 40% by RECIST criteria (Figure),15 including a complete response (CR) rate of 17%, which is higher than those reported in the previous analysis.16 Patients in cohort 8 achieved an ORR of 43%15 and a CR rate of 10%. Tumor reduction of ≥80% by week 36 was 42% in the concurrent cohorts 1 to 3, 53% in cohort 2, 28% in cohort 8, and 34% in the sequenced cohorts. Aggregate clinical activity rate that includes unconventional responses, which are increasingly being reported with this class of agents, was 49% in cohorts 1 to 3. In comparison, patients in the sequenced cohorts achieved an ORR of 41%15 and a CR rate of 6%. In the concurrent cohorts 1 to 3, the 1- and 2-year OS rates were 85% and 79%, respectively. Cohort 2, with nivolumab 1 mg/kg and ipilimumab 3 mg/kg, was associated with 1- and 2-year OS rates of 94% and 88%, respectively, which is the dose/schedule being evaluated in phase 3 studies. In the sequenced cohorts, the 1-year OS was lower (70%), and was thought to be partly attributable to residual levels of plasma ipilimumab. In all of the concurrent cohorts (n=94), the rate of grade 3/4 AEs with concurrent use of nivolumab and ipilimumab was 64%; the majority of these were biochemical laboratory abnormalities including elevations in lipase (15%), alanine transaminase (12%), and aspartate transaminase (11%). Grade 3/4 AEs reported in all concurrent cohorts included gastrointestinal (14%), hepatic (14%), skin (9%), endocrine (3%), renal (3%), and pulmonary (2%) toxicities; 1 treatment-related death was reported due to sepsis in the setting of colitis. Perspective Although impressive response rates and durability are observed with the combination of nivolumab and ipilimumab, toxicity is considerable, with grade 3 and 4 AEs occurring in 64% of patients, albeit mostly biochemical. Randomized trials showing convincing superiority of this combination over single-agent anti–PD-1 therapy are going to be necessary before this ap-

proach can be recommended. Accrual to these trials has been completed and results are awaited with interest. -Sanjiv S. Agarwala, MD

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Ipilimumab as Adjuvant Therapy in Stage III Melanoma There is an unmet need for effective agents in the adjuvant treatment of patients with stage III melanoma who are at high risk for relapse. It has been estimated that the 5-year risk of relapse rates are 71% for stage IIIB and 85% for stage IIIC patients.17 The European Organisation for Research and Treatment of Cancer 18071 trial was initiated to assess the efficacy and safety of ipilimumab, a drug that has demonstrated survival benefit in advanced disease, as adjuvant therapy in patients with stage IIIA, B, or C melanoma who had a complete resection. Eggermont and colleagues presented results from this large, randomized, double-blind trial at ASCO and ESMO 2014.18,19 In this trial, 951 patients were randomized to receive ipilimumab 10 mg/kg (n=475) or placebo q3w (n=476) for 4 doses (induction), then every 3 months for up to 3 years until completion, disease recurrence, or unacceptable toxicity (maintenance). The primary end point was recurrence-free survival (RFS); secondary end points included OS and distant metastasis-free survival. At a median follow-up of 2.7 years, there was a significant prolongation of RFS with ipilimumab therapy compared with placebo (26.1 months vs 17.1 months), with a 25% reduction in risk of recurrence (hazard ratio [HR], 0.75; P=.0013). The mean 3-year RFS rates were 46.5% and 34.8% for the ipilimumab and placebo cohorts, respectively. Improvement in RFS was achieved for all patient subgroups assessed, including stages IIIA/IIIB/IIIC, microscopic or macroscopic lymph nodes, and with or without an ulcerated primary lesion. In particular, post-hoc analysis showed that the RFS benefit of ipilimumab therapy was higher in patients with microscopic disease than in those with palpable nodes (57.6% vs 37.8%; HR, 0.65; P=.004). Grade 3/4 immune-related AEs reported with ipilimumab therapy were 42% versus 2.5% with placebo; these included gastrointestinal events such as diarrhea and colitis (16% vs 0.8%), hepatic toxicity (10.7% vs 0.2%), and endocrinopathies such as hypophysitis and hypothyroidism (8.5% vs 0%). There were 5 treatment-related fatalities, including 3 patients with colitis (2 with gastrointestinal perforations), 1 with myocarditis, and 1 with GuillainBarre syndrome. Treatment discontinuation due to treatment-related AEs was higher with ipilimumab therapy than with placebo (48.8% vs 1.7%). Health-related quality-of-life assessment showed no clinically significant differences (≥10 points) between treatment arms in mean scores for global health status at any time. Perspectives This trial met its primary end point of improvement in RFS for ipilimumab over placebo. However, the dose used was 10 mg/kg, compared with the standard 3-mg/kg dose currently approved for the treatment of patients with advanced melanoma. Toxicity was considerable, with an unacceptable 5 treatment-related deaths. The use of adjuvant ipilimumab therapy will likely need to wait until results from the Eastern Cooperative Oncology Group (ECOG) 1609 trial20 become available, in which high-risk patients were randomized to either ipilimumab at 10 or 3 mg/kg or highdose interferon. -Sanjiv S. Agarwala, MD Results from this trial demonstrate that ipilimumab is an effective drug in the adjuvant setting. However, I agree that we need to wait for the results of the ECOG 1609 study.20 Patients who received ipilimumab at a dose of 10 mg/kg experienced significant toxicity compared with a standard dose, which can lead to noncompliance. In the adjuvant setting, we want to ensure that the patient continues to have good quality of life while reaping the benefits of treatment. -Amy Schippers, PA-C

NOVEL COMBINATION THERAPIES IN ADVANCED MELANOMA

Activating BRAF mutations are major drivers of the pathogenesis of cu-

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FACULTY PERSPECTIVES taneous melanoma, leading to constitutive activation of the mitogen-activated protein kinase (MAPK) pathway and promoting cellular proliferation, survival, and invasion.21 Selective pharmacologic inhibition of the BRAF mutational variants has demonstrated significant clinical efficacy in melanoma.21 Vemurafenib, a BRAF inhibitor that specifically targets the V600E or V600K BRAF mutations, is approved for patients with advanced melanoma in this setting. However, the responses achieved with BRAF inhibition alone are not durable and are associated with hyperproliferative skin toxicities such as cutaneous squamous cell carcinoma (cuSCC) and keratoacanthoma.21 It has been hypothesized that reactivation of components of the MAPK pathway contributes to the observed resistance to BRAF kinase inhibitors, and that inhibition of both BRAF and other downstream effectors of the pathway, such as MEK, may attenuate the oncogenic potential of this pathway, thus preventing or delaying the onset of BRAF inhibitor resistance. Based on this rationale, the combination of BRAF and MEK inhibitors is being clinically evaluated in melanoma. Therefore, the BRAF inhibitors dabrafenib and vemurafenib, as well as the MEK inhibitors trametinib and cobimetinib, were assessed as combination therapy in advanced melanoma, and have shown promising activity in early trials.22-24 A phase 1/2 trial of combined treatment with dabrafenib and trametinib was conducted by Flaherty and colleagues. Evaluable phase 2 patients (n=162) were randomized in 1:1:1 fashion to receive either 150 mg of dabrafenib twice daily plus once-daily trametinib 1 mg (combination 150/1) or 2 mg (combination 150/2), or 150 mg of dabrafenib monotherapy twice daily. Results showed that combination 150/2 significantly improved ORR compared with dabrafenib monotherapy (76% vs 54%; P=.03). Median PFS was 9.4 months vs 5.8 months, respectively. In addition, a reduction in hyperproliferative skin toxicities was observed with combination therapy compared with dabrafenib alone.22 Updated analysis of the survival data presented at ASCO 2014 confirmed these results, with a median OS of 25.0 months reported for the 150/2 combination versus 20.2 months reported for dabrafenib monotherapy.23 The results of this study led to the approval of dabrafenib plus trametinib combination therapy in January 2014 in the United States for patients with metastatic melanoma. A phase 1b study of 129 patients with advanced BRAF V600â&#x20AC;&#x201C;mutated melanoma demonstrated that combined therapy with vemurafenib plus cobimetinib at maximum tolerated doses was well tolerated. Among 66 patients who had recently progressed on vemurafenib, combination therapy resulted in an ORR of 15% and a median PFS of 2.8 months.24 Patients who had never received a BRAF inhibitor (n=63) achieved an ORR of 87% and a median PFS of 13.7 months. Frontline Dabrafenib Plus Trametinib Versus Dabrafenib Plus Placebo in BRAF V600E/K Mutation-Positive Melanoma At ASCO 2014, Long and colleagues presented results of the COMBI-d study, a randomized, double-blind, placebo-controlled phase 3 trial that was conducted to confirm the superiority of dabrafenib plus trametinib versus dabrafenib plus placebo as frontline therapy in patients with unresectable or metastatic BRAF V600E/K mutation-positive melanoma.25 In this study, 423 BRAF mutation-positive patients were randomized to receive dabrafenib 150 mg twice daily plus either trametinib 2 mg/day or placebo; the primary end point was investigator-assessed PFS. At a median follow-up of 9 months, there was a 25% reduction in the risk of progression when patients were treated with the combination of dabrafenib plus trametinib compared with dabrafenib plus placebo, which was statistically significant (HR for investigator-assessed PFS, 0.75; P=.035). Although the study end points were met, the improvement in median PFS was very modest, from 8.8 months with placebo to 9.3 months with the combination therapy. The investigators hypothesized that unequal censoring at the beginning of the trial (majority due to clinical progression or commencing anticancer therapy) and the aligning of the plateau of the dabrafenib Kaplan-Meier curve at the median for PFS might have contributed to the apparent modest median PFS. Moreover, in preplanned sensitivity analysis that included clinical progressors and patients who started anticancer therapy, the median PFS for dabrafenib was 7.6 months and 7.2 months, respectively.25 Patients treated with dabrafenib plus trametinib combination therapy also achieved higher ORR compared with dabrafenib plus placebo (67% vs 51%,

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respectively; P=.0015), although the CR rates achieved were similar (10% vs 9%). At the interim analysis of 9 months, a significant improvement in OS was also achieved with dabrafenib plus trametinib combination therapy compared with dabrafenib alone, with an HR of 0.63 favoring the combination therapy (P=.023). It is notable that a higher number of patients died on the dabrafenib arm versus the combination arm (55 vs 40).25 The AE rates, both all grades and grade 3/4, were similar between the 2 treatment groups. Common toxicities in the combination arm included pyrexia, which occurred more frequently (51% vs 28%) and with higher severity (grade 3, 6% vs 2%) in patients who received combination therapy versus those who received dabrafenib alone. The incidence of BRAF inhibitor-related AEs such as cuSCC (2% vs 9%), hyperkeratosis (3% vs 32%), skin papilloma (1% vs 21%), hand-foot syndrome (5% vs 27%), and alopecia (7% vs 26%) were lower in the combination arm. Conversely, the MEK inhibitor-related AEs such as diarrhea, hypertension, and rash were higher in the combination arm. A higher percentage of patients required dose modifications due to AEs in the combination arm compared with the dabrafenib arm. Common grade 3/4 AEs were cuSCC (9%), increased alkaline phosphatase levels (9%), and anemia (7%).25

The responses achieved with BRAF inhibition alone are not durable and are associated with hyperproliferative skin toxicities such as cutaneous squamous cell carcinoma and keratoacanthoma. Frontline Dabrafenib Plus Trametinib Versus Vemurafenib in BRAF V600E/K Mutation-Positive Melanoma To further establish the superiority of the BRAF plus MEK inhibition over BRAF inhibition alone, the randomized, double-blind phase 3 COMBI-v trial compared frontline treatment with dabrafenib plus trametinib therapy versus vemurafenib alone in patients with unresectable or metastatic BRAF V600E/K mutation-positive melanoma. In this trial, 704 eligible patients were randomized 1:1 to receive either dabrafenib 150 mg BID plus trametinib 2 mg QD or vemurafenib 960 mg BID as first-line therapy. Results were reported by Robert and colleagues at ESMO 2014.26 A prespecified interim OS analysis was performed when 77% of the total number of expected deaths required for the protocol-specified final analysis was observed; it was prespecified that the study could be stopped for efficacy if the one-sided P value was <.0107. The OS analysis showed that treatment with dabrafenib plus trametinib resulted in a significant prolongation of median OS (not reached) compared with vemurafenib monotherapy (17.2 months), and was associated with a 31% reduction in the risk of death (HR, 0.69; P=.005). The Independent Data Monitoring Committee recommended stopping the study based on the demonstration of this OS benefit, which crossed the prespecified efficacy stopping boundary for dabrafenib plus trametinib combination therapy. The improvement in PFS (11.4 months vs 7.3 months; HR, 0.56; P<.001) and ORR (P<.001) also favored the dabrafenib plus trametinib arm compared with vemurafenib alone; DOR was 13.8 months and 7.5 months, respectively.26 Although AE rates were generally similar in both arms and consistent with previous reports, the incidence of grade 3 arthralgias, rash, alopecia, hyperkeratosis, photosensitivity, and skin papilloma were higher in vemurafenib-treated patients, whereas grade 3 pyrexia was higher in the combination therapy cohort.26 Frontline Dabrafenib Plus Vemurafenib Plus Cobimetinib Plus Placebo in BRAF V600E/K Mutation-Positive Melanoma In the same first-line setting of unresectable advanced or metastatic BRAF V600E/K mutation-positive melanoma, McArthur and colleagues conducted a randomized placebo-controlled phase 3 coBRIM trial that evaluated first-line vemurafenib plus cobimetinib compared with vemurafenib therapy. Results were presented at ESMO 2014 and simultaneously published in the New England Journal of Medicine.27,28 In this trial, 495 patients were randomized 1:1 to receive either vemurafenib 960 mg BID plus cobimetinib 60 mg

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CONTINUING EDUCATION daily (combination group) or vemurafenib plus placebo (control group) in a 28-day treatment cycle. In the intent-to-treat population, a significant prolongation of median PFS was observed in the combination group compared with the control group (9.9 months vs 6.2 months, respectively; HR, 0.51; P<.001), and a 49% reduction in the risk of progression. The ORR was also significantly higher in the combination arm compared with control (68% vs 45%; P<.001), including a higher rate of CRs (10% vs 4%). The PFS benefits also extended to different patient subgroups analyzed. Interim OS analysis showed that the combination therapy was associated with a 9-month OS rate of 81%, compared with 73% with vemurafenib and placebo, and a 35% reduction in the risk of death (HR, 0.65; P=.046), which did not cross the prespecified stopping boundary. In terms of safety, patients who received vemurafenib plus cobimetinib combination therapy experienced a higher incidence of grade 3/4 AEs than those in the control group (62% vs 58%); however, treatment discontinuations due to drug-related AEs were similar between the 2 cohorts. There was a higher rate of serious retinopathy, gastrointestinal events, photosensitivity, and laboratory abnormalities in the vemurafenib plus cobimetinib arm compared with control, the majority of which were grade 1/2 severity. In addition, the incidence of secondary cutaneous neoplasms was lower with combination therapy (2%) compared with vemurafenib alone (11%).27,28 Perspectives These 3 trials taken in aggregate show the superiority of combination anti-BRAF and anti-MEK therapy compared with anti-BRAF therapy alone in patients with advanced melanoma who harbor the BRAF mutation. The combination of dabrafenib and trametinib is already approved in the United States, and it is expected that, based on the results of the coBRIM trial, the combination of vemurafenib and cobimetinib will follow suit. The superior efficacy in response rates and survival—coupled with a generally lower toxicity profile than that of either agent alone—makes this a winning combination and the standard of care for front-line therapy for patients with BRAF-mutated melanoma, when targeted therapy is selected. The question of which sequence to use—targeted therapy followed by immunotherapy or the other way around—must await the conduct of planned randomized trials; until then, clinicians must continue to use disease burden, symptoms, and aggressiveness of disease as decision factors. -Sanjiv S. Agarwala, MD The findings from these 3 trials thoroughly demonstrate how effective the anti-BRAF and -MEK combination is in patients who have advanced melanoma. Using this combination in patients with the BRAF mutation has decreased toxicity while providing excellent response rates. Although clinical trials are ongoing, the United States will hopefully be approving more of these combinations to provide additional treatment options for providers and patients. -Amy Schippers, PA-C The results from the 3 trials described above demonstrate the advantages of combining dabrafenib with trametinib in the treatment of patients with advanced melanoma. As clinicians, we must ensure that patients who are prescribed combination regimens remain adherent to therapy. Given the short-term response to single pathway inhibition in advanced melanoma, it is clear that complementary pathway inhibition with agents such as these is preferred. -Atheer A. Kaddis, PharmD

References 1. McDermott D, Lebbe C, Hodi FS, et al. Durable benefit and the potential for long-term survival with immunotherapy in advanced melanoma. Cancer Treat Rev. 2014;40:1056-1064. 2. Fong L, Small EJ. Anti–cytotoxic T-lymphocyte antigen-4 antibody: the first in an emerging class of immunomodulatory antibodies for cancer treatment. J Clin Oncol. 2008;26:5275-5283. 3. Dolan DE, Gupta S. PD-1 pathway inhibitors: changing the landscape of cancer immunotherapy. Cancer Control. 2014;21:231-237.

4. Wolchok JD, Weber JS, Maio M, et al. Four-year survival rates for patients with metastatic melanoma who received ipilimumab in phase II clinical trials. Ann Oncol. 2013;24: 2174-2180. 5. Hodi FS, O’Day SJ, McDermott DF, et al. Improved survival with ipilimumab in patients with metastatic melanoma. N Engl J Med. 2010;363:711-723. 6. Topalian SL, Hodi FS, Brahmer JR, et al. Safety, activity, and immune correlates of anti–PD-1 antibody in cancer. N Engl J Med. 2012;366:2443-2454. 7. Topalian SL, Sznol M, McDermott DF, et al. Survival, durable tumor remission, and longterm safety in patients with advanced melanoma receiving nivolumab. J Clin Oncol. 2014;32: 1020-1030. 8. Ribas A, Hodi S, Keddord R, et al. Efficacy and safety of the anti-PD-1 monoclonal antibody MK-3475 in 411 patients (pts) with melanoma (MEL). J Clin Oncol (ASCO Annual Meeting Abstracts). 2014;32(suppl):Abstract LBA9000^. 9. Hamid O, Robert C, Ribas A, et al. Randomized comparison of two doses of the anti–PD-1 monoclonal antibody MK-3475 for ipilimumab-refractory (IPI-R) and IPI-naive (IPI-N) melanoma (MEL). J Clin Oncol (ASCO Annual Meeting Abstracts). 2014;32(suppl):Abstract 3000. 10. Robert C, Joshua AM, Weber J, et al. Pembrolizumab (pembro; MK-3475) for advanced melanoma (MEL): randomized comparison of two dosing schedules. Ann Oncol (ESMO Annual Meeting Abstracts). 2014;25(suppl 5):Abstract LBA34. 11. Hodi FS, Sznol M, Kluger HM, et al. Long-term survival of ipilimumab-naive patients (pts) with advanced melanoma (MEL) treated with nivolumab (anti-PD-1, BMS-936558, ONO4538) in a phase I trial. J Clin Oncol (ASCO Annual Meeting Abstracts). 2014;32(suppl): Abstract 9002. 12. McDermott D, Kluger H, Sznol M, et al. Long-term survival of ipilimumab-naïve patients (pts) with advanced melanoma (MEL) treated with nivolumab (anti–PD-1; BMS-936558, ONO-4538) in a phase 1 trial. Ann Oncol (ESMO Annual Meeting Abstracts). 2014;25(suppl 5):Abstract 1088PD. 13. Weber JS, Minor DR, D’Angelo SP, et al. A phase 3 randomized, open-label study of nivolumab (anti-PD-1; BMS-936558; ONO-4538) versus investigator’s choice chemotherapy (ICC) in patients with advanced melanoma after prior anti-CTLA-4 therapy. Ann Oncol (ESMO Annual Meeting Abstracts). 2014;25(suppl 5):Abstract LBA3_PR. 14. Sznol M, Kluger HM, Callahan MK, et al. Survival, response duration, and activity by BRAF mutation (MT) status of nivolumab (NIVO, anti-PD-1, BMS-936558, ONO-4538) and ipilimumab (IPI) concurrent therapy in advanced melanoma (MEL). J Clin Oncol (ASCO Annual Meeting Abstracts). 2014;32(suppl):Abstract LBA9003^. 15. Kluger H, Sznol M, Callahan M, et al. Survival, response duration, and activity by BRAF mutation (MT) status in a phase 1 trial of nivolumab (anti-PD-1, BMS-936558, ONO-4538) and ipilimumab (IPI) concurrent or sequenced therapy in advanced melanoma (MEL). Ann Oncol (ESMO Annual Meeting Abstracts). 2014;25(suppl 5):Abstract 10850. 16. Wolchok JD, Kluger H, Callahan MK, et al. Nivolumab plus ipilimumab in advanced melanoma. N Engl J Med. 2013;369:122-133. 17. Romano E, Scordo M, Dusza SW, et al. Site and timing of first relapse in stage III melanoma patients: implications for follow-up guidelines. J Clin Oncol. 2010;28:3042-3047. 18. Eggermont AM, Chiarion-Sileni V, Grob JJ, et al. Ipilimumab versus placebo after complete resection of stage III melanoma: initial efficacy and safety results from the EORTC 18071 phase III trial. J Clin Oncol (ASCO Annual Meeting Abstracts). 2014;32(suppl):Abstract LBA9008. 19. Eggermont AM, Grob J, Wolchok J, et al. Efficacy, safety, and quality of life (QoL) data from the EORTC 18071 phase III trial of ipilimumab (Ipi) versus placebo after complete resection of stage III melanoma. Ann Oncol (ESMO Annual Meeting Abstracts). 2014;25(suppl 5): Abstract 7029. 20. ClinicalTrials.gov. Ipilimumab or high-dose interferon alfa-2b in treating patients with highrisk stage III-IV melanoma that has been removed by surgery. http://clinicaltrials.gov/show/ NCT01274338. Accessed October 21, 2014. 21. Khattak M, Fisher R, Turajlic S, et al. Targeted therapy and immunotherapy in advanced melanoma: an evolving paradigm. Ther Adv Med Oncol. 2013;5:105-118. 22. Flaherty KT, Infante JR, Daud A, et al. Combined BRAF and MEK inhibition in melanoma with BRAF V600 mutations. N Engl J Med. 2012;367:1694-1703. 23. Flaherty KT, Daud A, Weber JS, et al. Updated overall survival (OS) for BRF113220, a phase 1-2 study of dabrafenib (D) alone versus combined dabrafenib and trametinib (D+T) in pts with BRAF V600 mutation-positive (+) metastatic melanoma (MM). J Clin Oncol (ASCO Annual Meeting Abstracts). 2014;32(suppl):Abstract 9010^. 24. Ribas A, Gonzalez R, Pavlick A, et al. Combination of vemurafenib and cobimetinib in patients with advanced BRAF(V600)-mutated melanoma: a phase 1b study. Lancet Oncol. 2014; 15:954-965. 25. Long GV, Stroyakovsky DL, Gogas H, et al. COMBI-d: a randomized, double-blinded, phase III study comparing the combination of dabrafenib and trametinib to dabrafenib and trametinib placebo as first-line therapy in patients (pts) with unresectable or metastatic BRAFV600E/K mutation-positive cutaneous melanoma. J Clin Oncol (ASCO Annual Meeting Abstracts). 2014;32(suppl):Abstract 9011^. 26. Robert C, Karaszewska B, Schachter J, et al. COMBI-v: a randomised, open-label, phase III study comparing the combination of dabrafenib (D) and trametinib (T) with vemurafenib (V) as first-line therapy in patients (pts) with unresectable or metastatic BRAF V600E/K mutation-positive cutaneous melanoma. Ann Oncol (ESMO Annual Meeting Abstracts). 2014;25 (suppl 5):Abstract LBA4_PR. 27. McArthur G, Ascierto P, Larkin J, et al. Phase 3, double-blind, placebo-controlled study of vemurafenib versus vemurafenib + cobimetinib in previously untreated BRAFV600 mutationpositive patients with unresectable locally advanced or metastatic melanoma (NCT01689519). Ann Oncol (ESMO Annual Meeting Abstracts). 2014;25(suppl 5):Abstract LBA5_PR. 28. Larkin J, Ascierto PA, Dreno B, et al. Combined vemurafenib and cobimetinib in BRAFmutated melanoma. N Engl J Med. 2014 Sep 29 [Epub ahead of print].

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