Vol 6, No 7
Cancer Center Profile
Vanderbilt University School of Nursing Research in Oncology Symptom Management By Alice Goodman
The Importance of the NursePatient Interaction in Optimizing Treatment With Ipilimumab for Advanced Melanoma By Dana Monroe, RN, OCN, BSN San Francisco Oncology Associates San Francisco, California
dvanced melanoma has remained an intractable malignancy for decades, with dacarbazine the only approved therapy and high-dose interleukin-2 limited by significant toxicity. Survival has not improved in more than 30 years.1 Melanoma cure rates are
high for localized, thin primary lesions; however, once the tumor has spread, only around 15% of patients survive 5 years.2 Although the clinical utility of melanoma vaccines has been disappointing, melanoma is inherently a highly immunogenic Continued on page 23
Genetic Counseling Sheila Ridner and colleagues at the Vanderbilt University School of Nursing: (back row, left to right) Melissa Adair, Emily Galford, Bethany Rhoten, Lauren Kagan, and Jessica Harbison; and (front row, left to right) Sheila Ridner and Nancy Kidd.
anderbilt University School of Nursing is affiliated with Vanderbilt University School of Medicine and the Ingram Cancer Center, one of the National Cancer Institute (NCI)– designated Centers of Excellence. The School of Nursing, located in Nashville, Tennessee, values excellence and innovation in advancing the art and science of nursing. The school has a 4-fold mission in the areas of academics, faculty practice, research, and informatics. Committed to evolving in response to innovations in these fields, the school is committed to transactions that integrate technology and embrace cultural and academic diversity. Continued on page 5
Highlights From the Multinational Association of Supportive Care in Cancer Annual Meeting By Alice Goodman
ith the growing number of cancer survivors in the United States and around the world, supportive care has become of even greater importance for these patients. At the recent Multinational Association of Supportive Care in Cancer (MASCC) annual meeting, held June
27-29, 2013, in Berlin, Germany, more than 1400 attendees could choose from a wealth of presentations to enhance their knowledge of supportive care and improve cancer care outcomes. Below are selected brief summaries of highlights from the meeting. Continued on page 7
Genetic Testing for BRCA1/2 By Cristi Radford, MS, CGC, Ambry Genetics; Angela Long, Breast Investigators
he announcement this spring by Angelina Jolie that she had undergone a risk-reducing double mastectomy after learning she carried a mutation in the BRCA1 gene, as well as the recent US Supreme Court decision on gene patenting, has resulted in an influx of questions to both genetic providers and support organizations about hereditary breast cancer. Below are some of the questions encountered by Angela Long, president of Breast Investigators.
Is BRCA1/2 the only hereditary breast cancer syndrome? No. BRCA1/2 are genes that help prevent breast, ovarian, and several other cancers. When the genes have mutations, individuals are at increased risk of developing the associated cancers. Often, individuals with a mutation in BRCA1 and/or BRCA2 are referred to as having hereditary breast and ovarian cancer syndrome, also known as HBOC. Although BRCA1/2 mutations Continued on page 18
inside Conference News: MASCC
Lymphedema in Head and Neck Cancer. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 7 Importance of Evaluating Swallowing in Advanced Cancer. . . . 8 Naloxegol for Opioid-Induced Constipation. . . . . . . . . . . . . . . . . . . . . . . . . 8 Managing Oral Mucositis. . . . . . . . . . . . 8 High Marks for Nutritional Supplement in Localized Prostate Cancer. . . . . . . . . . . . . . . . . . . 22
©2013 Green Hill Healthcare Communications, LLC
Noteworthy Numbers . . . . . . .
Complimentary CE Considerations in Multiple Myeloma —Ask the Experts: Combination Versus Sequential Therapy Complete the pretest, posttest, and evaluation online at www.mlicme.org/P13008C.html
See page 10
Investigating ABT-199 (GDC-0199) in Chronic Lymphocytic Leukemia Phase II Open-Label Study of the Efficacy and Safety of ABT-199 in Patients With Relapsed or Refractory Chronic Lymphocytic Leukemia Harboring the 17p Deletion N=100
ABT-199 is an investigational agent that has not been approved by regulatory agencies for the use under investigation in this trial. Primary Endpoint
• Overall response rate
• • • • • • • •
Complete remission rate Partial remission rate Duration of response Progression-free survival Time to progression Overall survival Percentage of patients who move on to stem-cell transplant Safety and tolerability of ABT-199
Key Inclusion Criteria • Adult patients ≥18 years of age • Diagnosis of CLL that meets 2008 IWCLL NCI-WG criteria (relapsed/refractory after receiving ≥1 prior line of therapy and 17p deletion) • ECOG performance score of ≤2 • Adequate bone marrow function • Adequate coagulation, renal, and hepatic function, per laboratory reference range
NCT#01889186 Reference: ClinicalTrials.gov.
@ 2013 Genentech USA, Inc. All rights reserved. BIO0001961500 Printed in USA.
To learn more about this study, please visit www.ClinicalTrials.gov.
Editorial Board EDITOR-IN-CHIEF
PhD(c), MSN, APRNBC, AOCN Cleveland Clinic Taussig Cancer Institute Cleveland, OH
Elizabeth Bilotti, RN, MSN, APRN, BC, OCN
John Theurer Cancer Center Hackensack University Medical Center Hackensack, NJ
Catherine Bishop, DNP, NP, AOCNP
Cassandra J. Hammond, RN,
Dolores “Jeff” Nordquist, RN, MS,
PhD, RN, AOCN
Avid Education Partners, LLC Sharpsburg, MD
Mayo Clinic Rochester, MN
Northern Michigan University Independent Oncology & Palliative Care Consultant Marquette, MI
Melinda Oberleitner, RN,
Karla Wilson, RN,
RN, BSN, OCN Novant Health Presbyterian Cancer Center Charlotte, NC
Patricia Irouer Hughes, RN, MSN,
MSN, FNP-C, CPON
DNS, APRN, CNS
City of Hope National Medical Center Duarte, CA
Jayshree Shah, NP
Pharmacy John F. Aforismo,
College of Nursing and Allied Health Professions University of Louisiana Lafayette, LA
Johns Hopkins Kimmel Cancer Center/Sibley Infusion Washington, DC
Piedmont Healthcare Rex, GA
John Theurer Cancer Center Hackensack University Medical Center Hackensack, NJ
Deena Damsky Dell, MSN, RN-BC,
University of Southern California Norris Cancer Center & Hospital Los Angeles, CA
NYU Clinical Cancer Center New York, NY
Somerset Medical Center Somerville, NJ
Sandra E. Kurtin,
Lori Stover, RN,
Patient Advocacy Peg Ford
Arizona Cancer Center Tucson, AZ
Western Pennsylvania Cancer Institute Pittsburgh, PA
Ovarian Cancer Alliance San Diego, CA
Joseph D. Tariman,
Social Work Carolyn Messner,
Fox Chase Cancer Center Philadelphia, PA
DNP, APRN, AOCN Genentech New London, NH
RN, MN, CNS, AOCN City of Hope National Medical Center Duarte, CA
Constance Engelking, RN,
MS, CNS, OCN
The CHE Consulting Group, Inc. Mt. Kisco, NY
Amy Ford, RN,
BSN, OCN Biodesix, Inc. Dallas, TX
NP, MSN, ACNP-C
RN, MS, AOCN, ANP-C
MSN, RN, NP-C, OCN
John Theurer Cancer Center Hackensack University Medical Center Hackensack, NJ
Kena C. Miller, RN, MSN, FNP
Roswell Park Cancer Institute Buffalo, NY
Patricia Molinelli, MS, RN, APN-C, AOCNS
Somerset Medical Center Somerville, NJ
MSN, NP, ANP-BC, AOCNP
PhD, APRN, BC
BSc Pharm, RPh, FASCP RJ Health Systems International, LLC Wethersfield, CT
Nutrition Karen Connelly, RD, CSO
Northwestern University Myeloma Program Chicago, IL
DSW, MSW, LCSW-R, BCD
Jacqueline Marie Toia, RN, MS, DNP
Genetic Counseling Cristi Radford,
Northwestern University Myeloma Program Chicago, IL
Pamela Hallquist Viale, RN, MS,
CS, ANP, AOCN Saratoga, CA
CancerCare New York, NY
Ambry Genetics Sarasota, FL
Managed Care and Pharmaceutical Management Burt Zweigenhaft, BS
OncoMed Onco360 Great Neck, NY
Sharon S. Gentry, RN, MSN, AOCN
Novant Health Derrick L. Davis Cancer Center Winston-Salem, NC
Ellen A. Neylon, MSN, FNP-BC, CCRP, OCN
Columbia University Medical Center Center for Lymphoid Malignancies New York, NY
Connie Visovsky, RN, PhD, APRN
University of South Florida College of Nursing Tampa, FL
Isabell Castellano, RN
Bristol-Myers Squibb Children’s Hospital Robert Wood Johnson University Hospital New Brunswick, NJ
Jeanne Westphal, RN
Meeker County Memorial Hospital Litchfield, MN
August 2013 I VOL 6, NO 7
From The Editor PUBLISHING STAFF Senior Vice President, Sales & Marketing Philip Pawelko firstname.lastname@example.org
Group Director, Sales & Marketing John W. Hennessy email@example.com Publisher Russell Hennessy firstname.lastname@example.org Editorial Director Kristin Siyahian email@example.com Managing Editor Kristen Olafson firstname.lastname@example.org Copy Editors Mollie Friedman Peggy Roeske Editorial Assistant Jennifer Brandt
n last month’s issue of The Oncology Nurse-APN/PA (TON), we published a letter from Cindy Covington. Cindy, an infusion nurse from Georgia, was responding to MMA’s “The Devil Is in the Details” column (see the TON April issue). MMA discussed how some of her needs as a hospitalized patient were not met and she thought her nurses should be able Beth Faiman, PhD(c), to help. Cindy’s letter and MMA’s MSN, APRN-BC, AOCN article inspired our reader poll: Do Editor-in-Chief you think the role of oncology nurses has changed when it comes to meeting the basic care needs of patients? The comments were varied, although almost all respondents agreed that the role of the oncology nurse has changed. One commenter said “the tasks mentioned in the MMA article are outside the art and science of nursing….The business of nursing has been elevated to
caring for patients in a highly technological way, and unfortunately providing the services mentioned in the article is not what nurses are taught in nursing school. Cutting toenails is the business of either a family member or a podiatrist….These tasks are certainly nice—but I am not aware of any institution that would advocate for the cutting of toenails of any patient, let alone one getting chemotherapy.” How do we balance the expanding role of nursing with the expectations patients have about their basic care needs? Cindy noted in her letter that “nurses have had to wear so many new hats that it has become nearly impossible to fulfill the patient’s basic needs.” MMA had to leave her hometown, and therefore the majority of her support network, to receive treatment at one of the nation’s top cancer centers, where she was often hospitalized for weeks at a time. How can we, and our institutions, help these patients? There are no easy solutions and these are difficult issues to address in the changing healthcare environment. As MMA said, “the devil is in the details.” l
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Do patients talk to you about genetic testing for themselves or their families?
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August 2013 I VOL 6, NO 7
he recent US Supreme Court decision regarding gene patenting and the coverage of Angelina Jolie regarding her healthcare decisions after learning that she carried the BRCA1 mutation have
brought the issue of genetic testing to the forefront. Has all of this coverage triggered patients to ask for more information about genetic counseling and genetic testing? Are patients talking to you about genetic testing?
Go to www.TheOncologyNurse.com to answer the question and add your comments.
The Oncology Nurse-APN/PA®, ISSN 1944-9798 (print); ISSN 1944-9801 (online) is published 11 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 ©2013 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: email@example.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.
Cancer Center Profile
Vanderbilt University School of Nursing Continued from cover
What is your role at the school of nursing? Sheila Ridner (SR): Eighty percent of my time is spent on research in oncology symptom management in 2 areas: lymphedema, primarily in patients with head and neck cancer (HNC), and biobehavioral science.
How do you treat lymphedema in patients with HNC? SR: We are doing a small pilot study to evaluate the effect of standard massage therapy on the movement of internal fluid in HNC. This is the only therapy known to help lymphedema. Our preliminary findings suggest that massage can help. We plan to look at the effect of preemptive therapies in patients with HNC undergoing chemoradiation.
atic adverse event associated with treatment of HNC.
What type of biobehavioral research are you doing? SR: We conducted a randomized controlled trial to determine the benefits of expressive writing in breast can-
cer survivors with lymphedema. We just received funding from NCI to conduct a 2-year randomized trial in HNC patients using a tailored yoga program to help with the musculoskeletal complications and swelling due to treatment. Continued on page 6
Investigators Study of the long-term safety and efficacy of darbepoetin alfa in anemic patients with Non-Small Cell Lung Cancer (NSCLC) receiving chemotherapy Phase 3 study with approximately 3,000 subjects at 500 study sites globally KEY ELIGIBILITY CRITERIA*
• Stage IV NSCLC
• Overall survival
• Receiving 1st-line myelosuppressive
• Progression-free survival
• Hemoglobin (Hb) ≤ 11 g/dL
• Incidence of ≥ 1 red blood cell (RBC) transfusion or Hb ≤ 8.0 g/dL
• ECOG score ≤ 1
Can you give me some examples of your research projects? SR: Chemotherapy and radiation commonly cause damage to the lymphatic system and soft tissue structures in patients with HNC, although this was not well known or well described in the United States until we started doing our studies. We have done studies on techniques for measuring the lymphatic changes and blood flow in the arms of patients with breast cancer, and have pioneered work on self-measurement of lymphedema with bioelectric impedance devices. In HNC, we are looking for genetic markers and biomarkers associated with lymphedema and fibrosis. Our studies have shown that HNC patients swell internally as well as externally, and in fact, these patients appear to develop lymphedema sooner in the course of treatment and go through progression faster than breast cancer patients. We have found that surgeons or ENT [ear, nose, and throat] physicians who use endoscopy to look for tumor regrowth can actually visualize internal lymphedema. At first, these physicians thought that patients were not swelling internally because they were focused on looking for tumor regrowth; when they were asked to assess internal swelling on nasal endoscopy, they were surprised to see that it was relatively common. We are measuring and recording physical findings in these patients, and drawing cytokine levels to see if there is an inflammatory component with the lymphedema.
What are the trends in HNC? SR: We are seeing more women and more younger people with HNC due to HPV [human papillomavirus] infection. It is not well known in the US that lymphedema occurs in these patients. However, we have clearly identified lymphedema as a problem-
Darbepoetin alfa 500-mcg Q3W
2:1 Randomization (darbepoetin alfa:placebo)
End of Investigational Product
End of Treatment Period
Disease progression or end of chemotherapy treatment
*Complete inclusion/exclusion criteria and additional study details can be found in the protocol. ECOG = Eastern Cooperative Oncology Group; Q3W = once every 3 weeks.
For more information, please email Cory Docken/Getty Images
The Oncology Nurse-APN/PA spoke with Sheila Ridner, PhD, RN, FAAN, the Martha Rivers Ingram Professor of Nursing at Vanderbilt University School of Nursing, about her research interests and the role of the oncology nurse/advanced nurse practitioner.
Studyfirstname.lastname@example.org or call 1-866-965-0782. Products under investigational study have not been approved by the FDA for the use under investigation in this trial.
© 2013 Amgen Inc. All rights reserved. Not for Reproduction.
2/12/13 9:38 AM August 2013 I VOL 6, NO 7 5
Cancer Center Profile
Vanderbilt University School of Nursing Continued from page 5 Why yoga? What are you excited about in the SR: Diaphragmatic breathing helps field of oncology? to move the lymphatic fluid. We SR: I am excited about raising awareplan to study an 8-week program that ness of the problem of lymphedema in includes several yoga postures, breath- HNC patients. If lymphedema is not ing techniques, and meditation tech- controlled, patients can end up in the niques and compare outcomes with ICU with tracheotomies. The ability a non-yoga control group. We will to identify, measure, and treat lymphvideotape the program for patients to edema in HNC will ultimately lead GBC2013Asize20813_Layout 2/8/13 11:12 AM Page to1 better quality of life for patients use in their home yoga 1practice.
and wiser use of healthcare resources. Another avenue of research is use of laser therapy during radiation for HNC, which has been helpful with arm lymphedema in breast cancer patients. Investigators in Tasmania report that laser therapy helps mucositis and also reduces internal swelling in HNC. The goal is to help people with HNC
"! ! !
! Professor Rob Coleman, MBBS, MD, FRCP Yorkshire Cancer Research Professor of Medical Oncology Director, Sheffield Cancer Research Centre Associate Director, National Institute for Health Research Cancer Research Network Department of Oncology, Weston Park Hospital Sheffield, United Kingdom Jorge E. Cortes, MD Chair, CML and AML Sections D.B. Lane Cancer Research Distinguished Professor for Leukemia Research Department of Leukemia, Division of Cancer Medicine The University of Texas MD Anderson Cancer Center Houston, TX
* 3:00 pm - 7:00 pm
5:30 pm - 7:30 pm
Welcome Reception and Exhibits
8:15 am - 8:30 am
Welcome to the Second Annual Conference of the Global Biomarkers Consortiumâ€”Setting the Stage for the Meeting Professor Rob Coleman, MBBS, MD, FRCP
8:15 am - 11:45 am
General Session I â€˘ Personalized Medicine in Oncology: Evolution of Cancer Therapy from Nonspecific Cytotoxic Drugs to Targeted Therapies â€˘ Taking Stock of Molecular Oncology Biomarkers â€˘ Genomics â€˘ Bioinformatics â€˘ Validating Biomarkers for Clinical Use in Solid Tumors - Professor Rob Coleman, MBBS, MD, FRCP â€˘ Validating Biomarkers for Clinical Use in Hematologic Malignancies Jorge E. Cortes, MD â€˘ The Challenges of Biomarker-Based Clinical Trials â€˘ Keynote Lecture: Understanding Cancer at the Molecular Level
12:00 pm - 1:00 pm
1:15 pm - 4:30 pm
General Session II â€˘ Introduction to Case Studies - Jorge E. Cortes, MD â€˘ Case Studies: Optimal, Value-Based Use of Molecular Biomarkers in Oncology: The Expertâ€™s Perspective on How I Treat My Patients, Part I â€˘ Lung Cancer â€˘ Breast Cancer â€˘ Multiple Myeloma â€˘ Prostate Cancer â€˘ Leukemia â€˘ Lymphoma â€˘ Panel Discussion: Management Controversies and Accepted Guidelines for the Personalized Management of Solid Tumors and Hematologic Malignancies â€˘ Keynote Lecture: The Medical-Legal Issues Surrounding the Use of Biomarkers in Oncology
The only global meeting dedicated to advancing the understanding of value and clinical impact of biomarker research in oncology. Guided by the expertise of leaders in this field, participants will receive a thorough understanding of the current and future landscape of the relevance of tumor biomarkers and how to effectively personalize cancer care in the clinical setting.
This meeting will be directed toward medical oncologists and hematologists, pathologists, geneticists, advanced practice oncology nurses, research nurses, clinical oncology pharmacists, and genetic counselors involved in the management of patients with solid tumors or hematologic malignancies, and interested in the use of molecular tumor biomarkers to help optimize patient care.
Upon completion of this activity, the participant will be able to: â€˘ Assess emerging data and recent advances in the discovery of molecular biomarkers and their impact on the treatment of patients with solid tumors or hematologic malignancies â€˘ Discuss the role of molecular biomarkers in designing personalized therapy for patients with solid tumors or hematologic malignancies â€˘ Outline the practical aspects of integrating molecular biomarkers into everyday clinical practice in the treatment of patients with cancer
This activity is jointly sponsored by Medical Learning Institute Inc, Center of Excellence Media, LLC, and Core Principle Solutions, LLC.
4:30 pm - 6:30 pm
Grant requests are currently being reviewed by numerous supporters. Support will be acknowledged prior to the start of the educational activities.
Symposium/Product Theater General Session III â€˘ Review of Saturdayâ€™s Presentations and Preview of Today - Jorge E. Cortes, MD â€˘ Case Studies: Optimal, Value-Based Use of Molecular Biomarkers in Oncology: The Expertâ€™s Perspective on How I Treat My Patients, Part II â€˘ Melanoma â€˘ Colorectal Cancer and Other GI Malignancies â€˘ MDS â€˘ Myeloproliferative Neoplasms â€˘ Keynote Lecture: Promises and Challenges of Personalized Medicine in Improving Cancer Care â€˘ Tumor Board: Challenging Cases in the Use of Biomarkers in Managing Solid Tumors (attendee-contributed cases) â€˘ Tumor Board: Challenging Cases in the Use of Biomarkers in Managing Hematologic Malignancies (attendee-contributed cases)
12:00 pm - 1:00 pm
1:15 pm - 3:00 pm
General Session IV â€˘ Keynote Lecture: Making Personalized Medicine a Reality: The Realization of Genomic Medicine â€˘ The Future of Personalized Medicine: Measuring Clinical Outcomes â€˘ Cost-Effective Technologies That Can Drive Therapeutic Decision Making â€˘ Regulatory Perspectives on PMO â€˘ PMO: The Payerâ€™s Perspective â€˘ Panel Discussion: Can We Afford PMO? A Value-Based Analysis â€˘ Practical Considerations in Incorporating PMO into Everyday Cinical Management â€˘ Reimbursement Challenges â€˘ Closing Remarks
Medical Learning Institute Inc Provider approved by the California Board of Registered Nursing, Provider Number 15106, for 12.5 contact hours.
The Medical Learning Institute Inc is accredited by the Accreditation Council for Pharmacy Education as a provider of continuing pharmacy education. Completion of this knowledge-based activity provides for 12.5 contact hours (1.25 CEUs) of continuing pharmacy education credit. The Universal Activity Number for this activity is (To be determined).
EARLY BIRD REGISTRATION NOW OPEN! $175.00 until June 30, 2013
Meet the Experts/Networking/Exhibits
8:15 am - 11:45 am
*Agenda is subject to change.
August 2013 I VOL 6, NO 7
PMPMERSONALIZED EDICINE IN ONCOLOGY O
What advice would you give to people who are thinking of entering the field of oncology nursing? SR: I would say that your patients can teach you how to live your own life. Patients may not always acknowledge you, but they need you and appreciate you. In order to enter this field and remain in it, you have to care about people. Many people try it and leave because they have trouble facing death and dying on a daily basis. You also need to set personal boundaries so you can tolerate the sadness and stress.
7:00 am - 8:00 am
The Medical Learning Institute Inc designates this live activity for a maximum of 12.5 AMA PRA Category 1 Creditsâ„˘. Physicians should claim only the credit commensurate with the extent of their participation in the activity. This activity has been planned and implemented in accordance with the Essential Areas and policies of the Accreditation Council for Continuing Medical Education through the joint sponsorship of the Medical Learning Institute Inc and the Center of Excellence Media, LLC. The Medical Learning Institute Inc is accredited by the Accreditation Council for Continuing Medical Education to provide continuing medical education for physicians.
How has the role of the oncology nurse changed in the past decade? SR: Advanced practice oncology nurses are assuming growing responsibility for management of symptoms during and after treatment. Symptom management clinics are becoming more common. These advanced practice nurses can follow patients and measure their symptoms, order endoscopies, and make referrals to lymphedema therapists when indicated. Non-advanced practice nurses are also assuming a growing role in gathering information on the types of symptoms that patients have and assessing them, beyond their vital signs. The specialty of oncology is leading the way for broader responsibilities for nurses, and I think this will happen in other types of medical practices. What inspired you to become an oncology nurse? SR: In nursing school, I did a 2-year stint as an oncology assistant and I learned more about life in that job than I could have learned by simply living for 10 years. I was moved by the strengths that people have in facing terminal illness, and that was part of my inspiration. I still learn from my patients every day. After nursing school, I lived with my husband in Europe and worked with mental health patients. I eventually enrolled at Vanderbilt to get my PhD, and my dissertation was on lymphedema in breast cancer survivors. Those experiences led to my interest in lymphedema and biobehavioral research.
7:00 am - 8:00 am
who develop lymphedemaâ€”the so-called â€œthrowaway children in cancer care.â€?
If you were not an oncology nurse, what else would you be doing? SR: I would be a veterinarian in a rural area. I grew up on a farm that I now own and where I spend every weekend. I have seen how much help a rural veterinarian can provide to the community. People make a living from their animals, so keeping them healthy is vital to their livelihood. l www.TheOncologyNurse.com
Conference News: MASCC Conference News continued from cover
Lymphedema in Head and Neck Cancer Although little is known about the prevalence of lymphedema in head and neck cancer (HNC), a series of studies found that three-quarters of patients with HNC have problematic lymphedema, both internally and externally. â€œLymphedema is a significant problem affecting a majority of HNC patients. Treatments such as surgery, chemotherapy, radiation, and combined modality therapy can damage lymphatic structures, leading to scar tissue and fibrosis. Lymphedema can be detected noninvasively, and this can inform clinical practice,â€? stated Sheila Ridner, PhD, RN, FAAN, Vanderbilt University School of Nursing, Nashville, Tennessee.
These studies help characterize the prevalence, patterns, and assessment of lymphedema in HNC. The studies examined prevalence, symptoms, measurement techniques, and symptom assessment tools. Study 1 included 81 patients at least 3 months out from treatment. After a posttreatment interval of a median of 17.7 months, 75.3% had late-effect lymphedema; of these patients, 9.8% had external lymphedema exclusively, 39.4% had internal edema exclusively, and 50.8% had both types. Study 2 included 25 patients with HNC. Swelling (both internal and external) was measured before and after treatment at 6 and 12 weeks using digital photography and National Cancer Institute Common Terminology Criteria for Adverse Events (CTCAE) v.4.02. At baseline, digital photography identified external swelling more often than did CTCAE. Internal swelling was identified at baseline in 10 patients, and only 4 had been treated with surgery. Digital photography captured 100% of cases of internal swelling and 92% of cases identified by CTCAE. Study 3 included 100 patients and followed the time course and patterns of internal and external swelling over 36 weeks. Preliminary findings regarding external lymphedema using 3 different tools (Foldi, CTCAE-lymphedema, CTCAE-fibrosis) showed that by 36 weeks post treatment for HNC, >50% had lymphedema. Internal lymphedema, as documented via scoping procedures on the Patterson scale, was present in a few structures in 10% to 20% of patients prior to treatment. At 36 weeks post treatment, about 30% of patients had internal lymphede-
ma, and this was observed in more struc- and assessment of lymphedema in HNC. tures than noted prior to treatment. Ridner said that patients should be eduStudy 4 included 30 patients and found cated about lymphedema before, during, that 10 major symptoms were reported by and after treatment. Internal and exter>50% of patients. nal examinations should be conducted Taken together, these studies help to look for lymphedema, and signs and Bendamustine 7/18/13 11:59symptoms AM Page 2 of lymphedema should be evalcharacterizeAsize_071613_TON0210 the prevalence, patterns,
uated at each clinic visit. Patients should be referred to lymphedema treatments when indicated. Reference
Ridner S, Deng J, Murphy BA, et al. Lymphedema in patients with head and neck cancer. Support Care Cancer. 2013;21(suppl 1):S196. Abstract 0558.
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A 4-part series The publishers of The Oncology Nurse-APN/PA, The Oncology Pharmacist, and Personalized Medicine in Oncology are proud to present Faculty Perspectives: The History of Bendamustine series.
Part 1 of a 4-Part Series 2012
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Conference News: MASCC Importance of Evaluating Swallowing in Advanced Cancer A study reported that about 1 in 5 patients with advanced cancer have difficulty swallowing when admitted to the hospital; even at discharge, some still have problems. Difficulty swallowing is an independent predictor of survival in advanced cancer. These findings highlight the critical need for regular evaluation to ensure adequate nutrition and patient care, according to lead author Shiva Shrotriya, MD, Harry R. Horvitz Center for Palliative Medicine at the Cleveland Clinic Taussig Cancer Institute, Ohio. The study was based on electronic medical records of 249 patients with
solid tumors treated in an acute palliative medical unit from 2008 through 2011. Patients’ ability to swallow was evaluated
a sip of water without aspiration and a 3-ounce cup of water without aspiration. Mean age was 68 years, 57% were
Patients’ ability to swallow was evaluated by a routine swallow screen, preswallow test questionnaires, and a clinical swallow test.
by a routine swallow screen, preswallow test questionnaires, and a clinical swallow test. The clinical swallow test included
female, 71% were white, 25% were African American, and 4% “other”; 47% had metastatic disease. Mean length of
hospital stay was 8 to 10 days. On admission, 6% had difficulty swallowing, and 6% also had difficulty swallowing at discharge; 21% had difficulty swallowing during the hospital stay. “Most patients who underwent a formal clinical swallow test failed the routine swallow screen, and pneumonia/respiratory and gastrointestinal problems were common among those with difficulty swallowing,” Shrotriya stated. Reference
Shrotriya S, Thomas S, Timmer R, et al. Prevalence and incidence of difficulty swallowing in advanced cancer. Support Care Cancer. 2013;21(suppl 1):S188. Abstract 0535.
Naloxegol for Opioid-Induced Constipation Two large well-designed studies of patients with opioid-induced constipation (OIC) demonstrated that naloxegol rapidly improved stool frequency and did not compromise opioid-mediated analgesia. In both KODIAC-04 and KODIAC-05, participants were not patients with cancer, and AstraZeneca plans to study naloxegol to establish its safety and efficacy in patients with cancer pain. “Opioid-induced constipation is a major challenge in palliative care medicine for patients taking opioid analgesics who develop persistent constipation that does not respond to available treatments. Naloxegol holds promise for the treatment of OIC without interfering with opioid analgesia for pain,” said lead author Jan Tack, MD, PhD, Translational Research Center for Gastrointestinal Disorders, University of Leuven, Belgium. The KODIAC studies are part of a large development program for naloxegol, a peripherally acting mu-opioid– receptor antagonist under investigation for the treatment of patients with OIC. KODIAC-04 and KODIAC-05 were identically designed, phase 3 randomized, double-blind, placebo-controlled pivotal trials that evaluated 2 daily doses of this novel oral agent: 12.5 mg and 25 mg. In both studies, the 25 mg dose of naloxegol met both primary and secondary end points, but in KODIAC-05, the 12.5 mg dose failed to achieve statistical significance. KODIAC-04 included 641 patients taking 30 to 1000 morphine equivalents each week for pain who were randomized 1:1:1 to receive placebo or naloxegol 12.5 mg/day or 25 mg/day. Response was defined as having at least 3 spontaneous bowel movements per week, with an increase of at least 1 spontaneous bowel movement over baseline for at least 9 weeks and for at least 3 of the previous 4 weeks. Response rates
August 2013 I VOL 6, NO 7
were 29.4% for placebo, 40.8% for the lower dose (P = .015 vs placebo), and 44.4% for the higher dose (P = .001 vs placebo). KODIAC-05 included 696 patients similar to the population in KODIAC-04. Response rates were 29.3% for placebo, 34.9% for the 12.5 mg dose, and 39.7% for the 25 mg dose. Only the 25 mg dose was statistically significant compared with placebo (P = .021). For both trials, median time to first postdose laxation was significantly shorter for both doses of naloxegol compared with placebo (P <.001). No increase in pain scores or need for higher doses of opioids was observed in patients taking naloxegol. Adverse events (AEs) were more
frequent on naloxegol 25 mg and included abdominal pain, diarrhea, nausea and vomiting, and flatulence. Major cardiovascular events were rare and were similar across treatment groups. In KODIAC-04,
The KODIAC studies are part of a large development program for naloxegol. any AEs were reported in 46.9% of patients receiving placebo, 49.3% of patients taking naloxegol 12.5 mg, and 61.2% of those taking naloxegol 25 mg.
In KODIAC-05, any AEs were reported in 58.9%, 59.6%, and 69.0% of patients, respectively. Discontinuations due to AEs were higher in the 25 mg dose groups; in both trials about 5% of patients receiving either placebo or naloxegol 12.5 mg discontinued therapy because of AEs, compared with about 10% of those receiving the higher naloxegol dose. The rates of serious AEs were low in both trials, and occurred more frequently in the placebo and 12.5 mg dose groups than in the 25 mg dose groups. Reference
Tack J, Gralla R, Webster L, et al. Efficacy and safety of naloxegol in patients with opioid-induced constipation (OIC): results from 2 identical phase 3, prospective, randomized, multicenter, double-blind, controlled trials. Support Care Cancer. 2013;21(suppl 1):S260. Abstract 0737.
Managing Oral Mucositis MuGard has been approved in Europe for the prevention and treatment of oral mucositis (OM). It was found to be safe and effective in alleviating the signs and symptoms of OM in an interim analysis of the first patients enrolled in a randomized controlled clinical trial. The final results will be presented in the future and will be based on 120 patients. “There is no accepted prophylaxis or therapy for OM—a frequent and debilitating adverse event of concomitant chemoradiotherapy. Saline bicarbonate [SBC] rinse is recommended by the NCI [National Cancer Institute] as a standard for care for HNC [head and neck cancer]. We compared SBC versus MuGard to attenuate OM symptoms,” explained lead author Ron R. Allison, MD, 21st Century Oncology Carolina Radiation Medicine, Greenville, North Carolina. MuGard is a mucoadhesive oral wound rinse used to manage OM or stomatitis caused by radiotherapy and/ or chemotherapy and other types of oral mouth sores. Classified as a medical device, MuGard is a hydrated polymer system (oral hydrogel). When gently distributed within the mouth, the mucoadhesive formulation results in the formation of a protective coating over the oral mucosa. MuGard was previously shown to reduce
the incidence and severity of mucositis in patients with HNC undergoing radiation therapy, compared with data from historical control groups. In the study presented at MASCC 2013, 70 patients were treated with MuGard rinse every 3 hours up to 6 times per day over a period of 6 to 8 weeks versus SBC given on the same schedule. Patients completed the validated Oral Mucositis Daily Questionnaire (OMDQ) reporting mouth and throat soreness and other symptoms. The primary end point compared the efficacy of the 2 identically packaged oral rinses on reducing OM symptoms as determined by the area under the curve (AUC) of mouth and throat soreness as defined by the OMDQ. The interim analysis showed that treatment with oral MuGard was significantly superior to SBC, with a mean AUC of 58.9 versus 92.1 in the SBC group (P = .041). MuGard was also significantly better than SBC in alleviating other associated symptoms of OM. Reference
Allison RR, Ambrad AA, Arshoun YM, et al. The multi-institutional, randomized, double-blind, placebo-controlled trial to assess the efficacy of MuGard in mitigating oral mucositis (OM) in chemoradiation-treated (CRT) head and neck cancer patients. Support Care Cancer. 2013;21(suppl 1):S211. Abstract 0605.
Conference News continued on page 22
eO seri Vie nc es w olo on the gy line Nu a rse t .co m
CONQUERING THE ANCER ARE C C CONTINUUM
A 6-part series
FIRST ISSUE IN THE 2013 SERIES
CONQUERING THE ANCER CARE C The publishers of The Oncology CONTINUUM CONQUERING Nurse-APN/PA, The Oncology GHHC Conq Cancer Care Cont THE ANCER C I Pharmacist, and Personalized C O N T C ARE INUUM Medicine in Oncology are e h t g n i uer I q n o C proud to present our 2nd annual are r e c C n a CC O N T I N U U M Conquering the Cancer Care Continuum series. Conquering t Upcoming topics include: Cancer Carehe I CONTI N SECOND ANNUAL
D ISSUE ™ IN THE 2013 SE RIES SE C O N D ANN UAL
Changing the Image of Palliative Care Lillie D. Shockney, RN, BS, MAS
vention and relief of suffering by means of early identiam enthusiastic about this 6-part series titled Confication and impeccable assessment and treatment of quering the Cancer Care Continuum. Each edition of pain and other problems, physical, psychosocial, and CCCC will address an important topic in oncology ES RI SE spiritual.” (http://www.who.int/cancer/ management and offer expert stakeE 2013 TH IN UE ISS palliative/en/). Topics will IRD commentaries. THholder For too long, however, the image of include: palliative care, pain manageNU AN - AL O ND ™ palliative care has been tied exclusively SE Ccare, ment, hospice comprehensive to end-of-life care and focused solely on treatment planning, survivorship care, pain control. and the role of biosimilars in supportLillie D. Sho ckney, RN , BS, MA The articles that follow provide a ive care. In this issue, we address palS n part 2 of clear understanding of the intent of liative care. our Conqu series, the ering the Ca palliative care today, with the primary Palliation in cancer care is a topic focus is on ncer Care ma Continuum pai goal ending its identification that commonly makes people (medical well tic improvements n managem ent inabilitysolely .ofDe as surgic in ph spite drato overco provideddie for wh theile dying. providers as well as patients) uncom- we still hav al procedures des armaceasuticancer me it effe cal agecare nts, as igned ctivel in gre ea p con monly res Instead, palliative be pon asso- at pain. Family y, fearing they wil fortable. I recently had the opportunity cessful on beh long way to go to be to hel ™tro l pain, care should l memb d tha sucLillie D.alf Shockney, RN, of our nes patients. I was rec theirforlov ciated with quality-of-lifescare alled t their greatest fea ers, too, comto speak with members of our palliative MAS ly wa r is having one in gre tching a few utes of an entBS, to witold, blackcare team at Johns Hopkins and learned ern min- cancer patients and survivors, no mat- ease the at pain witho and ut a wa movie. A -white we suf cowboy ter what theirst-clinical outcome. that the word “palliative” comes from the fear these fering. Family me y to byword had a gun“palliare,” wil mb been sho slin , and t patients may not tell you about the sidewitness bef l be the final image ers tor att which means to disguise or cloak. 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I’m knife to bite betwe ey providers the purpose of sure back fort “comes effective age pain The World Health Organizationwamodified s how peoits origin the day enwith the disease.” However, with the imple coped this in medicine and the power of science,itsit treatmassociated with canly manprovements inal definition of palliative care as quo follows: “Palliative r to nu cer and en mb them with pain – liprovide you t. The following harthe d toquality art to anymore. Do not wait for your patients care is an approach that improves life and doesn’t somethhave call bite onof. Th icles with a we ing asking him to ma is is far fro alth of back BS, MAS Today him teinitiate he symptoms; be proac-tion associated m rised their to a discussion all pat problems as- . I wro ckney, RN, of patients and their families facing the ide said t sank and guidel with the inforhow surpabout ien hear Lillie D. 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Pain ste i iherpaiinit ien n clinph n, and time, psy s addressed here on sio als away ripti what to cir ts have trosinc ysical en s of descto ubl wh ch way his fully, concept it soc er e, at on olo s, d debett ho cle ial gic du tnes Base wever, intlimited aler and rance an (a hap al well-b tuaI lly abs pain was n and erpreting ely ill. e or adopted as newterminally ill cancer bad in the py faccal ent for som d can make quali eing, and con a ditio grav y sad facshe an cause the morning ver e) ifwas supporting our r families. ent that theirthe doctord adequate treatme patients. Accur ty of life viry evidno but t so bad thei ate assess ment ne doctor. 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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 third issue, experts from the Winship Cancer Institute of Emory University answer questions related to the use of combination and sequential therapies for MM. Sincerely, Sagar Lonial, MD Professor Vice Chair of Clinical Affairs Department of Hematology and Medical Oncology Winship Cancer Institute Emory University School of Medicine Atlanta, GA
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Director, Production & Manufacturing Alaina Pede Director, Creative & Design Robyn Jacobs Creative & Design Assistant Lora LaRocca Director, Digital Media Anthony Romano Web Content Managers David Maldonado Anthony Travean
Ajay K. Nooka, MD, MPH, FACP Assistant Professor of Hematology and Medical Oncology Winship Cancer Institute Emory University School of Medicine Atlanta, GA
Charise Gleason, MSN, ANP-BC, AOCNP Nurse Practitioner Winship Cancer Institute Emory University Atlanta, GA
Katherine Sanvidge Shah, PharmD, BCOP Hematology/Oncology Pharmacy Specialist Winship Cancer Institute Emory University Atlanta, GA
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Supported by educational grants from Onyx Pharmaceuticals and Millennium: The Takeda Oncology Company.
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This activity is jointly sponsored by Medical Learning Institute Inc and Center of Excellence Media, LLC.
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August 2013 I VOL 6, NO 7
CONSIDERATIONS IN MULTIPLE MYELOMA Sponsors This activity is jointly sponsored by Medical Learning Institute Inc and Center of Excellence Media, LLC. Commercial Support Acknowledgment This activity is supported by educational grants from Onyx Pharmaceuticals and Millennium: The Takeda Oncology Company. Target Audience The activity was developed for physicians, nurses, and pharmacists involved in the treatment of patients with multiple myeloma (MM). Purpose Statement The purpose of this activity is to enhance competence of physicians, nurses, and pharmacists concerning the treatment of MM. Physician Credit Designation The Medical Learning Institute Inc designates this enduring material for a maximum of 1.0 AMA PRA Category 1 Credits™. Physicians should claim only the credit commensurate with the extent of their participation in the activity. This activity has been planned and implemented in accordance with the Essential Areas and policies of the Accreditation Council for Continuing Medical Education through the joint sponsorship of the Medical Learning Institute Inc and the Center of Excellence Media, LLC. The Medical Learning Institute Inc is accredited by the Accreditation Council for Continuing Medical Education to provide continuing medical education for physicians. Registered Nurse Designation Medical Learning Institute Inc Provider approved by the California Board of Registered Nursing, Provider Number 15106, for 1.0 contact hour. Registered Pharmacy Designation The Medical Learning Institute Inc is accredited by the Accreditation Council for Pharmacy Education as a provider of continuing pharmacy education. Completion of this application-based activity provides for 1.0 contact hour (0.1 CEU) of continuing pharmacy education credit. The Universal Activity Number for this activity is 0468-9999-13-016-H01-P. Learning Objectives Upon completion of this activity, the participant will be able to: • Discuss existing and emerging therapeutic options for patients with newly diagnosed or relapsed/refractory MM and how to tailor therapy for individual patients
• Describe the pharmacokinetics and pharmacodynamics of novel agents when integrating these agents into treatment regimens for MM • Evaluate adverse event management strategies for patients with MM receiving novel therapies and multidrug regimens Disclosures Before the activity, all faculty and anyone who is in a position to have control over the content of this activity and their spouse/life partner will disclose the existence of any financial interest and/or relationship(s) they might have with any commercial interest producing healthcare goods/services to be discussed during their presentation(s): honoraria, expenses, grants, consulting roles, speakers’ bureau membership, stock ownership, or other special relationships. Presenters will inform participants of any off-label discussions. All identified conflicts of interest are thoroughly vetted by Medical Learning Institute Inc 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 associates of Medical Learning Institute Inc, the accredited provider for this activity, and Center of Excellence Media, LLC, do not have any financial relationships or relationships to products or devices with any commercial interest related to the content of this CME/CPE/CE activity for any amount during the past 12 months. Planners’ and Managers’ Disclosures William J. Wong, MD, MLI Reviewer, has nothing to disclose. Bobbie Perrin, RN, OCN, MLI Reviewer, has nothing to disclose. Shelly Chun, PharmD, MLI Reviewer, has nothing to disclose. Faculty Disclosures Sagar Lonial, MD, is on the Advisory Board for and is a Consultant to Bristol-Myers Squibb, Celgene Corporation, Millennium: the Takeda Oncology Company, Novartis, Onyx Pharmaceuticals, and sanofi-aventis. He does not intend to discuss any non–FDA-approved or investigational use for any products/devices. Ajay K. Nooka, MD, MPH, FACP, has nothing to disclose. He does not intend to discuss any non–FDA-approved or investigational use for any products/devices. Charise Gleason, MSN, ANP-BC, AOCNP, is a consultant for Celgene Corporation. She does intend to discuss either non–FDAapproved or investigational use for the following products/devices: agents currently used in clinical trials for MM. Katherine Sanvidge Shah, PharmD, BCOP, has nothing to disclose. She does intend to discuss either non–FDA-approved or in-
vestigational use for the following products/devices: MLN9708, ONX0912, vorinostat, panobinostat, and romidepsin. Disclaimer The information provided in this CME/CPE/CE activity is for continuing education purposes only and is not meant to substitute for the independent medical judgment of a healthcare provider relative to diagnostic and treatment options of a specific patient’s medical condition. Recommendations for the use of particular therapeutic agents are based on the best available scientific evidence and current clinical guidelines. No bias toward or promotion for any agent discussed in this program should be inferred. Instructions for Credit There is no fee for this activity. To receive credit after reading this CME/CPE/CE activity in its entirety, participants must complete the pretest, posttest, and evaluation. The pretest, posttest, and evaluation can be completed online at www.mlicme.org/P13008C. html. Upon completion of the evaluation and scoring 70% or better on the posttest, you will immediately receive your certificate online. If you do not achieve a score of 70% or better on the posttest, you will be asked to take it again. Please retain a copy of the certificate for your records. For questions regarding the accreditation of this activity, please contact Medical Learning Institute Inc at 609-333-1693 or email@example.com. For pharmacists, Medical Learning Institute Inc will report your participation in this educational activity to the NABP only if you provide your NABP e-Profile number and date of birth. For more information regarding this process or to get your NABP e-Profile number, go to www.mycpemonitor.net. Estimated time to complete activity: 1.0 hour Date of initial release: August 16, 2013 Valid for CME/CPE/CE credit through: August 16, 2014
SCAN HERE to Download the PDF or Apply for Credit. To use 2D barcodes, download the ScanLife app: • Text “scan” to 43588 • Go to www.getscanlife.com on your smartphone’s Web browser, and select “Download” • Visit the app store for your smartphone
Understanding Combination and Sequential Therapy in Multiple Myeloma Ajay K. Nooka, MD, MPH, FACP
Assistant Professor of Hematology and Medical Oncology Winship Cancer Institute Emory University School of Medicine, Atlanta, GA
Introduction Over the past decade, an increased knowledge of multiple myeloma (MM) and of the physiologic factors affecting its growth and proliferation have led to the development and approval of numerous targeted agents, including bortezomib, thalidomide, lenalidomide, carfilzomib, and pomalidomide. Given the expanding treatment armamentarium for the disease, physicians are often faced with the question of whether to offer patients combination or sequential therapy. In this article, Ajay K. Nooka, MD, MPH, FACP, discusses this issue in the context of the latest data from clinical trials, and provides insights on practices that contribute to optimal patient care.
What are the advantages and disadvantages of sequential versus combination therapy in MM? The term sequential therapy refers to treatment with drug regimens administered one after another in a chronological fashion rather than concomitantly,
while the term combination therapy alludes to more than one drug treatment administered concurrently. The best example of combination therapy in the era of modern antimyeloma treatment originates from combining a proteasome inhibitor (PI) with an immunomodulatory drug (IMiD). The PI bortezomib combined with the IMiD lenalidomide exhibited synergy in preclinical models, and newly diagnosed patients in a phase 1/2 trial achieved high overall response rates (ORRs) of 100% with greater than one-third of patients achieving a complete response (CR)/near-complete response.1 These results are not limited to the induction setting. For example, consolidation with bortezomib/thalidomide/ dexamethasone (VTD) following autologous stem cell transplantation (ASCT) has induced molecular responses by upgrading the quantitative polymerase chain reaction (qPCR)-positivity to qPCR-negativity, suggesting that combination therapies may be able to deliver molecular responses, where conventional agents failed to achieve similar responses.2 Sequential therapy can be interpreted in more than one way. First, it can mean sequential administration of therapies, switching to a new regimen following disease progression. Second, it can mean a predefined sequence of therapies, each new regimen following the previous therapy without evidence of disease progression. The best example in recent myeloma literature is that of a phase 2 feasibility study in which sequential bortezomib and dexamethasone (VD) for 6 cycles, followed by thalidomide and dexamethasone (TD) maintenance therapy until progression following ASCT, demonstrated that a prolonged sequential weekly regimen is feasible and well tolerated, with post-ASCT CR upgraded by more than one-third during maintenance therapy, with no further increase in grade 3/4 peripheral neuropathy (PN).3
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CONTINUING EDUCATION The underlying concept of sequential therapy arises from the idea of preserving therapeutic options for later use in the disease course. Another potential advantage of sequential therapy is to limit the toxicities associated with combination therapies. This notion presumes that curing the disease is not the primary goal, and that progression-free survival (PFS) as well as overall survival (OS) are equivalent with both sequential and combination therapies. This argument is largely supported by data from historical ineffective combinations of chemotherapy when compared with a standard melphalan and prednisone (MP) regimen. Due to the low ORR for any of these historical regimens, it is not surprising that the use of sequential therapy was as ineffective as combination therapy. However, with the use of newer, more active agents such as IMiDs and PIs, as well as a better understanding of the biology of the disease, reconsideration of sequential therapy is warranted. Combination approaches with currently available highly effective regimens are more effective at inducing durable responses than sequential single agents. The rationale seems logical: myeloma cells follow Gompertzian rather than exponential kinetics, which forms the basis for ASCT, suggesting enhanced susceptibility to combination therapies with the goal of minimizing residual tumor burden and deepening the response. In addition, combination therapies have allowed for targeting induced-pathway dependence. The exposure of malignant cells to a single agent often results in preferential overactivation of a survival pathway that can be targeted by using the second agent as part of a combination strategy. Also, combination therapies can lead to synergistic mechanisms of tumor apoptosis, allowing for better overall response and depth of response when compared with single-agent therapy. This notion presumes that achieving depth of response with a safe and tolerable durable therapy actually results in survival improvement. The downside to this approach is the lack of long-term data confirming that combination therapies provide a survival advantage over singleagent therapy. However, with a better understanding of clonal dynamics and recent description of “clonal tides,” along with evidence of the existence of clonal heterogeneity at diagnosis, the argument is in favor of combination therapies over sequential therapies, especially when the intent is to eradicate both the dominant and minor clones that emerge at relapse.4 Which factors can affect the order of agents used in a sequential approach to therapy? In the current fast-paced era of antimyeloma therapies, with practices rapidly adapting to novel combination treatment strategies, it may not be feasible to conduct a study randomizing to sequential or combination therapies with a primary end point of OS, especially when data suggest that improved depth of response translates to PFS and OS advantage. A retrospective outcomes analysis evaluated whether the sequence of treating with lenalidomide-based therapy followed by bortezomib-based therapy versus bortezomib-based therapy followed by lenalidomide-based therapy improved outcomes. This study included 208 patients and reported that sequence of therapy was not predictive of OS, except in patients with renal failure, where bortezomib-based first-line therapy was recommended.5 In another study, the Myeloma Research Council XI randomized patients receiving cyclophosphamide/thalidomide/dexamethasone (CTD) or cyclophosphamide/lenalidomide/dexamethasone (CRD) who had not achieved at least a partial response to receive either no further therapy or a triplet combination of cyclophosphamide/bortezomib/dexamethasone (CVD). A mean paraprotein reduction of 74% from the start of CVD was observed, suggesting that a bortezomib-based combination therapy would have delivered these responses at the start.6 These results were confirmed in a meta-analysis of phase 3 trials of bortezomib-based induction therapies, suggesting that the addition of bortezomib to the induction regimen not only improved response rates but also resulted in prolonged PFS and OS.7 Similar data in transplant-ineligible patients were reported in the phase 3 VISTA trial.8 OS was prolonged with the combination of bortezomib/melphalan/prednisone (VMP) compared with patients who received first-line MP followed by salvage bortezomib, suggesting a survival advantage with combination therapies. OS from start of subsequent therapy was similar following the VMP and MP regimens, suggesting that combination therapies do not induce more resistant relapses.9 These observations add strength to the argument that combination therapies—especially those including bortezomib in the induction setting—improve response rates and further outcomes. As myeloma is mainly a disease of elderly patients, with a median age at diagnosis of 69 years,8 approximately 50% of patients are not transplant eligible at
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the time of diagnosis. Also, due to the prevalence of MM in the elderly, it is not uncommon to encounter patients who are frail, exhibit poor functional status, and have multiple comorbidities. These patients are more susceptible to treatment-related adverse events, may have lower tolerability for full drug doses, and may be on other medications that interact with their antimyeloma treatment. The question of whether these patients can tolerate combination therapies is always challenging. Taking age into consideration, beneficial results of the VISTA trial demonstrated a median survival advantage of 13 months with combination therapies.9 Taking frailty into consideration, a gentler approach of combination therapies with lower intensity dosage regimens improves the safety profile and thus optimizes treatment outcomes. A plan for further reduction in dosages is recommended with close monitoring.10 One of the most notable concepts to which the myeloma community has quickly adapted in recent years is the recognition of risk stratification, spanning from the most indolent to the most aggressive forms on the MM spectrum. The majority of myeloma-treating physicians accept genetically defined risk stratification and the fact that high-risk patients have poorer survival outcomes compared with other patients with MM. At the least, combination therapies, preferably including an IMiD and a PI, are agreed upon as best for induction in this high-risk patient group. Early genomic data support this approach of targeting all coexisting disease subclones with aggressive combination therapies and avoiding sequential single-agent therapy in high-risk patients.4 Moreover, data also suggest that by using sequential therapy early in the disease course, early suboptimal treatment of myeloma may sometimes preferentially eradicate the more indolent clone, thus leaving room for expansion of the aggressive clone.4 A similar rationale supports combination therapies in the maintenance setting in high-risk patients; early clinical data concur with these findings.11 What are the latest data regarding the safety and efficacy of combination regimens in MM? In newly diagnosed myeloma patients, triplet regimens have been proven to be highly effective in delivering high-quality durable responses with a satisfactory toxicity profile. The combinations of IMiDs and a PI demonstrated synergy as previously described and resulted in quality responses.1 With the use of next-generation PIs and IMiDs, much deeper response rates have been observed. Moving a step further, combinations of newer monoclonal antibodies and histone deacetylase inhibitors have the potential to augment the quality of responses and translate into improved PFS and OS. Figure 1 illustrates the upgraded responses achieved with doublets to triplets with various combinations of newer agents and signifies the importance of combination therapies.1,12-16 In contrast to the robust evidence supporting the advantages of treating newly diagnosed patients with combination therapies, using a similar approach when treating patients with relapsed/refractory MM has proven more challenging. Often these patients have already been treated with multiple agents and may have more comorbidities secondary to the disease itself or due to prior treatment-related effects. Salvage regimens used in this setting previously resulted in inadequate responses and shorter duration of response, as shown in Figure 2.17-28 However, the addition of liposomal doxorubicin to bortezomib prolonged median PFS to 9.3 months among bortezomib-naive patients versus 6.5 months for bortezomib alone, showing the value of a combination approach.23 More recently, a phase 3 trial in the relapsed setting comparing VTD with TD reported PFS of 19 months for the VTD arm, representing the longest PFS in a relapsed setting and highlighting the importance of combination therapy.28 Various methods have been utilized to address the issue of overlapping toxicity with combination therapy (eg, increased grade 3 PN): dose or schedule modification of the agents, route of administration of bortezomib, newer IMiDs to decrease PN, and newer PIs such as carfilzomib and oprozomib are potential options. However, the key principle of combination therapy yielding effective reduction of disease burden and improving PFS will guide us in defining future studies. The role of quadruplet therapies remains unclear at this time. In both transplant-eligible and -ineligible populations, regimens such as lenalidomide/bortezomib/cyclophosphamide/dexamethasone (RVCD), bortezomib/cyclophosphamide/ thalidomide/dexamethasone (VCTD), lenalidomide/bortezomib/doxorubicin/ dexamethasone (RVDD), and bortezomib/melphalan/prednisone/thalidomide (VMPT) have been evaluated, with outcomes similar to triplet therapies, albeit with higher toxicities. With appropriate dosage modifications to reduce the risk of toxicity, these regimens can be administered in some patients, if the objective is to
CONSIDERATIONS IN MULTIPLE MYELOMA
Figure 2. Upgraded responses observed with doublets to triplets in combination therapy for patients with relapsed/ refractory myeloma.17-28
achieve greater depth of response, demonstrated as higher molecular remissions. Rather than using the historically ineffective alkylator-based therapy in these combination regimens, investigational biological agents hold promise. ♦ References
1. Richardson PG, Weller E, Lonial S, et al. Lenalidomide, bortezomib, and dexamethasone combination therapy in patients with newly diagnosed multiple myeloma. Blood. 2010;116:679-686. 2. Cavo M, Pantani L, Petrucci MT, et al. Bortezomib-thalidomide-dexamethasone is superior to thalidomide-dexamethasone as consolidation therapy after autologous hematopoietic stem cell transplantation in patients with newly diagnosed multiple myeloma. Blood. 2012;120:9-19. 3. Sahebi F, Frankel PH, Farol L, et al. Sequential bortezomib, dexamethasone, and thalidomide maintenance therapy after single autologous peripheral stem cell transplantation in patients with multiple myeloma. Biol Blood Marrow Transplant. 2012;18:486-492. 4. Keats JJ, Chesi M, Egan JB, et al. Clonal competition with alternating dominance in multiple myeloma. Blood. 2012;120:1067-1076. 5. Patel AM, Ho VQ, Shain KH, et al. Sequence of therapy in multiple myeloma: does it matter?: retrospective evaluation of patients with multiple myeloma who have received bortezomib followed by lenalidomide or vice versa. Blood (ASH Annual Meeting Abstracts). 2011;118: Abstract 3979. 6. Pawlyn C, Davies FE, Gregory WM, et al. Sequential immunomodulatory drug (IMiD) and proteosome inhibitor therapy improves response rates in newly diagnosed multiple myeloma: preliminary results from the Myeloma XI trial. Blood (ASH Annual Meeting Abstracts). 2012;120:Abstract 335. 7. Nooka AK, Kaufman JL, Behera M, et al. The improved efficacy of bortezomib containing induction regimens (BCIR) versus non-bortezomib containing induction regimens (NBCIR) in transplant-eligible patients with multiple myeloma (MM): meta-analysis of phase III randomized controlled trials (RCTs). Blood (ASH Annual Meeting Abstracts). 2011;118:Abstract 3994. 8. San Miguel JF, Schlag R, Khuageva NK, et al; for the VISTA Trial Investigators. Bortezomib plus melphalan and prednisone for initial treatment of multiple myeloma. N Engl J Med. 2008;359:906-917. 9. San Miguel JF, Schlag R, Khuageva NK, et al. Continued overall survival benefit after 5 years’ follow-up with bortezomib-melphalan-prednisone (VMP) versus melphalan-prednisone (MP) in patients with previously untreated multiple myeloma, and no increased risk of second primary malignancies: final results of the phase 3 VISTA trial. Blood (ASH Annual Meeting Abstracts). 2011;118:Abstract 476. 10. Palumbo A, Bringhen S, Ludwig H, et al. Personalized therapy in multiple myeloma according to patient age and vulnerability: a report of the European Myeloma Network (EMN). Blood. 2011;118:4519-4529. 11. Kaufman JL, Nooka AK, Muppidi S, et al. Survival outcomes of early autologous stem cell transplant (ASCT) followed by lenalidomide, bortezomib, and dexamethasone (RVD) maintenance in patients with high-risk multiple myeloma (MM). J Clin Oncol (ASCO Annual Meeting Proceedings). 2012;30(15 suppl):Abstract 8100. 12. Harousseau J-L, Attal M, Avet-Loiseau H, et al. Bortezomib plus dexamethasone is superior to vincristine plus doxorubicin plus dexamethasone as induction treatment prior to autologous stem-cell transplantation in newly diagnosed multiple myeloma: results of the IFM 2005-01 phase III trial. J Clin Oncol. 2010;28:4621-4629. 13. Cavo M, Tacchetti P, Patriarca F, et al. Bortezomib with thalidomide plus dexamethasone compared with thalidomide plus dexamethasone as induction therapy before, and consolida-
CR/nCR indicates complete response/near-complete response; C, cyclophosphamide; D, dexamethasone; PR, partial response; R, lenalidomide; T, thalidomide; V, bortezomib; VGPR, very good partial response.
PL D bi no st at
CR/nCR ≥VGPR ≥PR
100 90 80 70 60 50 40 30 20 10 0 T
Response Rates (%)
Response Rates (%)
Figure 1. Upgraded responses observed with doublets to triplets in combination therapy for patients with newly diagnosed myeloma.1,12-16
C indicates cyclophosphamide; D, dexamethasone; PLD, pegylated liposomal doxorubicin; PR, partial response; R, lenalidomide; T, thalidomide; V, bortezomib; VGPR, very good partial response.
tion therapy after, double autologous stem-cell transplantation in newly diagnosed multiple myeloma: a randomised phase 3 study. Lancet. 2010;376:2075-2085. 14. Rajkumar SV, Jacobus S, Callander NS, et al; for the Eastern Cooperative Oncology Group. Lenalidomide plus high-dose dexamethasone versus lenalidomide plus low-dose dexamethasone as initial therapy for newly diagnosed multiple myeloma: an open-label randomised controlled trial. Lancet Oncol. 2010;11:29-37. 15. Jakubowiak AJ, Dytfeld D, Griffith KA, et al. A phase 1/2 study of carfilzomib in combination with lenalidomide and low-dose dexamethasone as a frontline treatment for multiple myeloma. Blood. 2012;120:1801-1809. 16. Kaufman JL, Shah JJ, Laubach JP, et al. Lenalidomide, bortezomib, and dexamethasone (RVD) in combination with vorinostat as front-line therapy for patients with multiple myeloma (MM): results of a phase 1 study. Blood (ASH Annual Meeting Abstracts). 2012;120:Abstract 336. 17. Singhal S, Mehta J, Desikan R, et al. Antitumor activity of thalidomide in refractory multiple myeloma. N Engl J Med. 1999;341:1565-1571. 18. Richardson PG, Schlossman RL, Weller E, et al. Immunomodulatory drug CC-5013 overcomes drug resistance and is well tolerated in patients with relapsed multiple myeloma. Blood. 2002;100:3063-3067. 19. Richardson PG, Sonneveld P, Schuster MW, et al; for the Assessment of Proteasome Inhibition for Extending Remissions (APEX) Investigators. Bortezomib or high-dose dexamethasone for relapsed multiple myeloma. N Engl J Med. 2005;352:2487-2498. 20. Dimopoulos MA, Zervas K, Kouvatseas G, et al. Thalidomide and dexamethasone combination for refractory multiple myeloma. Ann Oncol. 2001;12:991-995. 21. Weber DM, Chen C, Niesvizky R, et al. Lenalidomide plus dexamethasone for relapsed multiple myeloma in North America. N Engl J Med. 2007;357:2133-2142. 22. Jagannath S, Barlogie B, Berenson J, et al. A phase 2 study of two doses of bortezomib in relapsed or refractory myeloma. Br J Haematol. 2004;127:165-172. 23. Orlowski RZ, Nagler A, Sonneveld P, et al. Randomized phase III study of pegylated liposomal doxorubicin plus bortezomib compared with bortezomib alone in relapsed or refractory multiple myeloma: combination therapy improves time to progression. J Clin Oncol. 2007;25:3892-3901. 24. Richardson PG, Alsina M, Weber DM, et al. Phase II study of the pan-deacetylase inhibitor panobinostat in combination with bortezomib and dexamethasone in relapsed and bortezomib-refractory multiple myeloma (PANORAMA 2). Blood (ASH Annual Meeting Abstracts). 2011;118:Abstract 814. 25. Richardson PG, Jagannath S, Jakubowiak AJ, et al. Phase II trial of lenalidomide, bortezomib, and dexamethasone in patients (pts) with relapsed and relapsed/refractory multiple myeloma (MM): updated efficacy and safety data after >2 years of follow-up. Blood (ASH Annual Meeting Abstracts). 2010;116:Abstract 3049. 26. Davies FE, Wu P, Jenner M, Srikanth M, Saso R, Morgan GJ. The combination of cyclophosphamide, Velcade and dexamethasone (CVD) induces high response rates with comparable toxicity to Velcade alone (V) and Velcade plus dexamethasone (VD). Haematologica. 2007;92: 1149-1150. 27. Lonial S, Jakubowiak AJ, Jagannath S, et al. A phase 2 study of elotuzumab in combination with lenalidomide and low-dose dexamethasone in patients with relapsed/refractory multiple myeloma. Blood (ASH Annual Meeting Abstracts). 2011;118:Abstract 303. 28. Garderet L, Iacobelli S, Moreau P, et al. Superiority of the triple combination of bortezomib-thalidomide-dexamethasone over the dual combination of thalidomide-dexamethasone in patients with multiple myeloma progressing or relapsing after autologous transplantation: the MMVAR/IFM 2005-04 randomized phase III trial from the Chronic Leukemia Working Party of the European Group for Blood and Marrow Transplantation. J Clin Oncol. 2012;30: 2475-2482.
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Nursing Considerations for Combination Therapy in Multiple Myeloma Charise Gleason, MSN, ANP-BC, AOCNP Nurse Practitioner Winship Cancer Institute Emory University, Atlanta, GA
Introduction Although there has been significant clinical benefit seen with newer regimens for multiple myeloma (MM), challenges remain, including the occurrence of adverse events (AEs). As a member of the cancer care team, it is the nurse’s responsibility to anticipate which toxicities and complications are likely to occur with treatment, to employ the necessary interventions, and to counsel patients accordingly. In this article, Charise Gleason, MSN, ANP-BC, AOCNP, discusses effective nursing strategies in the setting of combination antimyeloma therapy, and shares her perspectives on preventing and managing side effects related to the use of specific novel agents.
What are some of the effective supportive care strategies that can be used for controlling AEs associated with frontline combination regimens in transplant-eligible patients? Management of MM has changed dramatically with the introduction of newer therapies.1 There are currently several frontline regimens available for the treatment of transplant-eligible patients, as outlined in the latest guidelines from the National Comprehensive Cancer Network.2 Common induction regimens include bortezomib, thalidomide, and dexamethasone (VTD), lenalidomide, bortezomib, and dexamethasone (RVD), bortezomib plus dexamethasone (VD), and cyclophosphamide, bortezomib, and dexamethasone (CyBorD).2 Treatment for symptomatic myeloma is first stratified based on transplant eligibility. Clinical considerations when choosing an induction regimen include tumor burden, hypercalcemia, renal status, cytogenetic abnormalities, performance status, and preexisting comorbidities.2-4 During induction, patients may develop treatment-related toxicities such as peripheral neuropathy (PN), infection, gastrointestinal (GI) toxicities, and thrombosis (deep vein thrombosis/pulmonary embolism [DVT/PE]), all of which require careful monitoring and effective management strategies. Peripheral Neuropathy Neuropathy remains a major challenge in the treatment of patients with MM. The nursing implications related to this toxicity are far-reaching and encompass patient education, frequent monitoring of symptoms, and participation in multidisciplinary decisions to adjust drug dose or schedule, and in some cases, to interrupt or discontinue treatment. Obtaining an accurate assessment of PN at baseline is critical to patient follow-up. After baseline evaluation, close monitoring at each visit promotes early detection.5 Patient education is actually an important component of this process, since a well-informed patient knows what signs and symptoms to report to the cancer care team. Nurses must distinguish between neuropathy related to the myeloma disease process and neuropathy that is related to treatment.5 Myeloma-related PN is mainly sensory or sensorimotor; typical symptoms include paresthesias, hyperesthesias, numbness, and tingling that typically start distally and move proximally.5-8 Treatment-related PN, on the other hand, is typically symmetrical, distal, and progressive, and symptoms may vary depending on the agent being administered.5,9-15 For example, the 2 antimyeloma agents most commonly associated with PN—bortezomib and thalidomide—have different PN symptom profiles.
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Bortezomib-induced PN is predominantly sensory and mild, although up to 15% of patients report severe sensory and motor PN.5 Symptoms of bortezomib-induced PN include burning, hyperesthesia, hypoesthesia, paresthesia, discomfort, numbness, pain, and weakness.5,12,13 In contrast, thalidomide-induced PN may be permanent, and symptoms may even occur after the cessation of therapy.5,9,10 PN associated with thalidomide tends to be sensory/sensorimotor neuropathy, with tingling or painful distal paresthesia affecting the feet or hands, with a loss of sensation in the lower limbs.5 Muscle weakness or tremor may also occur.5 Both bortezomib and thalidomide have been associated with lower-extremity weakness, although this symptom is more commonly seen with thalidomide use.14,15 Bortezomib has traditionally been administered by the intravenous (IV) route, but recent data suggest that the subcutaneous (SC) route may help to minimize PN in bortezomib-treated patients.15,16 SC administration of bortezomib is comparable to IV administration in systemic availability and response rates.15,16 A randomized trial by Moreau and colleagues reported a reduction in bortezomib-induced PN with the SC route, from 53% to 38% for all grades of PN, and from 16% to 6% in grade 3 /4 PN. At our center, we are now using SC bortezomib in our induction regimens and have found a significant decrease in patient chair time. Pharmacologic treatment of PN includes the use of pregabalin, gabapentin, tricyclic antidepressants, opioids, duloxetine, and topical interventions such as local lidocaine patches, cocoa butter, or menthol ointment.17,18 Duloxetine is the first drug to be evaluated in a randomized trial to treat painful chemotherapy-induced PN. In this trial (N=231),19 Smith and colleagues observed that 5 weeks of duloxetine treatment decreased pain severity compared with placebo among patients with grade ≥1 sensory neuropathy. When documenting PN, nurses can grade severity via National Cancer Institute (NCI) toxicity criteria for neuropathy.20 These criteria are listed for peripheral motor and peripheral sensory neuropathy and are available at http://ctep. cancer.gov. Grading ranges from grade 1 (asymptomatic neuropathy with clinical observation of some deficits) to severe, symptomatic neuropathies of grade ≥3. Infection Patients with MM are at an increased risk for infection, which is the leading cause of death in this patient population.21 Any treatment that produces myelosuppression—including lenalidomide, cyclophosphomide, dexamethasone, and bortezomib—can further increase the risk of opportunistic infections. Patients need to be educated on the importance of infection control practices such as good general hygiene, hand washing, oral care, and central line maintenance. Prompt reporting of symptoms and appropriate treatment are essential to avoid severe infections and treatment interruption. Herpes zoster reactivation has been reported with bortezomib-containing regimens.22,23 Therefore, prophylaxis with an antiviral agent (eg, acyclovir) is important in regimens containing bortezomib and is effective in reducing the risk for zoster reactivation. The herpes zoster vaccination is not recommended, although patients should receive the pneumococcal and influenza vaccines.24 The use of IV immunoglobulin may help with recurrent infections, although no randomized trials support this practice. Gastrointestinal Toxicities GI toxicities such as nausea and vomiting, diarrhea, and constipation can occur with numerous antimyeloma therapies, including lenalidomide, thalidomide, and bortezomib.25 In the transplant-eligible patient who receives melphalan for conditioning in autologous stem cell transplantation, these AEs can be very severe and may lead to life-threatening GI mucositis.26 Toxicities such as these have a marked impact on quality of life and may lead to poor adherence to therapy, loss of appetite, decreased function, anxiety, and social isolation.25 The International Myeloma Foundation Nurse Leadership Board recommends routine assessment and active intervention to manage the GI effects of
CONSIDERATIONS IN MULTIPLE MYELOMA
lenalidomide, thalidomide, and bortezomib.25 Recommended assessment methodology applies NCI grading criteria to findings from history-taking, symptom self-report, examination, and laboratory testing for electrolytes and other chemistries.25 Assessment should always include an evaluation of patient-related factors that may predispose individuals to GI effects, as these may lead to exacerbation of symptoms during antimyeloma therapy. These include age (eg, >65 years for constipation and diarrhea, but <50 years for nausea) and improper diet (eg, low fiber intake for constipation), as well as additional medications, comorbidities, and surgical/medical procedures (eg, radiation therapy for emesis).25 At the outset of therapy, it is important for nurses to educate patients and caregivers on the risk for GI toxicities and on the importance of good hydration, a diet with sufficient fiber, and the basics of proper nutrition. When a GI event occurs, education on appropriate interventions such as the use of antiemetics, laxatives, or antidiarrheals should be provided, and reinforced as needed. Patients may need robust support from nurses to help them cope with the physical and psychosocial effects of these AEs and to adhere to bowel regimens and other protocols. Venous Thromboembolic Events Thrombosis is a complication observed with certain malignancies and their treatment, and it is especially common in myeloma, which may be associated with a “background” incidence of venous thromboembolic events of 5% to 10%.27,28 The immunomodulatory drugs (IMiDs) thalidomide and lenalidomide further elevate the risk of thrombosis.27-29 A review of select studies that were conducted without mandated antithrombotic prophylaxis suggests that the risk of thrombosis with thalidomide plus dexamethasone ranges from 12% to 15%— about 4 to 5 times higher than with single-agent dexamethasone.27 Similar results have been seen with lenalidomide and dexamethasone.27 Individual risk factors, quite apart from MM or antimyeloma therapy, may add substantially to patients’ risk. These additional factors include older age, previous DVT/PE, immobilization, trauma, central venous catheter, surgery, and some medications (eg, erythropoietin).28-30 Moreover, certain drugs in combination with an IMiD elevate risk; notable among these are high-dose dexamethasone and doxorubicin.30 Antithrombotic prophylaxis is generally recommended for patients receiving therapy that includes an IMiD. The current recommendation for patients with low (0-1) additional risk factors is aspirin 81 mg to 325 mg once daily; when a patient has high (≥2) additional risk factors, recommended prophylaxis is either low-molecular-weight heparin (enoxaparin 40 mg/day or its equivalent) or warfarin to an international normalized ratio of 2 to 3.30 What are some common toxicities associated with newer agents being used in the relapsed/refractory setting? At our center, we treat patients experiencing relapsed/refractory disease with several novel agents, including carfilzomib and pomalidomide. It is imperative that nurses become familiar with the toxicity profiles of these and other therapies being utilized in this setting for MM. Carfilzomib is a next-generation IV proteasome inhibitor,31 approved by the US Food and Drug Administration (FDA) for relapsed and/or refractory MM. In pivotal clinical trials, the most common AEs of all grades reported with this agent include fatigue (55.5%), anemia (46.8%), nausea (44.9%), thrombocytopenia (36.3%), dyspnea (34.6%), diarrhea (32.7%), and pyrexia (30.4%).32 Carfilzomib is associated with a lower incidence of severe PN than thalidomide or the other available proteasome inhibitor, bortezomib; incidence of grade 3 PN was 1% in clinical trials.32 Nurses who administer carfilzomib must be alert to rare but potentially serious infusion reactions and tumor lysis syndrome.32 To ward off these problems, slower infusion (eg, over ≥10 minutes), prehydration, and optional posthydration fluids, and pretreatment steroid prophylaxis are recommended approaches. Pomalidomide is a next-generation oral immunomodulatory agent that has been approved by the FDA for the treatment of relapsed and refractory MM. Pomalidomide in combination with low-dose dexamethasone has demonstrated clinical activity in patients following relapse after multiple lines of therapy, including patients who are refractory to lenalidomide and bortezomib.33-36 Common AEs reported in pivotal trials with single-agent pomalidomide include fatigue/asthenia (55%), neutropenia (52%), anemia (38%), constipation
(36%), nausea (36%), diarrhea (34%), dyspnea (34%), upper respiratory tract infection (32%), and back pain (32%).37 The risk for PN is lower with this agent than with thalidomide; the incidence of neuropathy was 10% in pivotal trials with single-agent pomalidomide. Data from a recent phase 1/2 trial showed comparable AEs with pomalidomide alone (POM) or in combination with low-dose dexamethasone (POM+LoDex).36 Discontinuations due to AEs were 7% and 12% for the 2 treatment groups, respectively. Incidence rates of PN, DVT, and renal failure reported with POM compared with POM+LoDex, respectively, were as follows: 7% vs 10%, 2% vs 1%, and 2% vs 1%. Pomalidomide should be taken without food and given at least 2 hours before/ after meals.37 Nurses should educate patients and caregivers on antithrombotic prophylaxis, infection risk, fatigue, and the importance of adhering to a consistent schedule. ♦ References
1. Kumar SK, Rajkumar SV, Dispenzieri A, et al. Improved survival in multiple myeloma and the impact of novel therapies. Blood. 2008;111:2516-2520. 2. National Comprehensive Cancer Network (NCCN). NCCN Clinical Practice Guidelines in Oncology™: Multiple Myeloma. V2.2013. http://www.nccn.org. Accessed June 2, 2013. 3. Stadtmauer EA. Tailoring initial treatment for newly diagnosed, transplantation-eligible multiple myeloma. Oncology. 2010;24(suppl 2):7-13. 4. Niesvizky R, Coleman M, Mark T. Best practices in the management of newly diagnosed multiple myeloma patients who will not undergo transplant. Oncology. 2010;24(suppl 2):14-21. 5. Richardson PG, Delforge M, Beksac M, et al. Management of treatment-emergent peripheral neuropathy in multiple myeloma. Leukemia. 2012;26:595-608. 6. Kyle RA. Monoclonal proteins in neuropathy. Neurol Clin. 1992;10:713-734. 7. Ropper AH, Gorson KC. Neuropathies associated with paraproteinemia. N Engl J Med. 1998;338:1601-1607. 8. Palumbo A, Facon T, Sonneveld P, et al. Thalidomide for treatment of multiple myeloma: 10 years later. Blood. 2008;111:3968-3977. 9. Mothy B, El-Cheikh J, Yakoub-Agha I, et al. Peripheral neuropathy and new treatments for multiple myeloma: background and practical recommendations. Haematologica. 2010;95: 311-319. 10. Thalomid [package insert]. Summit, NJ: Celgene Corporation; February 2013. 11. San Miguel JF, Richardson PG, Orlowski RZ, et al. Risk of second primary malignancies (SPMs) following bortezomib (Btz)-based therapy: analysis of four phase 3 randomized controlled trials in previously untreated or relapsed multiple myeloma (MM). Blood (ASH Annual Meeting Abstracts). 2011;118:Abstract 2933. 12. Richardson PG, Briemberg H, Jagannath S, et al. Frequency, characteristics, and reversibility of peripheral neuropathy during treatment of advanced multiple myeloma with bortezomib. J Clin Oncol. 2006;24:3113-3120. 13. Richardson PG, Sonneveld P, Schuster MW, et al. Bortezomib or high-dose dexamethasone for relapsed multiple myeloma. N Engl J Med. 2005;352:2487-2498. 14. Sonneveld P, Jongen JLM. Dealing with neuropathy in plasma-cell dyscrasias. Hematology (ASH Education Program Book). 2010:423-430. 15. Berkowitz A, Walker S. Bortezomib-induced peripheral neuropathy in patients with multiple myeloma. Clin J Oncol Nurs. 2012;16:86-89. 16. Moreau P, Pylypenko H, Grosicki S, et al. Subcutaneous versus intravenous administration of bortezomib in patients with relapsed multiple myeloma: a randomised, phase 3, non-inferiority study. Lancet Oncol. 2011;12:431-440. 17. Tariman J, Love G, McCullagh E, et al. Peripheral neuropathy associated with novel therapies in patients with multiple myeloma: consensus statement of the IMF Nurse Leadership Board. Clin J Oncol Nurs. 2008;12(suppl):29-35. 18. Delforge M, Bladé J, Dimopoulos MA, et al. Treatment-related peripheral neuropathy in multiple myeloma: the challenge continues. Lancet Oncol. 2010;11:1086-1095. 19. Smith EM, Pang H, Cirrincione C, et al. Effect of duloxetine on pain, function, and quality of life among patients with chemotherapy-induced painful peripheral neuropathy: a randomized clinical trial. JAMA. 2013;309:1359-1367. 20. National Cancer Institute Cancer Therapy Evaluation Program. Common Terminology Criteria for Adverse Events (CTCAE), v4.03. http://ctep.cancer.gov/protocolDevelopment/electronic_ applications/ctc.htm. Accessed August 7, 2013. 21. Ludwig H, Zojer N. Supportive care in multiple myeloma. Best Pract Res Clin Haematol. 2007; 20:817-835. 22. Kim SJ, Kim K, Kim BS, et al. Bortezomib and the increased incidence of herpes zoster in patients with multiple myeloma. Clin Lymphoma Myeloma. 2008;8:237-240. 23. Chanan-Khan A, Sonneveld P, Schuster MW, et al. Analysis of herpes zoster events among bortezomib-treated patients in the phase III APEX study. J Clin Oncol. 2008;26:4784-4790. 24. Wood SK, Payne JK. Cancer-related infections. J Adv Pract Oncol. 2011;2:356-371. 25. Smith LB, Bertolotti P, Curran K, et al. Gastrointestinal side effects associated with novel therapies in patients with multiple myeloma: consensus statement of the IMF Nurse Leadership Board. Clin J Oncol Nurs. 2008;12:37-51. 26. Sharma SK, Handoo A, Choudhary D, Dhamija G, Gupta N. Severe gastrointestinal mucositis following high dose melphalan therapy for multiple myeloma. World J Gastroenterol. 2013;19:784-785. 27. Zonder JA. Thrombotic complications of myeloma therapy. Hematology (ASH Education Program Book). 2006:348-355.
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Pharmacologic Considerations in the Era of Novel Therapies for Multiple Myeloma Katherine Sanvidge Shah, PharmD, BCOP Hematology/Oncology Pharmacy Specialist Winship Cancer Institute Emory University, Atlanta, GA
Introduction The development of more effective drugs has led to better response rates and prolonged survival in multiple myeloma (MM). When choosing among these therapies, it is essential to consider factors such as pharmacologic profiles and drug–drug interactions to ensure optimal patient outcomes. In this article, Katherine Sanvidge Shah, PharmD, BCOP, discusses new directions in antimyeloma treatment and provides insight into the mechanism of action of both approved and investigational agents being used in combination and sequential therapies.
What are some of the drug–drug and drug–dietary interactions that may occur with commonly used agents for MM? When patients are treated with the proteasome inhibitor (PI), bortezomib, it is important to counsel them on possible dietary modifications they may need to make. In vitro and in vivo data suggest that several components of green tea and green tea extract can antagonize the antimyeloma effectiveness of this agent.1 In MM cell lines, epigallocatechin gallate and several other polyphenols have interfered with the proteasome-inhibiting actions of bortezomib and prevented tumor cell death.2 Patients should be instructed to avoid consuming green tea and its extract while receiving concomitant bortezomib. Ascorbic acid or vitamin C is another supplement of concern.3 Studies have shown that vitamin C can inhibit the activity of bortezomib through direct binding between the hydroxyl group of the antioxidant agent and the boronic acid of the PI. This binding decreases the affinity of the PI for the chymotrypsin-like subunit of the proteasome, thus decreasing the anticancer effect.4 This was confirmed in a study by Perrone and colleagues, which showed that a dose-dependent effect of ascorbic acid decreased the effectiveness of bortezomib.5 It is recommended that patients do not exceed 500 mg of ascorbic acid a day and that they separate administration by at least 12 hours before or after bortezomib administration, given the fact that the half-life of oral ascorbic acid is 10 hours.5 In general, it is probably best to instruct patients to avoid extra vitamin C supplementation and vitamin C–containing multivitamins during bortezomib therapy. St. John’s wort (hypericum perforatum) should also be avoided, since it has the potential to induce the cytochrome P450 34A enzyme system and therefore decrease bortezomib plasma concentrations.6 A drug–drug interaction that is unavoidable due to the therapeutic efficacy of the regimen is the one that occurs when the immunomodulatory drug (IMiD) lenalidomide is combined with dexamethasone. The concern with this regimen is the significantly increased risk of thromboembolism. In 2 studies of patients with relapsed or refractory MM, the incidence of grade 3/4 venous thromboembolic events (VTEs) was significantly higher when these agents were used together than when dexamethasone was administered alone (11.4%-14.7% vs 3.4%4.6%, respectively).7,8 Currently, it appears the best options for VTE prophylaxis with this combination are low-molecular-weight heparin or warfarin (with a targeted international normalized ratio of 2-3), especially in cases in which highdose dexamethasone is prescribed.9 Aspirin is another option for VTE prophylaxis, particularly when low-dose dexamethasone is utilized.10 Of course, it is also essential to educate patients on the signs and symptoms of VTE, such as erythematous, warm, swollen, or painful extremities for deep vein thrombosis, and shortness of breath, pain upon inspiration, and cough for pulmonary embolism.10
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Can you discuss how next-generation agents may help to improve outcomes in MM? Several new agents are allowing for extended, durable responses and disease control, which are allowing patients with MM to live longer. PIs have been proven to be one of the major milestones in the MM treatment landscape, leading to improved outcomes in the frontline as well as relapsed/refractory settings. Carfilzomib, a next-generation PI, differs from bortezomib in that it exhibits irreversible and sustained inhibition on the proteasome, is more potent, and is more selective in its action, which may translate to fewer side effects such as neuropathy.11 On July 20, 2012, the US Food and Drug Administration granted accelerated approval to carfilzomib for the treatment of patients with MM who have received at least 2 prior therapies, including bortezomib and an IMiD, and have demonstrated disease progression on or within 60 days of the completion of the last therapy. Approval was based on results of the open-label, single-arm phase 2b study, PX-171-003-A1. The overall response rate (ORR) was 22.9%, with a duration of response of 7.8 months.11 Although carfilzomib is currently approved at a standard dose of 27 mg/m2 infused over 2 to 10 minutes, it is being investigated at higher doses with a prolonged infusion time of 30 minutes to prevent infusion-related reactions. Due to the projected shortage of oncologists/nurses and the potential for decreased availability of infusion sites, increased efforts into the safety and efficacy of oral chemotherapeutic options is essential. Fortunately, there are several orally bioavailable PIs currently under investigation. MLN9708 (ixazomib), an orally available, second-generation PI, is a dipeptidyl boronic acid that is rapidly hydrolyzed in water and converts into MLN2238, the active form which potently, reversibly, and selectively inhibits the proteasome, primarily binding to the β5 subunit of the 20S proteasome. MLN9708 exhibits a shorter proteasome dissociation half-life (18 minutes vs 110 minutes), a larger volume of distribution, and increased pharmacodynamic effects in tissues compared with bortezomib.12 This agent is the first oral PI to enter clinical trials, and it is currently being evaluated in both once-weekly and biweekly schedules in the relapsed/refractory setting.13-15 In addition, the upcoming phase 3, randomized, double-blind, multicenter, TOURMALINEMM2 trial will compare MLN9708 plus lenalidomide and dexamethasone with placebo plus lenalidomide and dexamethasone in nontransplant patients with newly diagnosed MM. Another orally available PI currently under investigation is ONX-0912 (oprozomib), a structural analog of carfilzomib that is currently being investigated in phase 1 and 2 trials (See Table).16 Pomalidomide is a novel, third-generation IMiD, with immunomodulatory, antiangiogenic, and direct antimyeloma activity. Created by chemical modifications to the structural backbone of thalidomide, pomalidomide exhibits more potent anti-inflammatory activity and appears to demonstrate a more favorable toxicity profile.17 This has translated into clinical efficacy even in heavily pretreated patients. For example, Jagannath and colleagues recently reported on results of a multicenter, randomized, open-label phase 2 study (MM-002) evaluating the safety and efficacy of pomalidomide (POM) alone or in combination with low-dose dexamethasone (POM+LoDEX) in 221 patients with relapsed and refractory MM who have received multiple prior therapies, including lenalidomide and bortezomib.18 ORRs were 34% in the POM+LoDEX group and 15% in the POM alone group. The median duration of response (for patients who achieved ≥PR) was 45 months in the POM+LoDEX group and 31 months in the POM group. Results of a subanalysis based on age (≥65 years vs <65 years) showed that age had no impact on the duration or depth of response. The median progression-free survival for the overall population was 4.6 months for those who received POM+LoDEX and 2.6 months for those who received POM.
CONSIDERATIONS IN MULTIPLE MYELOMA
Table. Next-generation Oral Proteasome Inhibitors for MM16
or improvement to PR. Grade 3/4 AEs included thrombocytopenia (64%) and peripheral neuropathy (8%).23 ♦
Pattern of Inhibition
Clinical Trial Investigation
Phase 1, 2, and 3
Fatigue, thrombocytopenia, N/V, diarrhea
Phase 1 and 2
N/V, diarrhea, abdominal pain, fatigue, decreased appetite
MM indicates multiple myeloma; N/V, nausea/vomiting.
What investigational histone deacetylase inhibitors are showing promise in MM? Histone deacetylase (HDAC) inhibitors promote the acetylation of histone proteins, thereby decondensing chromatin to its active form and reversing epigenetic silencing of transcription factors and tumor suppressor genes which regulate cell growth. HDAC inhibitors have been shown to inhibit proliferation and induce apoptosis in MM cell lines. Although HDAC inhibitors have failed to improve outcomes when used as single agents, they appear to be synergistic both in vitro and in vivo when combined with other anti-MM agents, particularly PIs. The molecular basis underlying this synergism appears to be multifactorial and involves interference with protein degradation as well as the interaction of myeloma cells with microenvironment.19 Vorinostat has been evaluated in the Vorinostat Clinical Trials in Hematologic and Solid Malignancies (VANTAGE) study program. The phase 2 VANTAGE 095 trial evaluated this agent in combination with bortezomib in bortezomib-refractory patients with MM (>2 prior therapies, N=143).20 Results suggest that the combination of vorinostat and bortezomib is active in patients whose disease is considered refractory to prior bortezomib and IMiDs, with an ORR of 17% reported in this trial. The median overall survival (OS) was 11.2 months with a 2-year OS rate of 32%. This combination therapy was generally well tolerated, with thrombocytopenia and gastrointestinal toxicities being the most common adverse events (AEs) reported. The safety and efficacy of panobinostat in combination with carfilzomib is being evaluated in a phase 1/1b trial in patients with relapsed/refractory MM.21 The primary grade ≥3 toxicities were hematologic (thrombocytopenia, anemia, and neutropenia) and were manageable. Clinical benefit rate was determined to be 38%. Additionally, the triplet combination of panobinostat, bortezomib, and dexamethasone is currently being evaluated in a phase 3, randomized, placebo-controlled trial (PANORAMA-1).22 Romidepsin has also been investigated as triple therapy with bortezomib and dexamethasone in a phase 1/2 trial of patients with relapsed or refractory MM (patients having received ≥1 previous therapy). Encouraging activity was observed, with 72% of patients experiencing a minor response or better, and 4 of 6 patients (67%) who were refractory to bortezomib achieving disease stability
1. Liu FT, Agrawal SG, Movasaghi Z, et al. Dietary flavonoids inhibit the anticancer effects of the proteasome inhibitor bortezomib. Blood. 2008;112:3835-3846. 2. Golden EB, Lam PY, Kardosh A, et al. Green tea polyphenols block the anticancer effects of bortezomib and other boronic acid-based proteasome inhibitors. Blood. 2009;113:5927-5937. 3. Catley L, Anderson KC. Velcade and vitamin C: too much of a good thing? Clin Cancer Res. 2006;12:3-4. 4. Llobet D, Eritja N, Encinas M, et al. Antioxidants block proteasome inhibitor function in endometrial carcinoma cells. Anticancer Drugs. 2008;19:115-124. 5. Perrone G, Hideshima T, Ikeda H, et al. Ascorbic acid inhibits antitumor activity of bortezomib in vivo. Leukemia. 2009;23:1679-1686. 6. Velcade (bortezomib) for Injection. Detailed View: Safety Labeling Changes Approved by FDA Center for Drug Evaluation and Research (CDER). www.fda.gov/Safety/MedWatch/ SafetyInformation/SafetyRelatedDrugLabelingChanges/ucm123444.htm. Accessed August 6, 2013. 7. Dimopoulos M, Spencer A, Attal M, et al. Lenalidomide plus dexamethasone for relapsed or refractory multiple myeloma. N Engl J Med. 2007;357:2123-2132. 8. Weber DM, Chen C, Niesvizky R, et al. Lenalidomide plus dexamethasone for relapsed multiple myeloma in North America. N Engl J Med. 2007;357:2133-2142. 9. Palumbo A, Rajkumar SV, Dimopoulos MA, et al. Prevention of thalidomide- and lenalidomide-associated thrombosis in myeloma. Leukemia. 2008;22:414-423. 10. Hirsh J. Risk of thrombosis with lenalidomide and its prevention with aspirin. Chest. 2007;131:275-277. 11. diCapua Siegel DS, Martin T, Wang M, et al. Results of PX-171-003-A1, an open-label, single-arm, phase 2 (Ph 2) study of carfilzomib (CFZ) in patients (pts) with relapsed and refractory multiple myeloma (MM). Blood (ASH Annual Meeting Abstracts). 2010;116:Abstract 985. 12. Kupperman E, Lee EC, Cao Y, et al. Evaluation of the proteasome inhibitor MLN9708 in preclinical models of human cancer. Cancer Res. 2010;70:1970-1980. 13. Kumar S, Bensinger WI, Reeder CB, et al. Weekly dosing of the investigational oral proteasome inhibitor MLN9708 in patients with relapsed and/or refractory multiple myeloma: results from a phase 1 dose-escalation study. Blood (ASH Annual Meeting Abstracts). 2011;118:Abstract 816. 14. Richardson PG, Baz R, Wang L, et al. Investigational agent MLN9708, an oral proteasome inhibitor, in patients (Pts) with relapsed and/or refractory multiple myeloma (MM): results from the expansion cohorts of a phase 1 dose-escalation study. Blood (ASH Annual Meeting Abstracts). 2011;118:Abstract 301. 15. Lonial S, Baz RC, Wang M, et al. Phase I study of twice-weekly dosing of the investigational oral proteasome inhibitor MLN9708 in patients (pts) with relapsed and/or refractory multiple myeloma (MM). J Clin Oncol. 2012;30:Abstract 8017. 16. Lawasut P, Chauhan D, Laubach J, Hayes C, et al. New proteasome inhibitors in myeloma. Curr Hematol Malig Rep. 2012;7:258-266. 17. Schey S, Ramasamy K. Pomalidomide therapy for myeloma. Expert Opin Investig Drugs. 2011;20:691-700. 18. Jagannath S, Richardson PG, Hofmeister C, et al. Pomalidomide with or without low-dose dexamethasone in relapsed and refractory multiple myeloma: updated analysis. Haematologica. 2013;13(suppl 1):S143-S144. Poster P-210. 19. Hideshima T, Richardson PG, Anderson KC. Mechanism of action of proteasome inhibitors and deacetylase inhibitors and the biological basis of synergy in multiple myeloma. Mol Cancer Ther. 2011;10:2034-2042. 20. Siegel DS, Dimopoulos MA, Yoon SS, et al. VANTAGE 095: Final results from a global, single-arm, phase 2b trial of vorinostat in combination with bortezomib in salvage multiple myeloma patients. Haematologica. 2012;97(supp 1):119. Abstract 0294. 21. Shah JJ, Thomas SK, Weber DM, et al. Phase 1/1b study of the efficacy and safety of the combination of panobinostat + carfilzomib in patients with relapsed and/or refractory multiple myeloma. Blood (ASH Annual Meeting Abstracts). 2012;120:Abstract 4081. 22. Panobinostat or placebo with bortezomib and dexamethasone in patients with relapsed multiple myeloma (PANORAMA-1). NCT01023308. http://clinicaltrials.gov/ct2/show/NCT01023308. Accessed August 6, 2013. 23. Harrison SJ, Quach H, Link E, et al. A high rate of durable responses with romidepsin, bortezomib, and dexamethasone in relapsed or refractory multiple myeloma. Blood. 2011; 118:6274-6283.
Nursing Considerations for Combination Therapy in Multiple Myeloma
Continued from page 15
28. Kristinsson SY. Thrombosis in multiple myeloma. Hematology (ASH Education Program Book). 2010:437-444. 29. Boyle EM, Fouquet G, Manier S, et al. Immunomodulator drug-based therapy in myeloma and the occurrence of thrombosis. Expert Rev Hematol. 2012;5:617-626. 30. Palumbo A, Rajkumar SV, Dimopoulos MA, et al. Prevention of thalidomide- and lenalidomide-associated thrombosis in myeloma. Leukemia. 2008;22:414-423. 31. Nooka A, Gleason C, Casbourne D, Lonial S. Relapsed and refractory lymphoid neoplasms and multiple myeloma with a focus on carfilzomib. Biologics Targets Ther. 2013;7:13-32. 32. Kyprolis [package insert]. South San Francisco, CA: Onyx Pharmaceuticals; July 2012. 33. Lacy MQ, Hayman SR, Gertz MA, et al. Pomalidomide (CC4047) plus low dose dexamethasone (Pom/dex) is active and well tolerated in lenalidomide refractory multiple myeloma (MM). Leukemia. 2010;24:1934-1939.
34. Lacy M, Gertz MA, Hayman SR, et al. Activity of pomalidomide plus dexamethasone (Pom/ dex) in dual lenalidomide/bortezomib refractory multiple myeloma (MM). J Clin Oncol (ASCO Annual Meeting Proceedings). 2010;28(suppl):Abstract 8002. 35. Lacy MQ, Hayman SR, Gertz MA, et al. Pomalidomide (CC4047) plus low-dose dexamethasone (Pom/dex) is highly effective therapy in relapsed multiple myeloma. Blood (ASH Annual Meeting Abstracts). 2008;112:Abstract 866. 36. Richardson PG, Siegel DS, Vij R, et al. Randomized, open label phase 1/2 study of pomalidomide (POM) alone or in combination with low-dose dexamethasone (LoDex) in patients (pts) with relapsed and refractory multiple myeloma who have received prior treatment that includes lenalidomide (LEN) and bortezomib (BORT): phase 2 results. Blood (ASH Annual Meeting Abstracts). 2011;118:Abstract 634. 37. Pomalyst [package insert]. Summit, NJ: Celgene Corporation; February 2013.
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Genetic Testing for BRCA1/2 Continued from cover are currently believed to account for the majority of known hereditary breast and ovarian cancer cases, it is estimated that between 10% and 25% of individuals with breast cancer have an underlying gene mutation that has placed him or her at an increased risk of developing breast cancer. The risk conveyed by the gene mutation may increase breast cancer risk anywhere from 2- to 20+-fold.1 Additionally, individuals may be at risk for a variety of other cancers, including skin, colorectal, uterine, ovarian, prostate, thyroid, etc. For this reason, it is imperative that an individual deemed at risk for a hereditary breast cancer syndrome be assessed for all possible syndromes via targeted genetic testing. Genetic diagnosis allows an individual’s healthcare team to develop a personalized surveillance and treatment plan targeting the cancers he or she is at high risk of developing. Additionally, it allows family members to be tested for the familial mutation in the family.
It is imperative that an individual deemed at risk for a hereditary breast cancer syndrome be assessed for all possible syndromes via targeted genetic testing.
that negatively affect gene function. Myriad Genetics enhanced their BRCA1/2 test in August 2002 to include 5 large rearrangements, followed in August 2006 by the addition of the BRACAnalysis Large Rearrangement Test, also known as BART, on select high-risk samples and for patients who elected to have the test.6 In 2012, the test began to shift to
Important Safety Information WARNINGS AND PRECAUTIONS: • Treatment with ISTODAX has been associated with thrombocytopenia, leukopenia (neutropenia and lymphopenia), and anemia; therefore, monitor these hematological parameters during treatment with ISTODAX and modify the dose as necessary • Serious and sometimes fatal infections have been reported during treatment and within 30 days after treatment with ISTODAX and the risk of life threatening infections may be higher in patients with a history of extensive or intensive chemotherapy • Electrocardiographic (ECG) changes have been observed with ISTODAX • In patients with congenital long QT syndrome, a history of significant cardiovascular disease, and patients taking anti-arrhythmic medicines or medicinal products that lead to significant QT prolongation, appropriate cardiovascular monitoring precautions should be considered, such as monitoring electrolytes and ECGs at baseline and periodically during treatment • Ensure that potassium and magnesium are within the normal range before administration of ISTODAX • Tumor lysis syndrome has been reported during treatment with ISTODAX. Patients with advanced stage disease and/or high tumor burden should be closely monitored and appropriate precautions taken, and treatment should be instituted as appropriate • ISTODAX may cause fetal harm when administered to a pregnant woman. Advise women to avoid pregnancy while receiving ISTODAX. If this drug is used during pregnancy, or if the patient becomes pregnant while taking ISTODAX, the patient should be apprised of the potential hazard to the fetus (Pregnancy Category D) ADVERSE REACTIONS: Peripheral T-Cell Lymphoma The most common Grade 3/4 adverse reactions (>5%) regardless of causality in Study 3 (N=131) were thrombocytopenia (24%), neutropenia (20%), anemia (11%), asthenia/fatigue (8%), and leukopenia (6%), and in Study 4 (N=47) were neutropenia (47%), leukopenia (45%), thrombocytopenia (36%), anemia (28%), asthenia/fatigue (19%), pyrexia (17%), vomiting (9%), and nausea (6%). Infections were the most common type of serious adverse event reported in Study 3 (N=131) and Study 4 (N=47). In Study 3, 25 patients (19%) experienced a serious infection, including 6 patients (5%) with serious treatment-related infections. In Study 4, 11 patients (23%) experienced a serious infection, including 8 patients (17%) with serious treatment-related infections. The most common adverse reactions regardless of causality in Study 3 (N=131) were nausea (59%), asthenia/fatigue (55%), thrombocytopenia (41%), vomiting (39%), diarrhea (36%), and pyrexia (35%), and in Study 4 (N=47) were asthenia/fatigue (77%), nausea (75%),
thrombocytopenia (72%), neutropenia (66%), anemia (62%), leukopenia (55%), pyrexia (47%), anorexia (45%), vomiting (40%), constipation (40%), and diarrhea (36%).
Cutaneous T-Cell Lymphoma The most common Grade 3/4 adverse reactions (>5%) regardless of causality in Study 1 (N=102) were infections (11%) and asthenia/fatigue (8%), and in Study 2 (N=83) were lymphopenia (37%), infections (33%), neutropenia (27%), leukopenia (22%), anemia (16%), asthenia/fatigue (14%), thrombocytopenia (14%), hypophosphatemia (10%), vomiting (10%), dermatitis/exfoliative dermatitis (8%), hypermagnesemia (8%), hyperuricemia (8%), hypocalcemia (6%), nausea (6%), and pruritus (6%). Infections were the most common type of serious adverse event reported in both Study 1 (N=102) and Study 2 (N=83) with 8 patients (8%) in Study 1 and 26 patients (31%) in Study 2 experiencing a serious infection. The most common adverse reactions regardless of causality in Study 1 (N=102) were nausea (56%), asthenia/fatigue (53%), infections (46%), vomiting (34%), and anorexia (23%) and in Study 2 (N=83) were nausea (86%), asthenia/fatigue (77%), anemia (72%), thrombocytopenia (65%), ECG ST-T wave changes (63%), neutropenia (57%), lymphopenia (57%), infections (54%), anorexia (54%), vomiting (52%), hypocalcemia (52%), hyperglycemia (51%), hypoalbuminemia (48%), leukopenia (46%), dysgeusia (40%), and constipation (39%). DRUG INTERACTIONS: • ISTODAX is metabolized by CYP3A4. Avoid concomitant use with strong CYP3A4 inhibitors and potent CYP3A4 inducers if possible • Caution should also be exercised with concomitant use of moderate CYP3A4 inhibitors and P-glycoprotein (P-gp, ABCB1) inhibitors • Physicians should carefully monitor prothrombin time (PT) and International Normalized Ratio (INR) in patients concurrently administered ISTODAX and warfarin sodium derivatives USE IN SPECIFIC POPULATIONS: • Because many drugs are excreted in human milk and because of the potential for serious adverse reactions in nursing infants from ISTODAX, a decision should be made whether to discontinue nursing or discontinue the drug, taking into account the importance of the drug to the mother • Patients with moderate and severe hepatic impairment and/or patients with end-stage renal disease should be treated with caution
Please see full Prescribing Information, including WARNINGS AND PRECAUTIONS and ADVERSE REACTIONS.
ISTODAX® is a registered trademark of Celgene Corporation. ©2012 Celgene Corporation 09/12 US-IST120024
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If you were tested several years ago or longer and were found to be negative for BRCA1 and BRCA2, are there new tests available to determine if you truly have an inherited gene mutation? What is BART? Yes. The field of inherited cancer genetics is constantly evolving. Individuals considered at risk to carry an inherited gene mutation should contact their
ing on the group analyzed, up to 10% of mutations may be large deletions or duplications.6 Most of these large rearrangements cannot be detected by traditional polymerase chain reaction (PCR)–based sequencing reactions. Therefore, depending on the methods of gene analysis used, B:8.75”a separate test may be needed to findT:8.125” large rearrangements
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Is Myriad Genetics the only laboratory that performs BRCA1/2 testing? BRCA testing became commercially available in 1996, and Myriad Genetics was granted patents on BRCA1/2 in the late 1990s. As a result, Myriad quickly became the sole provider of BRCA1/2 testing in the United States.2-4 However, on June 13, 2013, the US Supreme Court ruled that naturally occurring DNA is not patent eligible merely because it has been isolated, as it is a product of nature.5 As a result, Ambry Genetics and the University of Washington began offering BRCA1/2 testing that week, with many other laboratories announcing plans to offer testing for BRCA1/2 shortly.
genetic provider on an annual basis to determine if new tests are available. Depending on when an individual underwent testing for BRCA1/2 mutations, he or she may need additional testing for BRCA1/2. Germline mutations in BRCA1/2 are typically single-base changes or small deletions/insertions; however, depend-
Genetic Counseling Integrated BRACAnalysis, reflecting the inclusion of BART as part of BRCA1/2 gene analysis.7 Therefore, depending on when an individual underwent testing for BRCA1/2 mutations, he or she may not have had the most comprehensive test, and additional testing for BRCA1/2 mutations may be warranted. National guidelines reference consideration of other inherited cancer syndromes, such as those caused by
mutations in the TP53 and PTEN genes, when BRCA1/2 test results are negative.8 Similar to BRCA1/2, these genes place an individual at increased risk of developing breast cancer; however, they also place an individual at high risk for other cancers, such as sarcomas, brain tumors, uterine cancer, thyroid cancer, and colorectal cancer. Additionally, “inherited cancer panels,” which became commercially available
in the spring of 2012, examine multiple genes associated with an inherited risk of developing a cancer. The genes included on any given panel vary depending on the laboratory performing the test and the cancer sites of interest and may include both moderately and highly penetrant genes. For example, a recent abstract presented at the 2013 American Society of Clinical Oncology Annual Meeting evaluated 249 African
American breast cancer survivors referred for genetic counseling for mutations in 18 known breast cancer genes using a “cancer panel.”9 Almost 1 in 4 study participants (22%) were found to carry a germline mutation, including mutations in BRCA1, BRCA2, CHEK2, PALB2, ATM, and PTEN. Therefore, individuals with negative BRCA1/2 test results who were not assessed for genes other Continued on page 20
INDICATIONS THE FIRST AND ONLY • Treatment of peripheral T-cell lymphoma (PTCL) in patients DRUG APPROVED IN BOTH who have received at least one prior therapy PTCL AND CTCL • Treatment of cutaneous T-cell lymphoma (CTCL) in patients who have received at least one prior systemic therapy These indications are based on response rate. Clinical benefit such as improvement in overall survival has not been demonstrated.
RECHARGE THE POSSIBILITIES
www.istodax.com Please see Important Safety Information on adjacent page. Please see Brief Summary of full Prescribing Information on following pages.
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Genetic Testing for BRCA1/2 Continued from page 19 than BRCA1/2 should contact their provider to determine if further genetic testing for other genes is warranted. If you are a breast cancer survivor of several years, would it be beneficial to have genetic counseling/testing?
Genetic testing has medical management implications for survivors and/or family members at every stage of the cancer continuum. For newly diagnosed women with breast cancer, a genetic diagnosis may affect surgical decisions and/or the use of radiotherapy. For survivors of several
years, a woman may opt to have a risk-reducing mastectomy or undergo increased breast surveillance. Additionally, testing may uncover other types of cancers she is at increased risk of developing. Knowing this information allows her healthcare team to work with her to develop a per-
ISTODAX® (romidepsin) for injection For intravenous infusion only The following is a brief summary only; see full prescribing information for complete product information. 1 INDICATIONS AND USAGE ISTODAX is indicated for: • Treatment of cutaneous T-cell lymphoma (CTCL) in patients who have received at least one prior systemic therapy. • Treatment of peripheral T-cell lymphoma (PTCL) in patients who have received at least one prior therapy. These indications are based on response rate. Clinical benefit such as improvement in overall survival has not been demonstrated. 2 DOSAGE AND ADMINISTRATION 2.1 Dosing Information The recommended dose of romidepsin is 14 mg/m2 administered intravenously over a 4-hour period on days 1, 8 and 15 of a 28-day cycle. Cycles should be repeated every 28 days provided that the patient continues to benefit from and tolerates the drug. 2.2 Dose Modification Nonhematologic toxicities except alopecia • Grade 2 or 3 toxicity: Treatment with romidepsin should be delayed until toxicity returns to ≤Grade 1 or baseline, then therapy may be restarted at 14 mg/m2. If Grade 3 toxicity recurs, treatment with romidepsin should be delayed until toxicity returns to ≤Grade 1 or baseline and the dose should be permanently reduced to 10 mg/m2. • Grade 4 toxicity: Treatment with romidepsin should be delayed until toxicity returns to ≤Grade 1 or baseline, then the dose should be permanently reduced to 10 mg/m2. • Romidepsin should be discontinued if Grade 3 or 4 toxicities recur after dose reduction. Hematologic toxicities • Grade 3 or 4 neutropenia or thrombocytopenia: Treatment with romidepsin should be delayed until the specific cytopenia returns to ANC ≥1.5×109/L and/or platelet count ≥75×109/L or baseline, then therapy may be restarted at 14 mg/m2. • Grade 4 febrile (≥38.5°C) neutropenia or thrombocytopenia that requires platelet transfusion: Treatment with romidepsin should be delayed until the specific cytopenia returns to ≤Grade 1 or baseline, and then the dose should be permanently reduced to 10 mg/m2. 2.3 Instructions for Preparation and Intravenous Administration ISTODAX should be handled in a manner consistent with recommended safe procedures for handling cytotoxic drugs. 4 CONTRAINDICATIONS None. 5 WARNINGS AND PRECAUTIONS 5.1 Hematologic Treatment with ISTODAX can cause thrombocytopenia, leukopenia (neutropenia and lymphopenia), and anemia; therefore, these hematological parameters should be monitored during treatment with ISTODAX, and the dose should be modified, as necessary [See Dosage and Administration (2.2) and Adverse Reactions (6)]. 5.2 Infection Serious and sometimes fatal infections, including pneumonia and sepsis, have been reported in clinical trials with ISTODAX. These can occur during treatment and within 30 days after treatment, and the risk of life threatening infections may be higher in patients with a history of extensive or intensive chemotherapy [See Adverse Reactions (6)]. 5.3 Electrocardiographic Changes Several treatment-emergent morphological changes in ECGs (including T-wave and ST-segment changes) have been reported in clinical studies. The clinical significance of these changes is unknown [See Adverse Reactions (6)]. In patients with congenital long QT syndrome, patients with a history of significant cardiovascular disease, and patients taking anti-arrhythmic medicines or medicinal products that lead to significant QT prolongation, appropriate cardiovascular monitoring precautions should be considered, such as the monitoring of electrolytes and ECGs at baseline and periodically during treatment. Potassium and magnesium should be within the normal range before administration of ISTODAX [See Adverse Reactions (6)]. 5.4 Tumor Lysis Syndrome Tumor lysis syndrome (TLS) has been reported to occur in 1% of patients with tumor stage CTCL and 2% of patients with Stage III/IV PTCL. Patients
sonalized management plan that prevents future cancers or diagnoses them at the earliest, most treatable stage. Genetic testing in the palliative care setting is also beneficial. If a causative gene mutation is identified, this information allows family members to be tested and, if results are
with advanced stage disease and/or high tumor burden should be closely monitored, appropriate precautions should be taken, and treatment should be instituted as appropriate. 5.5 Use in Pregnancy There are no adequate and well-controlled studies of ISTODAX in pregnant women. However, based on its mechanism of action and findings in animals, ISTODAX may cause fetal harm when administered to a pregnant woman. In an animal reproductive study, romidepsin was embryocidal and resulted in adverse effects on the developing fetus at exposures below those in patients at the recommended dose of 14 mg/m2/week. If this drug is used during pregnancy, or if the patient becomes pregnant while taking ISTODAX, the patient should be apprised of the potential hazard to the fetus [See Use in Specific Populations (8.1)]. 6 ADVERSE REACTIONS 6.1 Clinical Trials Experience Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice. Cutaneous T-Cell Lymphoma The safety of ISTODAX was evaluated in 185 patients with CTCL in 2 single arm clinical studies in which patients received a starting dose of 14 mg/m2. The mean duration of treatment in these studies was 5.6 months (range: <1 to 83.4 months).
Common Adverse Reactions Table 1 summarizes the most frequent adverse reactions (> 20%) regardless of causality using the National Cancer Institute-Common Terminology Criteria for Adverse Events (NCI-CTCAE, Version 3.0). Due to methodological differences between the studies, the AE data are presented separately for Study 1 and Study 2. Adverse reactions are ranked by their incidence in Study 1. Laboratory abnormalities commonly reported (> 20%) as adverse reactions are included in Table 1. Table 1. Adverse Reactions Occurring in >20% of Patients in Either CTCL Study (N=185) Study 1 Study 2 (n=102) (n=83) Grade 3 Grade 3 Adverse Reactions n (%) All or 4 All or 4 Any adverse reaction 99 (97) 36 (35) 83 (100) 68 (82) Nausea 57 (56) 3 (3) 71 (86) 5 (6) Asthenia/Fatigue 54 (53) 8 (8) 64 (77) 12 (14) Infections 47 (46) 11 (11) 45 (54) 27 (33) Vomiting 35 (34) 1 (<1) 43 (52) 8 (10) Anorexia 23 (23) 1 (<1) 45 (54) 3 (4) Hypomagnesemia 22 (22) 1 (<1) 23 (28) 0 Diarrhea 20 (20) 1 (<1) 22 (27) 1 (1) Pyrexia 20 (20) 4 (4) 19 (23) 1 (1) Anemia 19 (19) 3 (3) 60 (72) 13 (16) Thrombocytopenia 17 (17) 0 54 (65) 12 (14) Dysgeusia 15 (15) 0 33 (40) 0 Constipation 12 (12) 2 (2) 32 (39) 1 (1) Neutropenia 11 (11) 4 (4) 47 (57) 22 (27) Hypotension 7 (7) 3 (3) 19 (23) 3 (4) Pruritus 7 (7) 0 26 (31) 5 (6) Hypokalemia 6 (6) 0 17 (20) 2 (2) Dermatitis/Exfoliative dermatitis 4 (4) 1 (<1) 22 (27) 7 (8) Hypocalcemia 4 (4) 0 43 (52) 5 (6) Leukopenia 4 (4) 0 38 (46) 18 (22) Lymphopenia 4 (4) 0 47 (57) 31 (37) Alanine aminotransferase increased 3 (3) 0 18 (22) 2 (2) Aspartate aminotransferase increased 3 (3) 0 23 (28) 3 (4) Hypoalbuminemia 3 (3) 1 (<1) 40 (48) 3 (4) Electrocardiogram ST-T wave changes 2 (2) 0 52 (63) 0 Hyperglycemia 2 (2) 2 (2) 42 (51) 1 (1) Hyponatremia 1 (<1) 1 (<1) 17 (20) 2 (2) Hypermagnesemia 0 0 22 (27) 7 (8) Hypophosphatemia 0 0 22 (27) 8 (10) Hyperuricemia 0 0 27 (33) 7 (8)
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Genetic Counseling positive, for them to take preventive steps. If test results are negative, the family members may not need increased screening for cancer. Sometimes an individual in palliative care is the only cancer survivor available for genetic testing. As genetic testing is most informative when it is performed on the individual most likely to have an inherited gene muta-
tion, the option of testing a survivor is no longer an option after he or she passes. l References
1. Hollestelle A, Wasielewski M, Martens JW, et al. Discovering moderate-risk breast cancer susceptibility genes. Curr Opin Genet Dev. 2010;20(3):268-276. 2. Williams-Jones B. History of a gene patent: tracing the development and application of commercial BRCA testing. Health Law J. 2002;10:123-146. 3. American Civil Liberties Union (ACLU). Legal challenge to human gene patents: BRCA genes and pat-
Serious Adverse Reactions Infections were the most common type of SAE reported in both studies with 8 patients (8%) in Study 1 and 26 patients (31%) in Study 2 experiencing a serious infection. Serious adverse reactions reported in > 2% of patients in Study 1 were sepsis and pyrexia (3%). In Study 2, serious adverse reactions in > 2% of patients were fatigue (7%), supraventricular arrhythmia, central line infection, neutropenia (6%), hypotension, hyperuricemia, edema (5%), ventricular arrhythmia, thrombocytopenia, nausea, leukopenia, dehydration, pyrexia, aspartate aminotransferase increased, sepsis, catheter related infection, hypophosphatemia and dyspnea (4%). Most deaths were due to disease progression. In Study 1, there were two deaths due to cardiopulmonary failure and acute renal failure. In Study 2, there were six deaths due to infection (4), myocardial ischemia, and acute respiratory distress syndrome. Discontinuations Discontinuation due to an adverse event occurred in 21% of patients in Study 1 and 11% in Study 2. Discontinuations occurring in at least 2% of patients in either study included infection, fatigue, dyspnea, QT prolongation, and hypomagnesmia. Peripheral T-Cell Lymphoma The safety of ISTODAX was evaluated in 178 patients with PTCL in a sponsor-conducted pivotal study (Study 3) and a secondary NCI-sponsored study (Study 4) in which patients received a starting dose of 14 mg/m2. The mean duration of treatment and number of cycles in these studies were 5.6 months and 6 cycles. Common Adverse Reactions Table 2 summarizes the most frequent adverse reactions (≥ 10%) regardless of causality, using the NCI-CTCAE, Version 3.0. The AE data are presented separately for Study 3 and Study 4. Laboratory abnormalities commonly reported (≥ 10%) as adverse reactions are included in Table 2. Table 2. Adverse Reactions Occurring in ≥10% of Patients with PTCL in Study 3 and Corresponding Incidence in Study 4 (N=178) Study 3 Study 4 (N=131) (N=47) Grade 3 Grade 3 Adverse Reactions n (%) All or 4 All or 4 Any adverse reactions 127 (97) 86 (66) 47 (100) 40 (85) Gastrointestinal disorders Nausea 77 (59) 3 (2) 35 (75) 3 (6) Vomiting 51 (39) 6 (5) 19 (40) 4 (9) Diarrhea 47 (36) 3 (2) 17 (36) 1 (2) Constipation 39 (30) 1 (<1) 19 (40) 1 (2) Abdominal pain 18 (14) 3 (2) 6 (13) 1 (2) Stomatitis 13 (10) 0 3 (6) 0 General disorders and administration site conditions Asthenia/Fatigue 72 (55) 11 (8) 36 (77) 9 (19) Pyrexia 46 (35) 7 (5) 22 (47) 8 (17) Chills 14 (11) 1 (<1) 8 (17) 0 Edema peripheral 13 (10) 1 (<1) 3 (6) 0 Blood and lymphatic system disorders Thrombocytopenia 53 (41) 32 (24) 34 (72) 17 (36) Neutropenia 39 (30) 26 (20) 31 (66) 22 (47) Anemia 32 (24) 14 (11) 29 (62) 13 (28) Leukopenia 16 (12) 8 (6) 26 (55) 21 (45) Metabolism and nutrition disorders Anorexia 37 (28) 2 (2) 21 (45) 1 (2) Hypokalemia 14 (11) 3 (2) 8 (17) 1 (2) Nervous system disorders Dysgeusia 27 (21) 0 13 (28) 0 Headache 19 (15) 0 16 (34) 1 (2) Respiratory, thoracic and mediastinal disorders Cough 23 (18) 0 10 (21) 0 Dyspnea 17 (13) 3 (2) 10 (21) 2 (4) Investigations Weight decreased 13 (10) 0 7 (15) 0 Cardiac disorders Tachycardia 13 (10) 0 0 0
ents—frequently asked questions. http://www.aclu.org/ files/pdfs/freespeech/brca_qanda.pdf. Published May 27, 2009. Accessed July 23, 2013. 4. Kesselheim AS, Mello MM. Gene patenting—is the pendulum swinging back? N Engl J Med. 2010; 362(20):1855-1858. 5. Association for Molecular Pathology et al v Myriad Genetics, Inc., et al, 569 US 1 2 (2013). http://www.supremecourt.gov/ opinions/12pdf/12-398_1b7d.pdf. Accessed July 23, 2013. 6. Judkins T, Rosenthal E, Arnell C, et al. Clinical significance of large rearrangements in BRCA1 and BRCA2. Cancer. 2012;118(21):5210-5216. 7. Myriad Genetic Laboratories, Inc. Integrated
Serious Adverse Reactions Infections were the most common type of SAE reported. In Study 3, 25 patients (19%) experienced a serious infection, including 6 patients (5%) with serious treatment-related infections. In Study 4, 11 patients (23%) experienced a serious infection, including 8 patients (17%) with serious treatment-related infections. Serious adverse reactions reported in ≥ 2% of patients in Study 3 were pyrexia (7%), pneumonia, sepsis, vomiting (5%), cellulitis, deep vein thrombosis, (4%), febrile neutropenia, abdominal pain (3%), chest pain, neutropenia, pulmonary embolism, dyspnea, and dehydration (2%). In Study 4, serious adverse reactions in ≥ 2 patients were pyrexia (17%), aspartate aminotransferase increased, hypotension (13%), anemia, thrombocytopenia, alanine aminotransferase increased (11%), infection, dehydration, dyspnea (9%), lymphopenia, neutropenia, hyperbilirubinemia, hypocalcemia, hypoxia (6%), febrile neutropenia, leukopenia, ventricular arrhythmia, vomiting, hypersensitivity, catheter related infection, hyperuricemia, hypoalbuminemia, syncope, pneumonitis, packed red blood cell transfusion, and platelet transfusion (4%). Deaths due to all causes within 30 days of the last dose of ISTODAX occurred in 7% of patients in Study 3 and 17% of patients in Study 4. In Study 3, there were 5 deaths unrelated to disease progression that were due to infections, including multi-organ failure/sepsis, pneumonia, septic shock, candida sepsis, and sepsis/cardiogenic shock. In Study 4, there were 3 deaths unrelated to disease progression that were due to sepsis, aspartate aminotransferase elevation in the setting of Epstein Barr virus reactivation, and death of unknown cause. Discontinuations Discontinuation due to an adverse event occurred in 19% of patients in Study 3 and in 28% of patients in Study 4. In Study 3, thrombocytopenia and pneumonia were the only events leading to treatment discontinuation in at least 2% of patients. In Study 4, events leading to treatment discontinuation in ≥ 2 patients were thrombocytopenia (11%), anemia, infection, and alanine aminotransferase increased (4%). 6.2 Postmarketing Experience No additional safety signals have been observed from postmarketing experience. 7 DRUG INTERACTIONS 7.1 Coumadin or Coumadin Derivatives Prolongation of PT and elevation of INR were observed in a patient receiving ISTODAX concomitantly with warfarin. Although the interaction potential between ISTODAX and Coumadin® (a registered trademark of BristolMyers Squibb Pharma Company) or Coumadin derivatives has not been formally studied, physicians should carefully monitor PT and INR in patients concurrently administered ISTODAX and Coumadin or Coumadin derivatives [See Clinical Pharmacology (12.3)]. 7.2 Drugs that Inhibit or Induce Cytochrome P450 3A4 Enzymes Romidepsin is metabolized by CYP3A4. Although there are no formal drug interaction studies for ISTODAX, strong CYP3A4 inhibitors (e.g., ketoconazole, itraconazole, clarithromycin, atazanavir, indinavir, nefazodone, nelfinavir, ritonavir, saquinavir, telithromycin, voriconazole) may increase concentrations of romidepsin. Therefore, co-administration with strong CYP3A4 inhibitors should be avoided if possible. Caution should be exercised with concomitant use of moderate CYP3A4 inhibitors. Co-administration of potent CYP3A4 inducers (e.g., dexamethasone, carbamazepine, phenytoin, rifampin, rifabutin, rifapentine, phenobarbital) may decrease concentrations of romidepsin and should be avoided if possible. Patients should also refrain from taking St. John’s Wort. 7.3 Drugs that Inhibit Drug Transport Systems Romidepsin is a substrate of the efflux transporter P-glycoprotein (P-gp, ABCB1). If ISTODAX is administered with drugs that inhibit P-gp, increased concentrations of romidepsin are likely, and caution should be exercised. 8 USE IN SPECIFIC POPULATIONS 8.1 Pregnancy Pregnancy Category D [See Warnings and Precautions (5.5)]. There are no adequate and well-controlled studies of ISTODAX in pregnant women. However, based on its mechanism of action and findings in animals, ISTODAX may cause fetal harm when administered to a pregnant woman. In an animal reproductive study, romidepsin was embryocidal and resulted in adverse effects on the developing fetus at exposures below those in patients at the recommended dose. If this drug is used during pregnancy, or if the patient becomes pregnant while taking ISTODAX, the patient should be apprised of the potential hazard to the fetus. Romidepsin was administered intravenously to rats during the period of organogenesis at doses of 0.1, 0.2, or 0.5 mg/kg/day. Substantial resorption or post-implantation loss was observed at the high-dose of 0.5 mg/kg/day, a maternally toxic dose. Adverse embryo-fetal effects were Cosmos Communications
BRACAnalysis® to include BART™. http:// dlizdzz43r5o67.cloudfront.net/sales-aids/Integrat ed+BRACAnalysis+to+Include+BART.pdf. Accessed July 23, 2013. 8. NCCN Clinical Practice Guidelines in Oncology: Genetic/ Familial High-Risk Assessment: Breast and Ovarian. Version 1.2013. http://www.nccn.org/professionals/physician_gls/ f_guidelines.asp. Accessed July 23, 2013. 9. Churpek JE, Walsh T, Zheng Y, et al. Inherited mutations in breast cancer genes in African American breast cancer patients revealed by targeted genomic capture and next-generation sequencing. J Clin Oncol. 2013;31(suppl):Abstract CRA1501.
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Conference News: MASCC Conference News continued from page 8
High Marks for Nutritional Supplement in Localized Prostate Cancer A food supplement containing pomegranate seed, green tea, broccoli, and turmeric taken twice a day significantly lowered prostate-specific antigen (PSA) levels compared with placebo in men with local-
ized prostate cancer, according to the results of a double-blind, placebo-controlled clinical trial. Use of the supplement allowed more men to remain on observation alone, without having to resort to salvage
noted at romidepsin doses of ≥0.1 mg/kg/day, with systemic exposures (AUC) ≥0.2% of the human exposure at the recommended dose of 14 mg/m2/week. Drug-related fetal effects consisted of folded retina, rotated limbs, and incomplete sternal ossification.
seen in mice after 4 weeks of drug administration at higher doses. Seminal vesicle and prostate organ weights were decreased in a separate study in rats after 4 weeks of daily drug administration at 0.1 mg/kg/day (0.6 mg/m2/day), approximately 30% the estimated human daily dose based on body surface area. Romidepsin showed high affinity for binding to estrogen receptors in pharmacology studies. In a 26-week toxicology study in rats, atrophy was seen in the ovary, uterus, vagina and mammary gland of females administered doses as low as 0.1 mg/kg/dose (0.6 mg/m2/dose) following the clinical dosing schedule. This dose resulted in AUC0-inf. values that were 0.3% of those in patients receiving the recommended dose of 14 mg/m2/dose. Maturation arrest of ovarian follicles and decreased weight of ovaries were observed in a separate study in rats after four weeks of daily drug administration at 0.1 mg/kg/day (0.6 mg/m2/day). This dose is approximately 30% the estimated human daily dose based on body surface area
8.3 Nursing Mothers It is not known whether romidepsin is excreted in human milk. Because many drugs are excreted in human milk and because of the potential for serious adverse reactions in nursing infants from ISTODAX, a decision should be made whether to discontinue nursing or discontinue the drug, taking into account the importance of the drug to the mother. 8.4 Pediatric Use The safety and effectiveness of ISTODAX in pediatric patients has not been established. 8.5 Geriatric Use Of the approximately 300 patients with CTCL or PTCL in trials, about 25% were > 65 years old. No overall differences in safety or effectiveness were observed between these subjects and younger subjects; however, greater sensitivity of some older individuals cannot be ruled out. 8.6 Hepatic Impairment No dedicated hepatic impairment study for ISTODAX has been conducted. Mild hepatic impairment does not alter pharmacokinetics of romidepsin based on a population pharmacokinetic analysis. Patients with moderate and severe hepatic impairment should be treated with caution [See Clinical Pharmacology (12.3)]
16 HOW SUPPLIED/STORAGE AND HANDLING Keep out of reach of children. Procedures for proper handling and disposal of anticancer drugs should be considered. Several guidelines on this subject have been published1-4 [See References (15)]. 17 PATIENT COUNSELING INFORMATION See FDA-approved patient labeling. 17.1 Instructions • Nausea and Vomiting Nausea and vomiting are common following treatment with ISTODAX. Prophylactic antiemetics are recommended to be used in all patients. Advise patients to report these symptoms so that appropriate treatment can be instituted [See Adverse Reactions (6)]. • Low Blood Counts Patients should be informed that treatment with ISTODAX can cause low blood counts and that frequent monitoring of hematologic parameters is required. Patients should be instructed to report fever or other signs of infection, significant fatigue, shortness of breath, or bleeding [See Warnings and Precautions (5.1)]. • Infections Patients should be informed that infections may occur during treatment with ISTODAX. Patients should be instructed to report fever, cough, shortness of breath with or without chest pain, burning on urination, flu-like symptoms, muscle aches, or worsening skin problems [See Warnings and Precautions (5.2]. • Tumor Lysis Syndrome Patients at risk of tumor lysis syndrome (i.e, those with advanced stage disease and/or high tumor burden) should be monitored closely for TLS and appropriate measures taken if symptoms are observed [See Warnings and Precautions (5.4)]. • Use in Pregnancy If pregnancy occurs during treatment with ISTODAX, female patients should be advised to seek immediate medical advice and counseling. [See Warnings and Precautions (5.5)]. • Patients should be instructed to read the patient insert carefully.
8.7 Renal Impairment No dedicated renal impairment study for ISTODAX has been conducted. Based upon the population pharmacokinetic analysis, renal impairment is not expected to significantly influence drug exposure. The effect of end-stage renal disease on romidepsin pharmacokinetics has not been studied. Thus, patients with end-stage renal disease should be treated with caution [See Clinical Pharmacology (12.3)] 10 OVERDOSAGE No specific information is available on the treatment of overdosage of ISTODAX. Toxicities in a single-dose study in rats or dogs, at intravenous romidepsin doses up to 2.2 fold the recommended human dose based on the body surface area, included irregular respiration, irregular heart beat, staggering gait, tremor, and tonic convulsions. In the event of an overdose, it is reasonable to employ the usual supportive measures, e.g., clinical monitoring and supportive therapy, if required. There is no known antidote for ISTODAX and it is not known if ISTODAX is dialyzable. 12 CLINICAL PHARMACOLOGY 12.2 Pharmacodynamics Cardiac Electrophysiology The effect of romidepsin on the heart-rate corrected QTc/QTcF was evaluated in 26 subjects with advanced malignancies given romidepsin at doses of 14 mg/m2 as a 4-hour intravenous infusion, and at doses of 8, 10 or 12 mg/m2 as a 1–hour infusion. Patients received premedications with antiemetics. No large changes in the mean QTc interval (> 20 milliseconds) from baseline based on Fridericia correction method were detected in the trial. Small increase in mean QT interval (< 10 milliseconds) and mean QT interval increase between 10 to 20 milliseconds cannot be excluded because of the limitations in the trial design. Romidepsin was associated with a delayed concentration-dependent increase in heart rate in patients with advanced cancer with a maximum mean increase in heart rate of 20 beats per minute occurring at the 6 hour time point after start of romidepsin infusion for patients receiving 14 mg/m2 as a 4-hour infusion. 13 NONCLINICAL TOXICOLOGY 13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility Carcinogenicity studies have not been performed with romidepsin. Romidepsin was not mutagenic in vitro in the bacterial reverse mutation assay (Ames test) or the mouse lymphoma assay. Romidepsin was not clastogenic in an in vivo rat bone marrow micronucleus assay when tested to the maximum tolerated dose (MTD) of 1 mg/kg in males and 3 mg/kg in females (6 and 18 mg/m2 in males and females, respectively). These doses were up to 1.3-fold the recommended human dose, based on body surface area.
surgery, radiation, or androgen-deprivation therapy (ADT). Called Pomi-T, the supplement is commercially available. Previous animal models and phase 2 studies demonstrated that these polyphenol-rich foods have
Manufactured for: Celgene Corporation Summit, NJ 07901 Manufactured by: Ben Venue Laboratories, Inc. Bedford, OH 44146 or Baxter Oncology GmbH Halle/Westfalen, Germany ISTODAX® is a registered trademark of Celgene Corporation © 2010-2012 Celgene Corporation. All Rights Reserved. U.S. Patents: 4,977,138; 7,608,280; 7,611,724 ISTBAXPI.004/PPI.004 03/12
Based on non-clinical findings, male and female fertility may be compromised by treatment with ISTODAX. In a 26-week toxicology study, romidepsin administration resulted in testicular degeneration in rats at 0.33 mg/kg/dose (2 mg/m2/dose) following the clinical dosing schedule. This dose resulted in AUC0-inf. values that were approximately 2% the exposure level in patients receiving the recommended dose of 14 mg/m2/dose. A similar effect was
Thomas R, Williams M, Bellamy P. A polyphenol rich whole food supplement reduces PSA progression in men with prostate cancer in a double blind placebo controlled RCT—the UK national Pomi-T study. Support Care Cancer. 2013;21(suppl 1):S33. Abstract 0040. Cosmos Communications
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anticancer effects. The study presented at MASCC 2013 is the first adequately powered, randomized, controlled phase 3 trial of Pomi-T (natureMedical Products) in men with localized prostate cancer. The study was also presented at the 2013 American Society of Clinical Oncology Annual Meeting. The investigators enrolled 203 men (average age, 74 years) whose PSA was rising after radiotherapy or surgery for localized prostate cancer. They were managed with active surveillance (59%) or watchful waiting (41%), and randomized to receive 2 capsules of Pomi-T per day or placebo for 6 months. At 6 months of follow-up, median rise in PSA was 14.7% in the Pomi-T group versus 78.5% in the placebo group, representing a 63.8% difference favoring the supplement (P = .0008). PSA levels were stable or lower than baseline in significantly more men in the supplement group: 46% versus 14%, representing a 32% difference (P = .00001). At follow-up, fewer men taking Pomi-T were assigned to any form of radiation, surgery, or ADT (7.4% vs 26%; P = .01). There were no significant differences between the 2 groups in laboratory measurements of cholesterol, blood pressure, serum glucose, C-reactive protein, or adverse events. Taking the supplement allowed more men to continue on active surveillance: 92.6% for Pomi-T versus 74% for placebo. “These results are awesome. We didn’t expect such a big response. This can change practice, because men and their doctors look at their PSA as a deciding factor in whether to continue on active management,” stated lead author Robert Thomas, MD, consulting oncologist at Bedford Hospital and Addenbrooke’s, part of Cambridge University Hospitals, United Kingdom. Importantly, this supplement is well tolerated and may even improve digestion and urinary symptoms, Thomas said. It is easy for men to stay on therapy with the supplement, and men are more amenable to taking a nutritional supplement than an active drug, especially hormone therapy. This product does not appear to act on hormones. The investigators plan to study Pomi-T in men with different stages of prostate cancer, as well as those taking ADT. The study was not funded by the makers of Pomi-T. l
The Importance of the Nurse-Patient Interaction... Continued from cover tumor, and the fact that some patients with metastatic melanoma can survive for many years after treatment with interleukin-2 has kept the prospect of successful immunotherapy as an option.3 Cytotoxic T-lymphocyte antigen-4 (CTLA-4) is the main negative regulator of the T-cell–mediated immune response, designed to prevent unwanted autoimmunity and turn the response off when no longer needed.4 Cells known as antigen-presenting cells use specialized cellular equipment to present the tumor antigen to the T-cell receptor. These structures bind together, triggering a first or “priming” signal (Figure 1).5 To become fully activated, however, a second or “activation” signal is needed. The activation signal is triggered when a specific receptor on the surface of the T cell binds with a ligand on the antigen-presenting cell. The resulting dual signaling leads to a fully functional T cell capable of killing tumor cells, but it also prompts the cell to start producing a negative regulator molecule, CTLA-4. CTLA-4, which is manufactured within the T cell in direct response to antigen exposure, migrates to the cell surface where it triggers a third delayed signal that switches off T-cell activity to prevent it from causing unwanted damage to healthy tissues. Such “switched off” T cells remain primed (that is, capable of recognizing the target tumor antigen), but are inactive because of the negative signaling of CTLA-4. In the context of cancer, especially advanced disease where antigen exposure is continuous, this homeostatic mechanism is a disadvantage and hinders antitumor immunity. In essence, CTLA-4 acts like an “immunologic brake”; thus, blocking CTLA-4 should release this brake and intensify the antitumor immune response. Ipilimumab (Yervoy, Bristol-Myers Squibb Company), a fully human monoclonal antibody, is a novel T-cell potentiator that blocks CTLA-4 and has demonstrated improved survival in two phase 3 randomized trials in previously treated patients with advanced melanoma.6,7 In the first trial, up to 46% of patients were still alive at 1 year after starting ipilimumab therapy, and up to 24% were still alive at 2 years.6 More recently, a second phase 3 trial demonstrated significantly higher overall survival in patients who received ipilimumab in combination with dacarbazine compared with those receiving dacarbazine alone.7 Because of its unique immunologic mechanism of action, ipilimumab produces some specific and unusual response patterns and mechanism-related adverse
Table 1 Types of Responses Seen During Ipilimumab Therapy9,10
Category by Standard Criteria
Survival Benefit With Ipilimumab Has Been Observed
Response in baseline (index) lesions
PR or CR
Slow, steady decline in total tumor burden
SD [ PR or CR
Response after an initial increase in total tumor burden
PD [ PR or CR
Response in primary and new lesions during or after the appearance of other new lesions (mixed response)
Abbreviations: CR, complete response; PD, progressive disease; PR, partial response; SD, stable disease.
events, which differ from those seen after chemotherapy or older immunotherapies.8 For example, responses can evolve over differing time periods in different patients, depending on the individual functionality of each patient’s immune system.8 Sometimes responses are preceded by apparent tumor growth, and prolonged disease stabilization can occur.9,10 Alongside potentiation of the antitumor T-cell response, however, ipilimumab’s removal of the “immunologic brake” by blocking CTLA-4 also diminishes the patient’s tolerance to his/her own healthy tissues, thereby producing a characteristic spectrum of immune-related adverse events (irAEs).9,11-16 For ipilimumab to be effective, nurses must become familiar with differences in response patterns and toxicities and learn how to communicate them to patients and fellow healthcare professionals.
tional response criteria may not pick up responses to this agent.17,18 For example, responses may be delayed and can occur even after apparent disease progression.8,9 Some of the response patterns seen in studies with ipilimumab, several of which are different from responses to traditional therapies, are shown in Table 1.9,10 Survival benefits have been associated with all of these response patterns, even for patients with apparent disease progression by conventional criteria.9 A relatively high proportion of patients receiving ipilimumab achieve stable disease and appear to survive as long as those achieving an objective response (Table 2).6,9,19-21 This represents a new response paradigm, since prolonged stable disease is not generally achieved after chemotherapy.10 This variability in response is consistent with not only the time necessary to mount an adequate immune
For ipilimumab to be effective, nurses must become familiar with differences in response patterns and toxicities and learn how to communicate them to patients and fellow healthcare professionals.
Ipilimumab Response Patterns and Assessment Following chemotherapy, which directly attacks tumor tissue, either responses occur within a few weeks or treatment failure is recorded. Both the Response Evaluation Criteria In Solid Tumors and the World Health Organization criteria were developed with chemotherapy in mind and have been tailored to define responses based on a drug having a cytotoxic mode of action.17 However, because ipilimumab’s mechanism of action works by harnessing the patient’s own immune system, these conven-
response but also interpatient variability in immune activity. Moreover, tumor enlargement during treatment with ipilimumab may not necessarily represent tumor growth, as would be associated with disease progression, but may be a result of the accumulation of activated lymphocytes, producing a localized inflammatory response and edema at the tumor site.17,22 Such infiltration would reflect antitumor activity and not tumor tissue growth. Therefore, later assessment and repeat assessment are necessary to confirm whether the disease has progressed.
Nurses are uniquely positioned to educate patients and caregivers on the difference between ipilimumab treatment and conventional chemotherapy and to explain that delayed response or apparent disease progression does not necessarily mean that ipilimumab treatment has failed, as might be the case with chemotherapy. Because responses typically evolve gradually and can pass through stages of apparent progression, stability, and, ultimately, sometimes partial or complete response,8,10,18 this has important implications for managing patient expectations and concerns. For these reasons, the recommended response monitoring for ipilimumab therapy states that the first assessment should be performed no sooner than 12 weeks after treatment starts (ie, at the end of the induction period), compared with chemotherapy response assessment, which is typically done after 6 to 8 weeks of treatment.10 If, at this first assessment, the patient’s cancer seems to be progressing, it is important to emphasize that repeat radiologic assessment after at least 4 weeks is needed to confirm that progression is “true” and ongoing before declaring that treatment has failed. These key differences in timing must be explained to the patient and caregiver, especially if they are familiar with chemotherapy. This approach ensures continuation of therapy to allow enough time for a response to occur, unless there are other reasons why the patient cannot receive further dosing—such as clinical deterioration or serious adverse events (see next section). Patients who have been treated with ipilimumab should continue regular assessment of their disease status, since it is not uncommon for responses to occur several months after therapy has stopped.23 Ipilimumab Adverse Events Overview and General Principles of Care Ipilimumab produces irAEs associated directly with its mechanism of action (Figure 1).5 As with responses, symptoms do not always develop early in treatment but may occur after several months have passed since completion of ipilimumab treatment. It is important to communicate to patients that these irAEs are predictable and manageable as long as they are detected early and are not allowed to worsen unchecked; although these irAEs may appear to be similar to those experienced with chemotherapy, they are different and require prompt attention from a healthcare team. It is also important to stress the need to report irAEs early so they do not progress to the point of needing to discontinue therapy. Continued on page 24
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The Importance of the Nurse-Patient Interaction... Continued from page 23 Table 2 Response Rates, Rates of Stable Disease, Median Overall Survival, and Survival Rates in Phase 2 and Phase 3 Trials of Ipilimumab in Metastatic Melanoma6,9,19-21 Type of Study
Median OS (months)
47% (1 year) 40% (18 months) 33% (2 years)
O’Day et al19
62% (1 year) 42% (2 years)
Weber et al9
49% (1 year) 35% (18 months) 30% (2 years)
Wolchok et al20
39% (1 year) 30% (18 months) 24% (2 years)
45% (1 year) 21% (2 years) 9% (3 years)
Hersh et al21
2% (CR), 10% (PR)
46% (1 year) 33% (18 months) 24% (2 years)
Hodi et al6
Only patients receiving ipilimumab monotherapy or ipilimumab + placebo included; b10 mg/kg; c3 mg/kg; dN = 32; eP = .003 vs control group. Abbreviations: CR, complete response; OS, overall survival; PR, partial response; RR, response rate; SD, stable disease. Note that ipilimumab will be licensed for use at 3 mg/kg, although 10 mg/kg is under investigation.
MHC Peptide TCR
MHC B7 CTLA-4
Figure 1. How CTLA-4 “turns down” the T-cell immune response and blockade while ipilimumab reinstates it. When a tumor antigen is “presented” to the T cell by specialized equipment on an APC, a priming signal (signal 1) is initiated. This is followed by a second activation signal (signal 2) produced when an activation receptor on the T cell binds to an activation ligand on the APC. In response to sustained T-cell activation, CTLA-4 is up-regulated and competes successfully for the activation ligand on the APC. This interrupts the second activation signal, and the T cell becomes primed but dormant. Ipilimumab effectively binds to CTLA-4 so it can no longer compete for the activation ligand and interfere with the activation signal. This restores the T cell to an active state and thus potentiates the patient’s T-cell antitumor immune response. It also reduces tolerance to self-antigens, producing immune-related adverse events. Abbreviations: APC, antigen-presenting cell; CTLA-4, cytotoxic T-lymphocyte antigen-4; MHC, major histocompatibility complex; TCR, T-cell receptor. Reprinted from Seminars in Oncology, volume 37/issue 5, Hoos A, Ibrahim R, Korman A, et al, Development of ipilimumab: contribution to a new paradigm for cancer immunotherapy, 533-546, 2010, with permission from Elsevier. http://www.sciencedirect.com/science/journal/00937754.
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Ipilimumab irAEs most commonly include grade 1 and 2 toxicities, which usually resolve after symptomatic treatment with over-the-counter treatments (ie, hydroxyzine or diphenhydramine for rash, or loperamide for diarrhea). Less common but nonetheless significant toxicities include hepatitis and hypophysitis, and more rarely, uveitis, pancreatitis, and leukopenia. Persistent or more severe toxicities need prompt intervention, usually with oral or systemic corticosteroids, which would not be used for chemotherapy-related toxicities4,23,24; if patients experience irAEs that require corticosteroid treatment, reassure them that this will not affect clinical response to ipilimumab.9 Even higher-grade toxicities can be managed successfully on an outpatient basis, but ipilimumab should be withheld until symptoms resolve if the patient has grade 2 diarrhea or be permanently discontinued for any grade 3 or 4 toxicity. Immune-related colitis is the most common serious toxicity; if left untreated, it may lead to fatal bowel perforation, which is why any signs of cramping with or without diarrhea should be reported immediately. These symptoms require grading and proactive monitoring by the oncology nurse to ensure that any deterioration is spotted and promptly treated with corticosteroids. Other potentially life-threatening irAEs include hepatitis and hypopituitarism leading to acute adrenal crisis. Some patients may not report irAEs for fear of being taken off treatment. To manage this, it is advisable that nurses mention the possibility that more severe symptoms may require permanent treatment cessation. It helps to stress that the more quickly any symptoms are reported and managed, the greater the likelihood of being able to continue treatment. Approved Management Guidelines Recommended pathways (algorithms) for managing more severe toxicities with ipilimumab (grade 3 and 4) appear in Figure 2.25,26 This management information comes from both the author’s own clinical experience and the Risk Evaluation and Mitigation Strategy (REMS) program established by BristolMyers Squibb in coordination with the US Food and Drug Administration.25 Gastrointestinal toxicity. Grade 1 gastrointestinal irAEs usually respond to dietary modifications and treatment with loperamide, but grade 2 symptoms may require oral corticosteroid therapy (eg, prednisone 1 mg/kg once daily). If symptoms persist, ipilimumab treat-
Melanoma SYMPTOMS Grade 3 or 4
• Hospitalization required • Abdominal pain • Fever
SYMPTOMS Grade 3 or 4 • >5.0 x ULN for AST or ALT
• Analgesic (eg, morphine) may mask symptoms of perforation/ peritonitis; use with caution
•D o not use infiximab if perforation or sepsis is suspected or present
•O nce diarrhea and other symptoms are controlled, taper corticosteroid over ≥1 month • Permanently discontinue ipilimumab
• If no improvement within 3 days or LFT elevation during corticosteroid tapering not responsive to increase in corticosteroid dose, add immunosuppressive therapy (eg, mycophenolate mofetil)
TREATMENT • High-dose IV corticosteroid (eg, methylprednisolone 2 mg/kg qd or bid)
• P atients receiving immunosupppression for >4 weeks should be evaluated for prophylaxis of opportunistic infections • P ermanently discontinue ipilimumab
• Monitor LFTs frequently
• If no improvement within 5 days or relapse occurs, give single dose infliximab 5 mg/kg (unless contraindicated) • Permanently discontinue ipilimumab
• >3.0 x ULN for total bilirubin
• Dehydration (requiring IV fluids ≥24 hours)
• High-dose IV corticosteroid (eg, methylprednisolone 2 mg/kg qd or bid) • Abdominal pain with diarrhea should be evaluated for perforation or peritonitis
• ≥7 stools/day over baseline
• If LFTs stable/declining for 5 consecutive days, assess weekly until normalization • Once LFTs normalized, initate corticosteroid taper over ≥1 month • E levations in LFTs may respond to increased corticosteroid dose or slower taper • Permanently discontinue ipilimumab
• Intense or widespread; interfering with activities of daily living • IV fluids or tube feeding required • T otal parenteral nutrition indications
TREATMENT • High-dose IV corticosteroid (eg, methylprednisolone 2 mg/kg qd or bid)
•O nce symptoms are controlled, taper corticosteroid over ≥1 month
SYMPTOMS Grade 3 or 4
•C ontinue treatment with ipilimumab only if grade 3 symptoms improved to grade 1; otherwise, permanently discontinue ipilimumab
Figure 2. Algorithms for management of grade 3 and 4 irAEs to ipilimumab.25 Abbreviations: ALT, alanine aminotransferase; AST, aspartate aminotransferase; bid, twice a day; irAEs, immune-related adverse events; IV, intravenous; LFT, liver function test; qd, every day; ULN, upper limit of normal.
ment should be stopped until symptoms resolve. For grade 3 or 4 gastrointestinal symptoms, the patient should be treated with high-dose steroids; if symptoms do not resolve, consider alternative immunosuppressive therapy such as infliximab at 5 mg/kg (Figure 2).25,26 Liver toxicity. Blood work should include liver function tests prior to each dose of ipilimumab, including the first dose. For grade 1 or 2 liver toxicity, liver enzymes should be monitored and symptomatic treatment provided as needed. If liver function tests normalize but symptoms persist, corticosteroids are given and tapered over at least 1 month, and ipilimumab can be discontinued until symptoms resolve. Grade 3 and 4 symptoms require permanent discontinuation of ipilimumab therapy and high-dose intravenous (IV) corticosteroid treatment (eg, methylprednisolone 2 mg/kg once or twice daily), with the addi-
tion of immunosuppressive therapy (eg, mycophenolate mofetil) if symptoms persist (Figure 2).25 Skin toxicity. Although usually mild, serious toxicities, including Stevens-Johnson syndrome and toxic epidermal necrolysis, can occur. Mild or moderate itching or
Endocrine toxicity. Of these toxicities, thyroid abnormalities (hypo and hyper) and adrenal insufficiency are more commonly observed, but are usually manageable with hormone therapy (ie, levothyroxine, hydrocortisone); ipilimumab should be held until toxicity resolves to grade 1. For symptoms
There are many reports in the literature of immune-related adverse events serving as potential surrogate markers for clinical response to ipilimumab. rash can be managed symptomatically with antihistamines or topical corticosteroids, but persistent or grade 3 or 4 symptoms require permanent discontinuation of ipilimumab therapy and oral or systemic corticosteroids, tapered over ≥1 month once dermatitis is controlled (Figure 2).
that persist to grade 3 or 4, treatment with high-dose steroids in addition to hormonal therapy may be required, and ipilimumab should be permanently discontinued in this case. Less frequently, cases of hypopituitary (adrenal crisis) are observed; these cases
require immediate medical attention with high-dose steroids and hormonal replacement. Typically these patients require ongoing hormone therapy since the pituitary may not completely recover function.25 Efficacy and irAEs There are many reports in the literature of irAEs serving as potential surrogate markers for clinical response to ipilimumab.9,11-16 Although patients who develop irAEs, especially severe ones, are more likely to experience disease control and tend to survive longer, these outcomes can also occur in patients who do not develop irAEs or who have only mild symptoms.27 This phenomenon represents a delicate balancing act for the oncology nurse— between reassuring patients that irAEs are not necessarily a “bad thing” and avoiding raising expectations unrealistically or disheartening those patients who do not develop irAEs. Continued on page 26
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The Importance of the Nurse-Patient Interaction... Continued from page 25 To achieve this balance, it is best not to elaborate on the possible significance of irAEs until after they develop. If the patient reports symptoms of an irAE, it can be explained that these are a sign of a hyperstimulated immune system that may mean that he or she will be more likely to respond to treatment. As irAEs do arise, sharing information
on how ipilimumab works may help to encourage patients. One example at our clinic is when patients experience vitiligo, we educate them on the fact that depigmentation is possibly due to the immune system attacking their melanocytes. Patients who have read or heard about a potential link between irAEs and better responses
can be reassured that not all responders get these side effects. In our clinic, we have seen increased lymphocyte counts in responders as early as the second induction dose of ipilimumab; sharing these results with patients can reduce any anxiety and encourage them that the immune system appears to be overactive, even if there are no irAEs.
Table 3 Key Differences Between Similar Adverse Event Symptoms With Ipilimumab and Chemotherapy Adverse Event Gastrointestinal
Ipilimumaba • Affects lower bowel only, specific symptom is diarrhea, which may include cramping, abdominal pain, abdominal distension, and/or blood in the stool • Mild to moderate symptoms: usual management is with loperamide or similar agents, dietary changes, mesalamine (grade 1)
• Affects entire gastrointestinal tract, producing a range of symptoms (stomatitis, nausea, vomiting, heartburn, reflux, diarrhea, hemorrhoids) • Each problem is treated individually
• Moderate to severe symptoms: administer 1 to 2 mg/kg/day of prednisone or equivalent, bowel rest/IV hydration; infliximab may be necessary in patients with persistent or recurring symptoms Fatigue
• Should not worsen on ipilimumab treatment in the absence of disease progression or ongoing anemia
• Multifactorial: waxes/wanes with nadir and treatment regimen; may also be related to anemia, neutropenia, chemical imbalances, and/or disease progression
• Patients who have completed • Interventions can include growth induction and are entering the factors, transfusions, planning ADL, follow-up phase are asked to looking at sleep/exercise programs, report any changes in fatigue/endose delays/reductions ergy levels not explained by big • Cardiovascular and other comorbid energy expenditure in previous diseases may also be factors days (ie, returning to work, new exercise regimen) • Suggest a 0-10 scale to describe fatigue level and maintain an ongoing dialogue once baseline fatigue established Reflects the practice in our clinic. Abbreviations: ADL, activities of daily living; IV, intravenous. a
Table 4 Top 5 Questions Asked or Issues Raised During Patient/Nurse Interactions9,28 Question or Issue
When do side effects appear?
Side effects can occur anytime, usually no sooner than 4 to 6 weeks after starting treatment, though skin toxicities may start immediately. But they can occur weeks or even months after completing therapy.
What if this does not work?
Discuss treatment options with your doctor.
How long do side effects last?
It varies, but generally they resolve more quickly when reported at grade 1/2 vs waiting to report side effects. With proper treatment, the median time to resolution of grade 2-4 irAEs in clinical trials was approximately 6 weeks.28
When will I know if this is working?
First scans are done at 12 weeks; may be repeated 2 to 4 weeks later if response is not clear.
Won’t steroids negatively impact my immune system?
No, they are used short-term for most people, and previous studies have shown that steroid use does not affect response rates.9
Abbreviation: irAEs, immune-related adverse events.
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Role of Nurses It is vital to recognize, monitor, and manage irAEs promptly to prevent more serious consequences; establishing protocols based on the guidelines (Figure 2), which are reviewed regularly based on clinical experience, will help optimize irAE management in your facility and across others. Nurses play a key role because they are in regular contact with patients and can be most proactive in inquiring about any irAEs the patients may be experiencing. It is important to remember that even if some symptoms of irAEs are similar to those seen with chemotherapy, the underlying reasons are different, and because ipilimumab side effects have an immune-related etiology, they need to be managed very differently from side effects of chemotherapy. Nurses must understand these differences and communicate them effectively to patients (Table 3). Patient Education The Approach Oncology nurses play a pivotal role in supporting the successful implementation of ipilimumab therapy in the clinic. By the time they are prescribed ipilimumab, patients with advanced melanoma may well have received chemotherapy and/ or other immunotherapies, so their experience and expectations will be based on those treatments. Education on all aspects of ipilimumab therapy will be a vital component of each patient’s treatment plan, and oncology nurses are best placed to provide it. The REMS program packet provided to patients and physicians includes a checklist of items that can act as prompts for both nurse and patient to make sure that irAEs are recognized and reported as soon as they appear. There is also a medication guidelines handout to give to patients and a patient wallet card, which can be particularly useful in an emergency department situation. The most common questions asked by patients and caregivers as well as the appropriate responses are presented in Table 4.9,28 These basic principles can be tailored according to the audience (patient, caregiver, or peer education), as well as modified to allow for different patients’ abilities and/or willingness to take on this information (eg, kept to the main points only or expanded to include some background explanation). There is no “one size fits all,” and individually tailored education programs have been shown to improve outcomes in cancer patients.29 Consistency of messages is important.
Issues That May Arise Patients who are already familiar with other forms of therapy and/or who are receiving their ipilimumab treat-
Melanoma ment in an oncology suite alongside patients receiving other treatments may express concerns that their treatment is not working if they do not achieve a response soon after treatment has started or if they experience disease progression at first assessment. This is especially difficult for patients with palpable or visible tumors. These patients require reassurance and an explanation of why this may be happening. At our clinic, we treated a 45-year-old man with lung metastases and palpable axillary nodal metastases whose disease progressed through biochemotherapy. He became very depressed after starting ipilimumab because his axillary nodes got larger, by his account, at an even faster rate. Later, when he came for his third induction dose, his spirits had lifted because he reported that the nodes had stopped growing. By the fourth induction dose, the nodes had regressed and, after another 3 to 4 weeks, had disappeared. His scans at 12 weeks showed a dramatic decrease in his lung metastases as well. He achieved a complete response at 18 months, and currently, he continues in a complete response almost 4 years later. Other than vitiligo, he has not experienced any other significant adverse events. The approved ipilimumab administration and dosing is via IV at 3 mg/kg every 3 weeks (weeks 1, 4, 7, and 10).6 This means that the patient’s visits to your center may be relatively infrequent, and if the patient is not local, it may be impractical for him or her to attend more often, for example, if irAEs develop. Patients who live a long way from your treatment center, attending only for dosing and assessment, need additional support from their local community doctor or nurse. You can establish a relationship with these professionals and supply them with educational materials and symptom checklists for their own use and for them to use with patients.
Further Information Good sources of educational information can be found at the following websites: AIM at Melanoma Foundation (www.aimatmelanoma.org) Melanoma Research Foundation (www.melanoma.org) Conclusions Nurses play a pivotal role in ensuring the successful use of ipilimumab in the clinic. Since this agent has a novel mechanism of action, produces unique response patterns, and has characteristic irAEs, which are manageable with prompt recognition and treatment, appropriate education of patients and other healthcare professionals is important.
Ipilimumab is the first agent to show a survival benefit in previously treated patients with advanced melanoma.
With regular, ongoing nurse involvement in the patient’s treatment plan, ipilimumab can be given optimally to allow immune responses a chance to develop, while minimizing the impact of any irAEs. Ipilimumab is the first agent to show a survival benefit in previously treated patients with advanced melanoma, and it is vital to give optimal support to patients prescribed this drug so that they can benefit from it. The relationship and communication between nurses and their patients will be vital to achieving this goal. l
Acknowledgment The author takes full responsibility for the content of this publication and confirms that it reflects her viewpoint and medical expertise. The author also wishes to acknowledge StemScientific, funded by Bristol-Myers Squibb, for providing writing and editorial support. Neither Bristol-Myers Squibb nor StemScientific influenced the content of the manuscript, nor did the author receive financial compensation for authoring the manuscript. References
1. National Comprehensive Cancer Network. NCCN Clinical Practice Guidelines in Oncology: Melanoma. Version 2.2013. http://www.nccn.org. Accessed April 23, 2013. 2. Howlader N, Noone AM, Krapcho M, et al, eds. SEER Cancer Statistics Review, 1975-2009 (Vintage 2009 Populations), National Cancer Institute. Bethesda, MD. http://seer.cancer.gov/csr/1975_2009_pops09/, based on November 2011 SEER data submission, posted to the SEER web site, April 2012. Accessed April 23, 2013. 3. Atkins M, Kunkel L, Sznol M, Rosenberg S. High-dose recombinant interleukin-2 therapy in patients with metastatic melanoma: long-term survival update. Cancer J Sci Am. 2000;6(suppl 1):S11-S14. 4. Robert C, Ghiringhelli F. What is the role of cytotoxic T lymphocyte-associated antigen 4 blockade in patients with metastatic melanoma? Oncologist. 2009;14(8):848-861. 5. Hoos A, Ibrahim R, Korman A, et al. Development of ipilimumab: contribution to a new paradigm for cancer immunotherapy. Semin Oncol. 2010;37(5): 533-546. 6. Hodi FS, O’Day SJ, McDermott DF, et al. Improved survival with ipilimumab in patients with metastatic melanoma. N Engl J Med. 2010;363(8):711-723. 7. Robert C, Thomas L, Bondarenko I, et al. Ipilimumab plus dacarbazine for previously untreated metastatic melanoma. N Engl J Med. 2011;364(26):2517-2526. 8. Saenger YM, Wolchok JD. The heterogeneity of the kinetics of response to ipilimumab in metastatic melanoma: patient cases. Cancer Immun. 2008;8:1. 9. Weber J, Thompson JA, Hamid O, et al. A randomized, double-blind, placebo-controlled, phase II study comparing the tolerability and efficacy of ipilimumab administered with or without prophylactic budesonide in patients with unresectable stage III or IV melanoma. Clin Cancer Res. 2009;15(17):5591-5598. 10. Wolchok JD, Hoos A, O’Day S, et al. Guidelines for the evaluation of immune therapy activity in solid tumors: immune-related response criteria. Clin Cancer Res. 2009;15(23):7412-7420. 11. Attia P, Phan GQ, Maker AV, et al. Autoimmunity correlates with tumor regression in patients with metastatic melanoma treated with anti–cytotoxic T-lymphocyte antigen-4. J Clin Oncol. 2005; 23(25):6043-6053. 12. Phan GQ, Yang JC, Sherry RM, et al. Cancer regression and autoimmunity induced by cytotoxic T lymphocyte-associated antigen 4 blockade in patients with metastatic melanoma. Proc Natl Acad Sci U S A. 2003;100(14):8372-8377. 13. Blansfield JA, Beck KE, Tran K, et al. Cytotoxic T-lymphocyte–associated antigen-4 blockage can
induce autoimmune hypophysitis in patients with metastatic melanoma and renal cancer. J Immunother. 2005;28(6):593-598. 14. Beck KE, Blansfield JA, Tran KQ, et al. Enterocolitis in patients with cancer after antibody blockade of cytotoxic T-lymphocyte-associated antigen 4. J Clin Oncol. 2006;24(15):2283-2289. 15. Downey SG, Klapper JA, Smith FO, et al. Prognostic factors related to clinical response in patients with metastatic melanoma treated by CTLassociated antigen-4 blockade. Clin Cancer Res. 2007;13(22 pt 1):6681-6688. 16. Yang JC, Hughes M, Kammula U, et al. Ipilimumab (anti-CTLA4 antibody) causes regression of metastatic renal cell cancer associated with enteritis and hypophysitis. J Immunother. 2007;30(8):825-830. 17. Ribas A, Chmielowski B, Glaspy JA. Do we need a different set of response assessment criteria for tumor immunotherapy? Clin Cancer Res. 2009;15(23):71167118. 18. Ledezma B. Ipilimumab for advanced melanoma: a nursing perspective. Oncol Nurs Forum. 2009;36(1):97-104. 19. O’Day SJ, Maio M, Chiarion-Sileni V, et al. Efficacy and safety of ipilimumab monotherapy in patients with pretreated advanced melanoma: a multicenter single-arm phase II study. Ann Oncol. 2010;21(8):1712-1717. 20. Wolchok JD, Neyns B, Linette G, et al. Ipilimumab monotherapy in patients with pretreated advanced melanoma: a randomised, double-blind, multicentre, phase 2, dose-ranging study. Lancet Oncol. 2010;11(2):155-164. 21. Hersh EM, O’Day SJ, Powderly J, et al. A phase II multicenter study of ipilimumab with or without dacarbazine in chemotherapy-naïve patients with advanced melanoma. Invest New Drugs. 2011;29(3):489-498. 22. Hodi FS, Butler M, Oble DA, et al. Immunologic and clinical effects of antibody blockade of cytotoxic T lymphocyte-associated antigen 4 in previously vaccinated cancer patients. Proc Natl Acad Sci U S A. 2008;105(8):3005-3010. 23. Ridolfi L, Ridolfi R. Anti-CTLA-4 therapy in melanoma: role of ipilimumab (MDX-010). Expert Rev Dermatol. 2009;4(3):199-210. 24. Chin K, Ibrahim R, Berman D, et al. Treatment guidelines for the management of immune-related adverse events in patients treated with ipilimumab, an anti-CTLA4 therapy. Ann Oncol. 2008;19(suppl 8):viii244-viii245. Abstract 787P. 25. YERVOY (ipilimumab) immune-mediated adverse reaction management guide. Bristol-Myers Squibb; 2011. https://www.hcp.yervoy.com/pdf/rems-manage ment-guide.pdf. Accessed April 23, 2013. 26. Minor DR, Chin K, Kashani-Sabet M. Infliximab in the treatment of anti-CTLA4 antibody (ipilimumab) induced immune-related colitis. Cancer Biother Radiopharm. 2009;24(3):321-325. 27. Lutzky J, Wolchok J, Hamid O, et al. Association between immune-related adverse events (irAEs) and disease control or overall survival in patients (pts) with advanced melanoma treated with 10 mg/kg ipilimumab in three phase II clinical trials. J Clin Oncol. 2009;27(suppl)(15s). Abstract 9034. 28. Dummer R, Maio M, Hamid O, et al. Time to onset and resolution of immune-related adverse events associated with ipilimumab therapy in patients with advanced melanoma. Poster presented at: Perspectives in Melanoma XIV; September 17-18, 2010; Amsterdam, the Netherlands. Poster P-0004. 29. Jahraus D, Sokolosky S, Thurston N, Guo D. Evaluation of an education program for patients with breast cancer receiving radiation therapy. Cancer Nurs. 2002;25(4):266-275.
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August 2013 I VOL 6, NO 7
Immunotherapies Take Center Stage in Melanoma By Audrey Andrews Data continue to build for the use of immunotherapy in the treatment of patients with metastatic melanoma. At the 2013 American Society of Clinical Oncology (ASCO) Annual Meeting, several sessions focused on recent advances in melanoma, including new ways to boost the activity of current therapies, the development of a new class of immunotherapy, and a new form of immunotherapy—an oncolytic vaccine.
Photos by © ASCO/Scott Morgan 2013.
only 2 patients discontinued because of adverse events. “We found that efficacy and safety were similar in ipilimumab-naive patients and those who had received prior treatment with ipilimumab,” Ribas noted.
F. Stephen Hodi, Jr, MD
Lynn M. Schuchter, MD
Growth Factors Give Ipilimumab a Boost Investigators presented data showing that the activity of ipilimumab was boosted by the addition of granulocyte macrophage colony-stimulating factor (GM-CSF). The phase 2 study reported improved overall survival (OS) with the combination versus ipilimumab alone.1 “Adding GM-CSF to ipilimumab improved survival and also tolerability of treatment. These data represent an important avenue for combining cytokine therapy with immune checkpoint blockade,” said F. Stephen Hodi, Jr, MD, director of the Melanoma Center at Dana-Farber Cancer Institute, Boston, Massachusetts, speaking at an ASCO press briefing. GM-CSF works within the immune system by enhancing granulocytes and macrophages, while the antibody ipilimumab “takes the brakes off” immune blockade, allowing the body itself to fight the tumor, Hodi explained. The Eastern Cooperative Oncology Group (ECOG) E1608 trial randomly assigned 245 patients with previously treated metastatic melanoma to receive ipilimumab and maintenance treatment, or the same plus the growth factor sargramostim. The addition of GM-CSF to ipilimumab significantly improved OS from a median time of 12.7 months with ipilimumab alone to 17.5 months, a 36% reduction in mortality (P = .014). A surprising and encouraging finding was that tolerability was actually better with the combination than with the single agent, he reported. “With both drugs commercially available, these findings have implications for the current treatment of melanoma patients,” Hodi suggested. “At the same time, we still need to clarify the best way to apply these findings in everyday practice.” Lynn M. Schuchter, MD, program
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Mario Sznol, MD
leader of the Melanoma and Cutaneous Malignancies Program at Abramson Cancer Center of the University of Pennsylvania, Philadelphia, commented that because both drugs are approved, physicians could start using this combination immediately, though she questioned whether third-party payers would reimburse for the growth factors. New Class of Anti–PD-1 Blockade Agents May Be a Blockbuster A new class of immunotherapeutic agents blocks the programmed death-1 (PD-1) and PD-1 ligand (PD-L1), and helps keep T cells primed and ready to attack tumor
Kim A. Margolin, MD
receiving the optimal dose of 3 mg/kg (the dose chosen for further development), and median OS was 20 months for this population; responses were prompt and averaged 24 months in duration, Sznol reported. “We are in an era of remarkable advances for melanoma,” he said. “Median survival with vemurafenib is 16 months. For ipilimumab it is similar. But here, with nivolumab it’s 16.8 months [across all dose levels], and the median duration of response of 2 years [across all dose levels] is one of the highest numbers I have seen.” Antonio Ribas, MD, associate pro-
“Adding GM-CSF to ipilimumab improved survival and also tolerability of treatment. These data represent an important avenue for combining cytokine therapy with immune checkpoint blockade.” F. Stephen Hodi, Jr, MD
cells. This class of agents is poised to again change the standard of care in melanoma, according to melanoma experts. Interest in these agents is so great than an entire clinical science symposium was devoted to this drug class at ASCO. Long-term follow-up of an expanded phase 1 trial of the PD-1 inhibitor nivolumab in heavily pretreated patients showed that median OS approached 17 months across all dose levels (0.1, 0.3, 1, 3, or 10 mg/kg), with a very favorable toxicity profile, reported Mario Sznol, MD, professor of medical oncology in the Melanoma Program at the Yale Cancer Center, New Haven, Connecticut.2 In this study of 107 patients who received nivolumab, response rates reached 41% among those patients
fessor of hematology-oncology and surgical oncology at the University of California Los Angeles, presented early data for lambrolizumab, the anti–PD-1 agent that recently received “breakthrough therapy” status by the US Food and Drug Administration (FDA). He discussed preliminary results of an ongoing phase 1b expansion trial of patients with melanoma at the clinical science symposium on anti–PD-1.3 Lambrolizumab was administered every 2 or 3 weeks until disease progression or unacceptable toxicity. Of the 294 enrolled patients, 179 did not receive ipilimumab and 115 patients were pretreated with ipilimumab. As of December 2012, the median response duration had not been reached, and
Dual Blockade With PD-1 Packs Bigger Punch By combining the cytotoxic Tlymphocyte antigen-4 (CTLA-4)– blocking antibody ipilimumab and the PD-1 blocker nivolumab, investigators achieved deep, rapid, and durable tumor responses in a phase 1 study presented by Jedd D. Wolchok, MD, PhD, an oncologist at Memorial Sloan-Kettering Cancer Center, New York.4 The study results were published online simultaneously with the presentation.5 Among the 53 patients receiving concurrent treatment, 53% had an objective response at the maximum dose associated with an acceptable level of adverse events, with ≥80% tumor reduction, including 18% who achieved a complete response. After a median follow-up of 13 months, 90% of responders were still stable. The estimated 1-year survival rate with this regimen was 82%. Grade 3 or 4 adverse events were reported in 53% of the patients in the concurrent-regimen group. “The proportion of patients with a rapidly declining tumor burden is reminiscent of responses to targeted pathway inhibitors, yet the durability of these responses maintains consistency with the long-lasting nature of immunotherapy in prior studies,” Wolchok said at the ASCO clinical science symposium on anti–PD-1. The paper’s discussant, Walter J. Urba, MD, PhD, director of cancer research at Providence Cancer Center in Oregon, predicted that PD-1 blockade is “certainly going to change the state of the care of patients with melanoma once again.” Harnessing an Oncolytic Virus The cancer-killing virus talimogene laherparepvec (T-VEC) is the first oncolytic virus to produce a treatment benefit in melanoma. T-VEC directly kills tumor cells and elicits a host response that indirectly targets distant metastases as well, explained Howard I. Kaufman, MD, cancer program director at Rush University Medical Center, Chicago, Illinois.6
Melanoma The phase 3 OncoVEX Pivotal Trial in Melanoma (OPTiM) study randomized 436 patients with advanced melanoma to receive intratumoral injections of T-VEC or subcutaneous injections of GM-CSF. The virus significantly improved durable responses (≥6 months) compared with GM-CSF (16.3% vs 2.1%; P <.0001), meeting the study’s end point, Kaufman reported. Median time to treatment failure was 8.2 months versus 2.9 months with GM-CSF, a 58% reduction in progression (P <.0001). In the interim analysis, median OS was 23.3 months with T-VEC and 19.0 months with GM-CSF. The treatment was also very well tolerated, he said.
“We are in an era of remarkable advances for melanoma.” Mario Sznol, MD
Kim A. Margolin, MD, of the Seattle Cancer Care Alliance, commented that because GM-CSF is not a standard treatment for metastatic melanoma, it may not be a good comparator for the novel therapy. She suggested the best use of T-VEC may be in combination with another immune mediator such as ipilimumab. “Targeting immunoinhibitory pathways is providing a new strategy for immunotherapy…There are synergies among inhibitory pathways. Coblockade enables better rescue of exhausted T cells and therapeutic efficacy than blockade of a single inhibitory pathway,” said Arlene H. Sharpe, MD, PhD, codirector of the Harvard Institute of Translational Immunology at Harvard Medical School, Boston, at the ASCO clinical science symposium. According to Sharpe and other melanoma experts, combinations of these expensive novel therapies may prove the most efficacious, and a number of such regimens are entering clinical trials. Two New Therapies Approved for Advanced Melanoma On May 29, 2013, just before the ASCO meeting, the FDA approved 2 new therapies, which do not target the immune system, for patients with advanced melanoma and BRAF mutation: dabrafenib (Tafinlar) targets patients with the V600E mutation, and trametinib (Mekinist) targets patients with the BRAF V600E or V600K mutation. Both therapies were approved by the FDA with a companion diagnostic test. l
Clinical Oncology Annual Meeting; May 31-June 4, 1. Hodi FS, Lee SJ, McDermott DF, et al. Multicenter, 2013; Chicago, IL. randomized phase II trial of GM-CSF (GM) plus 3. Ribas A, Robert C, Daud A, et al. Clinical efficacy ipilimumab (Ipi) versus Ipi alone in metastatic melaand safety of lambrolizumab (MK-3475, Anti-PD-1 noma: E1608. J Clin Oncol. 2013;31(suppl):Abstract monoclonal antibody) in patients with advanced melCRA9007. Presented at: 2013 American Society of anoma. J Clin Oncol. 2013;31(suppl):Abstract 9009. Clinical Oncology Annual Meeting; May 31-June 4, Presented at: 2013 American Society of Clinical 2013; Chicago, IL. Oncology Annual Meeting; May 31-June 4, 2013; 2. Sznol M, Kluger HM, Hodi SF, et al. Survival Chicago, IL. and long-term follow-up of safety and response in 4. Wolchok JD, Kluger HM, Callahan MK, et al. Safety patients (pts) with advanced melanoma (MEL) in a and clinical activity of nivolumab (anti-PD-1, BMSphase I trial of nivolumab (anti-PD-1; BMS-936558; 936558, ONO-4538) in combination with ipilimumab ONO-4538). J Clin Oncol. 2013;31(suppl):Abstract in patients (pts) with advanced melanoma (MEL). CRA9006. Presented at: 2013 American Society of J Clin Oncol. 2013;31(suppl):Abstract 9012. Presented VBCC0112_VBMAsize_Layout 1 2/15/12 3:28 PM Page 2
at: 2013 American Society of Clinical Oncology Annual Meeting; May 31-June 4, 2013; Chicago, IL. 5. Wolchok JD, Kluger H, Callahan MK, et al. Nivolumab plus ipilimumab in advanced melanoma. N Engl J Med. 2013;369(2):122-133. 6. Andtbacka RHI, Collichio FA, Amatruda T, et al. OPTiM: a randomized phase III trial of talimogene laherparepvec (T-VEC) versus subcutaneous (SC) granulocyte-macrophage colony-stimulating factor (GM-CSF) for the treatment (tx) of unresected stage IIIB/C and IV melanoma. J Clin Oncol. 2013;31(suppl):Abstract LBA9008. Presented at: 2013 American Society of Clinical Oncology Annual Meeting; May 31-June 4, 2013; Chicago, IL.
VISIT THE NEW ONLINE RESOURCE FOR NURSES AND THE ENTIRE MULTIPLE MYELOMA CARE TEAM
“Quality care is everyone’s business.” Beth Faiman, PhD(c), MSN, APRN-BC, AOCN Nurse Practitioner, Multiple Myeloma Program Cleveland Clinic Taussig Cancer Institute Cleveland, OH
Value-BasedCare IN Myeloma
RESOURCE CENTER FOR PAYERS, PROVIDERS, AND THE ENTIRE CANCER CARE TEAM
Value-Based Care in Myeloma delivers exclusive interviews and perspectives related to cost, quality, and access issues. Special sections for VA-based clinicians, advanced practice nurses, and pharmacists will also focus on the unique challenges in the management of multiple myeloma.
www.ValueBasedMyeloma.com Value-Based Care in Myeloma is a publication of Engage Healthcare Communications, a member of The Lynx Group. © 2012 All rights reserved. VBCC0112_VBMAsizeGH
August 2013 I VOL 6, NO 7
Melanoma Protecting the skin from the sun should be considered a year-round necessity because our skin is constantly exposed to the sun’s ultraviolet rays and is thus susceptible to melanoma. However, it’s summertime, the season in which sun protection is viewed as most essential, so before heading out for some fun in the sun, take a closer look at these melanoma statistics.
The American Cancer Society (ACS) reports that “about 76,690 new melanomas will be diagnosed (about 45,060 in men and 31,630 in women) and about 9480 people are expected to die of melanoma (about 6280 men and 3200 women)” in 2013.1 According to the American Society of Clinical Oncology, the overall 5-year survival rate for melanoma is 91%, and some patients require only an initial surgery to remove the tumor.2 However, melanoma that has metastasized to other organs has a survival rate of only 15%.2 For patients with metastatic or unresectable melanoma, the drugs dabrafenib (Tafinlar) and trametinib (Mekinist) were approved by the US Food and Drug Administration on May 29, 2013.3 According to the Cancer. Net website, the first sign of melanoma is often a change in the color, feel, shape, or size of a mole on the skin.4 Monthly self-examinations of the skin can help detect this deadly disease at an early stage, allowing for a greater chance of survival, the ACS advises.5 The National Cancer Institute’s Cancer Trends Progress Report–2011/2012 Update states, “The percentage of adults who report being sunburned has 30
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increased since 2005,” howProject1_Layout 5/9/13 3:03measures PM Page 1 ever, by 1some “70% of adults…protect themselves from the sun.”6
Sources 1. http://www.cancer.org/cancer/skincancer-melanoma/detailedguide/melanoma-skin-cancer-key-statistics. 2. http://www.cancer.net/cancer-types/melanoma/statistics. 3. http://www.fda.gov/NewsEvents/Newsroom/PressAnnouncements/ucm354199.htm. 4. http://www.cancer.net/cancer-types/melanoma/symptoms. 5. http://www.cancer.org/cancer/skincancer-melanoma/detailedguide/melanoma-skin-cancer-new-research. 6. http://progressreport.cancer.gov/doc_detail.asp?pid=1&did=2011&chid=101&coid=1011&mid=#links.
Fourth Annual Navigation and
November 15-17, 2013 • The Peabo PRELIMINARY AGENDA* FRIDAY, NOVEMBER 15 12:00 pm - 12:30 pm Welcome • Conference Co-Chairs: Sharon Gentry, RN, MSN, AOCN, CBCN Lillie D. Shockney, RN, BS, MAS 12:30 pm - 2:00 pm PRE-CONFERENCE WORKSHOPS Basic Navigation Track • Tricia Strusowski, MS, RN • Nicole Messier, RN, BSN OR Advanced Navigation Track • Elaine Sein, RN, BSN, OCN, CBCN • Danelle Johnston, RN, MSN, OCN, CBCN 2:00 pm - 2:45 pm BREAK IN THE EXHIBIT HALL 2:45 pm - 3:30 pm General Session 1: Top 10 Best Practices • Moderators – Conference Co-Chairs: Sharon Gentry, RN, MSN, AOCN, CBCN Lillie D. Shockney, RN, BS, MAS 3:30 pm - 5:00 pm Administrator’s Track • Mandi Pratt-Chapman, MA • Michele O’Brien, MSN, ACNS-BC, RN, BA OR
5:00 pm - 6:00 pm 6:00 pm - 8:00 pm
Case Manager’s Track FREE TIME Welcome Reception/Posters in the Exhibit Hall
SATURDAY, NOVEMBER 16 6:30 am - 7:30 am
Breakfast/Product Theater (non–CME-certified activity) 7:45 am - 8:00 am Welcome and Introductions • Conference Co-Chairs: Sharon Gentry, RN, MSN, AOCN, CBCN Lillie D. Shockney, RN, BS, MAS 8:00 am - 8:30 am General Session 2: The Future of AONN (The AONN Business Meeting) • Sharon Gentry, RN, MSN, AOCN, CBCN • Lillie D. Shockney, RN, BS, MAS 8:30 am - 9:15 am General Session 3: Community Needs and Navigation • Lillie D. Shockney, RN, BS, MAS, on behalf of the Global Breast Health Initiative • Jennifer Klemp, PhD, MPH, MS 9:15 am - 10:00 am General Session 4: Development and Application of Evidence-Based Guidelines in Cancer Care: The NCCN Perspective • Liz Danielson, MHA 10:00 am - 10:45 am BREAK IN THE EXHIBIT HALL 10:45 am - 11:30 am Keynote: Update on Guidelines • Linda Ferris, PhD 11:45 am - 12:45 pm Lunch/Product Theater (non–CME-certified activity) 1:00 pm - 1:45 pm General Session 5: Onco-Politic Barriers • Dan O’Connor 1:45 pm - 2:30 pm General Session 6: Addressing Disparities of Care • Swann Arp Adams, PhD, MS • Michelle Weaver Knowles, RNC, BSN
2:30 pm - 3:15 pm 3:15 pm - 3:45 pm 3:50 pm - 4:35 pm
4:35 pm - 5:20 pm 5:30 pm - 7:30 pm
General Session 7: Oncology Medical Home BREAK IN THE EXHIBIT HALL General Session 8: Meeting the Needs of the Adult and Child Survivor Throughout the Life Span • Christy Roberts, RN, BSN, OCN General Session 9: The Role of Complementary Therapies in Navigation • Linda Lee, MD, AGAF Poster Award Reception
SUNDAY, NOVEMBER 17 6:30 am - 7:30 am
Breakfast/Product Theater (non–CME-certified activity) 7:45 am - 8:00 am Welcome and Introductions • Conference Co-Chairs: Sharon Gentry, RN, MSN, AOCN, CBCN Lillie D. Shockney, RN, BS, MAS 8:30 am - 8:45 am General Session 10: Navigator’s Role in Tumor Boards • Laurie Mathis, RN, BS, MAS 8:45 am - 10:30 am DISEASE SITE–SPECIFIC BREAKOUTS • Breast Cancer Navigation & Survivorship • Karen Dow Meneses, PhD, RN, FAAN • Vinnie Myers • Thoracic Oncology Navigation • Gean Brown, RN, OCN • GI & Colorectal Cancer Navigation • Darcy Doege, RN, BSN • Kristen Vogel, MS, CGC • GYN Cancers Navigation • Penny Daugherty, BSN, RN, OCN • Prostate Cancer Navigation • Head, Neck, & Neuro Navigation • Tamara Bowen, RN, BSN, MHA • Pediatric Oncology • Kathy Ruble, RN, CPNP, PhD • Hematology/Oncology Navigation • Melanoma Navigation • Sherry Riggins, RN, BSN, OCN 10:30 am - 11:15 am BREAK IN THE EXHIBIT HALL 11:15 am - 12:00 pm General Session 11: Understanding the Role of the Primary Care Physician • Michael Kolodziej, MD 12:15 pm - 1:15 pm Lunch/Product Theater (non–CME-certified activity) 1:30 pm - 2:15 pm General Session 12: Navigator’s Role in End-of-Life Care • Lillie D. Shockney, RN, BS, MAS 2:15 pm - 3:00 pm General Session 13: Music & Medicine: A Dynamic Partnership • Deforia Lane, PhD, MT-BC 3:00 pm - 3:15 pm Conclusion of the Conference/Final Remarks • Conference Co-Chairs: Sharon Gentry, RN, MSN, AOCN, CBCN Lillie D. Shockney, RN, BS, MAS *Preliminary agenda, subject to change.
Sorafenib Effective in Metastatic Differentiated Thyroid Cancer By Audrey Andrews
orafenib has become the first drug in years to prove effective in the treatment of differentiated thyroid cancer (DTC) that has become resistant to radioactive iodine (RAI), according to phase 3 study results reported at the 2013 American
Society of Clinical Oncology (ASCO) Annual Meeting. DTC is the most common subtype of thyroid cancer―and its incidence is rising. DTC is rarely fatal, although up to 15% of patients become resistant to the current standard of care, RAI, and can
die as a result. For this group, there has never been an effective treatment, said Marcia S. Brose, MD, PhD, assistant professor of otorhinolaryngology, head and neck surgery, at the University of Pennsylvania Perelman School of Medicine, Philadelphia.
ody Memphis • Memphis, Tennessee CONFERENCE CO-CHAIRS Program Director: Lillie D. Shockney, RN, BS, MAS University Distinguished Service Associate Professor of Breast Cancer Depts of Surgery and Oncology Adm Director, Johns Hopkins Breast Center Adm Director, Johns Hopkins Cancer Survivorship Programs Associate Professor, JHU School of Medicine Depts of Surgery, Oncology & Gynecology and Obstetrics Associate Professor, JHU School of Nursing Baltimore, MD
FACULTY* Swann Arp Adams, PhD, MS Tamara Bowen, RN, BSN, MHA Gean Brown, RN, OCN
Penny Daugherty, BSN, RN, OCN Darcy Doege, RN, BSN Karen Dow Meneses, PhD, RN, FAAN Linda Ferris, PhD Sharon Gentry, RN, MSN, AOCN, CBCN
Jennifer Klemp, PhD, MPH, MS Michael Kolodziej, MD Deforia Lane, PhD, MT-BC Linda Lee, MD, AGAF
AONN’s Fourth Annual Conference will continue to advance the navigation profession by expanding the scope of educational sessions, networking opportunities, and poster presentations. In addition, this year’s conference will address the evolving challenges of program improvement, the role of personalized medicine, and implementing best practices in navigation, survivorship, and psychosocial care.
This activity was developed for oncology nurse navigators, patient navigators, social workers, and case managers.
CONTINUING EDUCATION INFORMATION
Learning Objectives Upon completion of this activity, the participant will be able to: • Discuss the evolution of the role of navigation in healthcare. • Assess strategies for navigating diverse patient populations by cancer type and environmental factors. • Define methods for providing patient support and guidance in the age of personalized cancer care. • Evaluate best practices regarding survivorship and psychosocial care.
Nicole Messier, RN, BSN Vinnie Myers Michele O’Brien, MSN, ACNS-BC, RN, BA
Liz Danielson, MHA
Danelle Johnston, RN, MSN, OCN, CBCN
Sharon Gentry, RN, MSN, AOCN, CBCN Breast Nurse Navigator Derrick L. Davis Forsyth Regional Cancer Center Winston-Salem, NC
Laurie Mathis, RN, CBCN, OCN
Dan O’Connor Mandi Pratt-Chapman, MA Sherry Riggens, RN, BSN, OCN Christy Roberts, RN, BSN, OCN Kathy Ruble, RN, CPNP, PhD Elaine Sein, RN, BSN, OCN, CBCN Lillie D. Shockney, RN, BS, MAS Tricia Strusowski, MS, RN Kristen Vogel, MS, CGC Michelle Weaver Knowles, RNC, BSN *For full information visit www.aonnonline.org
This activity is jointly sponsored by Medical Learning Institute Inc, Center of Excellence Media, LLC, and Core Principle Solutions, LLC.
COMMERCIAL SUPPORT ACKNOWLEDGMENT
Grant requests are currently being reviewed by numerous supporters. Support will be acknowledged prior to the start of the educational activities.
REGISTERED NURSE DESIGNATION
Medical Learning Institute Inc. Provider approved by the California Board of Registered Nursing, Provider Number 15106, for up to 16.25 contact hours.
2013 CONFERENCE REGISTRATION
“We have had no effective drugs for these patients for many years, so it is very exciting to have an oral drug that halts cancer growth for several months,” she said at a press briefing. “This is the first time we have had a systemic treatment that can help them.” Remission Prolonged by 5 Months The 89-center DECISION (Study of Sorafenib in Locally Advanced or Metastatic Patients with Radioactive Iodine Refractory Thyroid Cancer) trial enrolled 417 patients who had become resistant to RAI. Patients were randomly assigned to sorafenib 400 mg twice daily or placebo. If the disease progressed, the placebo recipients could cross over to receive sorafenib. The median progression-free survival was 10.8 months in the sorafenib arm versus 5.8 months in the placebo arm, for a 42% reduction in mortality that was highly significant (P <.0001). Median overall survival has not been reached in either arm, but a difference is unlikely to emerge, as 70% of patients have crossed over to receive active treatment, Brose said. Partial responses were observed in 12.2% of the sorafenib arm versus 0.5% of the placebo arm. There were no complete responses in the study. Stable disease was achieved by 42% of patients taking sorafenib, reflecting a disease control rate of 54% with the drug, compared with 34% with placebo. New Standard of Care? Commenting on this study at the ASCO plenary session, Ezra Cohen, MD, associate professor of medicine at the University of Chicago, Illinois, said, “These patients finally have options.” Cohen was enthusiastic about the data, but he reminded oncologists that “not all iodine-refractory patients need treatment.” He noted that 25% of placebo recipients did not progress while participating in the trial and that most RAI-refractory patients are asymptomatic. According to Cohen, the choice to use sorafenib should be based on the presence of symptoms as well as the location and growth rate of the disease. He also noted that DTC that becomes refractory to vascular endothelial growth factor receptor (VEGF) inhibitors such as sorafenib “is an emerging entity that needs to be addressed.” l Reference
Brose MS, Nutting C, Jarzab B, et al. Sorafenib in locally advanced or metastatic patients with radioactive iodine-refractory differentiated thyroid cancer: the phase III DECISION trial. J Clin Oncol. 2013;31(suppl):Abstract 4. Presented at: 2013 American Society of Clinical Oncology Annual Meeting; May 31-June 4, 2013; Chicago, IL.
August 2013 I VOL 6, NO 7
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