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DECEMBER 2013

www.TheOncologyNurse.com

VOL 6, NO 11

OVARIAN CANCER

CANCER CENTER PROFILE

Scripps Cancer Center— Stevens Division at Scripps Memorial Hospital Meeting the Needs of Patients

Antiangiogenesis Pursued in High-Risk Ovarian Cancer Alice Goodman

A

ngiogenesis is an active area of clinical research in ovarian cancer, but proving that this approach extends overall survival (OS) has been somewhat challenging thus far. Michael Bookman, MD, reviewed studies of antiangiogenesis in highgrade serous ovarian cancer at the 2013 Chemotherapy Foundation Symposium, held in New York City. Bookman is the director of medical oncology at the University of Arizona Cancer Center in Tucson.

“High-grade serous ovarian cancer is the most common subtype of epithelial ovarian cancer and it remains highly lethal. New approaches are needed beyond angiogenesis,” he told listeners. “The key questions to consider in antiangiogenic trials are the best targets, the preferred strategy, and the optimal setting for these studies,” Bookman said. “We need predictive biomarkers and we need to think about how we measure success in clinical trials.” Continued on page 8

THE PATIENT’S VOICE Some of the team at the Scripps Cancer Center—Stevens Division (left to right): Paula Thomas, Eileen Gaudette, Janine Rodriguez, Cathleen Sugarman, and Jaime Malone.

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he Scripps Cancer Center—Stevens Division is located at Scripps Memorial Hospital in La Jolla, California, and is part of the San Diego County–wide Scripps Health cancer care network. The center is committed to working with cancer patients from diagnosis through treatment. As 1 of only 2 Integrated Network Cancer Programs in California (as designated by the American College of Surgeons), Scripps Health encompasses the oncology resources of 5 hospital campuses, a broad network of cancer care specialists and affiliated physicians, and the renowned Scripps research professionals. In addition to providing a full continuum of cancer care for patients, the center offers cancer prevention and early detection services and access to educational and social support services.

The Other Side of the Stethoscope Tania Homonchuk, MD

I

am 60 years old and an ovarian cancer survivor. I’m also an emergency department doctor who usually is treating people, making diagnoses, and being the one in charge. However, much the same as most women with ovarian cancer, my diagnosis came out of the blue with minimal symptoms at an advanced stage. I found myself for once on the other side, as a patient. I’m happy to say that I am now 2½ years disease-free from my last treatment in January 2011. The start of my story is in 2009. I

NEWS BRIEFS Alice Goodman

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he field of ovarian cancer is an active area of research, with a number of potential approaches showing promise in improving outcomes. Targeted therapies have made advances in this disease, and experts are learning how best to exploit these. A selection of news high-

lights on ovarian cancer, from the European Cancer Congress (ECCO/ ESMO/ESTRO), the Chemotherapy Foundation Symposium, and the AACR-NCI-EORTC International Conference on Molecular Targets and Cancer Therapeutics, follows.

Continued on page 16

INSIDE

Continued on page 30

Ovarian Cancer in the News

was working full time in the emergency department with the usual 8- to 12-hour shifts of days, evenings, and nights. That year I was pretty busy working in both Sacramento and San Diego, keeping up with one son in college and his rowing regattas, and another son who was a junior in high school, active in sports and with college applications coming up. In 2010 I scaled back to working just in San Diego with a perfect number of shifts, more time at home, working out more,

OVARIAN CANCER

Neoadjuvant Chemotherapy a Reasonable Option for Advanced Ovarian Cancer . . . . . . . . . . . . . . . . . . . . .

THROUGH THE EYES OF AN ADVOCATE. . . . . . . . . . . . . . . . . . . . . . . .

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Important Steps in the Conquest of Ovarian Cancer

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Resources for Patients, Survivors, Providers, Researchers, and Supporters. . . . . . . . . . . . . . . . . . . . . . . .

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YOU VOTED FOR

EMPOWERING PATIENTS AND SURVIVORS. . . . . . . . . . . . . . . . . . . . . . .

12

ONE Award

A Thrust Into Vulnerability

Continued on page 9 ©2013 Green Hill Healthcare Communications, LLC

The 2013

Find out who won on page 28


Take a bite out of G-CSF acquisition costs*

*Based on wholesale acquisition cost (WAC) of all short-acting G-CSF products as of November 11, 2013. WAC represents published catalogue or list prices and may not represent actual transactional prices. Please contact your supplier for actual prices.

Indication » GRANIXTM (tbo-filgrastim) Injection is a leukocyte growth factor indicated for reduction in the duration of severe neutropenia in patients with nonmyeloid malignancies receiving myelosuppressive anticancer drugs associated with a clinically significant incidence of febrile neutropenia.

Important Safety Information » Splenic rupture: Splenic rupture, including fatal cases, can occur following the administration of human granulocyte colony-stimulating factors (hG-CSFs). Discontinue GRANIX and evaluate for an enlarged spleen or splenic rupture in patients who report upper abdominal or shoulder pain after receiving GRANIX.

» Acute respiratory distress syndrome (ARDS): ARDS can occur in patients receiving hG-CSFs. Evaluate patients who develop fever and lung infiltrates or respiratory distress after receiving GRANIX, for ARDS. Discontinue GRANIX in patients with ARDS.

» Allergic reactions: Serious allergic reactions, including anaphylaxis, can occur in patients receiving hG-CSFs. Reactions can occur on initial exposure. Permanently discontinue GRANIX in patients with serious allergic reactions. Do not administer GRANIX to patients with a history of serious allergic reactions to filgrastim or pegfilgrastim.


NOW AVAILABLE

GRANIX is a new option in short-acting G-CSF therapy TM

» GRANIX demonstrated a 71% reduction in duration of severe neutropenia (DSN) vs placebo1 – GRANIX significantly reduced DSN when compared to placebo (1.1 days vs 3.8 days; p<0.001)1 – Efficacy was evaluated in a multinational, multicenter, randomized, controlled, Phase III study of chemotherapy-naïve patients with high-risk breast cancer receiving doxorubicin (60 mg/m2 IV bolus)/docetaxel (75 mg/m2)1

» Safety was evaluated in 3 Phase III clinical trials1

Important Safety Information (continued) » Use in patients with sickle cell disease: Severe and sometimes fatal sickle cell crises can occur in patients with sickle cell disease receiving hG-CSFs. Consider the potential risks and benefits prior to the administration of GRANIX in patients with sickle cell disease. Discontinue GRANIX in patients undergoing a sickle cell crisis.

» Potential for tumor growth stimulatory effects on malignant cells: The granulocyte colonystimulating factor (G-CSF) receptor, through which GRANIX acts, has been found on tumor cell lines. The possibility that GRANIX acts as a growth factor for any tumor type, including myeloid malignancies and myelodysplasia, diseases for which GRANIX is not approved, cannot be excluded.

» Most common treatment-emergent adverse reaction: The most common treatment-emergent adverse reaction that occurred in patients treated with GRANIX at the recommended dose with an incidence of at least 1% or greater and two times more frequent than in the placebo group was bone pain.

Please see brief summary of Full Prescribing Information on adjacent page. For more information, visit GRANIXhcp.com. Reference: 1. GRANIX TM (tbo-filgrastim) Injection Prescribing Information. North Wales, PA: Teva Pharmaceuticals; 2013.

©2013 Cephalon, Inc., a wholly-owned subsidiary of Teva Pharmaceutical Industries Ltd. GRANIX is a trademark of Teva Pharmaceutical Industries Ltd. All rights reserved. FIL-40190 October 2013.


NOTEWORTHY NUMBERS

Ovarian Cancer On November 3, Freedom Plaza in Washington, DC, was an emotional center of activity as the third annual National Race to End Women’s Cancer began and ended there. The Foundation for Women’s Cancer, established by the Society of Gynecologic Oncologists, sponsors the event to raise awareness and research funds for all gynecologic cancers. Ovarian cancer, which has the highest mortality of the gynecologic cancers, is our focus this month.

Annually, there are more than 22,000 new cases of ovarian cancer in the United States, represent-

ing only 1.3% of all new cancer diagnoses; however, more than 186,000 women are currently esti-

BRIEF SUMMARY OF PRESCRIBING INFORMATION FOR GRANIX™ (tbo-filgrastim) Injection, for subcutaneous use SEE PACKAGE INSERT FOR FULL PRESCRIBING INFORMATION 1 INDICATIONS AND USAGE GRANIX is indicated to reduce the duration of severe neutropenia in patients with non-myeloid malignancies receiving myelosuppressive anti-cancer drugs associated with a clinically significant incidence of febrile neutropenia. 4 CONTRAINDICATIONS None. 5 WARNINGS AND PRECAUTIONS 5.1 Splenic Rupture Splenic rupture, including fatal cases, can occur following administration of human granulocyte colony-stimulating factors. In patients who report upper abdominal or shoulder pain after receiving GRANIX, discontinue GRANIX and evaluate for an enlarged spleen or splenic rupture. 5.2 Acute Respiratory Distress Syndrome (ARDS) Acute respiratory distress syndrome (ARDS) can occur in patients receiving human granulocyte colony-stimulating factors. Evaluate patients who develop fever and lung infiltrates or respiratory distress after receiving GRANIX, for ARDS. Discontinue GRANIX in patients with ARDS. 5.3 Allergic Reactions Serious allergic reactions including anaphylaxis can occur in patients receiving human granulocyte colony-stimulating factors. Reactions can occur on initial exposure. The administration of antihistamines‚ steroids‚ bronchodilators‚ and/or epinephrine may reduce the severity of the reactions. Permanently discontinue GRANIX in patients with serious allergic reactions. Do not administer GRANIX to patients with a history of serious allergic reactions to filgrastim or pegfilgrastim. 5.4 Use in Patients with Sickle Cell Disease Severe and sometimes fatal sickle cell crises can occur in patients with sickle cell disease receiving human granulocyte colony-stimulating factors. Consider the potential risks and benefits prior to the administration of human granulocyte colony-stimulating factors in patients with sickle cell disease. Discontinue GRANIX in patients undergoing a sickle cell crisis. 5.5 Potential for Tumor Growth Stimulatory Effects on Malignant Cells The granulocyte colony-stimulating factor (G-CSF) receptor through which GRANIX acts has been found on tumor cell lines. The possibility that GRANIX acts as a growth factor for any tumor type, including myeloid malignancies and myelodysplasia, diseases for which GRANIX is not approved, cannot be excluded. 6 ADVERSE REACTIONS The following potential serious adverse reactions are discussed in greater detail in other sections of the labeling: • Splenic Rupture [see Warnings and Precautions (5.1)] • Acute Respiratory Distress Syndrome [see Warnings and Precautions (5.2)] • Serious Allergic Reactions [see Warnings and Precautions (5.3)] • Use in Patients with Sickle Cell Disease [see Warnings and Precautions (5.4)] • Potential for Tumor Growth Stimulatory Effects on Malignant Cells [see Warnings and Precautions (5.5)] The most common treatment-emergent adverse reaction that occurred at an incidence of at least 1% or greater in patients treated with GRANIX at the recommended dose and was numerically two times more frequent than in the placebo group was bone pain. 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 clinical practice. GRANIX clinical trials safety data are based upon the results of three randomized clinical trials in patients receiving myeloablative chemotherapy for breast cancer (N=348), lung cancer (N=240) and non-Hodgkin’s lymphoma (N=92). In the breast cancer study, 99% of patients were female, the median age was 50 years, and 86% of patients were Caucasian. In the lung cancer study, 80% of patients were male, the median age was 58 years, and 95% of patients were Caucasian. In the non-Hodgkin’s lymphoma study, 52% of patients were male, the median age was 55 years, and 88% of patients were Caucasian. In all three studies a placebo (Cycle 1 of the breast cancer study only) or a nonUS-approved filgrastim product were used as controls. Both GRANIX and the non-US-approved filgrastim product were administered at 5 mcg/kg subcutaneously once daily beginning one day after chemotherapy for at least five days and continued to a maximum of 14 days or until an ANC of ≥10,000 x 106/L after nadir was reached. Bone pain was the most frequent treatment-emergent adverse reaction that occurred in at least 1% or greater in patients treated with GRANIX at the

4

mated to be living with ovarian cancer, and 14,000 women die of this disease each year.1

recommended dose and was numerically two times more frequent than in the placebo group. The overall incidence of bone pain in Cycle 1 of treatment was 3.4% (3.4% GRANIX, 1.4% placebo, 7.5% non-US-approved filgrastim product). Leukocytosis In clinical studies, leukocytosis (WBC counts > 100,000 x 106/L) was observed in less than 1% patients with non-myeloid malignancies receiving GRANIX. No complications attributable to leukocytosis were reported in clinical studies. 6.2 Immunogenicity As with all therapeutic proteins, there is a potential for immunogenicity. The incidence of antibody development in patients receiving GRANIX has not been adequately determined. 7 DRUG INTERACTIONS No formal drug interaction studies between GRANIX and other drugs have been performed. Drugs which may potentiate the release of neutrophils‚ such as lithium‚ should be used with caution. Increased hematopoietic activity of the bone marrow in response to growth factor therapy has been associated with transient positive bone imaging changes. This should be considered when interpreting bone-imaging results. 8 USE IN SPECIFIC POPULATIONS 8.1 Pregnancy Pregnancy Category C There are no adequate and well-controlled studies of GRANIX in pregnant women. In an embryofetal developmental study, treatment of pregnant rabbits with tbo-filgrastim resulted in adverse embryofetal findings, including increased spontaneous abortion and fetal malformations at a maternally toxic dose. GRANIX should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus. In the embryofetal developmental study, pregnant rabbits were administered subcutaneous doses of tbo-filgrastim during the period of organogenesis at 1, 10 and 100 mcg/kg/day. Increased abortions were evident in rabbits treated with tbo-filgrastim at 100 mcg/kg/day. This dose was maternally toxic as demonstrated by reduced body weight. Other embryofetal findings at this dose level consisted of post-implantation loss‚ decrease in mean live litter size and fetal weight, and fetal malformations such as malformed hindlimbs and cleft palate. The dose of 100 mcg/kg/day corresponds to a systemic exposure (AUC0-24) of approximately 50-90 times the exposures observed in patients treated with the clinical tbo-filgrastim dose of 5 mcg/kg/day. 8.3 Nursing Mothers It is not known whether tbo-filgrastim is secreted in human milk. Because many drugs are excreted in human milk, caution should be exercised when GRANIX is administered to a nursing woman. Other recombinant G-CSF products are poorly secreted in breast milk and G-CSF is not orally absorbed by neonates. 8.4 Pediatric Use The safety and effectiveness of GRANIX in pediatric patients have not been established. 8.5 Geriatric Use Among 677 cancer patients enrolled in clinical trials of GRANIX, a total of 111 patients were 65 years of age and older. No overall differences in safety or effectiveness were observed between patients age 65 and older and younger patients. 8.6 Renal Impairment The safety and efficacy of GRANIX have not been studied in patients with moderate or severe renal impairment. No dose adjustment is recommended for patients with mild renal impairment. 8.7 Hepatic Impairment The safety and efficacy of GRANIX have not been studied in patients with hepatic impairment. 10 OVERDOSAGE No case of overdose has been reported.

©2013 Cephalon, Inc., a wholly owned subsidiary of Teva Pharmaceutical Industries Ltd. All rights reserved. GRANIX is a trademark of Teva Pharmaceutical Industries Ltd. Manufactured by: Sicor Biotech UAB Vilnius, Lithuania U.S. License No. 1803 Distributed by: Teva Pharmaceuticals USA, Inc. North Wales, PA 19454 Product of Israel FIL-40045 July 2013 This brief summary is based on TBO-003 GRANIX full Prescribing Information.

DIGITAL

A combination of heat and doxorubicin delivered with nanotechnology can kill up to 95% of ovarian cancer cells.2 Researchers at Oregon State University have developed and evaluated a new treatment for drug-resistant ovarian cancer by which engineered iron oxide nanoparticles act as a delivery system for doxorubicin and also heat cancer cells remotely when the particles are exposed to an alternating magnetic field. For women with ovarian cancer, treatment by a gynecologic oncologist yields significantly better surgical results and overall survival, and women who receive appropriate treatment are 34% less likely to die. In the United States, however, more than 60% of patients with ovarian cancer do not receive the correct therapy.3 Sources 1. http://seer.cancer.gov/statfacts/html/ovary.html. 2. http://ir.library.oregonstate.edu/xmlui/handle/1957/ 43046. 3. http://awomanshealth.com/what-every-womanshould-know-about-gynecologic-cancer/.

www.TheOncologyNurse.com

DECEMBER 2013 I VOL 6, NO 11

724-37388

Of women diagnosed with ovarian cancer, 15% have early stage localized disease, which has a 5-year survival rate of 91.9%.1 At time of diagnosis, 61% of patients have metastatic disease, which has a 5-year survival rate of 27.3%.1

CMYK Vers

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Job Number: 20262 Revision No: 0


EDITORIAL BOARD EDITOR-IN-CHIEF

Beth Faiman,

Shannon Hazen, RN, BSN, OCN

PhD(c), MSN, APRNBC, AOCN

Novant Health Presbyterian Cancer Center Charlotte, NC

Catherine Bishop,

Patricia Irouer Hughes, RN, MSN,

Cleveland Clinic Taussig Cancer Institute Cleveland, OH

DNP, NP, AOCNP

Melinda Oberleitner, RN,

Karla Wilson,

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

City of Hope National Medical Center Duarte, CA

Jayshree Shah, NP

Pharmacy John F. Aforismo,

DNS, APRN, CNS

John Theurer Cancer Center Hackensack University Medical Center Hackensack, NJ

Johns Hopkins Kimmel Cancer Center/Sibley Infusion Washington, DC

BSN, OCN

Deena Damsky Dell, MSN, RN-BC,

Taline Khoukaz,

Gary Shelton,

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

NYU Clinical Cancer Center New York, NY

AOCN, LNC

Fox Chase Cancer Center Philadelphia, PA

Wendy DiSalvo,

DNP, APRN, AOCN Genentech New London, NH

Denice Economou,

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

Piedmont Healthcare Rex, GA

NP, MSN, ACNP-C

MSN, NP, ANP-BC, AOCNP

Sandra E. Kurtin,

Lori Stover, RN,

Arizona Cancer Center Tucson, AZ

Western Pennsylvania Cancer Institute Pittsburgh, PA

Ann McNeill,

Joseph D. Tariman,

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

BSN

PhD, APRN, BC

Northwestern University Myeloma Program Chicago, IL

Jacqueline Marie Toia, RN, MS, DNP

Northwestern University Myeloma Program Chicago, IL

Pamela Hallquist Viale, RN, MS,

CS, ANP, AOCN Saratoga, CA

RN, MSN, FNP-C, CPON

BSc Pharm, RPh, FASCP RJ Health Systems International, LLC Wethersfield, CT

Nutrition Karen Connelly, RD, CSO

Somerset Medical Center Somerville, NJ

Patient Advocacy Peg Ford

Ovarian Cancer Alliance San Diego, CA

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

Genetic Counseling Cristi Radford, MS, CGC

Ambry Genetics Sarasota, FL

Managed Care and Pharmaceutical Management Burt Zweigenhaft, BS

OncoMed Onco360 Great Neck, NY

Sharon S. Gentry,

Ellen A. Neylon,

RN, MSN, AOCN, CBCN

MSN, FNP-BC, CCRP, OCN

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

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

Cassandra J. Hammond, RN,

Dolores “Jeff” Nordquist, RN, MS,

Avid Education Partners, LLC Sharpsburg, MD

Mayo Clinic Rochester, MN

MSN, CRNP

www.TheOncologyNurse.com

CS, FNP

Connie Visovsky,

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

Rita Wickham,

PhD, RN, AOCN

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

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

DECEMBER 2013 I VOL 6, NO 11

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FROM THE EDITOR PUBLISHING STAFF Senior Vice President, Sales & Marketing Philip Pawelko ppawelko@the-lynx-group.com Group Director, Sales & Marketing John W. Hennessy jhennessy2@the-lynx-group.com Publisher Russell Hennessy rhennessy@the-lynx-group.com Editorial Director Kristin Siyahian ksiyahian@the-lynx-group.com Managing Editor Kristen Olafson kolafson@the-lynx-group.com Copy Editors Mollie Friedman Peggy Roeske Editorial Assistant Jennifer Brandt Production Manager Stephanie Laudien

THE LYNX GROUP

T

his month’s issue of The Oncology Nurse-APN/PA (TON) has a focus on ovarian cancer. We update you with some of the latest research as presented at the European Cancer Congress (ECCO/ESMO/ESTRO), the Chemotherapy Foundation Symposium, and the AACR-NCIEORTC International Conference on Molecular Targets and Cancer Beth Faiman, PhD(c), Therapeutics. MSN, APRN-BC, AOCN In addition, Peg Ford reflects on Editor-in-Chief “how things have changed not only in treatment, but also in research” since she became involved in the world of medicine as an advocate after her own battle with ovarian cancer. Peg states “Because ovarian cancer is very heterogeneous molecularly, the need for personalized precision treatment is advancing the interest and focus of the scientific world.” She tells us about some early-stage studies, including of the “PapGene” test, a 3-in-1 screening for gynecologic cancers. Be sure to see Peg’s list of resources for all involved in the

President/CEO Brian Tyburski

READER POLL

Chief Operating Officer Pam Rattananont Ferris Vice President of Finance Andrea Kelly Director, Human Resources Blanche Marchitto Associate Director, Content Strategy & Development John Welz

Have you treated patients who are healthcare professionals?

Associate Editorial Director, Projects Division Terri Moore Director, Quality Control Barbara Marino Quality Control Assistant Theresa Salerno

o Yes

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 Trevean Digital Programmer Michael Amundsen Meeting & Events Planner Linda Sangenito Senior Project Managers Andrea Boylston Jini Gopalaswamy Project Coordinators Jackie Luma Deanna Martinez IT Specialist Carlton Hurdle Executive Administrator Rachael Baranoski Office Coordinator Robert Sorensen

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DECEMBER 2013 I VOL 6, NO 11

fight against ovarian cancer—from patients and survivors to researchers and healthcare providers. The Patient’s Voice column for this month was written by Tania Homonchuk. Tania is an emergency room doctor who is an ovarian cancer survivor. Her story from “the other side of the stethoscope” gives us a unique perspective on how a woman copes with receiving this diagnosis (“How do you tell your kids you have cancer?”) and subsequent treatments. Tania encourages us all to “think about nonspecific symptoms differently and keep ovarian cancer in mind—it is so silent and for many the journey to diagnosis is long and arduous.” Be sure to read Angela Long’s article, “A Thrust Into Vulnerability.” She notes that she has found it bewildering how differently patients and survivors perceive their cancer journeys. Angela discusses how “vulnerability” is the key that shapes one’s experience with cancer, a realization she came to after viewing a TED talk by Brené Brown. Brown believes that the ability to accept this vulnerability can lead individuals to “turn life’s challenges into gateways to courage, compassion, and connection.” Angela’s insight can help us all as we work with patients and survivors. All of us at TON wish you the best for 2014. l

o No

©iStockphoto.com/Slobodan Vasic

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ania Homonchuk gives us a unique perspective— she is an emergency room doctor who was diagnosed with stage 3C ovarian cancer. She tells us that her “journey since diagnosis has been chock-full of experiences on the patient side of things.” Tania points out that “the nursing care was so important: first the focus on small steps

and then getting stronger to get on with the rest of the treatment.” Have you been involved with the treatment of other healthcare professionals who have received a cancer diagnosis? Please let us know about your experience in providing care for a patient who is used to being on “the other side of the stethoscope.”

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: editorial@greenhillhc.com. YEARLY SUBSCRIPTION RATES: United States and possessions: individuals, $105.00; institutions, $135.00; single issues, $17.00. Orders will be billed at individual rate until proof of status is confirmed. Prices are subject to change without notice. Correspondence regarding permission to reprint all or part of any article published in this journal should be addressed to REPRINT PERMISSIONS DEPARTMENT, Green Hill Healthcare Communications, LLC, 1249 South River Road, Suite 202A, Cranbury, NJ 08512. The ideas and opinions expressed in The Oncology Nurse-APN/PA® do not necessarily reflect those of the Editorial Board, the Editorial Director, or the Publisher. Publication of an advertisement or other product mentioned in The Oncology Nurse-APN/PA® should not be construed as an endorsement of the product or the manufacturer’s claims. Readers are encouraged to contact the manufacturer with questions about the features or limitations of the products mentioned. Neither the Editorial Board nor the Publisher assumes any responsibility for any injury and/or damage to persons or property arising out of or related to any use of the material contained in this periodical. The reader is advised to check the appropriate medical literature and the product information currently provided by the manufacturer of each drug to be administered to verify the dosage, the method and duration of administration, or contraindications. It is the responsibility of the treating physician or other healthcare professional, relying on independent experience and knowledge of the patient, to determine drug dosages and the best treatment for the patient. Every effort has been made to check generic and trade names, and to verify dosages. The ultimate responsibility, however, lies with the prescribing physician. Please convey any errors to the Editorial Director.

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Now enrolling

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

Secondary Endpoints

• 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.


OVARIAN CANCER Antiangiogenesis Pursued in High-Risk Ovarian Cancer Continued from cover Trials of Primary Therapy Studies of frontline therapy have shown that primary therapy with weekly paclitaxel appears to be more effective than other schedules. The value of incorporating antiangiogenesis into up-front regimens is based on exploratory analysis of phase 3 trials, he said. To date, the addition of an angiogenesis inhibitor, typically bevacizumab, to chemotherapy improves progression-free survival (PFS) but does not extend OS. Two trials of up-front treatment for high-grade serous ovarian cancer, ICON7 and GOG-0218, showed a modest difference in PFS and no difference in OS with the addition of the anti–vascular endothelial growth factor (VEGF) therapy bevacizumab compared with platinum-based chemotherapy. However, exploratory analysis suggests that patients with moderateto high-risk bulky disease have better outcomes with bevacizumab. A contrary finding in the AGOOVAR12 trial that compared che-

motherapy plus or minus nintedanib showed a slight PFS benefit, but in an exploratory analysis, the low-risk group did better with nintedanib. In addition, nintedanib inhibits VEGF receptor, fibroblast growth factor receptor, and platelet-derived growth factor receptor, and targets tumor cells directly; thus it may have a different effect than bevacizumab, Bookman said.

Weekly paclitaxel was identified as the preferred schedule for this drug, improving both PFS and OS. The next trial looked at weekly paclitaxel plus or minus bevacizumab. GOG-0262/ACRIN 6695 showed no difference in PFS with the addition of bevacizumab to chemotherapy. In an exploratory analysis, median PFS was 10.6 months in patients treated

In the primary surgery arm, 16% of patients underwent optimal debulking versus 40% in the neoadjuvant chemotherapy arm. Primary surgery was associated with more frequent toxicity, with 48% of patients experiencing grades 3 or higher toxicities versus 40% in the neoadjuvant chemotherapy arm. Grade 3 or 4 postoperative complications were reported in 24% of the primary surgery arm compared with 14% in the neoadjuvant chemotherapy arm. Neoadjuvant chemotherapy also led to shorter hospital stays: discharge within 14 days was possible in 74% of those in the primary surgery arm versus 92% in the neoadjuvant chemotherapy arm. Also, deaths within 28 days of treatment numbered 5 (5.6%) in the primary surgery arm compared with 1 (0.5%) in the neoadjuvant chemotherapy arm. The study also demonstrated noninferiority of neoadjuvant chemotherapy for survival outcomes: median PFS was 10.3 months for primary surgery versus 11.7 months for neoadjuvant chemotherapy, and OS was 22.8 months versus 24.5 months, respectively. In formal discussions of this trial, Jonathan S. Berek, MD, director of the Stanford Women’s Cancer Center, California, said that the patients enrolled in the MRC CHORUS trial had a worse prognosis and were a bit older, suggesting that patient selection is important when considering neoadjuvant chemotherapy versus surgery as primary treatment for advanced ovarian cancer. l

Trials in Advanced Recurrent Disease The OCEANS trial in platinum-sensitive disease showed that the addition of bevacizumab to chemotherapy improved PFS. The AURELIA study in platinum-resistant disease found that bevacizumab improved PFS. Both trials found no difference in OS favoring the addition of bevacizumab. “These studies suggest that bevacizumab is effective in improving PFS in both platinum-sensitive and platinum-resistant disease,” Bookman said. In a subset analysis of AURELIA, in which chemotherapy was selected by physician’s choice, the most striking benefits were observed when bevacizumab was added to weekly paclitaxel. No additional benefit was seen when bevacizumab was used with pegylated doxorubicin or topotecan, he noted. The ICON6 trial in recurrent disease found that when added to chemotherapy, cediranib—a potent inhibitor of VEGF tyrosine kinase—improved OS: median OS was 20.3 months without cediranib versus 26 months when this agent was added. The TRINOVA-1 trial evaluated the addition of trebananib to chemotherapy. Trebananib is an investigational antiangiogenesis recombinant peptide that inhibits the binding of angiopoietin 1 and 2 to the Tie2 receptor—a different target than that of bevacizumab. In that study, PFS was extended with trebananib. Survival results are not yet available. Trebananib has a different toxicity profile that includes edema, pleural effusion, ascites, and weight increase. Bookman suggested that these treatment-emergent adverse events may predict clinical response to this novel agent. The GOG-3001 trial is evaluating carboplatin/paclitaxel plus or minus trebananib, and the trial is beginning accrual. Remaining issues include the best target for antiangiogenesis—VEGF receptors, angiopoietin 1 and 2? “The cellular target of angiogenesis is not obvious,” Bookman continued. “It is not clear which is better—to target the vascular endothelium or directly target the tumor.” l

Reference

Reference

“The cellular target of angiogenesis is not obvious. It is not clear which is better—to target the vascular endothelium or directly target the tumor.” Michael Bookman, MD

The AGO-OVAR16 trial showed that maintenance therapy with pazopanib (a tyrosine kinase inhibitor) improved PFS but had no effect on survival.

with weekly paclitaxel minus bevacizumab and 14.2 months with the addition of bevacizumab. Thus, weekly paclitaxel and bevaciz-

Neoadjuvant Chemotherapy a Reasonable Option for Advanced Ovarian Cancer Alice Goodman

N

eoadjuvant chemotherapy was found equivalent to primary surgery followed by chemotherapy for patients with advanced ovarian cancer in the Medical Research Council Chemotherapy Or Upfront Surgery (MRC CHORUS) trial reported at the 2013 American Society of Clinical Oncology Annual Meeting. In this study, more patients who received neoadjuvant chemotherapy were able to undergo optimal debulking surgery and fewer had postoperative complications and deaths, but rates of progression-free survival (PFS) and overall survival (OS) were similar in both arms. Lead author Sean Kehoe, MD, John Radcliffe Hospital, Oxford, United Kingdom, said that because these patients were, in general, older and sicker than in some other recent trials, neoadjuvant chemotherapy was a good option in this subpopulation. MRC CHORUS joins the EORTC 55971 trial as the second randomized trial to show noninferiority of neoadjuvant chemotherapy compared with primary surgery in advanced ovarian cancer, he noted. From March 2004 to August 2010, 552 patients with stage III-IV ovarian cancer were enrolled in the MRC CHORUS trial. As 2 patients were randomized in error, the study population ultimately included 550 patients. Patients were randomized 1:1 to primary debulking surgery followed by 6 cycles of platinum-based chemotherapy (n=276) versus 3 cycles of neoadjuvant platinum-based chemotherapy followed by surgery and 3 cycles of chemotherapy (n=199). Treatment arms had comparable baseline characteristics: median age was 65.5 years; 20% were WHO Performance Status 2-3; median tumor size was 8 cm; and 25% were stage IV. About 79% of those in the primary surgery arm and 68% of those in the neoadjuvant chemotherapy arm had highgrade serous carcinoma, which is particularly lethal.

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DECEMBER 2013 I VOL 6, NO 11

umab had the best results. A biomarker substudy of GOG-0262 suggested that weekly paclitaxel by itself has antiangiogenic effects on tumor blood flow and tumor volume, Bookman noted.

Kehoe S, Hook J, Nankivell M, et al. Chemotherapy or upfront surgery for newly diagnosed advanced ovarian cancer: results from the MRC CHORUS trial. J Clin Oncol. 2013;31(suppl):Abstract 5500. Presented at: 2013 American Society of Clinical Oncology Annual Meeting; May 31-June 4, 2013; Chicago, IL.

Bookman M. Perspective on antiangiogenic trials in ovarian cancer. Presented at: 2013 Chemotherapy Foundation Symposium; November 7, 2013; New York, NY.

www.TheOncologyNurse.com


NEWS BRIEFS Continued from cover

The Developing Role of PARP Inhibition Poly (ADP ribose) polymerase (PARP) inhibitors show excellent activity in ovarian cancer. The optimal role of PARP inhibitors in ovarian cancer is not yet determined. Currently, 5 PARP inhibitors are in various stages of development, and the most widely studied is olaparib. PARP inhibitors cause multiple double-strand breaks in DNA. In tumor cells that harbor BRCA1 and BRCA2 mutations, these breaks cannot be repaired, leading to cell death. “The simple version is that PARP is important. PARP inhibitors lock the PARP enzyme on DNA and prevent normal DNA repair. These are DNAdamaging agents, and some subsets of patients may be more susceptible to PARP inhibition,” explained Elise C. Kohn, MD, National Institutes of Health, Bethesda, Maryland. She updated attendees on PARP inhibition in ovarian cancer at the 2013 Chemotherapy Foundation Symposium.1 The 5 PARP inhibitors under development include olaparib, rucaparib, niraparib, veliparib, and BMN-673. The first 3 are in registration studies, and the latter 2 are in phase 1/2 studies. “I have confidence that this new class of agents is exciting in ovarian cancer. Encourage patient participation in clinical trials,” she told listeners. Studies suggest that olaparib is more active in patients with germline BRCA mutations than in those without them, and platinum-sensitive patients seem to be the most responsive. Olaparib improved progression-free survival (PFS) as maintenance therapy in patients with platinum-sensitive ovarian cancer in a randomized controlled trial. In an updated analysis, olaparib improved PFS by 65% overall; a more robust effect on PFS was observed in patients with germline BRCA1 and BRCA2 mutations, with an 82% improvement in PFS. However, olaparib maintenance was also effective in those with BRCA wild-type mutations, improving PFS by 47%.2 The phase 2 AZ Study 41 showed a PFS benefit for olaparib/carboplatin/paclitaxel followed by olaparib maintenance versus carboplatin/paclitaxel followed by no further treatment; median PFS was 12.2 months with olaparib versus 9.6 months without.3 “These results were provocative,” Kohn said. “PARP inhibitors are still being investigated in a wide variety of ovarian cancer patients with and without mutations and in combination with other drugs,” she continued. A phase 1 trial of olaparib plus cediranib (VEGFR inhibitor) showed clinical benefit in ovarian cancer, and a randomized phase 2 study of this combination has been initiated. Biomarkers are needed to determine

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which patients will respond to PARP inhibition. Germline BRCA1 and BRCA2 mutations are predictive of response and duration of response, but other biomarkers are needed for patients without these mutations. It may be that a homologous recombinant defect (HRD) is a biomarker, but more studies are needed. “The HRD score is a provocative direction to study,” Kohn stated.

The optimal role of PARP inhibition remains to be determined; potential opportunities include prevention, after diagnosis, at first remission, concurrent with maintenance therapy, in platinum-sensitive recurrent ovarian cancer with chemotherapy, and in platinum-refractory patients. “We don’t know the answer,” Kohn told listeners. l

References

1. Kohn E. PARP inhibitors in ovarian cancer. Presented at: 2013 Chemotherapy Foundation Symposium; November 7, 2013; New York, NY. 2. Ledermann J, Harter P, Gourley C, et al. Olaparib maintenance therapy in platinum-sensitive relapsed ovarian cancer. N Engl J Med. 2012;366(15):1382-1392. 3. Oza AM, Cibula D, Oaknin A, et al. Olaparib plus paclitaxel plus carboplatin (P/C) followed by olaparib maintenance treatment in patients (pts) with platinum-sensitive recurrent serous ovarian cancer (PSR SOC): a randomized, open-label phase II study. J Clin Oncol. 2012;30(15 suppl):Abstract 5001.

Continued on page 10

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CONSIDERATIONS in

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

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NEWS BRIEFS Continued from page 9

Bevacizumab Appears to Benefit High-Risk Patients Two phase 3 trials presented at the 2013 European Cancer Congress suggest that the optimal role of bevacizumab will be in high-risk patients. AURELIA is the first phase 3 study to evaluate the addition of bevacizumab to chemotherapy in platinum-resistant ovarian cancer (defined as progression within 6 months of last platinum-containing therapy).1 The addition of bevacizumab to chemotherapy significantly improved progression-free survival (PFS) from 3.4 months to 6.7 months (P <.001), and median overall survival (OS) was improved from 13.3 months with chemotherapy alone to 16.6 months, but this did not reach statistical significance. Chemotherapy agents included paclitaxel, topotecan, and liposomal doxorubicin. “No single agent has shown superiority to weekly paclitaxel, topotecan, or liposomal doxorubicin. Median survival in platinum-resistant ovarian cancer is typically around 12 months,” said lead author

Petronella Witteveen, MD, DCOG, of University Medical Centre Utrecht, in the Netherlands. AURELIA randomized 361 patients to receive bevacizumab plus investigator’s choice of chemotherapy versus chemotherapy alone. Treatment was continued until disease progression, unacceptable toxicity, or consent withdrawal.

The difference in survival for high-risk patients given bevacizumab was clinically meaningful. At progression, patients in the chemotherapy arm were allowed to cross over to bevacizumab monotherapy; bevacizumab was discontinued after progression in the bevacizumab plus chemotherapy arm.

An exploratory subgroup analysis of OS suggested that weekly paclitaxel was the best partner for bevacizumab. In the weekly paclitaxel cohort, median OS was 22.4 months for bevacizumab versus 13.2 months in controls, representing a 35% relative improvement favoring bevacizumab. By contrast, in the cohort treated with liposomal doxorubicin, median OS was 13.7 months in those randomized to receive bevacizumab plus chemotherapy versus 14.1 months with chemotherapy only. For the topotecan-treated cohort, median PFS was 13.8 months for those treated with bevacizumab plus chemotherapy versus 13.3 months for chemotherapy only. “The effect of weekly paclitaxel should be considered exploratory and requires prospective validation,” Witteveen said. No new safety concerns were identified in an updated safety analysis. The main grade ≥3 toxicities in the bevacizumab arm were hypertension (7.8%) and proteinuria (2.2%).

Trebananib in Platinum-Sensitive Ovarian Cancer A new antiangiogenesis inhibitor with a different mechanism of action than bevacizumab shows promise in platinum-sensitive ovarian cancer, according to results of the phase 3 TRINOVA-1 trial presented at the 2013 meeting of the European Cancer Congress. Trebananib added to paclitaxel prolonged the time to disease progression or death by 52% compared with paclitaxel plus placebo (P <.001), said Bradley Monk, MD, Creighton University School of Medicine and University of Arizona Cancer Center, Phoenix. Although angiogenesis is a proven target in ovarian cancer, anti–vascular endothelial growth factor (VEGF) therapy (with bevacizumab) causes adverse effects. Trebananib is a different approach, targeting a non-VEGF angiogenesis factor—angiopoietin 1 and angiopoietin 2. The hope is that this approach will be effective and have fewer adverse effects than a VEGF-targeted strategy, Monk said. TRINOVA-1 enrolled 919 women with recurrent epithelial ovarian cancer and randomized them to receive treatment with weekly intravenous (IV) trebananib 15 mg/kg plus weekly IV paclitaxel (3 weeks on, 1 week off) or with placebo plus weekly paclitaxel (3 weeks on, 1 week off). Patients were treated until disease progression, toxicity, or withdrawal of consent. Patients were stratified according to progression-free interval, measurable disease, and geographic region. At baseline, patients had received up to 3 prior cytotoxic regimens and had a progression-free interval of <12 months. One prior regimen failed in 40% of patients, 2 prior therapies in 40%, and 3 prior therapies in 20%. Monk presented primary progression-free survival (PFS) and interim overall survival (OS) results of this international trial. At a median follow-up of 10 months, median PFS was 7.2 months in the trebananib group and 5.4 months for placebo (hazard ratio, 0.66; 95% confidence interval, 0.56-0.76; P <.001). A prespecified subgroup analysis found that trebananib improved PFS in all subgroups. Overall response rate was

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38% with trebananib versus 30% with placebo (most were partial responses). Trebananib did not appear to increase toxicity when added to paclitaxel, according to the safety analysis. The rate of adverse events of any grade was similar between the 2 treatment arms: 96% for trebananib and 97% for placebo. The major toxicity of trebananib was edema: 57% versus 26% (any grade) for those in the placebo arm. Very few grade ≥3 adverse events were reported with trebananib. No increase in VEGF-associated adverse effects was seen with trebananib (ie, hypertension, proteinuria, wound healing complications, arterial thrombotic events). Neutropenia and anemia were more common in the placebo arm, and neurotoxicity was more common in the trebananib arm, which may be attributable to increased exposure to paclitaxel in that arm. An interim OS analysis showed a difference of approximately 2 months favoring trebananib (19 months vs 17.3 months for the placebo arm), but this is only a preliminary analysis, Monk reminded listeners. TRINOVA-1 incorporated patient-reported outcomes using 3 different quality-of-life questionnaires: Functional Assessment of Cancer Therapy-Ovarian (FACT-O), Ovarian Cancer Screening (OCS), and EuroQol 5-dimension (EQ5D). On these measures, no quality-of-life differences were reported between the 2 treatment arms. Trebananib is continuing to be developed for ovarian cancer. The formal discussant of this trial, Antonio Casado, MD, Hospital Universitario San Carlos, Madrid, Spain, said, “Weekly paclitaxel and trebananib could be an option in patients who progress within 12 months after 1 to 3 previous lines of therapy.” l Reference

Monk BJ, Poveda A, Vergote I, et al. A phase III, randomized, double-blind trial of weekly paclitaxel plus the angiopoietin 1 and 2 inhibitor, trebananib, or placebo in women with recurrent ovarian cancer: TRINOVA-1. Presented at: 2013 European Cancer Congress; September 27-October 1, 2013; Amsterdam, the Netherlands. Abstract LBA41.

The ICON7 trial evaluated bevacizumab in women with newly diagnosed ovarian cancer. The primary analysis (previously reported) showed a median PFS of 17.3 months for chemotherapy alone versus 19 months for bevacizumab added to chemotherapy (P = .004).2 In the final survival analysis presented at the European Cancer Congress, median OS was 58 months in the study for both arms; however, poor-prognosis patients experienced a 4.8-month prolongation of survival (from 34.5 months to 39.3 months) if they received bevacizumab.3 “The survival benefit in the overall trial of 0.9 months is not clinically meaningful. However in the high-risk subgroup, bevacizumab did show a clinically meaningful benefit of 4.8 months,” said Amit Oza, MD, Princess Margaret Cancer Centre, University of Toronto, Canada. The international study randomized 1528 women to 6 cycles of every-3-week carboplatin/paclitaxel versus carboplatin/ paclitaxel plus bevacizumab for 5 or 6 cycles followed by bevacizumab for 12 additional every-3-week cycles until disease progression. Patients were prestratified according to stage, extent of debulking, and time of therapy. A third of the women were considered high risk (stage III with >1 cm residual disease, stage IV, and nondebulked). At a median follow-up of 49 months, PFS was not significantly different between the 2 arms, similar to the first interim analysis presented previously. Over 4 years, the difference between the 2 curves was gradually eroded, Oza said. Because the curves are nonproportional, the final OS analysis was conducted using a restricted means analysis, and the difference between the 2 arms was 0.9 months, which was not statistically or clinically meaningful. In a predefined high-risk subgroup of patients, the curves for the 2 arms separated and the bevacizumab arm was superior throughout the study, with a 4.8-month improvement over the control arm. Oza said the difference in survival for high-risk patients given bevacizumab was clinically meaningful. l References

1. Witteveen P, Lortholary A, Fehm T, et al. Final overall survival (OS) results from AURELIA, an open-label randomized phase III trial of chemotherapy (CT) with or without bevacizumab (BEV) for platinum-resistant ovarian cancer. Presented at: 2013 European Cancer Congress; September 27-October 1, 2013; Amsterdam, the Netherlands. Abstract LBA5. 2. Perren TJ, Swart AM, Pfisterer J, et al; the ICON7 investigators. A phase 3 trial of bevacizumab in ovarian cancer. N Engl J Med. 2011;365:2484-2496. 3. Oza AM, Perren TJ, Swart AM, et al. ICON7: final overall survival results in the GCIG phase III randomized trial bevacizumab in women with newly diagnosed ovarian cancer. Presented at: 2013 European Cancer Congress; September 27-October 1, 2013; Amsterdam, the Netherlands. Abstract LBA6.

www.TheOncologyNurse.com


NEWS BRIEFS BMN-673: Investigational PARP Inhibitor events occurring in <30% of patients were myelosuppression, fatigue, nausea, and alopecia. BioMarin Pharmaceuticals has mount-

Reference

Wainberg ZA, de Bono JS, Mina L, et al. Update on firstin-man trial of novel oral PARP inhibitor BMN 673 in patients with solid tumor. Presented at: Molecular Targets and Cancer Therapeutics; October 22, 2013; Boston, MA. Abstract C295.

S:7.25”

NOW RECRUITING

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*

PRIMARY ENDPOINT

• Stage IV NSCLC

• Overall survival

• Receiving 1st-line myelosuppressive

SECONDARY ENDPOINTS

chemotherapy

• 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

Darbepoetin alfa 500-mcg Q3W

2:1 Randomization (darbepoetin alfa:placebo)

End of Investigational Product

End of Treatment Period

Long-term Follow-up

Placebo Q3W

Week 0

Week 1

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.

Cory Docken/Getty Images

For more information, please email Study-20070782@amgen.com 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.

AOCO3X0071_Recruitment782_AdAsize_r3.indd 1

www.TheOncologyNurse.com

ed a phase 3 study of BMN-673 versus physician’s choice of capecitabine, eribulin, gemcitabine, or vinorelbine in metastatic breast cancer. l

S:9.75”

The investigational poly (ADP ribose) polymerase (PARP) inhibitor BMN673 achieved an objective response rate (ORR) of >40% and delayed disease progression by >6 months in patients with heavily pretreated advanced BRCA-related breast and ovarian cancers in a phase 1 trial. The first-in-human study was reported at the AACR-NCI-EORTC International Conference on Molecular Targets and Cancer Therapeutics held in Boston, Massachusetts, in October 2013. Lead author Zev A. Wainberg, MD, Jonsson Comprehensive Cancer Center at the University of California Los Angeles, called the novel agent “the most potent PARP inhibitor in clinical development.” He said the drug had optimized pharmaceutical properties and can be given orally with a long half-life that allows once-daily dosing. “BMN-673 has high single-agent antitumor activity in ovarian and breast cancer patients with deleterious germline mutations of BRCA1 and BRCA2. The duration of response and progression-free survival appear to be promising in this early-phase trial,” Wainberg commented at a press conference. The study enrolled 87 patients with a variety of cancers: breast, ovarian, small cell lung cancer, and Ewing sarcoma. All patients had received a mean of 3 prior regimens (range, 1-13). Phase 1 response data were reported for 18 patients with germline BRCAmutated breast cancer, 28 patients with germline BRCA-mutated ovarian cancer, 24 patients with Ewing sarcoma, and 12 patients with small cell lung cancer. In 26 evaluable patients with BRCAmutated ovarian cancer, ORR was 46% and clinical benefit rate (including response rate and stable disease) was 82%. Median duration of response was 26.9 weeks, and median progression-free survival was 33.4 weeks. Among 18 patients with BRCAmutated breast cancer, 44% responded including 1 complete response. The rate of clinical benefit was 72%, with stable disease for at least 24 weeks. When patients received the recommended clinical dose of 1 mg/day for phase 2, ORR went up to 50% and the clinical benefit went up to 86%. Among patients with ovarian cancer, 70% had significant reductions in CA-125, several had no change, and 1 patient had an increase in CA-125. Responses were also seen in the small cell lung cancer cohort, where no BRCA mutations were observed. No responses were seen in patients with Ewing sarcoma. BMN-673 was tolerable in general. The most common drug-related adverse

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EMPOWERING PATIENTS AND SURVIVORS

A Thrust Into Vulnerability

T:17

Angela Long

“You can’t get to courage without walking through vulnerability.” –Brené Brown

A

s a cancer survivor and advocate, it has bewildered me how differently cancer patients and survivors perceive their cancer journeys. This variation in outlook ranges from being stuck in a state of fear, anger, shame, or blame, to viewing cancer as a “gift.” While watching Dr Brené Brown’s TED talk on vulnerability, which can be defined as “uncertainty, risk, and emotional exposure,” I realized that this is a key element in what shapes one’s cancer experience. Brown refers to her “breakdown/ spiritual awakening” and the year she spent in therapy coming to grips with her own vulnerability, a process she sought in her effort to research the factors that determine who suffers and who thrives through life’s ups and downs. Unlike Brown, cancer patients are not seeking opportunities to face their vulnerability. Much like Alice’s fall down the rabbit hole, hearing the words “you have cancer” thrusts us quite suddenly into a world of inescapable vulnerability. In an instant, our health, mortality, self-identity, independence, and relationships are all in question. An overwhelming sense of vulnerability haunts us through, and often after, the cancer journey. Despite the shock, pain, and fear that come with a cancer diagnosis, there are those who not only bounce back, but feel their lives have been improved by their cancer experience. According to Brown, these wholehearted individuals have the ability to cultivate courage, compassion, and connection in their daily lives and hence experience positive growth from even the most negative situations. Brown finds that a common thread among the wholehearted is their ability to embrace vulnerability and own their story. We are conditioned to believe that vulnerability is a sign of weakness and thus avoid situations that remind us of our own. Once diagnosed with cancer, we experience a level of vulnerability few of us ever imagined. Time and support from others enable some of us to process, accept, and adapt to the multitude of changes thrust upon us by a cancer diagnosis, while others never quite accept nor adjust to life

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n tio a dic n I L TC P ne -Li d 2n

ISTODAX® (romidepsin) for injection is indicated for treatment of peripheral T-cell lymphoma (PTCL) in patients who have received at least one prior therapy. This indication is based on response rate. Clinical benefit such as improvement in overall survival has not been demonstrated.

RECHARGE THE POSSIBILITIES

• Efficacy and safety evaluated in the largest prospective single-arm PTCL study (Study 3, N=131)1 • Studied in a pretreated, histologically diverse PTCL population1 • Patients could be treated until disease progression at their discretion and that of the investigator1

Important Safety Information WARNINGS AND PRECAUTIONS • Treatment with ISTODAX® (romidepsin) 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. 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, 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 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%).

ISTODAX® is a registered trademark of Celgene Corporation. © 2013 Celgene Corporation 07/13 US-IST130001a

S:7” T:8.125”

www.istodax.com

www.TheOncologyNurse.com


7.5”

EMPOWERING PATIENTS AND SURVIVORS with and after cancer. Brown counsels that it is those who can accept and even embrace their vulnerability who turn life’s challenges into gateways to courage, compassion, and connection.

Courage: While we may view vulnerability in ourselves as weakness, we often perceive it as courage in others. It takes courage to show our imperfections, let go of who we

think we should be, and accept who we are. Norma, a metastatic cancer survivor, said, “I found that with 6 broken vertebrae in my back, I couldn’t do many things I used to, which made

me (independent me) have to ask for help. My condition made me have to request special considerations, better chairs, cushions, closer parking, etc. Continued on page 14

Demonstrated efficacy in PTCL after at least 1 prior therapy in Study 3a1

15% ~60% 25%

(19/130) Complete Response Rate (CR+CRu) by independent central review (95% CI: 9.0, 21.9) • Similar complete response rates in the 3 major PTCL subtypes (NOS, AITL, ALCL)

9.2 months

(11/19) of Complete Responses (CR+CRu) exceeded • Follow-up was discontinued in the remaining 8 patients prior to 9.2 months (33/130) Objective Response Rate (CR+CRu+PR) by independent central review (95% CI: 18.2, 33.8)

1.8 months a

(~2 cycles) median time to Objective Response

Efficacy based on 130 patients with histological confirmation by independent central review.1

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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%).

DRUG INTERACTIONS • Monitor prothrombin time and International Normalized Ratio in patients concurrently administered ISTODAX (romidepsin) and warfarin sodium derivatives • Romidepsin is metabolized by CYP3A4 Monitor patients for toxicity related to increased romidepsin exposure and follow dose modifications for toxicity when ISTODAX is initially co-administered with strong CYP3A4 inhibitors Avoid co-administration of ISTODAX with rifampin and other potent inducers of CYP3A4 • Exercise caution with concomitant use of ISTODAX and P-glycoprotein (P-gp, ABCB1) inhibitors

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 Brief Summary of Full Prescribing Information, including WARNINGS AND PRECAUTIONS and ADVERSE REACTIONS, on the following pages. Reference: 1. ISTODAX [package insert]. Summit, NJ: Celgene Corp; 2013.

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A Thrust Into Vulnerability Continued from page 13 I hated drawing attention to myself that way, but it was unavoidable. This to me was courage, courage to accept that things had changed, that my old carefree and healthy existence was gone, and that I could either give up or pull up my big-girl panties and move forward. I chose the latter.”

Compassion: In our search for compassion, we need someone who embraces us for both our strengths and our struggles. Compassion is a relationship between equals. We draw from our own experiences of struggle and fear so that we can be present and empathize with the strug-

gles and fears of others. One’s cancer experience can be a vast resource to draw from when offering support to others. In knowing our own suffering, we often develop the desire to alleviate the suffering of others. Compassion leads us not only to help others, but also to accept help T:7”

from others. After my diagnosis, I found it difficult to request and accept help from others. Brown suggests that when we find it difficult to accept or ask for help without self-judgment, we are likely to subconsciously judge those who need our help. “Until we can receive with an open heart, we are

Only

monitored, appropriate precautions should be taken, and treatment should be instituted as appropriate.

ISTODAX® (romidepsin) for injection For intravenous infusion only The following is a Brief Summary of the Prescribing Information for the peripheral T-cell lymphoma indication only; see Full Prescribing Information for complete product information.

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. 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

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1 INDICATIONS AND USAGE ISTODAX is indicated for: • Treatment of peripheral T-cell lymphoma (PTCL) in patients who have received at least one prior therapy. This indication is 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. 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 with advanced stage disease and/or high tumor burden should be closely


EMPOWERING PATIENTS AND SURVIVORS never really giving with an open heart. When we attach judgment to receiving help, we knowingly or unknowingly attach judgment to giving help.” In learning compassion, we open ourselves to truly reciprocal relationships and deeper human connections. Connection: Support is important during a cancer journey, but connection is often intrinsic to one’s emo-

Even within the cancer community, survivors can have a difficult time finding connection.

tional healing. Nothing creates a sense of connection for cancer patients like the words “me too.” It was not until

I was able to connect with someone who had “walked in my shoes” that I really felt understood. This connec-

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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%).

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 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. 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.

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.

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)]. 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. Manufactured for: Celgene Corporation Summit, NJ 07901 Manufactured by: Ben Venue Laboratories, Inc. Bedford, OH 44146 or

Angela Long

Baxter Oncology GmbH Halle/Westfalen, Germany ISTODAX® is a registered trademark of Celgene Corporation © 2010-2013 Celgene Corporation. All Rights Reserved.

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

U.S. Patents: 4,977,138; 7,608,280; 7,611,724 ISTBSPTCL.005 06/13

Cosmos Communications

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A Journey of Discovery When courage, compassion, and connection become a regular practice, they develop into incredible gifts in our life, even when our teacher is cancer. It is through our vulnerabilities that we truly discover these gifts. It takes breaking through our conditioned resistance to vulnerability, removing our protective armor, and allowing others to see who we truly are. While cancer is a physical disease, the scars extend deep into our emotional and spiritual lives. Though never a preferred or desired route, a cancer journey can transform our lives, opening our hearts to new levels of love, joy, and enlightenment. l

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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%). 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 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 Cytochrome P450 3A4 Enzymes Romidepsin is metabolized by CYP3A4. Strong CYP3A4 inhibitors increase concentrations of romidepsin. In a pharmacokinetic drug interaction trial the strong CYP3A4 inhibitor ketoconazole increased romidepsin (AUC0-∞) by approximately 25% [See Clinical Pharmacology (12.3)]. Monitor for toxicity related to increased romidepsin exposure and follow the dose modifications for toxicity [see Dosage and Administration (2.2)] when romidepsin is initially co-administered with strong CYP3A4 inhibitors (e.g., ketoconazole, itraconazole, clarithromycin, atazanavir, indinavir, nefazodone, nelfinavir, ritonavir, saquinavir, telithromycin, voriconazole). 7.3 Drugs that Induce Cytochrome P450 3A4 Enzymes Avoid co-administration of ISTODAX with rifampin. In a pharmacokinetic drug interaction trial with co-administered rifampin (a strong CYP3A4 inducer), romidepsin exposure was increased by approximately 80% and 60% for AUC0-∞ and Cmax, respectively [See Clinical Pharmacology (12.3)]. Typically, co-administration of CYP3A4 inducers decrease concentrations of drugs metabolized by CYP3A4. The increase in exposure seen after co-administration with rifampin is likely due to rifampin’s inhibition of an undetermined hepatic uptake process that is predominantly responsible for the disposition of ISTODAX. It is unknown if other potent CYP3A4 inducers (e.g., dexamethasone, carbamazepine, phenytoin, rifabutin, rifapentine, phenobarbital, St. John’s Wort) would alter the exposure of ISTODAX. Therefore, the use of other potent CYP3A4 inducers should be avoided when possible. 7.4 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.

8.4 Pediatric Use The safety and effectiveness of ISTODAX in pediatric patients has not been established.

tion helped me to start processing my own journey, but even within the cancer community, survivors can have a difficult time finding connection. Jamie, a stage IV Hodgkin lymphoma survivor, commented, “Being a single young woman with cancer was awful, and I had no support or guidance. Since I didn’t have one of the more common female cancers, I had nobody to relate to during that time. I felt extremely alone.” A cancer diagnosis shows us who we can lean on without judgment or pity and those we cannot lean on at all. Vulnerability can act as a filter in this respect. It is typically transformational with all relationships, resulting in a strengthening of some relationships and dissolution of others. Trust is the foundation. Without trust, we cannot be honest about our feelings of vulnerability, and without honesty, we cannot feel genuinely connected to others.

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The Other Side of the Stethoscope Continued from cover and going to yoga. I had a normal primary doctor visit in November 2009 with a normal pelvic and rectal exam. So why, I wondered over March and April in 2010, was I not losing weight and did my pants seem tighter? I think I said something maybe a year before about bloating and all my weight going to the middle—but that was just “becoming matronly”—you know, the menopause thing. I just needed to watch my diet, drink less wine, and exercise correctly, right? And the indigestion, well what do you want when you eat cold food in fast bites between patients and charting or dictating? I had the same thing off and on over the years. Doesn’t everyone have TUMS in their work bag or glove compartment? The first week of May in 2010 I felt like my clothes were really tight. After coming home from a Saturday overnight shift, I finally laid down on the bed and palpated my abdomen. Uh oh, I thought, that feels like a mass. So I slept my usual 5 or 6 hours in the morning, but when I checked again Sunday afternoon, it was still there—making my first hope that it was a lump of stool less likely. OK, I’m thinking, what are the possibilities? Maybe it’s just a giant fibroid; it was a middle to right-sided mass that I could feel and was quite firm. Or, could it be colon cancer—I was overdue for another colonoscopy, but I had no polyps or anything amiss in 2003. Or, worst case scenario, ovarian cancer. Yes, I thought of it, but at that point, that was a death sentence in my mind and not an option I wanted to consider. I knew there was no breast, ovarian, or colon cancer in my family but that wasn’t enough. I didn’t say anything at home because I didn’t know very much; I just had worries. First thing the next day, Monday, May 10, I called my primary doctor and left a message with the office staff to tell her that “I felt a mass in my abdomen.” That caught her attention and she added me in at noon. She didn’t say much after my pelvic exam, but labs including CA-125 were ordered, drawn that day, and a request for an ultrasound was sent. I scheduled my ultrasound for the next morning. Tuesday, May 11, I

Tania Homonchuk and her family.

was at the community radiology center—they asked if I minded a student doing the exam. No problem, been there. But after a minute, the regular tech comes in and takes over—not a good sign. Transabdominal and intravaginal US, and hmmm, why were they doing extra views that I know are for intra-abdominal fluid? Thankfully the

which confirmed and defined the extent of my disease. No invasion of the liver or lungs but huge ovarian tumors, a coating of metastases on virtually everything else, and a large amount of ascites in the abdomen. I had also learned that my CA-125 was 2900, which was sky high. How do you deal with all of that? This is stuff that happens to other people. I

In all women the bloating, indigestion, back pain, or other miscellaneous “not feeling right” complaints certainly merit a closer look and at least inclusion of ovarian cancer in the differential.

radiologist had me come in to review the ultrasound and talk with me. He was very direct and told me that widespread ovarian cancer was the most likely diagnosis. He called my primary doctor while I was there, and she arranged insurance approval for a contrast CT that same afternoon. However, in the meantime I was in shock—I have metastatic ovarian cancer, I am going to die. I went home in tears to tell my husband. I went back for the CT in the afternoon,

went to my son’s track meet that same afternoon, and had several people comment that I was quiet—just tired from work I said. My primary doctor arranged a referral to a gynecologic oncologist the very next day. She fit me in quickly as a referral, and it didn’t matter that I had to wait a couple of hours in the office, because I was scared stiff. After a discussion of my cancer (I was stage 3C) and the options, the plan was urgent surgery followed by chemo. This was on

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Wednesday, May 12. My husband was due to go out of town on family business that Friday but the doctor wanted to do surgery on Monday. So he went the next day on May 13—which happened to be our anniversary—and returned on Saturday. Meanwhile, I was the organizer for an awards banquet that night at the high school, my younger son had his first AP exams that week, and the older one had finals week at Cal. How do you tell your kids you have cancer? There is no easy way and certainly no good time. Or as one friend pointed out when I worried about it, there just is no good time to have cancer. But the week went on, both boys were told in person, we did an online will—you know, one of those things you keep meaning to get around to—and I did the prep for surgery on Monday, May 17. The signs and symptoms of metastatic ovarian cancer were nothing for so long. I was menopausal, so bloating was nothing I paid attention to nor was indigestion. In retrospect, the eating less was probably early satiety. No pain until the day or two before surgery and not bad then. The tight pants and increased girth were partly mass and partly fluid— and at that point I was already in a late stage. However, in 1 week I went from feeling a mass to having surgery, and I am ever so grateful that my primary doctor saw me urgently and paid attention to my call, to the radiologist for including me in the verbal report and discussion with my primary doctor, and for the immediate referral to a gynecologic oncology specialist who saw me right away. I am very lucky in that regard, or I might not be here today to tell this story. Paying attention to those nonspecifics in women is important— like the “I just feel tired” complaint I hear from an 80-year-old woman that really is a heart attack. In all women the bloating, indigestion, back pain, or other miscellaneous “not feeling right” complaints certainly merit a closer look and at least inclusion of ovarian cancer in the differential. My journey since diagnosis has been chock-full of experiences on the patient side of things. First surgery with tumor removal, hysterectomy-oophorectomy, splenectomy, descending colon resection, appendectomy, node resection, omentectomy, and stripping of the bladder, ureters, and liver. I woke up in the ICU a day and a half later and 30 pounds lighter when they turned down the propofol drip. I was intubated, with an IJ central line, and later a PIC line, peripheral IV sites, multiple drains, Foley, and NG tube. No way was I rolling over, much less sit, stand, or walk. But it all happens. The nursing care was so important: first the focus on small

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THE PATIENT’S VOICE steps and then getting stronger to get on with the rest of the treatment. And the recognition that this was a scary time with so many unknowns, that empathy, meant a lot to me. I had a port placed and 6 months of chemo 3 weeks out of 4 with dose-dense taxol and carboplatin, and then IP or intraperitoneal chemo was planned. I lost my hair, which for me was a much more “in your face” reminder that I had cancer, and was fatigued. Still I gradually went back to long walks with the dog, yoga, and exercise. I did read about and take advantage of supplements and had acupuncture prior to chemo. My chemo was given at the gynecology-oncology office, which for me was a good sharing time. In the chemo room it was all women with gynecologic cancers, and the camaraderie was appreciated. The nursing care was focused on women with these cancers and associated treatments.

Think about how you would want to be treated as a patient—it is very different on the other side.

few weeks of fear. On the other hand, most of the time it is not on my mind. I returned to work part time and family life continues. But my perspective is certainly different. I also have tried to give back a bit and look to the future for ovarian cancer treatment. I am participating in the Survivors Teaching Students program of the Ovarian Cancer National Alliance, to tell our stories to nursing

and medical students and get the word out about the nonspecific signs and symptoms as well as the importance of risk factors and of having a gynecologic oncologist. I also have been fundraising with the Clearity Foundation, which helps women with resistant or recurrent ovarian cancer get genetic typing or blueprints of their cancer. This provides personalized information about the best treatment

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However in October during laparoscopy for abdominal port placement, I had too much scarring for IP chemo, so back I went to the drawing board. I opted for a second surgery after discussion with an oncologic surgeon who was recommended by my main gynecologic oncologist. Off of chemo for 2 months in preparation, in January 2011 I had a second major surgery with adhesion removal that freed up the intestines and liver, a periaortic node resection, resection of the cecum because it was adhered due to scar tissue, removal of the gallbladder, and multiple node biopsies. All were clean. Then heated intraperitoneal cisplatin in the OR—40-degree chemo swished around for a couple hours does a number on the GI tract! Another couple of days in the ICU, more drains, gastrostomy tube (which, by the way, was actually nicer than the NG tube, even if I did feel like a nursing home patient), subclavian line, then PIC again, and eventually recovery. Every 3 months I get my CA-125 and exam and have had a couple of follow-up MRI scans. So far so good, and I am thrilled to make the 2-year mark disease-free. But every 3 months I go into a couple weeks of building anxiety—what will my number be? And is that indigestion just indigestion? I have multiple sizes of jeans under the bed just in case I need them again. It really becomes a

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options for this disease that is so often diagnosed in a late stage and is so often recurrent. I encourage you to think about nonspecific symptoms differently and keep ovarian cancer in mind—it is so silent and for many the journey to diagnosis is long and arduous. And as a provider, think about how you would want to be treated as a patient—it is very different on the other side. l

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FROM THE

EDITOR-IN-CHIEF

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

to learn more!

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

Director, Quality Control Barbara Marino 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

FACULTY Kenneth C. Anderson, MD Director, Jerome Lipper Multiple Myeloma Center and LeBow Institute for Myeloma Therapeutics Kraft Family Professor of Medicine Harvard Medical School Dana-Farber Cancer Institute, Boston, MA

Tina Flaherty, ANP-BC, AOCN Nurse Practitioner Division of Hematologic Malignancies Dana-Farber Cancer Institute Boston, MA

Houry Leblebjian, PharmD, BCOP Clinical Pharmacy Specialist in MARCH 2013 • VOLUME 4 • NUMBER 2 Hematology/Oncology Dana-Farber Cancer Institute Boston, MA

Digital Programmer Michael Amundsen Senior Project Manager Andrea Boylston Project Coordinators Deanna Martinez Jackie Luma

Supported by educational grants from Onyx Pharmaceuticals and Millennium: The Takeda Oncology Company.

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Discussions in Personalized Treatment for Lymphoma: Do We Have Consensus? CONTRIBUTING FACULTY Chair Stephanie A. Gregory, MD

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The Elodia Kehm Chair of Hematology Professor of Medicine Director, Lymphoma Program Rush University Medical Center/Rush University Chicago, IL

Sonali M. Smith, MD

Associate Professor Section of Hematology/Oncology Director, Lymphoma Program The University of Chicago Medical Center Chicago, IL

Mitchell R. Smith, MD, PhD Director of Lymphoid Malignancies Program Taussig Cancer Institute Cleveland Clinic Cleveland, OH

Steve M. Horwitz, MD

Assistant Attending Medical Oncologist Lymphoma, Cutaneous Lymphomas, T-Cell Lymphoma Memorial Sloan-Kettering Cancer Center New York, NY

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DECEMBER 2013 I VOL 6, NO 11

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CONTINUING EDUCATION 6th Annual

DECEMBER 2013 • VOLUME 6 • NUMBER 5

CONSIDERATIONS in

Multiple Myeloma

ASK THE EXPERTS: Beyond Complete Responses Publishing Staff Group Director, Sales & Marketing John W. Hennessy john@greenhillhc.com Editorial Director Susan A. Berry susan@coexm.com Senior Copy Editor BJ Hansen Copy Editors Dana Delibovi Rosemary Hansen The Lynx Group President/CEO Brian Tyburski Chief Operating Officer Pam Rattananont Ferris Vice President of Finance Andrea Kelly Director, Human Resources Blanche Marchitto Associate Director, Content Strategy & Development John Welz Associate Editorial Director, Projects Division Terri Moore Director, Quality Control Barbara Marino Quality Control Assistant Theresa Salerno

LETTER

FROM THE

EDITOR-IN-CHIEF

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 6th 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 fifth issue, experts from the University of California, San Francisco answer questions related to the management of patients with MM who achieve complete responses. 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

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 Trevean Digital Programmer Michael Amundsen

FACULTY Jeffrey Wolf, MD Clinical Professor Department of Medicine Director, Myeloma Program University of California, San Francisco San Francisco, CA

Amy Marsala, NP Nurse Practitioner UCSF Helen Diller Family Comprehensive Cancer Center San Francisco, CA

Rebecca Young, PharmD, BCOP Clinical Pharmacist UCSF Medical Center Assistant Clinical Professor UCSF School of Pharmacy San Francisco, CA

Meeting & Events Planner Linda Sangenito Senior Project Managers Andrea Boylston Jini Gopalaswamy Project Coordinators Jackie Luma Deanna Martinez

Supported by educational grants from Onyx Pharmaceuticals and Millennium: The Takeda Oncology Company.

IT Specialist Carlton Hurdle Executive Administrator Rachael Baranoski

This activity is jointly sponsored by Medical Learning Institute Inc and Center of Excellence Media, LLC.

Office Coordinator Robert Sorensen Center of Excellence Media, LLC 1249 South River Road - Ste 202A Cranbury, NJ 08512

18

DECEMBER 2013 I VOL 6, NO 11

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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 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 0468-9999-13-026-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 nov-

el 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

Rebecca Young, PharmD, BCOP, has nothing to disclose. She does intend to discuss either non–FDA-approved or investigational use for the following products/devices: investigation of carfilzomib in newly diagnosed MM.

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.

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.

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 Dana Delibovi, Medical Writer, has nothing to disclose. She does not intend to discuss non–FDA-approved or investigational use for any products/devices. 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–FDAapproved or investigational use of any products/devices. Jeffrey Wolf, MD, is on the speaker’s bureau for Amgen, Celgene Corporation, Millennium: The Takeda Oncology Company, and Onyx Pharmaceuticals. He does intend to discuss either non–FDAapproved or investigational use for the following products/devices: MLN9708 and frontline carfilzomib. Amy Marsala, NP, has nothing to disclose. She does not intend to discuss non–FDA-approved or investigational use of any products/devices.

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/P13008E.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 cgusack@mlicme.org. 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: December 12, 2013 Valid for CME/CPE/CE credit through: December 12, 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

The Significance of Achieving Complete Response in Multiple Myeloma Jeffrey Wolf, MD

Clinical Professor, Department of Medicine Director, Myeloma Program University of California, San Francisco

Introduction Complete response (CR) is an extremely important goal of therapy for patients with multiple myeloma (MM). In this article, Jeffrey Wolf, MD, discusses recent data and consensus on the role of newer combination regimens in achieving and maintaining this endpoint, as well as the strong association of CR with survival outcomes, and the individualization of therapy for promoting optimal patient outcomes.

Which regimens are showing the greatest promise in terms of CR for newly diagnosed patients with MM? Today, the consensus in academic oncology is that triplet therapies are optimal for induction therapy; this approach is being adopted by more and more community oncologists as well. Commonly used triplet regimens with a robust evidence base in the transplant-eligible population include lenalidomide/bortezomib/dexamethasone (RVD) and cyclophosphamide/bortezomib/dexamethasone (CyBorD).1-3 These regimens provide high rates of very good partial re-

www.TheOncologyNurse.com

sponse or better (≥VGPR), including high rates of CR.2,3 In a phase 1/2 study by Richardson and colleagues, the CR/near-complete response (nCR) rate was 57% in newly diagnosed patients treated with RVD, in phase 2 and before proceeding to autologous stem cell transplantation (ASCT).2 In a phase 2 study by Reeder and colleagues, treatment with 4 cycles of CyBorD in newly diagnosed patients led to CR/nCR and VGPR rates of 46% and 71%, respectively.3 Two additional frontline 3-drug regimens are also showing promise, both of which include novel proteasome inhibitors. The first of these is carfilzomib/ lenalidomide/low-dose dexamethasone (CRd). In a phase 1/2 trial by Jakubowiak and colleagues, after a median of 22 cycles and a median follow-up of 25 months (during which only 7 of 53 patients underwent ASCT), 87% of those treated with CRd achieved ≥VGPR, including 64% who achieved CR.4 The second regimen is MLN9708 combined with lenalidomide and dexamethasone. Richardson and colleagues recently reported early phase 1/2 trial results (after a median of 6 cycles in phase 1 and a single cycle in phase 2), which showed that treatment with this triplet produced ≥VGPR in 9 of 19 patients with newly diagnosed MM.5 Clinicians await more mature data from these studies as well as from randomized, controlled, phase 3 trials enrolling larger cohorts of patients. RVD is under investigation in phase 3 trials designed to compare its efficacy with or without transplant, to determine whether this regimen produces deep enough responses to warrant delay of ASCT to first progression.6,7 Results from these trials will attempt to address the following controversial question: Will regimens that include novel, targeted drugs be effective enough to shift the current paradigm from early transplantation (just after induction) to delayed transplantation (at first relapse)?

DECEMBER 2013 I VOL 6, NO 11

19


CONTINUING EDUCATION

Figure. 12-year PFS and OS rates by depth of response after induction and ASCT (N=344).13

Survival parameter

40 35

35

Patients (%)

30

Table. Association Between Post-ASCT Response and Median EFS and OS (N=632)15

28 22

OS

19

20

16

16

15 10

10

11 8

8

5 0

0 CR

nCR

VGPR

PR

SD

nCR (months)

PR (months)

nCR vs PR, P value

nCR vs PR, P value

EFS

61

40

34

<.00001

.07

OS

NR

NR

61

.01

.04

ASCT indicates autologous stem cell transplantation; CR, complete response; EFS, event-free survival; nCR, near-complete response; NR, not reached; OS, overall survival; PR, partial response.

PFS

25

CR (months)

0

PD

Differences in median survival between CR versus nCR, CR versus VGPR, and CR versus PR were statistically significant in favor of CR (P≤.01). ASCT indicates autologous stem cell transplantation; CR, complete response; nCR, near-complete response; OS, overall survival; PD, progressive disease; PFS, progression-free survival; PR, partial response; SD, stable disease; VGPR, very good partial response.

For the population of patients not eligible for transplant, we are free to use melphalan as part of an induction regimen. Beyond that, there is no longer a marked difference in approach between transplant-eligible and -ineligible patients. The distinction between the groups has been blurred by the increasing use of the same regimens in both settings. However, we now tend to use melphalan less often in older, transplant-ineligible patients. We may tailor regimens a bit when treating elderly patients or those whose performance status renders them too vulnerable for transplant.8 For example, we have used a dose-adjusted regimen of RVD in which lenalidomide is given at 15 mg (instead of at the usual 25-mg dose), bortezomib is given weekly instead of twice weekly, and dexamethasone is reduced from 40 mg to 20 mg. In frail or otherwise compromised older patients, clinicians in both academic and community settings may elect to use a doublet instead of a triplet regimen. Lenalidomide plus low-dose dexamethasone is a 2-drug regimen with a strong evidence base in older patients.9 If a patient has a high-risk cytogenetic abnormality, such as translocation 4;14 or deletion 17p,10,11 we tend to use bortezomib plus dexamethasone, as long as there is no special concern regarding bortezomib-induced neurotoxicity.

As our therapies improve and we move closer to making myeloma a curable disease, we must absolutely strive for CR. Should CR always be the goal of antimyeloma therapy, or is ≥VGPR a sufficient goal? There is no question that the goal of treatment should be CR. Granted, some data have suggested that achievement of ≥VGPR in transplant-eligible patients is a robust indicator of prognosis.12 However, the observation that VGPR is “sufficient” in many patients does not entail that VGPR is a “good enough” goal. As our therapies improve and we move closer to making myeloma a curable disease, we must absolutely strive for CR. Right now, we have a small number of patients with MM who have achieved CR and are essentially cured. Some of the patients treated at our center who underwent ASCT in the 1990s have not relapsed. We are curing a small population, and we are going to cure more in time. To make this happen, the goal out of the gate must be CR. Major studies supply evidence for the value of CR. A retrospective, multicenter evaluation of 344 patients by Martinez-Lopez and colleagues assessed the long-term prognostic significance of response in MM after transplantation; pa-

tients were treated between 1989 and 1999.13 Both overall survival (OS) and progression-free survival were significantly prolonged in patients who attained CR after transplantation compared with those who attained nCR, VGPR, and partial response (PR). At 12 years of follow-up, the percentage of patients who survived was highest among the group that achieved CR (Figure).13 After 17 years, OS plateaued in all groups, but at a three-fold higher rate in patients who attained CR posttransplant versus those who achieved nCR/VGPR/PR at ASCT (35% vs 11%, respectively). Similar results were observed in an analysis of data from the prospective Grupo Español de Mieloma 2000 trial.14 In patients who achieved CR after ASCT, both event-free survival (EFS) and OS were significantly longer than in patients achieving nCR. The nCR group, in turn, had significantly longer OS (but not EFS) than those who achieved only PR (Table).14 In this trial, posttransplantation response was markedly influenced by pretransplantation response, underscoring the importance of aiming for CR from the start of treatment. Data from important trials of antimyeloma therapy—VISTA; Total Therapy 2, 3, and 5; and an older trial evaluating vincristine/doxorubicin/dexamethasone—showed a directly proportional relationship between CR and survival.15-18 For instance, in the phase 3 VISTA trial, which compared bortezomib/melphalan/prednisone versus melphalan plus prednisone alone in a nontransplant population, attaining CR was associated with a significantly longer time to progression and OS.15 These findings support the strategy of continuing therapy in transplant-ineligible patients until CR. Although there will always be concern regarding the tolerability of drug treatment, on the whole, current regimens are fairly tolerable. Specifically, we now have oral immunomodulators and can administer bortezomib by subcutaneous (SC) injection, which reduces the risk of peripheral neuropathy.19 The SC route is quickly becoming the standard of care in terms of bortezomib administration. We can also offer patients improved supportive care. Taken together, all of these factors enable us to offer highly effective therapies for longer periods of time. Does a patient’s age have an impact on how aggressively you strive for CR? Achieving CR is especially important in younger patients with MM. If we fail to produce a cure or a very long remission in these individuals, they will die of the disease well before their time. Young patients in nCR, VGPR, or PR after several induction cycles are the ones we generally take to ASCT sooner rather than later. We feel that they need to be consolidated to try to get them to CR. In some cases, we may also switch the induction regimen (eg, from CyBorD to RVD or vice versa), add a drug to a doublet regimen, or use other strategies to improve reponse. The point is that we make every effort to produce CR, working to support patients through any toxicities associated with more aggressive treatments. In many older patients, CR should also be the goal. The reality for this age group, however, is that frailty, comorbidities, and lower performance status may make it more difficult to push as hard.8 These patients may not tolerate the treatments or doses often required to attain CR. Sometimes, we must accept the fact that VGPR is the most that can be achieved without risking quality of life and severe cytopenias or infections. We also must remember that every patient, regardless of age, is unique and complex. A few patients achieve CR and never need treatment again. Others achieve CR and sustain it with single-agent maintenance therapy. Still others, typically with high-risk cytogenetics, may achieve CR, but the remission is short-lived; these patients require skillful selection of second-line and salvage therapies to keep new clones from growing out and causing progression.

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CONSIDERATIONS IN MULTIPLE MYELOMA

Nursing Strategies for Improved Outcomes in Multiple Myeloma Amy Marsala, NP

Nurse Practitioner UCSF Helen Diller Family Comprehensive Cancer Center San Francisco, CA

Introduction Although the benefits seen with newer multidrug regimens have significantly improved clinical outcomes, patients with multiple myeloma (MM) are often challenged by the development of adverse events (AEs) that may impact quality of life (QoL) and lead to delays or discontinuation of treatment. In this article, Amy Marsala, NP, discusses nursing strategies for preventing and managing these events in the era of novel agents, and how consideration of patient-related factors contributes to effective individualized care.

How do patient preferences and limitations affect the choice of agents or regimens used in the treatment of MM? Multiple factors can influence treatment selection for patients with MM. Two of the most important factors are high-risk cytogenetics and prior response to treatment, including length of progression-free survival, how well therapy was tolerated, and whether the patient is still experiencing lingering toxicites.1,2 From a patient perspective, choice of treatment may also be influenced by mode of administration and toxicity profiles of various therapies and the type of maintenance follow-up that is required.2,3 In patients who are older or who have complex comorbidities, treatment tolerability is often an issue. For such individuals, dosing and schedule adjustments may be necessary to reduce the likelihood of exacerbating existing conditions such as peripheral neuropathy (PN), myelosuppression, or thromboembolic complications.3 For many of our patients, travel time to the clinic, access to transportation, and degree of caregiver dependence may impact medication adherence and influence treatment decisions. Immunomodulatory drugs (IMiDs), such as lenalidomide and pomalidomide, as well as alkylating agents, such as melphalan and cyclophosphamide, have the advantage of being administered orally. In the outpatient setting, oral regimens offer greater convenience and consequently reduce certain barriers to adherence compared with regimens requiring attendance at the clinic for injections or infusions. Both lenalidomide and pomalidomide are typically dosed once daily on days 1 to 21 of repeated 28-day cycles.4,5 Melphalan and cyclophosphamide can be dosed weekly, which reduces daily pill burden.6,7 While daily dosing of agents can also lead to compliance issues, especially if complicated medication schedules or high pill burdens are involved, most patients still prefer oral administration over more invasive and lengthy intravenous (IV) administration. The first-in-class proteasome inhibitor bortezomib is available as either an IV infusion or a subcutaneous (SC) injection.8 SC bortezomib has become the preferred route at our center and requires less maintenance than IV bortezomib or the next-generation proteasome inhibitor, carfilzomib, which is typically administered as an IV infusion on 2 consecutive days for 3 weeks of a 4-week schedule.8,9 While total time of carfilzomib infusion is 2 to 10 minutes,9 medication preparation involving vein access and pre- and post-hydration results in a longer amount of chair time than IV bortezomib. The extra time and energy needed for IV treatments may be a deterrent for some patients, especially those who have remained in the workforce, are caring for young children, or must rely heavily on caregivers for transportation and support. Treatment-related toxicities impact the frequency and duration of clinical follow-up. Complete blood counts and chemistry panels are routinely drawn

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once weekly for patients receiving SC or IV medications, and less frequently for those receiving oral therapies.10 For patients with more aggressive MM or those with therapy-related hemodynamic instability, additional follow-up, including laboratory tests and possible blood or platelet transfusions, are often required if dose adjustments cannot be made without compromising disease control.10 Patients with relapsed/refractory MM are typically treated with combination regimens that include IMiDs, proteasome inhibitors, and/or alkylators plus dexamethasone.3 In this setting, the potential for cumulative toxicities must take precedence over patient preferences related to time commitments and routes of administration. To the best of their ability, clinicians should balance their efforts to minimize toxicities that are particularly distressing or which compromise QoL with maintaining control of the disease. How can chemotherapy-induced nausea and vomiting (CINV) be managed in patients receiving combination therapy? In the outpatient setting, the routine use of antiemetics has been reasonably effective in the management of CINV. Fortunately, novel antimyeloma agents are typically associated with lower rates of nausea and vomiting than older chemotherapeutic drugs used several decades ago. For example, bortezomib and lenalidomide are classified as having minimal emetogenic potential (<10% of patients experience emesis when antiemetics are not given).11 In fact, a recent cross-sectional cohort study reported that patients who had been treated for the previous 12 months with bortezomib, lenalidomide, and lower-dose alkylating agents reported symptoms of CINV as the least of all therapy-related toxicities.2 Similarly, carfilzomib and pomalidomide have demonstrated low to minimal emetogenic risk, especially when administered with dexamethasone.5,9 Some patients may be at increased risk for experiencing CINV. Female patients, those of younger age (<50 years), patients who are low regular alcohol users (<1 ounce per day), and those with a history of prior CINV all have elevated risk.11 Management of CINV should be approached similarly to management of pain, with an emphasis on prevention prior to onset of symptoms.10,11 It is important for clinicians to be mindful not only of acute CINV, which occurs 0 to 24 hours postchemotherapy, but delayed and breakthrough CINV as well, which may occur several days after chemotherapy, necessitating further antiemetic intervention.11 In accordance with antiemesis guidelines from the National Comprehensive Cancer Network, patients receiving chemotherapy with low risk of emetogenic potential should be treated prior to therapy with 1 or more antiemetic agents (Table).12 For patients who are at higher risk for CINV, 2 agents can be used. The concomitant use of dexamethasone to treat MM has also been effective as prophylaxis and treatment of nausea, although steroid use has its own toxicity profile that requires additional considerations.10 For patients with recurrent or unremitting CINV, or for patients receiving high-dose myeloablative therapies, including cy-

Table. Antiemetics for Patients Receiving IV Chemotherapy with Low Emetogenic Potential12 Metoclopramide 10-40 mg PO or IV (and then either every 4 or 6 hours as needed) or Dexamethasone 12 mg PO or IV daily or Prochlorperazine 10 mg PO or IV (and then every 6 hours as needed [maximum 40 mg/day]) Âą lorazepam, 0.5-2 mg PO or IV every 4 or 6 hours as needed Âą H2 blocker or proton pump inhibitor IV indicates intravenous; PO, by mouth.

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CONTINUING EDUCATION

Figure. Treatable contributing factors for cancer-related fatigue.14 Activity level

Malnutrition

Sleep disorders

Pain

Cancer-related fatigue

Emotional distress

• Depression • Anxiety

Noncancer comorbidities

• Endocrine dysfunction (hypothyroidism) • Infection • Cardiac dysfunction • Pulmonary dysfunction • Renal dysfunction • Hepatic dysfunction • Neurologic dysfunction

Anemia

Reprinted with permission.

clophosphamide >1500 mg or IV melphalan 200 mg/m2 while undergoing transplantation, more potent medications may be necessary. Palonosetron, a nextgeneration serotonin subtype-3 receptor antagonist, aprepitant, a neurokinin-1 receptor antagonist, and olanzapine, an antipsychotic, can be given prophylactically and during treatment, but may require more complex management.12 Clinical implications of CINV include an increased risk for malnutrition, dehydration (and subsequent electrolyte imbalances), and weakness, which can ultimately affect organ function.13 The social health impact of chronic CINV hinders patient participation in social and public events, decreases energy and mood, and may worsen overall performance status. Patients should be assessed during every follow-up visit for the presence and severity of CINV and its interference with QoL. They should be encouraged to eat foods that offer the greatest appeal and to prepare smaller, more frequent meals or snacks to minimize weight loss. Treatment of underlying gastrointestinal disturbances, such as gastrointestinal reflux, abdominal bloating and cramping, or bowel movement irregularities is also important. In addition, adjusting the dose of current antiemetics, switching to antiemetics of a different class, and adding additional therapies are viable approaches to ameliorate symptoms. What can be done to address chronic fatigue? Chronic fatigue continues to pose a great challenge for most patients undergoing active antimyeloma therapy.14 The multifactorial and complex nature of fatigue demands comprehensive management of chronic anemia and pain, physical deconditioning, emotional stress, depression, and sleep disturbances.15 Nurses play a critical role in screening patients to identify modifiable causes of fatigue and implementing interventions to improve health outcomes (Figure).14 Chronic fatigue is often compounded by chronic anemia, which can be secondary to therapy or may be due to the disease itself or comorbid conditions. Treatment-induced myelosuppression may require dose adjustments or even discontinuation of therapy if anemia is severe (hemoglobin <8 g/dL).16 Cautionary supplemental use of injectable erythropoiesis-stimulating agents, such as epoetin alfa weekly or darbepoetin alfa weekly or every 3 weeks, has been recommended for those with chemotherapy-related severe anemia, with the goal of raising hemoglobin to 10 mg/dL.16 For anemia and/or fatigue related to iron deficiency or general malnutrition, counseling patients on diet modifications may also improve overall energy. Another cause of fatigue is the likelihood for decreased activity due to chron-

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ic pain in patients with myeloma-related bone disease. Approximately 85% of patients with MM have or will develop lytic bone lesions or fractures, which inhibit daily activities and decrease functional status.2,17 Therefore, effective pain management through adequate disease control and the use of pain medications prescribed at the lowest effective doses is imperative. Procedural kyphoplasty for eligible patients and adjunctive use of bisphosphonates to manage bone pain and prevent new fracture and lesions are also recommended.17 Localized radiation therapy may also be implemented to palliate specific bone sites and soft tissue pains with the goal of alleviating pain and enabling increased physical activity.17 Fatigue is also compounded by generalized muscle atrophy and physical deconditioning, which occurs in approximately 50% of patients during active treatment.15 Considerable research has demonstrated that patients who participate in low to moderate physical activities on a routine basis of 3 to 4 times per week can decrease their overall fatigue as well as improve their sleep quality, mood, and functional status.15 Coordinating care with cancer exercise specialists or assisting patients to create modified exercise programs and resistance activities should be explored. Engaging in as much physical activity as patients can comfortably tolerate is critical to enhancing energy and improving QoL. In our clinic, we routinely monitor patients for their ability and motivation to be active and make recommendations accordingly. Facilitating periodic discussions with patients about their mood and perception of functional status as it corresponds with the ability to enjoy life should be practiced. Antidepressants such as paroxetine, bupropion, or fluoxetine can be given to augment mood, although for some patients these agents may increase sedation and alter sleep patterns.14 Research on the use of psycho-stimulants including methylphenidate and modafinil are inconclusive, but these agents have been shown to provide enhanced mood and energy for select patients, although they may cause other undesirable AEs.14 Medications such as lorazepam or clonazepam may reduce anxiety and promote sleep; these agents may also alleviate CINV.12 We also encourage patients to seek out formal support groups, spiritual resources, pet therapy, and the help of family and friends as valuable resources during and after treatment. ♦ References

1. Munshi NC, Anderson KC, Bergsagel L, et al; on behalf of the International Myeloma

Workshop Consensus Panel 2. Consensus recommendations for risk stratification in multiple myeloma: report of the International Myeloma Workshop Consensus Panel 2. Blood. 2011;117:4696-4700. 2. Jordan K, Proskorovsky I, Lewis P, et al. Effect of general symptom level, specific adverse events, treatment patterns, and patient characteristics on health-related quality of life in patients with multiple myeloma: results of a European, multicenter cohort study. Support Care Cancer. 2013 Oct 13. [Epub ahead of print]. 3. Castelli R, Gualtierotti R, Orofino N, et al. Current and emerging treatment options for patients with relapsed myeloma. Clinical Medicine Insights: Oncology. 2013;7:209-219. 4. Revlimid [package insert]. Summit, NJ: Celgene Corporation. November 2013. 5. Pomalyst [package insert]. Summit, NJ: Celgene Corporation. February 2013. 6. Alkeran Tablet [package insert]. Rockville, MD: ApoPharma USA, Inc. June 2011. 7. Cytoxan Tablets [package insert]. Princeton, NJ: Bristol-Myers Squibb. September 2005. 8. Velcade [package insert]. Cambridge, MA: Millennium Pharmaceuticals, Inc. 2012. 9. Kyprolis [package insert]. South San Francisco, CA: Onyx Pharmaceuticals, Inc. July 2012. 10. Polovich M, Whitford JM, Olsen M (eds). Chemotherapy and Biotherapy Guidelines and Recommendations for Practice. 3rd ed. Pittsburgh, PA: Oncology Nursing Society, 2009. 11. Navari RM. Management of chemotherapy-induced nausea and vomiting: focus on newer agents and new uses for older agents. Drugs. 2013;73:249-262. 12. National Comprehensive Cancer Network. NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines®): Antiemesis. Version 1.2013. http://www.nccn.org/ professionals/physician_gls/PDF/antiemesis.pdf. Accessed November 25, 2013. 13. Hesketh PJ. Chemotherapy-induced nausea and vomiting. N Engl J Med. 2008;358:2482-2494. 14. Carroll JK, Kohli S, Mustian KM, et al. Pharmacologic treatment of cancer-related fatigue. Oncologist. 2007;12(suppl 1):43-51. 15. Coleman EA, Goodwin JA, Coon SK, et al. Fatigue, sleep, pain, mood and performance status in patients with multiple myeloma. Cancer Nurs. 2011;34:219-227. 16. Miceli T, Colson K, Gavino M, Lilleby K; IMF Nurse Leadership Board. Myelosuppression associated with novel therapies in patients with multiple myeloma: consensus statement of the IMF Nurse Leadership Board. Clin J Oncol Nurs. 2008;12(suppl 3):13-20. 17. Terpos E, Moulopoulos LA, Dimopoulos MA. Advances in imaging and the management of myeloma bone disease. J Clin Oncol. 2011;29:1907-1915.

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CONSIDERATIONS IN MULTIPLE MYELOMA

Pharmacologic Perspectives on Novel Therapies in Multiple Myeloma Rebecca Young, PharmD, BCOP

Clinical Pharmacist, UCSF Medical Center Assistant Clinical Professor, UCSF School of Pharmacy San Francisco, CA

Introduction The development and approval of more effective drugs have led to better complete response (CR) rates and prolonged survival in multiple myeloma (MM). When choosing among these novel therapies, it is essential to consider factors such as pharmacologic profiles and dosing requirements to promote individualized care. In this article, Rebecca Young, PharmD, BCOP, discusses recent advances in the management of myeloma, including novel agents being incorporated into combination regimens and the role of bisphosphonates for improving patient outcomes.

How are newer frontline regimens improving outcomes in patients with MM? Survival of patients with MM has dramatically improved in recent years, as initial treatment has shifted from conventional chemotherapy to incorporation of novel therapies such as immunomodulatory drugs (IMiDs) and proteasome inhibitors. Thalidomide was the first novel IMiD to demonstrate clinical benefit in MM. A phase 3 randomized trial demonstrated significantly higher response rates in newly diagnosed patients who received thalidomide plus dexamethasone, compared with dexamethasone alone (63% vs 41%, respectively; P=.0017).1 Lenalidomide, a potent analogue of thalidomide with an improved toxicity profile—including lower rates of neurotoxicity—exerts a unique dual mechanism of action comprising both tumoricidal and immunomodulatory effects.2 Lenalidomide plus low-dose dexamethasone (Rd) has been associated with improved short-term overall survival (OS) with less toxicity compared with the historical standard of lenalidomide plus high-dose dexamethasone (RD). Newly diagnosed patients with MM were studied in an open-label noninferiority trial of lenalidomide 25 mg on days 1 to 21, plus either high-dose dexamethasone (40 mg on days 1-4, 9-12, and 17-20), or low-dose dexamethasone (40 mg on days 1, 8, 15, and 22). Interim analysis at 1 year showed that OS was higher with Rd than with RD (96% vs 87%; P=.0002). Low-dose dexamethasone was also better tolerated than high-dose dexamethasone, with less incidence of grade 3/4 toxicities within the first 4 months of treatment (35% vs 52%, respectively; P=.0001).3 Bortezomib, the first-in-class reversible proteasome inhibitor, has also transformed outcomes for patients with MM. Bortezomib-based therapy has been shown to improve survival in patients with translocation 4;14, a high-risk cytogenetic feature that typically confers poorer prognosis.4 Combination therapy with melphalan and prednisone plus either thalidomide or bortezomib has been shown to be effective in patients not eligible for transplant, producing significantly improved CR rates, time to progression, and OS.5,6 In the phase 3 randomized IFM 2005-01 trial, the combination of bortezomib plus dexamethasone (VD) demonstrated significantly higher rates of postinduction CR/near-complete response (nCR) (14.8% vs 6.4%), very good partial response ([VGPR] 37.7% vs 15.1%), and overall response rate ([ORR] 78.5% vs 62.8%) compared with vincristine/doxorubicin/dexamethasone (VAD) in transplant-eligible patients with MM. After a median follow-up of 32.2 months, progression-free survival (PFS) was slightly higher, though not statistically significant, with the VD regimen compared with the VAD regimen (36 months vs 29.7 months; P=.064).7 In a phase 2 clinical trial, cyclophosphamide/bortezomib/dexamethasone

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(CyBorD) as frontline therapy in 33 newly diagnosed patients with MM produced an ORR of 88% by intention-to-treat analysis. Patients received oral cyclophosphamide 300 mg/m2 (days 1, 8, 15, and 22), intravenous (IV) bortezomib 1.3 mg/m2 (twice weekly; days 1, 4, 8, and 11), and oral dexamethasone 40 mg (days 1-4, 9-12, and 17-20) every 28 days for 4 cycles. For those completing all 4 cycles of treatment (n=28), the ORR was 98% (including 71% in ≥VGPR and 46% CR/nCR).8 Despite the high response rates noted above, the investigators modified the treatment schedule for an additional 30 patients in an effort to decrease toxicity and treatment delays. Additional patients received the same weekly dose of cyclophosphamide, but were given once-weekly bortezomib 1.5 mg/m2 (days 1, 8, 15, and 22), and weekly dexamethasone in cycles 3 and 4. Although patients who received twice-weekly bortezomib had higher baseline advanced-stage disease, weekly bortezomib produced similar responses with less grade 3/4 toxicity. Fewer dose reductions of bortezomib and dexamethasone were required with once-weekly bortezomib, and rates of peripheral neuropathy (PN) were the same despite higher total bortezomib dose per cycle in the once-weekly versus the twice-weekly schedule (6.0 mg/m2 vs 5.2 mg/m2).9 A phase 1/2, multicenter trial by Richardson and colleagues was the first prospective study of lenalidomide/bortezomib/dexamethasone as treatment for patients with newly diagnosed MM (N=66).10 The phase 2 study portion established a maximum planned treatment dose of lenalidomide 25 mg (days 1-14), bortezomib 1.3 mg/m2 (days 1, 4, 8, and 11), and dexamethasone 20 mg (days 1, 2, 4, 5, 8, 9, 11, and 12) given every 3 weeks. In the phase 2 population, the partial response rate was 100%, with 74% of patients achieving ≥VGPR. Primary toxicities included PN (80%) and fatigue (64%), with only 27%/2% and 32%/3% grade 2/3. No treatment-related mortality was observed. What do pharmacists need to know about carfilzomib and pomalidomide? Carfilzomib, a next-generation epoxyketone-based proteasome inhibitor, is approved by the US Food and Drug Administration (FDA) 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 their last therapy.11 Two advantages that carfilzomib has over bortezomib are its ability to provide a more durable, irreversible inhibition of the proteasome, and its association with a lower incidence of PN. These characteristics and others are highlighted in the comparison of bortezomib and carfilzomib found in Table 1.12,13 Initial dose of carfilzomib is 20 mg/m2 on 2 consecutive days each week for 3 weeks (days 1, 2, 8, 9, 15, and 16) of a 28-day cycle. The dose should be increased on cycle 2 and subsequent cycles to 27 mg/m2.12 Doses should be capped at a body surface area of 2.2 m2. Higher doses and alternative infusion strategies are currently under investigation. Carfilzomib is a substrate of P-glycoprotein, and weakly inhibits cytochrome (CYP) 3A4 and P-glycoprotein.12,13 Carfilzomib received accelerated approval by the FDA in July 2012 based on Table 1. Comparison of Proteasome Inhibitors Approved for MM12,13 Chemical structure Inhibition type Administration route Cytochrome metabolism Half-life (minutes)

Bortezomib

Carfilzomib

Boronic acid

Epoxyketone

Reversible

Irreversible

IV/SC

IV

3A4, 2C19

Minimal

110

<30

IV indicates intravenous; MM, multiple myeloma; SC, subcutaneous.

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CONTINUING EDUCATION

Table 2. Recommended Dosing of Bisphosphonates for Prevention of SREs27,28 Clearance Creatinine (mL/min)

Zoledronic Acid (mg)a

Pamidronate (mg) 90 IV over at least 2 hours

>60

4

50-60

3.5

40-49

3.3

30-39

3

<30

Avoid use

30-90b IV over 4-6 hours

a

All doses infused IV over 15 minutes. In absence of formal guidelines, clinicians may consider reduced doses given over an extended interval of 4-6 hours based on individual patient risk assessment. IV indicates intravenous; SREs, skeletal-related events. b

results of a phase 2, open-label, single-arm trial that enrolled 266 heavily pretreated patients (≥2 prior therapies) with relapsed and/or refractory MM. Among the efficacy population (n=257), median duration of treatment was 3 months, and ORR was 23.7%.11,14 The efficacy of carfilzomib in frontline regimens for newly diagnosed patients with MM is the focus of ongoing investigation. Carfilzomib in combination with lenalidomide and dexamethasone as initial therapy has been evaluated in 2 phase 1/2 single-arm trials.15,16 Results from these studies have led to this combination being listed as a category 2A treatment option in the National Comprehensive Cancer Network guidelines for myeloma.17 Similar to bortezomib, no significant changes in pharmacokinetics in renally impaired patients have been observed with carfilzomib.14-16 In patients with high tumor burden, clinicians should monitor for signs/symptoms of tumor lysis syndrome. Prehydration with a minimum of 250 to 500 mL during cycle 1 of carfilzomib is recommended, and should be continued on subsequent cycles if necessary. Infusion reactions may occur immediately or within 24 hours of carfilzomib administration. Premedication with dexamethasone 4 mg to reduce the incidence and severity of infusion reactions is recommended during cycle 1, during escalation cycles, and as needed with subsequent cycles. Bone marrow suppression, especially thrombocytopenia, is a toxicity frequently observed with carfilzomib use. Other rare, but serious toxicities associated with this agent include cardiovascular complications (development or worsening of congestive heart failure, pulmonary edema, decreased left ventricular ejection fraction), pulmonary complications, and hepatotoxicity.18

Currently, it is unclear if patients will continue to benefit from bisphosphonate therapy after they achieve a CR. Pomalidomide, a next-generation oral immunomodulatory agent, is also approved by the FDA for the treatment of patients who have received at least 2 prior therapies, including bortezomib and an IMiD, and who have demonstrated disease progression on or within 60 days of therapy completion.19 In general, IMiDs suppress production of various cytokines that support tumor cell growth, alter bone marrow microenvironment, as well as inhibit angiogenesis. Pomalidomide is 10fold more potent than lenalidomide and up to 15,000 times more potent than thalidomide in inhibiting tumor necrosis factor-α.20 The recommended starting dose of pomalidomide is 4 mg once daily orally on days 1 to 21 of repeated 28-day cycles until disease progression.21 This agent is primarily metabolized by CYP3A4 and CYP1A2, and is a substrate for P-glycoprotein. Pomalidomide and its metabolites are excreted renally.21 Use of this agent should be avoided in patients with serum creatinine >3 mg/dL due to lack of safety data. A multicenter, randomized, open-label, phase 3 trial compared the efficacy and safety of pomalidomide plus low-dose dexamethasone versus high-dose dexamethasone alone in patients with MM who were refractory to both lenalidomide and bortezomib (N=455).22 At interim analysis (median follow-up, 4.2 months), PFS was significantly longer in patients who received pomalidomide and low-dose dexamethasone (3.6 months vs 1.9 months; P<.0001) compared

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with high-dose dexamethasone. Regimens containing pomalidomide and carfilzomib are promising. For example, interim results of a phase 1/2 trial evaluating a combination of carfilzomib/pomalidomide/low-dose dexamethasone in 32 heavily pretreated patients with relapsed and/or refractory MM suggest that this regimen is well tolerated with high response rates, even in patients with poorrisk cytogenetics such as deletion 17p.23 Pomalidomide is associated with a relatively low risk of PN compared with other IMiDs.13 Common grade 3/4 toxicities associated with the use of this agent include myelosuppression, fatigue, and infections.21 Pomalidomide should be administered on an empty stomach, and is only available through the Celgene Risk Evaluation and Mitigation Strategy program to prevent its administration during pregnancy, due to the risk of embryo-fetal toxicity. As with other IMiDs, the risk of thromboembolism is increased with administration of pomalidomide, requiring the need for thromboprophylaxis.21 What is the role of bisphosphonates in managing myeloma-related bone disease? Osteolytic bone disease, a common complication of myeloma, affects approximately 85% of patients at diagnosis.17 Bisphosphonates exert their effects by inhibiting osteoclast recruitment and maturation, and inducing osteoclast apoptosis. IV zoledronic acid and pamidronate, as well as oral clodronate (available outside of the United States) are the only agents approved for the treatment of myeloma-related bone disease.17 All patients with myeloma-related bone lesions at the time of diagnosis should be started on bisphosphonate therapy, repeated every 3 to 4 weeks, concurrently with induction chemotherapy. Use of bisphosphonates in asymptomatic (smoldering) or stage I disease is debatable. A recent Cochrane meta-analysis of 20 randomized controlled trials concluded that adding bisphosphonates to the treatment of MM reduced vertebral fractures and pain; the duration of therapy was typically 2 years.24 Subset data for patients receiving zoledronic acid for longer than 2 years demonstrated a continued reduction in skeletal-related events (SREs) and prolonged OS. Currently, it is unclear if patients will continue to benefit from bisphosphonate therapy after they achieve a CR. Use beyond 2 years is dependent on the patient’s response to therapy, as well as the physician's discretion. If bisphosphonate therapy is stopped after 2 years, it should be resumed at disease progression.25 Whether zoledronic acid is superior to pamidronate in preventing myeloma-related bone disease remains to be determined. The Cochrane meta-analysis reported that zoledronic acid is the only bisphosphonate to demonstrate superior OS compared with placebo in a randomized study.24 In a randomized, doubleblind, multicenter trial, zoledronic acid was found to be as effective as pamidronate in reducing pain, incidence of SREs, and delaying time to first SRE.26 Overall, zoledronic acid and pamidronate are equally well tolerated.27,28 Possible toxicities include bone pain, gastrointestinal disturbances, fatigue, fever, renal impairment, and hypocalcemia. Providers should monitor for renal dysfunction, and adjust doses appropriately. Standard and recommended dose adjustments are shown in Table 2.27,28 Osteonecrosis of the jaw (ONJ) is a rare but serious complication associated with prolonged bisphosphonate therapy. This event occurs more often with zoledronic acid than with pamidronate therapy.29 Preventive measures such as completing dental work-up prior to the start of bisphosphonates, waiting 6 to 8 weeks after invasive dental procedures prior to starting bisphosphonates, and maintaining good oral hygiene have been shown to decrease the incidence of ONJ.30 ♦ References

1. Rajkumar SV, Blood E, Vesole D, et al. Phase III clinical trial of thalidomide plus dexamethasone compared with dexamethasone alone in newly diagnosed multiple myeloma: a clinical trial coordinated by the Eastern Cooperative Oncology Group. J Clin Oncol. 2006;24:431-436. 2. Dimopoulos MA, Terpos E. Lenalidomide: an update on evidence from clinical trials. Blood Rev. 2010;24(suppl 1):S21-S26). 3. Rajkumar SV, Jacobus S, Callander NS, et al. Lenalidomide plus high-dose dexamethasone versus lenalidomide plus low-dose dexamethasone as initial therapy for newly diagnosed multiple myeloma: an open-label randomised control trial. Lancet Oncol. 2010;11:29-37. 4. Avet-Loiseau H, Leleu X, Roussel M, et al. Bortezomib plus dexamethasone induction improves outcome of patients t(4;14) myeloma but not outcome of patients with del(17p). J Clin Oncol. 2010;28:4630-4634. 5. Kapoor P, Rajkumar SV, Dispenzieri A, et al. Melphalana and prednisone versus melphalan, prednisone and thalidomide for elderly and/or transplant ineligible patients with multiple myeloma: a meta-analysis. Leukemia. 2011;25:689-696.

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CONSIDERATIONS IN MULTIPLE MYELOMA

6. Mateos M-V, Richardson PG, Schlag R, et al. Bortezomib plus melphalan and prednisone compared with melphalan and prednisone in previously untreated multiple myeloma: updated follow-up and impact of subsequent therapy in the phase III VISTA trial. J Clin Oncol. 2010;28:2259-2266. 7. Harousseau JL, 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. 8. Reeder CB, Reece DE, Kukreti V, et al. Cyclophosphamide, bortezomib and dexamethasone (CyBorD) induction for newly diagnosed multiple myeloma: high response rates in a phase II clinical trial. Leukemia. 2009;23:1337-1341. 9. Reeder CB, Reece DE, Kukreti V, et al. Once- versus twice-weekly bortezomib induction therapy with CyBorD in newly diagnosed multiple myeloma. Blood. 2010;115:3416-3417. 10. 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. 11. US Food and Drug Administration. Announcements. FDA approves Kyprolis for some patients with multiple myeloma. July 20, 2012. www.fda.gov/newsevents/newsroom/pressannouncements/ucm312920.htm. Accessed December 1, 2013. 12. Jain S, Diefenbach C, Zain J, et al. Emerging role of carfilzomib in treatment of relapsed and refractory lymphoid neoplasms and multiple myeloma. Core Evid. 2011;6:43-57. 13. El-Amm J, Tabbara IA. Emerging therapies in multiple myeloma. Am J Clin Oncol. 2013 Aug 7. [Epub ahead of print]. 14. Siegel DS, Martin T, Wang M, et al. A phase 2 study of single-agent carfilzomib (PX-171003-A1) in patients with relapsed and refractory multiple myeloma. Blood. 2012;120: 2817-2825. 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. Korde N, Zingone A, Kwok M, et al. Phase II clinical and correlative study of carfilzomib, lenalidomide, and dexamethasone (CRd) in newly diagnosed multiple myeloma (MM) patients. Blood (ASH Annual Meeting Abstracts). 2012;120. Abstract 732. 17. National Comprehensive Cancer Network (NCCN). NCCN Clinical Practice Guidelines in

Oncology (NCCN Guidelines®). Multiple Myeloma, V2. 2014. www.nccn.org. Accessed November 24, 2013. 18. Kyprolis [package insert]. South San Francisco, CA: Onyx Pharmaceuticals, Inc. July 2012. 19. US Food and Drug Administration. Announcements. FDA approves Pomalyst for advanced multiple myeloma. February 8, 2013. www.fda.gov/newsevents/newsroom/pressannouncements/ ucm338895.htm. Accessed December 5, 2013. 20. Corral LG, Haslett PA, Muller GW, et al. Differential cytokine modulation and T cell activation by two distinct classes of thalidomide analogues that are potent inhibitors of TNF-alpha. J Immunol. 1999;163:380-386. 21. Pomalyst [package insert]. Summit, NJ: Celgene Corporation. February 2013. 22. Dimopoulos MA, Lacy MQ, Moreau P, et al. Pomalidomide in combination with low-dose dexamethasone: demonstrates a significant progression free survival and overall survival advantage, in relapsed/refractory MM: a phase 3, multicenter, randomized, open-label study. Blood (ASH Annual Meeting Abstracts). 2012;120. Abstract 6. 23. Shah JJ, Stadtmauer EA, Abonour R, et al. A multi-center phase I/II trial of carfilzomib and pomalidomide with dexamethasone (Car-Pom-d) in patients with relapsed/refractory multiple myeloma. Blood (ASH Annual Meeting Abstracts). 2012;120. Abstract 74. 24. Mhaskar R, Redzepovic J, Wheatley K, et al. Bisphosphonates in multiple myeloma: a network meta-analysis. Cochrane Database Syst Rev. 2012;5:CD003188. 25. Terpos E, Roodman GD, Dimopoulos MA. Optimal use of bisphosphonates in patients with multiple myeloma. Blood. 2013;121:3325-3328. 26. Rosen LS, Gordon D, Kaminski M, et al. Long-term efficacy and safety of zoledronic acid compared with pamidronate disodium in the treatment of skeletal complications in patients with advanced multiple myeloma or breast carcinoma: a randomized, double-blind, multicenter, comparative trial. Cancer. 2003; 98:1735-1744. 27. Aredia [package insert]. East Hanover, NJ: Novartis Pharmaceuticals Corp. May 2012. 28. Zometa [package insert]. East Hanover, NJ: Novartis Pharmaceuticals Corp. September 2013. 29. Zervas K, Verrou E, Teleioudis Z, et al. Incidence, risk factors and management of osteonecrosis of the jaw in patients with multiple myeloma: a single-centre experience in 303 patients. Br J Haematol. 2006;134:620-623. 30. Dimopoulos MA, Kastritis E, Bamia C, et al. Reduction of osteonecrosis of the jaw (ONJ) after implementation of preventative measures in patients with multiple myeloma treated with zoledronic acid. Ann Oncol. 2009;20:117-120.

The Significance of Achieving Complete Response in Multiple Myeloma Continued from page 20 Newer technologies, notably genomic sequencing and testing after CR for minimal residual disease, hold the promise of enhancing our predictions of each patient’s clinical course. These technologies may also improve our ability to choose drugs and to determine when maintenance is warranted. The result will be greater personalization of care and a better chance at CR for more patients with MM. ♦ References

1. National Comprehensive Cancer Network (NCCN). NCCN Clinical Practice Guidelines in Oncology™: Multiple Myeloma. Version 2.2013. http://www.nccn.org. Accessed June 2, 2013. 2. 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. 3. Reeder CB, Reece DE, Kukreti V, et al. Cyclosphosphamide, bortezomib and dexamethasone (CyBorD) induction for newly diagnosed multiple myeloma: high response rates in a phase II clinical trial. Leukemia. 2009;23:1337-1341. 4. Jakubowiak AJ, Dytfeld D, Griffith KA, et al. Treatment outcome with the combination of carfilzomib, lenalidomide, and low-dose dexamethasone (CRd) for newly diagnosed multiple myeloma (NDMM) after extended follow-up. J Clin Oncol (ASCO Annual Meeting Abstracts). 2013;31(15 suppl):Abstract 8543. 5. Richardson PGG, Berdeja JG, Niesvizky R, et al. Oral weekly MLN9708, an investigational proteasome inhibitor, in combination with lenalidomide and dexamethasone in patients (pts) with previously untreated multiple myeloma (MM): a phase I/II study. J Clin Oncol (ASCO Annual Meeting Abstracts). 2012;30(15 suppl):Abstract 8033. 6. Randomized trial of lenalidomide, bortezomib, dexamethasone vs high-dose treatment with SCT in MM patients up to age 65 (DFCI 10-106). NCT01208662. http://www.clinicaltrials. gov/ct2/show/NCT01208662?term=RVD&rank=9. Accessed November 22, 2013. 7. Study comparing conventional dose combination RVD to high-dose treatment with ASCT in the initial myeloma up to 65 years (IFM/DFCI2009). NCT01191060. http://www.clinicaltrials. gov/ct2/show/NCT01191060?term=RVD&rank=2. Accessed November 22, 2013. 8. 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.

9. Rajkumar SV, Jacobus S, Callander NS, et al; 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. 10. Cavo M, Tacchetti P, Patriarca F, et al; GIMEMA Italian Myeloma Network. Bortezomib with thalidomide plus dexamethasone compared with thalidomide plus dexamethasone as induction therapy before, and consolidation therapy after, double autologous stem-cell transplantation in newly diagnosed multiple myeloma: a randomised phase 3 study. Lancet. 2010;376:2075-2085. 11. Neben K, Lokhorst HM, Jauch A, et al. Administration of bortezomib before and after autologous stem cell transplantation improves outcome in multiple myeloma patients with deletion 17p. Blood. 2012;119:940-948. 12. Harousseau J-L, Avet-Loiseau H, Attal M, et al. Achievement of at least very good partial response is a simple and robust prognostic factor in patients with multiple myeloma treated with high-dose therapy: long-term analysis of the IFM 99-02 and 99-04 trials. J Clin Oncol. 2009; 27:5720-5726. 13. Martinez-Lopez J, Blade J, Mateos M-V, et al. Long-term prognostic significance of response in multiple myeloma after stem cell transplantation. Blood. 2011;118:529-534. 14. Laheurta JJ, Mateos MV, Martinez-López J, et al. Influence of pre- and post-transplantation responses on outcome of patients with multiple myeloma: sequential improvement of response and achievement of complete response are associated with longer survival. J Clin Oncol. 2008; 26:5775-5782. 15. Harousseau J-L, Palumbo A, Richardson P, et al. Superior outcomes associated with complete response: analysis of the phase III VISTA study of bortezomib plus melphalan-prednisone versus melphalan-prednisone. Blood (ASH Annual Meeting Abstracts). 2008;112:Abstract 2778. 16. Barlogie B, Anaissie E, Haessler J, et al. Complete remission sustained 3 years from treatment initiation is a powerful surrogate for extended survival in multiple myeloma. Cancer. 2008;113: 355-359. 17. Usmani SZ, Waheed S, Van Rhee F, et al. Total Therapy 5 (TT5) for newly diagnosed highrisk multiple myeloma (HRMM): comparison with predecessor trials Total Therapy 3a and 3b (TT3 a/b). J Clin Oncol (ASCO Annual Meeting Abstracts). 2013;31(15 suppl):Abstract 8539. 18. Alexanian R, Weber D, Giralt S, et al. Impact of complete remission with intensive therapy in patients with responsive multiple myeloma. Bone Marrow Transplant. 2001;27:1037-1043. 19. 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.

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THROUGH THE EYES OF AN ADVOCATE

Important Steps in the Conquest of Ovarian Cancer Peg Ford

W

riting about ovarian cancer this month provided me with the chance to reflect on how things have changed not only in treatment, but also in research over the past several years since I entered the world of medicine as an advocate. In addition, I recently was invited to participate in a National Cancer Institute (NCI) site visit at Scripps Research Institute, where I was privileged to learn firsthand about the studies conducted at a cancer research lab, and to appreciate the challenges. As a layperson, my idea of the scientific world was of a distant sphere of higher learning where only the very few who were capable and trained could comprehend even the most basic science. Yet because of the emerging paradigm shift to include the patient stakeholder’s presence and voice in medicine, opportunities and support are available for individuals who wish to learn and become informed and involved advocates. I am grateful to have discovered these in my journey, and I am confident that more people will be able to participate and represent the patient community in the scientific arena, to the benefit of both communities. Strides have been made in ovarian cancer treatment options and there has been an increase in research since my entry into the world of advocacy in 2008 as an ovarian cancer survivor. However, mortality rates have not changed much, as most women when diagnosed with ovarian cancer have late-stage disease and, sadly, most will face recurrences. We still do not have a screening test for early detection of ovarian cancer, but researchers are endeavoring to change this. The one aspect that is certain—one the patient community is working hard to increase—is awareness, through education of medical students and outreach programs for the general public emphasizing that if detected in the early stage, the overall 5-year survival rate for the few women diagnosed at this point greatly increases from 45% to over 90%. The American Cancer Society estimates that about 22,400 women will be diagnosed with ovarian cancer in 2013 and that 14,230 women will die from the disease, which is the fifth leading cause of cancer deaths among women in this country. Approximately 1 in 72 women will develop ovarian cancer, and their risk of dying is 1 in 100. Generally, ovarian cancer is considered an older woman’s disease and although women have a higher risk as they age,

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Peg Ford with Luis Alberto Diaz, MD, of Johns Hopkins Kimmel Cancer Center and a researcher of the new “PapGene” test, a 3-in-1 screening test for gynecologic cancers. Photo taken on October 30, 2013, after a presentation by Diaz at Illumina, Inc.

more young women are facing this deadly disease. One such brave 25-year-old, Kristina Anderson, is attempting something quite extraordinary and certainly out of the ordinary as she is competing in the upcoming Miss Arizona pageant. She was diagnosed with a rare form of ovarian cancer last July and is determined to go forward on her own terms despite having to deal with this disease. Because ovarian cancer is very heterogeneous molecularly, the need for personalized precision treatment is advancing the interest and focus of the scientific

heated (to about 108 degrees) chemotherapy delivered directly into the patient’s abdomen for approximately 60 to 90 minutes. The new “PapGene” test, a 3-in1 screening for gynecologic cancers, combines a traditional Pap smear for cervical cancer with a DNA test for gene mutations linked to endometrial and ovarian cancers. According to lead researcher and MD-PhD candidate Isaac Kinde and Luis Alberto Diaz, MD, of Johns Hopkins Kimmel Cancer Center, the screening is not

Because ovarian cancer is very heterogeneous molecularly, the need for personalized precision treatment is advancing the interest and focus of the scientific world. world. Owing to its relative connections to the BRCA gene mutations in breast and other types of cancer (Lynch syndrome), ovarian cancer research efforts have increased. PARP inhibitors, vaccines, angiogenesis inhibitors, and targeted chemotherapy are all examples addressing this urgency, and a grateful patient community knows, without question, how important it is to support and fund research now more than ever. There is an experimental study at Columbia University Medical Center that uses hyperthermic intraoperative chemotherapy (HIPEC), also known as heated chemotherapy. After removing the tumor, the area is treated with

yet ready for clinical practice...but could this prove to be another important step toward a screening test? The PapGene screening uses advanced DNA sequencing technology to look for mutations in 12 genes associated with endometrial or ovarian cancers in cells collected for Pap smears. The PapGene test often found one or more of the mutations from the samples. In contrast, the samples from women without cancer showed no mutations. The screening proved highly sensitive for endometrial cancer: every woman known to have the disease tested positive for mutations. However, it captured only 40% of patients known to have ovarian cancer.

Interesting studies have been funded, including the prospect that man’s best friend could sense cancers. One anecdote supporting this possibility is a female patient whose dog was poking at her breast for months before she was diagnosed with stage III breast cancer. A study is currently under way regarding dogs and the detection of ovarian cancer. One extremely promising update from a study from the University of Texas MD Anderson Cancer Center is that gauging CA-125 (the protein recognized and used for predicting ovarian cancer recurrence, discovered by Robert Bast, MD, who is the study’s senior author) over time may be a screening tool for early stage in postmenopausal women at average risk for the disease. Karen Lu, MD, professor and chair of the Department of Gynecologic Oncology and the study’s corresponding author, indicated that research is ongoing and that she and her team plan to study other markers along with CA-125 to determine the screening impact of their combined change over time. This finding is certainly encouraging, but thus far is neither conclusive nor ready to change current practice, as a large, randomized prospective screening trial still needs to be conducted. However, such research is currently under way in the United Kingdom, where results from more than 200,000 women should be known by 2015. Of note are the diverse as well as private contributors funding the CA-125 study: it was supported by the NCI and was a research project of MD Anderson’s ovarian cancer Specialized Program of Research Excellence (SPORE; NCI P50 CA83639), the Bioinformatics Shared Resources of MD Anderson (CCSG NCI P30 CA16672), and the National Foundation for Cancer Research. Philanthropic support was also received from Golfers Against Cancer, the Tracy Jo Wilson Ovarian Cancer Foundation, the Mossy Foundation, the Norton family, and Stuart and Gaye Lynn Zarrow. In my work with newly diagnosed patients and those who are dealing with recurrences as they prepare to participate in the Ovarian Cancer Alliance of San Diego’s Outreach Programs (my organization), I am inspired to find that although heavy of heart, these women are struggling to fight this lethal disease and are thankful for the dedicated physicians and researchers who are working diligently to combat it. l

www.TheOncologyNurse.com


OVARIAN CANCER

Resources for Patients, Survivors, Providers, Researchers, and Supporters Peg Ford

Ovarian Cancer Alliance of San Diego www.ocaofsd.org Peg Ford, Cancer Research Advocate, Founder/Chair The Alliance strives to affect change in the way medical doctors consider the diagnosis and treatment of ovarian cancer; educate the medical community, patient organizations, and the community at large about early diagnosis; further research on evidence-based treatment options; and, ultimately, eradicate the disease.

National Ovarian Cancer Coalition (NOCC) www.ovarian.org The Coalition is committed to improving the survival rate and quality of life for women with ovarian cancer. Through national programs and local chapter initiatives, NOCC’s goal is to make more people aware of the early symptoms of the disease. In addition, NOCC provides information to assist the newly diagnosed patient as well as hope and support to survivors and caregivers.

The Clearity Foundation www.clearityfoundation.org The Foundation helps patients with ovarian cancer and their physicians in making better-informed treatment decisions based on the molecular profile of the tumor (the “tumor blueprint”), thus enabling a more individualized approach to therapy selection. Patient support services include lab test coordination, tumor blueprint interpretation, and clinical trial identification free of charge.

Ovarian Cancer National Alliance www.ovariancancer.org The Alliance advocates at a national level for increases in research funding for the development of an early detection test, improved healthcare practices, and life-saving treatment protocols. The Ovarian Cancer Symptom Diary App (www.ovariancancer.org/app) helps individuals learn about the risks, signs, and

FORCE (Facing Our Risk of Cancer Empowered) www.facingourrisk.org FORCE is a national nonprofit agency dedicated to improving the lives of individuals and families affected by hereditary breast and ovarian cancer. Information on cancer management and treatment, clinical trials and research, support, advocacy, and events is offered on the website. A toll-free helpline can be reached at 1-866-288-RISK. Foundation for Women’s Cancer www.foundationforwomenscancer. org The Foundation offers many awareness, educational, and fundraising programs as well as comprehensive information about gynecologic cancer risk prevention, early detection, and optimal treatments provided by gynecologic oncologists and other healthcare experts. Guidelines International Network (G-I-N) www.g-i-n.net G-I-N offers partnership opportunities for guideline organizations, assists in improving the efficiency and effectiveness of healthcare guideline development, and promotes best practices through opportunities for learning and the establishment of standards. G-I-N/North America provides a community for North American guideline users, developers, and other stakeholders to form partnerships and discuss regional guideline issues.

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symptoms of the disease. This first-ofits-kind application allows a woman to track symptoms that could indicate ovarian cancer, and alerts her if she should make an appointment with her doctor for further testing. Ovarian Cancer Research Fund www.ocrf.org The Ovarian Cancer Research Fund is the oldest and largest philanthropic organization in the United States funding ovarian cancer research. Through its auspices, more than $50 million has been granted to the most innovative and promising ovarian cancer research. Patient Advocate Foundation (PAF) www.patientadvocate.org/ myresources PAF advocates and mediates on behalf of patients to provide access to evolving therapies, therapeutic agents, and devices. Professional patient assis-

tance is offered by telephone, email, or live web chat. PAF’s free My Resource Search app is an easy-to-use tool for healthcare, financial, and insurance help that allows both insured and uninsured patients to identify the community and national programs that can assist in their healthcare needs. Society of Gynecologic Oncology (SGO) www.sgo.org With more than 1700 domestic and international members, SGO is the premier medical specialty society for healthcare professionals trained in the comprehensive management of gynecologic cancers. SGO contributes to the advancement of women’s cancer care by promoting research, providing education, raising standards of practice, advocating for patients and members, and collaborating with other national and global organizations. l

Pazopanib: First Positive Maintenance Trial Phoebe Starr

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revious trials of maintenance therapy for patients with ovarian cancer have failed to show improved survival. A study presented at the 2013 American Society of Clinical Oncology Annual Meeting is the first successful phase 3 trial in this setting—targeted therapy pazopanib extended progression-free survival (PFS) in women with ovarian cancer by a median of 5.6 months. Women enrolled in the trial were disease free after initial treatment with surgery and chemotherapy. “Pazopanib maintenance therapy prolongs the time the patient has control over the disease versus the time the disease controls the patient’s life. Pazopanib might be a valuable option for treatment of stage II to IV ovarian cancer,” stated lead author Andreas Du Bois, MD, PhD, professor of gynecologic oncology at the Kliniken EssenMitte in Germany. Although patients with ovarian cancer typically respond to initial therapy with surgery and chemotherapy, the relapse rate is about 75%. The rationale for maintenance therapy is to keep patients in remission, but studies to date have been disappointing. Given the cost and the added toxicity of maintenance therapy, demonstrating improved survival is important. Pazopanib is an oral multikinase inhibitor approved by the US Food and Drug Administration for the treatment of renal cell carcinoma and soft tissue sarcoma. Medication toxicities reported in the current trial were class specific to angiogenesis inhibitors: hypertension, elevated liver enzymes, neutropenia, and diarrhea.

Most Patients Had Advanced Disease The phase 3 multicenter trial enrolled 940 patients with advanced epithelial ovarian, fallopian tube, or primary peri-

toneal cancer. Eligibility criteria included patients with stage II to IV disease, but most patients had stage III or IV ovarian cancer. Participants were randomized in a 1:1 ratio to receive 800 mg of pazopanib orally versus placebo for 2 years after standard surgery and chemotherapy. The median time to disease progression was 17.9 months for the pazopanib group versus 12.3 months for the placebo group, representing a 5.6-month advantage for those on the targeted therapy. At 24 months, however, no significant difference in overall survival was observed. Longer follow-up is needed to see if there is an overall survival benefit. “There is currently no standard of care for maintenance therapy. Evidence continues to mount that targeting angiogenesis is important in ovarian cancer. The bottom line from several studies is that targeting angiogenesis is effective in ovarian cancer. These results show that pazopanib extends PFS as maintenance therapy, similar to the results of previous trials of bevacizumab,” said Carol Aghajanian, MD, chief of Gynecologic Medical Oncology Service at Memorial SloanKettering Cancer Center, New York City. “This large trial shows us that targeting multiple molecular cancer drivers can have a substantial impact on this cancer’s ability to grow,” Aghajanian said. “This study offers a realworld example of how the precision medicine era of cancer research is paying off in areas where no alternate approved drugs exist.” l Reference

Du Bois A, Floquet A, Weon Kim J, et al. Randomized, double-blind, phase III trial of pazopanib versus placebo in women who have not progressed after first-line chemotherapy for advanced epithelial ovarian, fallopian tube, or primary peritoneal cancer (AEOC): results of an international Intergroup trial (AGO-OVAR16). J Clin Oncol. 2013;31(suppl):Abstract LBA5503. Presented at: 2013 American Society of Clinical Oncology Annual Meeting; May 31-June 4, 2013; Chicago, IL.

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Oncology Nurse Excellence Award Winner Sponsored by

Libby Daniels Named Recipient at AONN+ Conference Lisa Neuman

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t the Academy of Oncology Nurse Navigators (AONN+) 4th Annual Conference in November, one outstanding nurse was recognized by her peers for her dedication and commitment to the profession. The 2013 ONE Award winner was Libby Daniels, RN, OCN, from Lexington Medical Center in West Columbia, South Carolina. Nominated by a colleague who is studying to be a nurse practitioner, Ms Daniels made a lasting impression on her in a very personal way. “Libby’s exceptional knowledge and patient skills became even more evident to me when the oncology experience became personal after my grandfather was diagnosed with stage IV lung cancer,” the colleague wrote. “Libby heard about my grandfather’s diagnosis, and even though he was not one of her patients, she immediately offered her assistance. Libby has been there for my whole family around the clock offering information, guidance, or just a listening ear—clearly illustrating that being an oncology nurse navigator is a way of life to her and not just a job. Some might say that oncology nursing is her ‘calling,’ and I would certainly agree.” In a phone interview held after she returned home from the conference, Ms Daniels reflected on the case that led to her nomination. “My colleague’s grandfather had recently been diagnosed with stage IV lung cancer. They were having some family dynamics going on about whether to do treatment or not. I basically said to my colleague, ‘That’s what I do. I’m a nurse navigator. I can meet your family, be the mediator, and explain all the pros and cons of the different courses of treatment for you.’ We held a family meeting where we let each family member talk about how they felt and what they thought

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DECEMBER 2013 I VOL 6, NO 11

The ONE Award presentation (left to right): Sharon Gentry, RN, MSN, AOCN, CBCN; Lillie D. Shockney, RN, BS, MAS; Pamela Cook, BSN, Bayer HealthCare; Libby Daniels, RN, OCN; and Emily Acland, Patient Access Network Foundation

would be best for their loved one,” she explained. “In talking to her grandparents, I found that he wanted to try che-

learned her grandfather had was that he and his wife were soon going to celebrate their 60th wedding anniversary. “His main concern,” Ms Daniels

“I feel like in nursing—and especially in oncology nursing—a lot of times you just have to listen because sometimes it’s not about wanting to live for 6 more months, it’s about the goals that the patient wants to reach and that’s very important.” —Libby Daniels, RN, OCN motherapy for his family. Through the process of talking to and getting to know the family, one of the main goals that I

continued, “and he just kept saying it over and over, was ‘I don’t want to be a vegetable.’ He kept talking about his

anniversary, how he and his wife had been married for 60 years, how they had always been together. They didn’t know what life was going to be like not being together.” There was a particularly heart-wrenching moment when the grandfather asked her, “Can the chemotherapy cure me?’’ and Ms Daniels had to tell him that it would not. That’s when the 3 of them—the patient and his wife and Ms Daniels—talked about his goals and how important his quality of life was to him. Ultimately, his “treatment goal” was to be married for 60 years. “I went back to my colleague and I said, ‘I really feel like the reason why he’s doing this chemotherapy is because he’s got a goal. His goal is to be married for 60 years.’ He ended up doing the treatment until he reached that goal, and he passed away on the day of their 60th wedding anniversary,” Ms Daniels reflected. Anyone can imagine what that experience would be like for the family of that patient. But what was that experience like for the nurse who navigated that patient to the end of his life, a patient who passed away on the very day of his 60th wedding anniversary? “When you’re in your 80s, you know life can come to an end, but life isn’t always about our lifespan. It’s about reaching goals and fulfilling dreams. That was the closest goal that he knew he was going to be able to reach. That was very important to him,” Ms Daniels explained. “It was very emotional for me, because my parents are not much younger than he and his wife. I know what it’s like to have spent that many years with someone. You’re celebrating spending your life together but at the same time you’re saying goodbye to one another. That’s very difficult,” she said. “When he asked me if he could be cured and I told him he couldn’t, yes,

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the I cried, because you can’t lie to your patient,” Ms Daniels continued. “You just can’t lie. It was hard for his son to hear that because the grandfather was the family patriarch. But he did it the way he wanted to. He did it with dignity, he reached his goal, and he was able to pass away on his terms.” “I feel like in nursing—and especially in oncology nursing—a lot of times you just have to listen because sometimes it’s not about wanting to live for 6 more months, it’s about the goals that the patient wants to reach and that’s very important,” Ms Daniels explained. “None of us know how long our life is going to be. But if there’s something big to look forward to—a wedding, or a grandbaby about to be born, or a grandchild about to graduate from college, they’re goals that these patients with cancer strive for, a reason to do that extra chemotherapy, to get a little bit stronger, to tough it out so they can reach their goal.” After the initial shock of hearing her name called as the ONE Award winner wore off, Ms Daniels had an amazing experience at the conference. “I was very humbled when a nurse from California, or one from Canada, or one from Minnesota, came up and said, ‘I voted for you,’” she shared. “I don’t know these nurses. To have that said to you by complete strangers is very, very humbling. I’ve met some new friends that I would have never met. And it’s just really cool to be able to sit and talk to other nurses and it’s OK to say all the gross things that we nurses talk about, because we all speak the same language.” Ms Daniels’ trip home from the conference was more than memorable as well, and not just because of weather delays. “I didn’t get home from the airport until after midnight,” she recalled, “and my parents were sitting there at the gate and they walked up to me and they could not stop hugging me. They said, ‘You will never know how proud we are of you.’” Her mother is a breast cancer survivor, and her father is a lung cancer survivor. “I am 52 years old, and my parents are my everything,” Ms Daniels explained. “They’re the reason why I do the things that I do. So when they said to me, ‘We couldn’t be prouder and we couldn’t wait to see your award,’ and that they had been sitting there in the airport until after midnight when they’re 75 years old and should have been at home in bed— they waited 2 hours because my plane was late—that moment was just priceless to me.” In addition to the plaque she received at the conference, Ms Daniels will be given $250 to donate to a charity of

www.TheOncologyNurse.com

her choice. She’s chosen the Lexington Medical Center Foundation. The foundation, which recently celebrated its 20th year of operation, is funded by the medical center’s employees. The hospital holds fundraising events such as Women’s Night Out and Cancer of Many Colors, where money is raised to help not just patients with cancer

ONE Award

but any patients within the hospital’s community who might need assistance. It even helps with employees who may have had a hard time or have gotten really sick. “A big part of the foundation’s success is because of employees giving back,” Ms Daniels explained. Ms Daniels wished to express her gratitude to AONN+, award sponsors

Bayer and the PAN Foundation, and all the nurses who voted for her. “You don’t often get a chance to be in a room with that many powerful women at one time,” Ms Daniels said. “So I am very grateful to the conference organizers and the sponsors for giving me the chance to attend the conference, and for the award that has made my parents so proud.” l

save the date

FiFth annual

Navigation and Survivorship Conference september 18-21, 2014 Walt disney World dolphin hotel orlando, Florida

www.AONNonline.org

AONN2014 Save the Date_120513

DECEMBER 2013 I VOL 6, NO 11

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CANCER CENTER PROFILE

Scripps Cancer Center... Continued from cover The Oncology Nurse-APN/PA spoke with Janine Rodriguez, RN, and Paula Thomas, LCSW, about their work at Scripps Cancer Center—Stevens Division at Scripps Memorial Hospital, 1 of the 5 campuses in the Scripps network.

Can you describe the services you provide for cancer patients? Janine Rodriguez (JR): I am the nurse navigator/clinical coordinator providing support for the patient through his or her treatments. I work with patients who have all types of cancer, and the majority of my work is with outpatients. Occasionally, I will see inpatients after a surgical procedure. Patients are referred to our support services by medical oncologists, surgeons, nurses on the oncology floor, or social workers, and we get selfreferrals as well. We call patients for a face-to-face interview after an initial diagnosis of cancer. For example, I might help them get a wig after their hair falls out from chemotherapy or direct a breast cancer patient to physical therapy if she develops lymphedema. I refer them to wellness classes, including yoga and meditation for de-stressing them, and nutritional support. In general, both Paula and I are patient advocates, and we are here to help meet their needs. Paula Thomas (PT): I am an outpatient oncology social worker at the Stevens Cancer Center. I offer psychosocial support and screen the patients for emotional distress. I also help them deal with financial issues, insurance, and transportation, linking them to resources to solve these problems. I also offer emotional support and provide an outlet for them to discuss their fears and anxieties openly, which they usually don’t want to do with their families. I also facilitate the Scripps Gynecological Cancer Support Group.

working with cancer patients the most challenging in this regard—probably because so much is unknown for them.

Janine Rodriguez, RN

Paula Thomas, LCSW

Tell me about that. PT: The group includes anywhere from 13 to 16 women who meet twice a month. Most of them have ovarian cancer, but women with other gynecologic cancers are also invited to join the group. I have been facilitating this group for about a year and a half, and it is flourishing. We deal with difficult issues, as most of these women are ovarian cancer patients at high risk of relapse and

recommend support group participation at the time of initial diagnosis. I usually wait until after about 8 to 12 weeks following initial diagnosis to suggest participation, because at this time women typically need support. JR: I am tangentially involved in helping to put on social events for the group. We are having a holiday tea next week, and it will be a lighthearted celebration.

“The patients and their families are so grateful for our help in allowing them to express themselves and in directing them to concrete resources for their problems.” Janine Rodriguez, RN

death. The group is incredible, helping women maintain resilience and providing compassion on this difficult journey. As you can imagine, the composition of the group changes with the loss of members. Because the discussion about loss can be overwhelming, I generally don’t

What are your biggest challenges in this work? PT: For me, I have to overcome and deal with my own fears associated with cancer death. I want to be careful not to transmit my fears to my patients. Even though I have worked in other settings where patients die, like hospice, I find

JR: I don’t have the same fears. I was an ICU nurse and an ER nurse for many years. My biggest challenge relates to organizational structure. With 5 different hospitals serving different patient populations, I want to ensure that all patients have equal access to our support services. It can be frustrating, because we don’t always have access to all the patients we would like to help.

What are your biggest rewards? JR: The patients and their families are so grateful for our help in allowing them to express themselves and in directing them to concrete resources for their problems. We might help a person living alone to get food, for example. The interaction with patients is my reward. PT: I would echo that. Waxing philosophical, social work is dirty work. You work in all kinds of settings where the problems are not pretty. But the reward is that you are giving a lifeline to a patient. It is a wonderful feeling to help distraught persons feel better so they can face the journey ahead. Not only do we provide services and connect patients with resources, but also, I will connect them with a therapist if they are having emotional problems. JR/PT: The other Cancer Center personnel include our medical director, James Sinclair, MD; our administrative assistant, Eileen Gaudette; and an advanced nurse practitioner (APN) Cathleen Sugarman; as well as a fulltime genetic counselor, Jaime Malone, MS, CGC. l

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Oncology On Canvas

SM

“Together they are stronger, brighter and no longer alone

in the journey of survivorship.” From Creating Connections of Hope and Light by a Healthcare Professional and 2012 entrant

Announcing the 2014 Lilly Oncology On Canvas Art Competition

Call for Entries | Deadline: June 30, 2014 “Some see paint. Others see hope. What do you see?” In 2004, more than 400 people across 23 countries saw those words and shared their cancer journeys with the world through art and narrative. Today, 10 years later, with more than 4,100 stories shared, many are still waiting to be told by the nearly 14 million cancer survivors today in the U.S.1 — in addition to millions of others who love and care for them. The 2014 competition marks a year-long commemoration of the 10-year anniversary. Oncology On CanvasSM is a program that was started in 2004 by Lilly Oncology to help address a great, unmet need in cancer care—a need that goes beyond medicine—to help those affected by cancer cope with the emotional toll of the disease. This biennial competition, presented by Lilly Oncology and the National Coalition for Cancer Survivorship (NCCS), invites people from the United States and Puerto Rico diagnosed with any type of cancer—as well as their families, friends, caregivers, and healthcare providers—to express, through art and narrative, the life-affirming changes that give their cancer journeys meaning. 1. American Cancer Society. Cancer Facts & Figures 2013. American Cancer Society Web site. http://www.cancer.org/Research/CancerFactsStatistics/ CancerFactsFigures2013/index. Accessed July 23, 2013. ON87677 10/2013 PRINTED IN USA ©2013, LILLY USA, LLC. ALL RIGHTS RESERVED.

Winners’ prizes consist of donations made in their name to the cancer-related charities of their choice. For further information about Lilly Oncology On Canvas, 2012 winners, an exhibit schedule and details on the competition— in addition to information on 10-year anniversary activities— please visit www.LillyOncologyOnCanvas.com, call 1-866-991-LOOC (5662), or e-mail artdirector@mylooc.com. Follow us on Find us on

at Facebook.com/LillyOncologyOnCanvas.

Tune in to our Pin our

at twitter.com/LlyOncOnCanvas. channel at youtube.com/LlyOncOnCanvas.

boards at pinterest.com/LlyOncOnCanvas.

To learn more about cancer survivorship tools and resources, visit the NCCS website at www.canceradvocacy.org.

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