February 2012, Vol 5, No 1 by The Oncology Nurse

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FEBRUARY 2012

www.TheOncologyNurse.com

VOL 5, NO 1

BEST PRACTICES

CANCER CENTER PROFILE

Medical City Cancer Resource Center, Dallas, Texas

Spotlight on Compassion Fatigue for Oncology Nurses By Alice Goodman

Empowerment, Education, Awareness

ith the growing number of cancer survivors, survivorship planning is getting a lot of attention. An important aspect of cancer survivorship is the effects on nurses, who become “secondary survivors,” of the toll cancer takes on patients and families. As such, nurses need to be aware of the possibility of “compassion fatigue.” “Check your own thermometer reading. On a quarterly basis, take the average

By Jan Tichenor, RN, MSN, CNS, OCN, and Juliet Morgan

number of deaths, codes, and times you are present for the delivery of bad news, and multiply this number by 4 for the yearly number, then multiply that number again by the number of years you have been an oncology nurse. That will show you that you have witnessed and been part of hundreds of these experiences. You need to treat your own feelings of loss as if you were a bereaved family relative,” Continued on page 8

BEST PRACTICES

Medical City oncology staff and volunteers in front of the CRC in the main lobby of the hospital. From left: Pat Terry, ACS Cancer Resource Center volunteer; Ann Giddens, ACS Community Manager for Health Initiatives; Annette Patterson, MS, CGC, Cancer Genetics Counselor; Jan Tichenor, RN, MSN, CNS, OCN, Breast/Gynecologic Oncology Navigator; Thomas Heffernan, MD, Gynecology/Oncology; Leslie Woodruff, Cancer Resource Center Coordinator; Wanda Strange, RN, OCN, Oncology Navigator; Faye Fowler, ACS Cancer Resource Center volunteer; June Brookshire, MS, LPC, Gynecologic Oncology Support Group Facilitator.

omprehensive cancer resource centers provide a supportive environment in which patients can obtain accurate, current information about their specific type of cancer and become active partners in their healthcare. Access to up-to-date information can play a significant role in helping patients and their family members cope effectively with the complexities of cancer. Knowledge empowers patients in terms of adjustment to their cancer, participat-

Continued on page 28

Can Safe Practices Be Contagious? By Shannon Hazen, RN, BSN, OCN Regional Oncology Education Coordinator, Presbyterian Cancer Center, Charlotte, North Carolina

recent study, published in August 2011 by Friese and colleagues, correlates the incidence of accidental chemotherapy exposure in outpatient infusion centers to several factors.1 Appearing first online in BMJ Quality and Safety, the article discusses staffing and resource availability, as well as adherence to safety practice standards and their contribution to higher chemotherapy expo-

sure event reporting. In summary, when the nurses sampled reported adequate staffing and resource availability, the reported incidence of accidental exposure to chemotherapy was lower. Similarly, when sampled nurses reported performing a 2-nurse check of chemotherapy doses frequently or very frequently, the reported rate of accidental exposure was also lower. Continued on page 8

CONFERENCE NEWS: SABCS AND ASH

Gene Array Test for Predicting Recurrence Risk in DCIS

INSIDE Genetic counselinG

By Alice Goodman

he Oncotype DX breast cancer assay for ductal carcinoma in situ (DCIS) is a strong and significant predictor of 10-year risk of recurrence in women with DCIS, according to a study presented at the CTRC-AACR San Antonio Breast Cancer Symposium (SABCS) held in December 2011. It is the first clinically validated genomic assay to predict risk

of local recurrence for women with DCIS, and it is now available from Genomic Health. The assay utilizes a panel of 12 genes to predict the risk of local recurrence with DCIS and invasive breast cancer over the next 10 years. The score derived from the assay will be useful for guiding decision making in women with

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Colorectal Cancer Survivors— Consider Inherited Polyposis Syndromes PHARMAcoeconoMics

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Should Everyone Be Required to Have Health Insurance? BReAst cAnceR

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Eribulin Associated With Less Neuropathy Than Ixabepilone in a Prospective, Randomized Study

Highest Risk of Discontinuing Endocrine Therapy Found Among Women With Symptoms From Previous Chemotherapy or Radiation for Breast Cancer .....

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nutRition WitH KARen

Warm and Hearty Lentils MultiPle MyeloMA

The Health Burden of Multiple Myeloma

TON_February2011_v9_TON 2/15/12 1:13 PM Page 2

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BRIEF SUMMARY CONSULT PACKAGE INSERT FOR FULL PRESCRIBING INFORMATION

HIGHLIGHTS OF PRESCRIBING INFORMATION These highlights do not include all the information needed to use Docetaxel Injection safely and effectively. See full prescribing information for Docetaxel.

HIGHLIGHTS OF PRESCRIBING INFORMATION These highlights do not include all the information needed to use Gemcitabine Injection safely and effectively. See full prescribing information for Gemcitabine Injection.

HIGHLIGHTS OF PRESCRIBING INFORMATION These highlights do not include all the information needed to use Topotecan Injection safely and effectively. See full prescribing information for Topotecan Injection.

Docetaxel Injection

Gemcitabine Injection

Topotecan Injection

For intravenous infusion only. Initial U.S. Approval: 1996

For Intravenous Infusion Only. Must Be Diluted Before Use. Initial U.S. Approval: 1996

Must be diluted before intravenous infusion Initial U.S. Approval: 1996

•

• •

WARNING: TOXIC DEATHS, HEPATOTOXICITY, NEUTROPENIA, HYPERSENSITIVITY REACTIONS, and FLUID RETENTION See full prescribing information for complete boxed warning Treatment-related mortality increases with abnormal liver function, at higher doses, and in patients with NSCLC and prior platinum-based therapy receiving docetaxel at 100 mg/m2 (5.1) Should not be given if bilirubin > ULN, or if AST and/or ALT > 1.5 x ULN concomitant with alkaline phosphatase > 2.5 x ULN. LFT elevations increase risk of severe or life-threatening complications. Obtain LFTs before each treatment cycle (8.6) Should not be given if neutrophil counts are < 1500 cells/mm3. Obtain frequent blood counts to monitor for neutropenia (4) Severe hypersensitivity, including very rare fatal anaphylaxis, has been reported in patients who received dexamethasone premedication. Severe reactions require immediate discontinuation of Docetaxel Injection and administration of appropriate therapy (5.4) Contraindicated if history of severe hypersensitivity reactions to docetaxel or to drugs formulated with polysorbate 80 (4) Severe fluid retention may occur despite dexamethasone (5.5)

CONTRAINDICATIONS • Hypersensitivity to docetaxel or polysorbate 80 (4) • Neutrophil counts of <1500 cells/mm3 (4) WARNINGS AND PRECAUTIONS • Acute myeloid leukemia: In patients who received docetaxel doxorubicin and cyclophosphamide, monitor for delayed myelodysplasia or myeloid leukemia (5.6) • Cutaneous reactions: Reactions including erythema of the extremities with edema followed by desquamation may occur. Severe skin toxicity may require dose adjustment (5.7) • Neurologic reactions: Reactions including. paresthesia, dysesthesia, and pain may occur. Severe neurosensory symptoms require dose adjustment or discontinuation if persistent. (5.8) • Asthenia: Severe asthenia may occur and may require treatment discontinuation. (5.9) • Pregnancy: Fetal harm can occur when administered to a pregnant woman. Women of childbearing potential should be advised not to become pregnant when receiving Docetaxel Injection (5.10, 8.1) ADVERSE REACTIONS Most common adverse reactions across all docetaxel indications are infections, neutropenia, anemia, febrile neutropenia, hypersensitivity, thrombocytopenia, neuropathy, dysgeusia, dyspnea, constipation, anorexia, nail disorders, fluid retention, asthenia, pain, nausea, diarrhea, vomiting, mucositis, alopecia, skin reactions, myalgia (6) To report SUSPECTED ADVERSE REACTIONS, contact Hospira, Inc. at 1-800-441-4100 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch

INDICATIONS AND USAGE Gemcitabine is a nucleoside metabolic inhibitor indicated for: • Ovarian cancer in combination with carboplatin (1.1) • Breast cancer in combination with paclitaxel (1.2) • Non-small cell lung cancer in combination with cisplatin (1.3) • Pancreatic cancer as a single-agent (1.4) DOSAGE AND ADMINISTRATION Gemcitabine Injection is for intravenous use only. • Ovarian cancer: 1000 mg/m2 over 30 minutes on Days 1 and 8 of each 21-day cycle (2.1) • Breast cancer: 1250 mg/m2 over 30 minutes on Days 1 and 8 of each 21-day cycle (2.2) • Non-small cell lung cancer: 4-week schedule, 1000 mg/m2 over 30 minutes on Days 1, 8, and 15 of each 28-day cycle: 3-week schedule; 1250 mg/m2 over 30 minutes on Days 1 and 8 of each 21-day cycle (2.3) • Pancreatic cancer: 1000 mg/m2 over 30 minutes once weekly for up to 7 weeks (or until toxicity necessitates reducing or holding a dose), followed by a week of rest from treatment. Subsequent cycles should consist of infusions once weekly for 3 consecutive weeks out of every 4 weeks (2.4) • Dose Reductions or discontinuation may be needed based on toxicities (2.1-2.4) DOSAGE FORMS AND STRENGTHS • 200 mg/5.26 mL injection vial (3) • 1 g/26.3 mL injection vial (3) • 2 g/52.6 mL injection vial (3) CONTRAINDICATIONS Patients with a known hypersensitivity to gemcitabine (4) WARNINGS AND PRECAUTIONS • Infusion time and dose frequency: Increased toxicity with infusion time >60 minutes or dosing more frequently than once weekly. (5.1) • Hematology: Monitor for myelosuppression, which can be dose-limiting. (5.2, 5.7) • Pulmonary toxicity: Discontinue Gemcitabine Injection immediately for severe pulmonary toxicity. (5.3) • Renal: Monitor renal function prior to initiation of therapy and periodically thereafter. Use with caution in patients with renal impairment. Cases of hemolytic uremic syndrome (HUS) and/or renal failure, some fatal, have occurred. Discontinue Gemcitabine Injection for HUS or severe renal toxicity. (5.4) • Hepatic: Monitor hepatic function prior to initiation of therapy and periodically thereafter. Use with caution in patients with hepatic impairment. Serious hepatotoxicity, including liver failure and death, have occurred. Discontinue Gemcitabine Injection for severe hepatic toxicity. (5.5) • Pregnancy: Can cause fetal harm. Advise women of potential risk to the fetus. (5.6, 8.1)

WARNING: BONE MARROW SUPPRESSION See full prescribing information for complete boxed warning. Do not give topotecan injection to patients with baseline neutrophil counts of less than 1,500 cells/mm3. In order to monitor the occurrence of bone marroww suppression, primarily neutropenia, which may be severe and result in infection and death, monitor peripheral blood cell counts frequently on all patients receiving topotecan injection. (5.1) CONTRAINDICATIONS • History of severe hypersensitivity reactions (e.g. anaphylactoid reactions) to topotecan or any of its ingredients (4) • Severe bone marrow depression (4) WARNINGS AND PRECAUTIONS • Bone marrow suppression. Administer topotecan injection only to patients with adequate bone marrow reserves. Monitor peripheral blood counts and adjust the dose if needed. (5.1) • Topotecan-induced neutropenia can lead to neutropenic colitis. (5.2) • Interstitial lung disease: Topotecan has been associated with reports of interstitial lung disease. Monitor patients for symptoms and discontinue Topotecan Injection if the diagnosis is confirmed. (5.3) • Pregnancy: Can cause fetal harm. Advise women of potential risk to the fetus. (5.4, 8.1) ADVERSE REACTIONS Small cell lung cancer: • The most common hematologic adverse reactions were: neutropenia (97%), leukopenia (97%), anemia (89%), and thrombocytopenia (69%). (6.1) • The most common (>25%) non-hematologic adverse reactions (all grades) were: nausea, alopecia, vomiting, sepsis or pyrexia/infection with neutropenia, diarrhea, constipation, fatigue, and pyrexia. (6.1) To report SUSPECTED ADVERSE REACTIONS, contact Hospira, Inc. at 1-800-441-4100 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch.

• Radiation toxicity. May cause severe and life-threatening toxicity. (5.8) ADVERSE REACTIONS The most common adverse reactions for the single-agent (≥20%) are nausea and vomiting, anemia, ALT, AST, neutropenia, leukopenia, alkaline phosphatase, proteinuria, fever, hematuria, rash, thrombocytopenia, dyspnea (6.1) To report SUSPECTED ADVERSE REACTIONS, contact Hospira, Inc. at 1-800-441-4100 or electronically at ProductComplaintsPP@hospira.com, or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch. See 17 for PATIENT COUNSELING INFORMATION Revised: 07/2011

Manufactured by: Hospira Australia Pty., Ltd., Mulgrave, Australia Manufactured by: Zydus Hospira Oncology Private Ltd., Gujarat, India Distributed by: Hospira, Inc., Lake Forest, IL 60045 USA GUJ DRUGS/G/28/1267

Manufactured by: Hospira Australia Pty Ltd Mulgrave VIC 3170 Australia Manufactured for: Hospira, Inc. Lake Forest, IL 60045 USA Product of Australia

Manufactured and Distributed by: Hospira, Inc. Lake Forest, IL 60045 USA Made in India

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Editorial Board EDITOR-IN-CHIEF

Cassandra J. Hammond, RN,

Melinda Oberleitner, RN,

Karla Wilson, RN,

MSN, CRNP

DNS, APRN, CNS

Avid Education Partners, LLC Sharpsburg, MD

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

City of Hope National Medical Center Duarte, CA

Elizabeth Bilotti,

Shannon Hazen,

Jayshree Shah, NP

RN, MSN, APRN, BC, OCN

RN, BSN, OCN

John Theurer Cancer Center Hackensack University Medical Center Hackensack, NJ

Beth Faiman, RN, MSN, APRN, BC, AOCN Cleveland Clinic Taussig Cancer Institute Cleveland, OH

John Theurer Cancer Center Hackensack University Medical Center Hackensack, NJ

Catherine Bishop, DNP, NP, AOCNP Virginia Cancer Care Lansdowne, VA

Novant Health Presbyterian Cancer Center Charlotte, NC

Patricia Irouer Hughes, RN, MSN, BSN, OCN Piedmont Healthcare Rex, GA

MSN, FNP-C, CPON

Pharmacy John F. Aforismo, BSc Pharm, RPh, FASCP

Gary Shelton,

RJ Health Systems International, LLC Wethersfield, CT

MSN, NP, ANP-BC, AOCNP NYU Clinical Cancer Center New York, NY

Nutrition Karen Connelly, RD, CSO

Deena Damsky Dell, MSN, RN-BC,

Taline Khoukaz,

Lori Stover, RN,

NP, MSN, ACNP-C

BSN

AOCN, LNC

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

Western Pennsylvania Cancer Institute Pittsburgh, PA

Wendy DiSalvo,

Sandra E. Kurtin,

DNP, APRN, AOCN

RN, MS, AOCN, ANP-C

Joseph D. Tariman, PhD,

Fox Chase Cancer Center Philadelphia, PA

Genentech New London, NH

Denice Economou, RN, MN, CNS, AOCN

APRN, BC

Arizona Cancer Center Tucson, AZ

Northwestern University Myeloma Program Chicago, IL

Ann McNeill,

Jacqueline Marie Toia, RN, MS, DNP

MSN, RN, NP-C, OCN

Northwestern University Myeloma Program Chicago, IL

Somerset Medical Center Somerville, NJ

Patient Advocate Peg Ford Ovarian Cancer Advocacy Alliance Coronado, CA

Social Work Carolyn Messner,

City of Hope National Medical Center Duarte, CA

John Theurer Cancer Center Hackensack University Medical Center Hackensack, NJ

Constance Engelking, RN,

Kena C. Miller,

MS, CNS, OCN

Roswell Park Cancer Institute Buffalo, NY

Saratoga, CA

Managed Care and Pharmaceutical Management Burt Zweigenhaft,

Amy Ford, RN,

Patricia Molinelli,

Connie Visovsky,

BSN, OCN

MS, RN, APN-C, AOCNS

RN, PhD, APRN

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

Innovex Dallas, TX

RN, MSN, FNP

Somerset Medical Center Somerville, NJ

DSW, MSW, LCSW-R, BCD CancerCare New York, NY

Pamela Hallquist Viale, RN, MS, CS, ANP, AOCN

University of South Florida College of Nursing Tampa, FL

BioPharma Partners LLC New York, NY

Isabell Castellano, RN Sharon S. Gentry, RN, MSN, AOCN Derrick L. Davis Forsyth Regional Cancer Center Winston-Salem, NC

February 2012 I VOL 5, NO 1

Dolores “Jeff” Nordquist, RN, MS,

Rita Wickham,

CS, FNP

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

Mayo Clinic Rochester, MN

PhD, RN, AOCN

Bristol-Myers Squibb Children’s Hospital Robert Wood Johnson University Hospital New Brunswick, NJ

Jeanne Westphal, RN Meeker County Memorial Hospital Litchfield, MN

www.TheOncologyNurse.com

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From the Editor

elcome to the first issue of The Oncology NurseAPN/PA (TON) for 2012. This is an exciting time for TON as we are now publishing 11 issues a year, expanding from 8 issues a year. This gives us the opportunity to provide you with even more information to help you in your day-to-day practice. In this issue, we tell you some of Beth Faiman, RN, MSN, the news coming out of the San APRN, BC, AOCN Antonio Breast Cancer Symposium Editor-in-Chief and the American Society of Hematology annual meeting— news that keeps us informed about what is happening in oncology and how these developments will affect our

PUBLISHING STAFF Senior Vice President, Sales & Marketing Philip Pawelko phil@greenhillhc.com Publisher John W. Hennessy john@greenhillhc.com Editorial Director Kristin Siyahian kristin@greenhillhc.com Managing Editor Kristen Olafson kristen@greenhillhc.com Quality Control Director Barbara Marino Production Manager Stephanie Laudien Business Manager Blanche Marchitto blanche@greenhillhc.com

everyday practice. Shannon Hazen presents the thoughtprovoking idea that safe practices in chemotherapy-related treatment can be contagious, while Karen Connelly tells us how lentils, as part of a plant-based diet, may decrease the risk of developing some cancers and are part of dietary recommendations for survivors. Her hummus and salad recipes are sure to tempt us into making lentils a part of our regular diet. Cristi Radford’s Genetic Counseling column tells us about inherited polyposis syndrome and how this may relate to survivors of colorectal cancer. As always, I encourage you to visit our Web site, www.TheOncologyNurse.com. Please answer this month’s Reader Poll about the health insurance mandate issue and let us know how you feel. Be sure to tell us what topics you want to see covered in TON. We want to hear from you, and we appreciate your feedback. ●

Executive Administrator Andrea Boylston

Recent FDA Updates

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The Oncology Nurse®-APN/PA, ISSN 1944-9798 (print); ISSN 1944-9801 (online) is published 8 times a year by Green Hill Healthcare Communications, LLC, 241 Forsgate Drive, Suite 205C, Monroe Twp, NJ 08831. Telephone: 732.656.7935. Fax: 732.656.7938. Copyright ©2012 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, 241 Forsgate Drive, Suite 205C, Monroe Twp, NJ 08831. E-mail: kristin@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, 241 Forsgate Drive, Suite 205C, Monroe Twp, NJ 08831. 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 mention 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.

Vismodegib Capsule Approved for Metastatic Basal Cell Carcinoma The FDA approved Erivedge (vismodegib; Genentech) capsule for the treatment of adults with metastatic basal cell carcinoma, or with locally advanced basal cell carcinoma that has recurred after surgery or who are not candidates for surgery, and who are not candidates for radiation. Basal cell carcinoma is the most common type of skin cancer, and vismodegib is the first drug approved by the FDA for metastatic basal cell carcinoma. Vismodegib inhibits the hedgehog pathway, a channel used by cells to communicate. Malfunctions in the hedgehog pathway are thought to play a role in several types of cancer, and this pathway is a focus of research. The hedgehog pathway is crucial to embryonic development. The most common adverse reactions (≥10%) for vismodegib were muscle spasms, alopecia, dysgeusia, weight loss, fatigue, nausea, diarrhea, decreased appetite, constipation, arthralgias, vomiting, and ageusia. Three of 10 premenopausal women developed amenorrhea in clinical trials. Vismodegib approval carries a black box warning for the risk of fetal death or severe birth defects. Ingenol Mebutate Gel Approved for Actinic Keratosis Picato (ingenol mebutate; LEO Pharma) gel was approved in January by the FDA for the topical treatment of actinic keratosis (AK) on the face, scalp, trunk, and extremities. AK is a precancerous condition caused by cumulative sun exposure that has the potential to progress to squamous cell carcinoma, which is the second most common type of skin cancer. AK is a dry, scaly, rough-textured patch or lesion that forms on the outermost layer of the skin after cumulative exposure

to ultraviolet light, including sunlight. Ingenol mebutate 0.015% gel is used once daily on the face and scalp for 3 consecutive days, and ingenol mebutate 0.05% gel is used once daily on the trunk and extremities for 2 consecutive days. In four phase 3 clinical studies of more than 1000 patients with AK, a higher proportion of those treated with ingenol mebutate gel (n=503) saw complete clearance of AKs in the field of treatment compared with placebo (n=502). The most common adverse events were local skin reactions, including erythema, flaking/scaling, crusting, and swelling. Pain, pruritus, and infection at the application site, as well as periorbital edema and headache, were other adverse events that occurred in ≥2% of individuals treated with ingenol mebutate gel.

Bevacizumab Approval for Breast Cancer Revoked The FDA revoked approval of the breast cancer indication for Avastin (bevacizumab; Genentech), ruling that the drug has not been proved to be safe and effective for that use. Bevacizumab remains on the market as approved for use for certain types of other cancers, including colon, kidney, lung, and brain (glioblastoma multiforme) cancer. Bevacizumab had received accelerated approval for the breast cancer indication in 2008; however, the FDA’s Oncologic Drugs Advisory Committee later recommended this approval be withdrawn. Bevacizumab’s manufacturer filed an appeal, and the FDA held a 2-day public hearing on the issue in June 2011. The FDA issued the decision to revoke the breast cancer indication for bevacizumab on November 18, 2011. The Oncology Nurse-APN/PA will address the implications of the FDA’s decision in an upcoming issue. ●

Check out our user-friendly Web site www.TheOncologyNurse.com In addition to Web-only exclusives, news coverage, and journal articles, you’ll have the opportunity to participate in our current reader poll.

BPA Worldwide membership applied for April 2011.

February 2012 I VOL 5, NO 1

www.TheOncologyNurse.com

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SARCOMA: THE ONLY THING PROGRESSING IS THE DISEASE T H E 5- YEAR S UR VIVAL RATE I S 17 % F OR PATIENTS WITH M E TAS TATIC S OF T TISSUE SA RC OMA , Y E T S IG NIF ICANT THERA PEUTIC A D VA NCEM ENTS AR E LA GGING. 1

NEW TREATMENTS ARE URGENTLY NEEDED.

Reference: 1. National Cancer Institute. Surveillance Epidemiology and End Results. seer.cancer.gov/statfacts/html/soft.html. Accessed March 19, 2010.

Merck Oncology

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Best Practices Spotlight on Compassion Fatigue for Oncology Nurses Continued from cover Deborah Boyle, RN, told an audience of nurses and other members of the oncology clinical care team at a symposium called “New Perspectives in Oncology Practice” held in conjunction with The Chemotherapy Foundation Symposium. Boyle is an oncology nurse at the

University of California Irvine Medical Center’s Chao Family Comprehensive Cancer Center in Orange. She defined compassion fatigue as the cost of caring for others in emotional pain. Compassion fatigue is distinct from burnout, which is related to

experiences and stresses that come from the work environment. One of the problems Boyle sees is that nurses often “swallow” the pain they experience treating very sick and dying patients as part of their job and neglect to acknowledge their own emo-

©iStockphoto.com/melnichuk_ira

“Each time you heal someone, you give away a piece of yourself, till at some time you will require healing.” —Native American proverb

tional response, leading to the “wounded healer” phenomenon, she said. “It is unrealistic not to expect to develop compassion fatigue. Our capacity for compassion and empathy is a core ability to do our work and also is at the core of our ability to be wounded by our work,” she noted. Signs of compassion fatigue include depression, fatigue, labile emotions, difficulty accepting praise or negative feedback, lack of attention to self, impatience with family members, and frustrations in human encounters. “Our sorrow accumulates. We need to recognize compassion fatigue and institute a self-care regimen, taking advantage of resources that may be available,” she continued. These include employee assistance programs, counseling, brown bag lunches, psychiatry nurse specialist support groups, and collegial acknowledgment of what a difficult job it is to work with people who have cancer. Boyle suggested that end-of-life care be integrated into nursing school curricula, so that nurses can become skilled at taking care of dying patients. Quoting a Native American proverb, she ended by saying, “‘Each time you heal someone, you give away a piece of yourself, till at some time you will require healing.’ Please leave this conference with a commitment to yourself!” ●

Can Safe Practices Be Contagious? Continued from cover This information leads the authors to suggest that these 2 particular practice issues, if attended to, may actually “protect oncology nurses from harm” and leads this author to wonder: can safety practices be, at least to some degree, contagious? Can we hope that safety improvements in any aspect of practice may improve the safety culture of the work environment overall? This would be an exciting concept to clinicians who work to overcome obstacles to evidencebased practice changes, only to see little progress made over long periods. There may be progress in related aspects of practice that has not been correlated, and a thorough analysis of associated factors, as was done in this study, could help to validate those. Though the above study did not draw any specific conclusions outside of the mentioned results, evidence on how training and practice guideline adherence impact exposure rates would be interesting and could be helpful in encouraging healthcare facilities to standardize staff education and more closely track compliance with standards. Perhaps a nurse who is trained in the

February 2012 I VOL 5, NO 1

...it is exciting to believe that when barriers are removed, the overall safety culture of a department can be improved incrementally with each change.

standardized ONS Chemotherapy Biotherapy Provider course is more attentive to the technical aspects of drug administration that can lead to exposure, such as failure to wear proper personal protective equipment, and experiences fewer or no exposures. Maybe a nurse who is trained to always perform a 2-nurse check of chemotherapy doses, and always does so, will also be inclined to ensure she always uses 2 patient identifiers at the bedside, thereby reducing the risk of “wrong patient” errors. Will an outpatient clinic manager, who carefully monitors nurse-to-patient ratio and staffing adequacy, be more committed to

safe handling guidelines in his or her department and promote medical surveillance for staff? Considering that various barriers exist to making safety-related practice changes, it is exciting to believe that when barriers are removed, the overall safety culture of a department can be improved incrementally with each change. Further studies will be needed to support this idea, but as the focus narrows on patient safety, worker safety should be similarly prioritized and studied. Though safe practice recommendations have existed since the 1980s, there is little regulatory monitoring or enforcement of these standards,

and compliance varies widely in outpatient and office settings.2 Hopefully studies like Friese’s will further persuade organizations to take increased steps toward ensuring the safety of healthcare workers handling chemotherapy and other hazardous drugs. For clinicians like myself who champion safe, evidence-based chemotherapy practices, this is an exciting study. Unfortunately, it supports that nurses are still becoming exposed to chemotherapy in their work environment at alarming rates. It also demonstrates that there is something we can do about it! Oncology nurses and oncology administrators committed to the goal of improving the safety in their chemotherapy treatment areas may find even the small successes of their efforts to be contagious! ● References 1. Friese CR, Himes-Ferris L, Frasier MN, et al. Structures and processes of care in ambulatory oncology settings and nurse-reported exposure to chemotherapy [published online ahead of print August 26, 2011]. BMJ Qual Saf. 2. Martin S, Larson E. Chemotherapy-handling practices of outpatient and office-based oncology nurses. Oncol Nurs Forum. 2003;30:575-581.

www.TheOncologyNurse.com

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ADCETR ADCETRIS A TR RI is the fir RIS first fi rsst appr a approved oved CD30directed dir rect cted e antibodyantibody-drug y-drug -dr cconjugate onjugate (ADC)

Indicated for the treatment of: • Hodgkin lymphoma (HL) after failure of autologous stem cell transplant (ASCT)1 • HL in patients who are not ASCT candidates after failure of at least 2 multiagent chemotherapy regimens1 • Systemic anaplastic large cell lymphoma (sALCL) after failure of at least 1 multiagent chemotherapy regimen1 The indications for ADCETRIS are based on response rate. There are no data available demonstrating improvement in patient-reported outcomes or survival with ADCETRIS.1

A ther therapeutic apeutic alt alternative ernative ffor or rrelapsed elapsed patients

73% objective response rate (95% CI: 65%-83%) in HL1 86% objective response rate (95% CI: 77%-95%) in sALCL1 BOXED BO XED WARNING WARNING Progressive multifocal leukoencephalopathy (PML): JC virus infection resulting in PML and death can occur in patients receiving ADCETRIS.1

Contraindication Contr aindication Concomitant use of ADCETRIS and bleomycin is contraindicated due to pulmonary toxicity.1

Peripheral Peripheral neur neuropathy opathy ADCETRIS treatment causes a peripheral neuropathy that is predominantly sensory. Cases of peripheral motor neuropathy have also been reported. ADCETRIS-induced peripheral neuropathy is cumulative. Treating physicians should monitor patients for symptoms of neuropathy, such as hypoesthesia, hyperesthesia, paresthesia, discomfort, a burning sensation, neuropathic pain or weakness and institute dose modifications accordingly.1

Infusion rreactions eactions Infusion-related reactions, including anaphylaxis, have occurred with ADCETRIS. Monitor patients during infusion. If an infusion reaction occurs, the infusion should be interrupted and appropriate medical management instituted. If anaphylaxis occurs, the infusion should be immediately and permanently discontinued and appropriate medical management instituted.1

Please see Brief Summary of full Prescribing Information, including Boxed WARNING, on the last page of this ad. Please see full Prescribing Information at ADCETRIS.com.

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ADCETRIS CE CETRIS is an ADC designed esigned e g tto o ttarget arget ccells ellls 1 expressing e x essing xpr g CD30 CD C

Antibody The antibody, brentuximab, specific for CD301

Cytotoxic Cytotoxic agent

Linker Linker A synthetic protease-cleavable linker that covalently attaches MMAE to the CD30-directed antibody and releases the agent within the target cell1

The synthetic microtubuledisrupting agent, monomethyl auristatin E (MMAE, vedotin), that induces target cell death1

CD30 is prevalent in both HL and sALCL2 • Binding of ADCETRIS to CD30 on the cell surface initiates internalization of the ADC-CD30 complex1 • Inside the cell, MMAE is released via proteolytic cleavage1 • Binding of released MMAE to tubulin disrupts the microtubule network, inducing apoptotic cell death1

Single-agent ADCETRIS was evaluated in two pivotal, phase 2, open-label, single-arm, multicenter trials: • 102 patients with HL who relapsed after ASCT1

Neutropenia Neutr openia Monitor complete blood counts prior to each dose of ADCETRIS and consider more frequent monitoring for patients with Grade 3 or 4 neutropenia. If Grade 3 or 4 neutropenia develops, manage by dose delays, reductions or discontinuation. Prolonged (≥1 week) severe neutropenia can occur with ADCETRIS.1

• 58 patients with relapsed sALCL1

T Tumor umor llysis ysis syndr syndrome ome

ADCETRIS 1.8 mg/kg was administered intravenously over 30 minutes every 3 weeks.1

Patients with rapidly proliferating tumor and high tumor burden are at risk of tumor lysis syndrome and these patients should be monitored closely and appropriate measures taken.1

Assessment of efficacy included objective response rate (complete remission plus partial remission) and duration of response evaluated by an independent review facility based on measures defined in the 2007 Revised Response Criteria for Malignant Lymphoma (modified).1,3

Pr Progressive ogressive multif multifocal ocal leukoencephalopathy leukoencephalopathy (PML) JC virus infection resulting in PML and death has been reported in ADCETRIS-treated patients. In addition to ADCETRIS therapy, other possible contributory factors include prior therapies and underlying disease that may cause immunosuppression. Consider the diagnosis of PML in any patient presenting with new-onset signs and symptoms of central nervous system abnormalities. Evaluation of PML includes, but is not limited to, consultation with a neurologist, brain MRI, and lumbar puncture or brain biopsy. Hold ADCETRIS if PML is suspected and discontinue ADCETRIS if PML is confirmed.1

Please see Brief Summary of full Prescribing Information, including Boxed WARNING, on the last page of this ad. Please see full Prescribing Information at ADCETRIS.com.

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ADCETRIS induc induced ed ccomplete omplete and partial rremissions emissions in clinic clinical al trials1 Efficacy Effic acy in rrelapsed elapsed patients1 Relapsed HL

Relapsed sAL sALCL CL

(N = 102)

(N = 58)

Median treatment duration: 27 weeks

Median treatment duration: 24 weeks

Duration Duration of rresponse esponse in months

Response, % (95% CI)

Complete remission (CR) Partial remission (PR) Objective response rate (ORR)

Response, % (95% CI)

Median (95% CI)

Range

1.4-21.9+

20.5

(23-42)

(12.0-NE*)

3.5

(32-49)

(2.2-4.1)

6.7 (4.0-14.8)

Median (95% CI)

Range

0.7-15.9+

13.2

(44-70)

(10.8-NE*)

2.1

(18-41)

(1.3-5.7)

1.3-18.7

(65-83)

Duration of response in months

1.3-21.9+

0.1-15.8+

12.6

(77-95)

(5.7-NE*)

0.1-15.9+

*Not estimable. +Follow-up was ongoing at the time of data submission.

• ADCETRIS demonstrated efficacy in sALCL patients with poor prognosis1 – 72% of sALCL patients had anaplastic lymphoma kinase (ALK)-negative disease, which has a worse prognosis than ALK-positive disease1,4

Adverse Adv erse reactions reactions occurring occurring in ≥20% ≥20% of patients rregardless egardless of ccausality ausality1

Adverse Adverse Reaction

HL (N = 102)

sALCL sAL CL (N = 58)

% of patients

Any Gr Grade ade

Gr Grade ade 3

Gr Grade ade 4

Any Grade Grade

Gr Grade ade 3

Gr Grade ade 4

Neutropenia

Peripheral sensory neuropathy

Fatigue

Nausea

Anemia

Upper respiratory tract infection

Diarrhea

Pyrexia

Rash

Thrombocytopenia

Cough

Vomiting

• 21% of patients discontinued therapy due to treatment-emergent adverse reactions1

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Conti Continue Con nti ntinue tr treatment eatment atment ment until ttil a maximum of 16 6 cy cycles, cles, d di disease pr progression ogr og ession or o u un unacceptable unacceptable ttoxicity oxic icityy1 ose is 1.8 1 8 mg/k m g administered only as an IV infusion over Recommended dose 30 minutes every 3 weeks e ks1 • Patients who have exp xperienc en ed a prior infusion-related reaction should be premedicated for subsequent infusions1 • Complette blood counts o oun should be monitored prior to each dose of ADCETRIS1

Most PN was Grade 1 or 2—no Grade 4 PN events were observed1 • 54% of patients experienced peripheral neuropathy (PN) in the pivotal trials1 • Grade 3 PN (sensory) was reported by 8% and 10% of patients in the HL and sALCL trials, respectively1 – 8% discontinued due to peripheral sensory neuropathy1 • Grade 3 PN (motor) was reported by 4% and 3% of patients in the HL and sALCL trials, respectively1 – 3% discontinued due to peripheral motor neuropathy1

Monitor patients for PN and institute dose modification accordingly1 New or worsening Grade 2 or 3

Hold dose until PN improves to Grade 1 or baseline and then restart at 1.2 mg/kg

Grade 4

Discontinue ADCETRIS

Improvement or resolution of PN symptoms was observed in the majority of patients during follow-up1: • 49% had complete resolution • 51% had residual PN at time of last evaluation (31% partial improvement, 20% no improvement)

Neutropenia should be managed by dose delay and reduction1 Grade 3 or 4 Recurrent Grade 4 despite use of growth factors

Hold dose until resolution to baseline or Grade 2 or lower Consider growth factor support for subsequent cycles Discontinue or reduce dose to 1.2 mg/kg

Please see Brief Summary of full Prescribing Information, including Boxed WARNING, on adjacent page. Please see full Prescribing Information at ADCETRIS.com. REFERENCES: 1. ADCETRIS [Prescribing Information]. Bothell, WA: Seattle Genetics Inc; 2012. 2. Haluska FG, Brufsky AM, Canellos GP P. The cellular biology of the Reed-Sternberg cell. Blood. 1994;84(4):1005-1019. 3. Cheson BD, Pfistner B, Juweid ME, et al; International Harmonization Project on Lymphoma. ymp Revised response criteria for malignant lymphoma. J Clin Oncol. 2007;25(5):579-586. 4. Savage KJ, Harris NL, Vose JM, et al; International Peripheral T-Cell Lymphoma Project. ALK- anaplastic large-cell lymphoma is clinically and immunophenotypically different from both ALK+ ALCL and peripheral T-cell lymphoma, not otherwise specified: report from the International Peripheral T-Cell Lymphoma Project. Blood. 2008;111(12):5496-5504. US/BV/2011/0029b

855.4SEAGEN (855.473.2436) SeaGenSecure.com

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Noteworthy Numbers The leading cause of cancer death among men and women is lung cancer. According to the American Cancer Society (ACS), more people die of lung cancer than of breast, colon, and prostate cancers combined. Because this deadly disease affects so many Americans, let’s delve into these lung cancer–related statistics.

Lung cancer (both small cell and non–small cell) is the second most common cancer

in both men (after prostate cancer) and women (after breast cancer).

Brief Summary of Prescribing Information (see Package Insert for full Prescribing Information)

WARNING: PROGRESSIVE MULTIFOCAL LEUKOENCEPHALOPATHY (PML) JC virus infection resulting in PML and death can occur in patients receiving ADCETRIS. Indications and usage

Approximately 14% of all new cancers are lung cancers.

ADCETRIS was studied in 58 patients with sALCL in a single arm clinical trial in which the recommended starting dose and schedule was 1.8 mg/kg intravenously every 3 weeks. Median duration of treatment was 24 weeks (range, 3 to 56 weeks). The most common adverse reactions (≥20%), regardless of causality, were neutropenia, anemia, peripheral sensory neuropathy, fatigue, nausea, pyrexia, rash, diarrhea, and pain. The most common serious adverse reactions experienced by patients with sALCL were septic shock (3%), supraventricular arrhythmia (3%), pain in extremity (3%), and urinary tract infection (3%).

Drug interactions

These indications are based on response rate. There are no data available demonstrating improvement in patient reported outcomes or survival with ADCETRIS. ADCETRIS (brentuximab vedotin) is indicated for treatment of patients with Hodgkin lymphoma (HL) after failure of autologous stem cell transplant (ASCT) or after failure of at least two prior multi-agent chemotherapy regimens in patients who are not ASCT candidates. ADCETRIS is indicated for treatment of patients with systemic anaplastic large cell lymphoma (sALCL) after failure of at least one prior multi-agent chemotherapy regimen.

In vitro data indicate that monomethyl auristatin E (MMAE) is a substrate and an inhibitor of CYP3A4/5.

Contraindications

Co-administration of ADCETRIS did not affect exposure to midazolam, a CYP3A4 substrate. MMAE does not inhibit other CYP enzymes at relevant clinical concentrations. ADCETRIS is not expected to alter the exposure to drugs that are metabolized by CYP3A4 enzymes.

Pulmonary toxicity: Concomitant use of ADCETRIS and bleomycin is contraindicated due to pulmonary toxicity. In a clinical trial that studied ADCETRIS with bleomycin as part of a combination regimen, the rate of non-infectious pulmonary toxicity was higher than the historical incidence reported with ABVD (adriamycin, bleomycin, vinblastine, dacarbazine). Patients typically reported cough and dyspnea. Interstitial infiltration and/or inflammation were observed on radiographs and computed tomographic imaging of the chest. Most patients responded to corticosteroids.

Warnings and precautions Peripheral neuropathy ADCETRIS treatment causes a peripheral neuropathy that is predominantly sensory. Cases of peripheral motor neuropathy have also been reported. ADCETRIS-induced peripheral neuropathy is cumulative. In the HL and sALCL clinical trials, 54% of patients experienced any grade of neuropathy. Of these patients, 49% had complete resolution, 31% had partial improvement, and 20% had no improvement. Of the patients who reported neuropathy, 51% had residual neuropathy at the time of their last evaluation. Monitor patients for symptoms of neuropathy, such as hypoesthesia, hyperesthesia, paresthesia, discomfort, a burning sensation, neuropathic pain or weakness. Patients experiencing new or worsening peripheral neuropathy may require a delay, change in dose, or discontinuation of ADCETRIS.

Infusion reactions Infusion-related reactions, including anaphylaxis, have occurred with ADCETRIS. Monitor patients during infusion. If anaphylaxis occurs, immediately and permanently discontinue administration of ADCETRIS and administer appropriate medical therapy. If an infusion-related reaction occurs, the infusion should be interrupted and appropriate medical management instituted. Patients who have experienced a prior infusion-related reaction should be premedicated for subsequent infusions. Premedication may include acetaminophen, an antihistamine and a corticosteroid.

Neutropenia Complete blood counts should be monitored prior to each dose of ADCETRIS and more frequent monitoring should be considered for patients with Grade 3 or 4 neutropenia. Prolonged (≥1 week) severe neutropenia can occur with ADCETRIS. If Grade 3 or 4 neutropenia develops, manage by dose delays, reductions, or discontinuations.

Tumor lysis syndrome Tumor lysis syndrome may occur. Patients with rapidly proliferating tumor and high tumor burden may be at increased risk of tumor lysis syndrome. Monitor closely and take appropriate measures.

Progressive multifocal leukoencephalopathy JC virus infection resulting in PML and death has been reported in ADCETRIS-treated patients. In addition to ADCETRIS therapy, other possible contributory factors include prior therapies and underlying disease that may cause immunosuppression. Consider the diagnosis of PML in any patient presenting with new-onset signs and symptoms of central nervous system abnormalities. Evaluation of PML includes, but is not limited to, consultation with a neurologist, brain MRI, and lumbar puncture or brain biopsy. Hold ADCETRIS dosing for any suspected case of PML and discontinue ADCETRIS dosing if a diagnosis of PML is confirmed.

Stevens-Johnson syndrome

Effect of other drugs on ADCETRIS CYP3A4 Inhibitors/Inducers: MMAE is primarily metabolized by CYP3A. Co-administration of ADCETRIS with ketoconazole, a potent CYP3A4 inhibitor, increased exposure to MMAE by approximately 34%. Patients who are receiving strong CYP3A4 inhibitors concomitantly with ADCETRIS should be closely monitored for adverse reactions. Co-administration of ADCETRIS with rifampin, a potent CYP3A4 inducer, reduced exposure to MMAE by approximately 46%.

Effect of ADCETRIS on other drugs

Use in specific populations Pregnancy Pregnancy Category D. There are no adequate and well-controlled studies with ADCETRIS in pregnant women. However, based on its mechanism of action and findings in animals, ADCETRIS can cause fetal harm when administered to a pregnant woman. Brentuximab vedotin caused embryo-fetal toxicities in animals at maternal exposures that were similar to human exposures at the recommended doses for patients with HL and sALCL. If this drug is used during pregnancy, or if the patient becomes pregnant while receiving this drug, the patient should be apprised of the potential hazard to the fetus. In an embryo-fetal developmental study, pregnant rats received 2 intravenous doses of 0.3, 1, 3, or 10 mg/kg brentuximab vedotin during the period of organogenesis (once each on Pregnancy Days 6 and 13). Drug-induced embryo-fetal toxicities were seen mainly in animals treated with 3 and 10 mg/kg of the drug and included increased early resorption (≥99%), post-implantation loss (≥99%), decreased numbers of live fetuses, and external malformations (i.e., umbilical hernias and malrotated hindlimbs). Systemic exposure in animals at the brentuximab vedotin dose of 3 mg/kg is approximately the same exposure in patients with HL or sALCL who received the recommended dose of 1.8 mg/kg every three weeks.

Nursing mothers It is not known whether brentuximab vedotin 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 ADCETRIS a decision should be made whether to discontinue nursing or to discontinue the drug, taking into account the importance of the drug to the mother.

Pediatric use The safety and effectiveness of ADCETRIS have not been established in the pediatric population. Clinical trials of ADCETRIS included only 9 pediatric patients and this number is not sufficient to determine whether they respond differently than adult patients.

Geriatric use Clinical trials of ADCETRIS did not include sufficient numbers of patients aged 65 and over to determine whether they respond differently from younger patients. Safety and efficacy have not been established. The kidney is a route of excretion for MMAE. The influence of renal impairment on the pharmacokinetics of MMAE has not been determined.

Hepatic impairment The liver is a route of clearance for MMAE. The influence of hepatic impairment on the pharmacokinetics of MMAE has not been determined.

Overdosage There is no known antidote for overdosage of ADCETRIS. In case of overdosage, the patient should be closely monitored for adverse reactions, particularly neutropenia, and supportive treatment should be administered.

Dosage and administration

Use in pregnancy

The recommended dose is 1.8 mg/kg administered only as an intravenous infusion over 30 minutes every 3 weeks. The dose for patients weighing greater than 100 kg should be calculated based on a weight of 100 kg. Do not administer as an intravenous push or bolus. Continue treatment until a maximum of 16 cycles, disease progression or unacceptable toxicity.

Adverse reactions ADCETRIS was studied as monotherapy in 160 patients in two phase 2 trials. Across both trials, the most common adverse reactions (≥10%), regardless of causality, were neutropenia, anemia, thrombocytopenia, lymphadenopathy, peripheral sensory neuropathy, peripheral motor neuropathy, headache, dizziness, fatigue, pyrexia, chills, pain, edema peripheral, upper respiratory tract infection, nausea, diarrhea, abdominal pain, vomiting, constipation, rash, pruritus, alopecia, night sweats, dry skin, cough, dyspnea, oropharyngeal pain, arthralgia, myalgia, back pain, pain in extremity, muscle spasms, insomnia, anxiety, decreased appetite and weight decreased. ADCETRIS was studied in 102 patients with HL in a single arm clinical trial in which the recommended starting dose and schedule was 1.8 mg/kg intravenously every 3 weeks. Median duration of treatment was 27 weeks (range, 3 to 56 weeks). The most common adverse reactions (≥20%), regardless of causality, were neutropenia, peripheral sensory neuropathy, fatigue, upper respiratory tract infection, nausea, diarrhea, anemia, pyrexia, thrombocytopenia, rash, abdominal pain, cough, and vomiting. The most common serious adverse reactions experienced by patients with HL include peripheral motor neuropathy (4%), abdominal pain (3%), pulmonary embolism (2%), pneumonitis (2%), pneumothorax (2%), pyelonephritis (2%), and pyrexia (2%).

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226,160 ■ 116,470 in men ■ 109,690 in women • An estimated 160,340 deaths ■ 87,750 in men ■ 72,590 in women • Deaths will account for approximately 27% of all cancer deaths

Lung cancer occurs more often in older people. From 2004-2008, the average age at the time of lung cancer diagnosis was approximately 71 years; the percentage of patients diagnosed according to age was approximately: • 0.2% between 20 and 34 • 1.6% between 35 and 44 • 8.8% between 45 and 54 • 20.9% between 55 and 64 • 31.1% between 65 and 74 • 29.0% between 75 and 84 • 8.3% for 85+ years of age

Since 1994, death rates have declined consistently for men at a rate of about 3% each year. Currently, the risk of developing lung cancer during a man’s lifetime is about 1 in 13.

Renal impairment

Stevens-Johnson syndrome has been reported with ADCETRIS. If Stevens-Johnson syndrome occurs, discontinue ADCETRIS and administer appropriate medical therapy. There are no adequate and well-controlled studies of ADCETRIS in pregnant women. However, based on its mechanism of action and findings in animals, ADCETRIS can cause fetal harm when administered to a pregnant woman. Brentuximab vedotin caused embryo-fetal toxicities, including significantly decreased embryo viability and fetal malformations, in animals at maternal exposures that were similar to human exposures at the recommended doses for patients with HL and sALCL. If this drug is used during pregnancy, or if the patient becomes pregnant while receiving the drug, the patient should be apprised of the potential hazard to the fetus.

The ACS’s most recent estimates for lung cancer in the United States for 2012 include: • New diagnoses totaling

General dosing information

Dose modification Peripheral Neuropathy: Peripheral neuropathy should be managed using a combination of dose delay and reduction to 1.2 mg/kg. For new or worsening Grade 2 or 3 neuropathy, dosing should be held until neuropathy improves to Grade 1 or baseline and then restarted at 1.2 mg/kg. For Grade 4 peripheral neuropathy, ADCETRIS should be discontinued. Neutropenia: Neutropenia should be managed by dose delays and reductions. The dose of ADCETRIS should be held for Grade 3 or 4 neutropenia until resolution to baseline or Grade 2 or lower. Growth factor support should be considered for subsequent cycles in patients who experience Grade 3 or 4 neutropenia. In patients with recurrent Grade 4 neutropenia despite the use of growth factors, discontinuation or dose reduction of ADCETRIS to 1.2 mg/kg may be considered.

ADCETRIS, SeaGen Secure and their logos are trademarks and Seattle Genetics and are US registered trademarks of Seattle Genetics, Inc. © 2012 Seattle Genetics, Inc., Bothell, WA 98021 All rights reserved. Printed in USA

US/BVP/2011/0150

After increasing for several decades, the death rates for women with lung cancer have stabilized since 2003. Currently, the possibility of developing lung cancer is lower for women than men—about 1 in 16. The 1-year survival rate for all people diagnosed with lung cancer is 43%. Sources: www.cancer.org/Cancer/Lung Cancer-Non-SmallCell/DetailedGuide/ non-small-cell-lung-cancer-key-statis tics; www.cancer.net/patient/Cancer+ Types/Lung+Cancer?sectionTitle=Statisti cs; http://seer.cancer.gov/statfacts/html/ lungb.html.

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Genetic Counseling

Colorectal Cancer Survivors— Consider Inherited Polyposis Syndromes By Cristi Radford, MS, CGC Sarasota Memorial Health Care System, Sarasota, Florida

Case Mark is a 52-year-old male recently diagnosed with colorectal cancer (CRC). He has 2 children—a 25-yearold son and a 30-year-old daughter. Additionally, he has a 5-year-old grandson and 2 sisters in their late 40s. His father is aged 76, and his mother died at age 72 of metastatic breast cancer (diagnosed at age 70). He has 2 paternal aunts, 2 paternal uncles, and 3 maternal aunts. All of these individuals have children. Both his maternal and paternal grandparents were older than 75 when they died. No other malignancies are reported, and Mark is unaware of any risk-reducing surgeries, such as hysterectomies, in the family. He states his ethnic background is western European and denies consanguinity. Should genetic consultation be considered? What else would you want to know? Background The majority of CRC cases are sporadic and not associated with family history. An individual is considered average risk for developing CRC if he or she has no personal history of cancer, adenoma, or inflammatory bowel disease and a family history negative for CRC or cancers related to Lynch syndrome (cancers associated with Lynch syndrome include endometrial, ovarian, stomach, small intestine, hepatobiliary tract, upper urinary tract, brain, and sebaceous). However, up to 25% of CRC cases are associated with a family history, and approximately 5% of cases are linked to a hereditary CRC syndrome. According to the NCCN guidelines (2011),1 an individual should be evaluated for a CRC syndrome when he or she: • Meets the Revised Bethesda Guidelines (used to diagnose Lynch syndrome) • Meets the Amsterdam Criteria (used to diagnose Lynch syndrome) • Has greater than 10 cumulative adenomas in his or her lifetime • Has multiple gastrointestinal hamartomatous polyps or hyperplastic polyps • Is from a family with a known hereditary cancer syndrome associated with CRC Distinguishing among the different

February 2012 I VOL 5, NO 1

inherited CRC syndromes is important because each has its own inheritance pattern and cancer risks. Thus, medical management for the patient and at-risk family members varies significantly based on the syndrome. Among the inherited CRC syndromes are Lynch syndrome (also called hereditary nonpolyposis CRC syndrome), familial adenomatous polyposis (FAP), attenuated FAP (AFAP), MYH-associated polyposis (MAP), Peutz-Jeghers syndrome, juvenile polyposis syndrome, serrated polyposis/ hyperplastic polyposis syndrome, and PTEN hamartoma tumor syndrome.

MAP was first described in 2002. Individuals typically present between the ages of 40 and 60 years. The colonic burden is often similar to that of AFAP.

Knowledge Applied to Mark At first glance, Mark’s personal and family history is unremarkable. Mark has multiple family members, and the only reported cancer is his mother’s breast cancer at age 70. Breast cancer is not highly associated with Lynch syndrome. Based on these characteristics, a referral to genetics would not be indicated. However, you would also want to know if other family members had colonoscopies, as well as obtain more information about Mark’s personal history. Upon inquiry, you learn that Mark’s father had his first colonoscopy about 8 years ago and was told he didn’t need another one until age 78. Based on this information you can infer that it is unlikely Mark’s father had adenomatous colon polyps. Mark is not sure if other family members have had colonoscopies. Additionally, you learn Mark was diagnosed with colon cancer during his first routine screening colonoscopy, and 42 adenomatous polyps were removed. As Mark has had more than 10 adenomas in

his lifetime, you recognize he is a candidate for genetic services. Differentials Depending on age of onset and family history, an individual with 42 cumulative adenomatous polyps is at risk for FAP, AFAP, and MAP. All 3 syndromes are associated with adenomatous polyps and a high risk for CRC. FAP and AFAP are associated with mutations in the APC gene and are inherited in an autosomal dominant pattern, while MAP is associated with mutations in the MYH gene and is inherited in an autosomal recessive pattern. Additionally, approximately 30% of the time FAP/AFAP is caused by a new mutation. Thus, neither parent has FAP/AFAP; however, the patient’s children would be at risk for inheriting the mutation. The typical age of onset for adenomatous colonic polyps in FAP is between 7 and 36 years.2 The syndrome is characterized by hundreds to thousands of polyps. Without treatment, the risk for CRC is nearly 100%. A clinical diagnosis of FAP is made when an individual has >100 colorectal adenomatous polyps or <100 colorectal adenomatous polyps and a relative with FAP.3 It is important to note that >100 colonic polyps can also be associated with MAP or a syndrome yet to be identified. Sometimes polyps are also found in the small intestine and stomach. Other cancers associated with FAP confer a ≤2% lifetime risk and include papillary thyroid, pancreatic, gastric, hepatoblastoma, and medulloblastoma. Individuals with FAP may also have osteomas, supernumerary teeth, odontomas, congenital hypertrophy of the retinal pigment epithelium (CHRPE), desmoids, and epidermoid cysts. In the 1950s, Gardner and Richards proposed that the association of multiple colonic polyps with “soft tumors” was due to a single pleiotropic gene.4 As a result, the term “Gardner syndrome” is sometimes used to describe individuals with colonic polyps, osteomas, and soft tissue tumors. Testing for mutations in the APC gene became commercially available in the 1990s.

At present, there is no consensus on the criteria for a clinical diagnosis of AFAP.3 Individuals with AFAP typically have <100 cumulative adenomatous polyps and/or present at a later age. Additionally, the polyps tend to be right-sided. The lifetime risk for CRC is estimated to be 70%.5 Similar to FAP, individuals are at risk for thyroid cancer and other upper gastrointestinal findings. However, unlike classical FAP, other extracolonic findings such as desmoid tumors and CHRPEs are rare. Genotype-phenotype correlations do exist. Therefore, molecular testing can sometimes help distinguish between AFAP and FAP. For example, mutations in the 5-prime and 3-prime section of the APC gene tend to be associated with AFAP. MAP was first described in 2002.6 Individuals typically present between the ages of 40 and 60 years. The colonic burden is often similar to that of AFAP. However, individuals with MAP have also been found to have few colonic polyps. Some authors suggest that relying solely on colonic burden to diagnose MAP will miss cases and propose that testing should also be considered in individuals with early-onset CRC whose tumors do not exhibit microsatellite instability and/or an autosomal recessive inheritance pattern.7,8 Duodenal adenomas are uncommon. As MAP is a relatively new syndrome, clinical data are limited. Therefore, the absolute risk for CRC and medical management for adenomas are not well characterized. Medical management tends to be similar to that for AFAP unless duodenal adenomatous polyps are identified. The Importance of Genetic Diagnosis for Mark As Mark presented at age 52 with CRC and 42 adenomas, the most likely differentials are AFAP or MAP. Since his family history is negative for CRC and colonic polyps, either syndrome is possible. Approximately 30% of the time an individual with an APC mutation is the first in the family to have the syndrome. Therefore, a family history is often not present. Similarly, as MAP is autosomal recessive, a family history is

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Genetic Counseling also rarely seen. A molecular diagnosis can help determine risk to family members. If the diagnosis is AFAP, Markâ&#x20AC;&#x2122;s children would have a 50% chance of carrying the same mutation. The risk to his sisters and other family members would depend on whether either of his parents carried the APC mutation. If the diagnosis is MAP, all of his children would be carriers, and their risk of having MAP would depend on maternal family history. However, Markâ&#x20AC;&#x2122;s sisters would have a 25% chance of having the syndrome. Determining the syndrome is also important for Markâ&#x20AC;&#x2122;s medical management. If Mark has AFAP, he would need annual thyroid examinations and a baseline upper endoscopy. The frequency of upper endoscopy would depend on whether polyposis was present. If Mark has MAP, upper endoscopy and side-viewing duodenoscopy would be recommended every 3 to 5 years.1 For either AFAP or MAP, medical management for colonic polyps would depend on the surgery pursued based on the location and prognosis of his CRC. However, if Mark did not have a diagnosis of CRC, medical management

Identifying the syndrome can help determine the most appropriate screening and surgical options for the patient and his or her at-risk family members.

syndromes include having more than 10 adenomas in a lifetime or a history of a hamartomatous polyp. Additionally, individuals with a family member known to have a hereditary cancer syndrome should be referred â&#x20AC;˘ As FAP, AFAP, and MAP have overlapping phenotypes, genetic testing may be useful in clarifying the syndrome. Identifying the syndrome can help determine the most appropriate screening and surgical options for the patient and his or her at-risk family members. Additionally, since the inheritance patterns differ, it will help determine which family members need presymptomatic genetic testing â&#x20AC;˘ Keep in mind that because of a

would depend on whether the adenoma burden was manageable by colonoscopy and polypectomy. If it wasnâ&#x20AC;&#x2122;t, then riskreducing surgery for prevention of CRC would be considered. In the case of AFAP, colectomy and ileorectal anastomosis is often the surgery of choice, followed by endoscopic evaluation of the rectum every 6 to 12 months. With MAP, the typical choice is subtotal colectomy or proctocolectomy.1 However, because of limited data on MAP, the roles of surgery and endoscopically manageable adenomas are not clearly defined. Take-Home Messages â&#x20AC;˘ When assessing a CRC survivor for referral to genetics, consider his or her history of colonic polyps. Indicators for referral for polyposis

30% de novo rate for FAP/AFAP and the autosomal recessive inheritance pattern of MAP, a patient with a polyposis syndrome may not have a family history â&#x2014;? References 1. NCCN Guidelines Version 2.2011. Colorectal Cancer Screening. http://www.nccn.org/professionals/ physician_gls/f_guidelines.asp. Accessed January 16, 2012. 2. Petersen GM, Slack J, Nakamura Y. Screening guidelines and premorbid diagnosis of familial adenomatous polyposis using linkage. Gastroenterology. 1991;100: 1658-1664. 3. Jasperson KW, Burt RW; GeneReviews. APC-associated polyposis conditions. http://www.ncbi.nlm.nih.gov/ books/NBK1345/. Updated October 27, 2011. Accessed January 16, 2012. 4. Gardner EJ, Richards RC. Multiple cutaneous and subcutaneous lesions occurring simultaneously with hereditary polyposis and osteomatosis. Am J Hum Genet. 1953;5:139-147. 5. Neklason DW, Stevens J, Boucher KM, et al. American founder mutation for attenuated familial adenomatous polyposis. Clin Gastroenterol Hepatol. 2008;6:46-52. 6. Al-Tassan N, Chmiel NH, Maynard J, et al. Inherited variants of MYH associated with G:Câ&#x2020;&#x2019;T:A mutations in colorectal tumors. Nat Genet. 2002;30:227-232. 7. Wang L, Baudhuin LM, Boardman LA, et al. MYH mutations in patients with attenuated and classic polyposis and with young-onset colorectal cancer without polyps. Gastroenterology. 2004;127:9-16. 8. Jo WS, Bandipalliam P, Shannon KM, et al. Correlation of polyp number and family history of colon cancer with germline MYH mutations. Clin Gastroenterol Hepatol. 2005;10:1022-1028.

9th Annual

A Advanced dvanced P Practice ractice Oncology Oncology Providers Symposium: P roviders S ymposium: IINNOVATION N N O VAT I O N THROUGH T H R O U G H PRACTICE PRACTICE SUNDA AY Y â&#x20AC;&#x201C; WEDNESDA AY, Y, M A R C H 2 â&#x20AC;&#x201C; 4 , 2 0 1 2 H I LT O N

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This two and a half day conference aims to update advanced practice providers on a wide variety of topics affecting practice today. The 2012 program will delve into the genetics and genomics of cancer, managing chemotherapy-induced side ef fects, fer tility preser vation, complementar y and alter native therapies, and developing sur vivorship and end-of-life care plans. The conference is designed to provide per tinent educational sessions along with ample networking oppor tunities for attendees. Conference Highlights s Comprehensive presentations of the latest advances in cancer diagnosis and treatment with a strong patient care focus s Small group workshops allowing for additional interaction with expert faculty on pertinent topics s Audience Response System used for instant feedback and interactive learning s Multiple networking and one-on-one discussion opportunities throughout the course sent to all attendees 6-8 weeks after the conference s USB drive containing synchronized audio and final presentations sent California Board of Registered Nursing, American Academy of Nurse Practitioners and American Academy of Physician Assistant CE credits available!

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February 2012 I VOL 5, NO 1

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New Data: 5-Year Median Follow-up

In combination with MP* vs MP alone for previously untreated multiple myeloma

VELCADE DELIVERED 13-MONTH OVERALL SURVIVAL ADVANTAGE At 3-Year Median Follow-up, VELCADE® (bortezomib)+MP Provided an OS Advantage Over MP That Was Not Regained With Subsequent Therapies ▼ Of the 69% of MP patients who received subsequent therapies, 50% received VELCADE or a VELCADE-containing regimen1

VELCADE is indicated for the treatment of patients with multiple myeloma. VELCADE is contraindicated in patients with hypersensitivity to bortezomib, boron, or mannitol. For Patient Assistance Information or Reimbursement Assistance, call 1-866-VELCADE (835-2233), Option 2, or visit VELCADE.com *Melphalan+prednisone. †

VISTA: a randomized, open-label, international phase 3 trial (N=682) evaluating the efficacy and safety of VELCADE in combination with MP vs MP in previously untreated multiple myeloma. The primary endpoint was TTP. Secondary endpoints were CR, ORR, PFS, and OS. At a pre-specified interim analysis (median follow-up 16.3 months), VcMP‡ resulted in significantly superior results for TTP, PFS, OS, and ORR. Further enrollment was halted and patients receiving MP were offered VELCADE in addition.

‡

VELCADE (Vc) in combination with MP.

Reference: 1. 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(13):2259-2266.

003448 milpro 5yr ton fa2 indd 1

TON_February2011_v9_TON 2/15/12 11:44 AM Page 17

UPDATED VISTA† TRIAL ANALYSIS (60.1-MONTH MEDIAN FOLLOW-UP) 100 90

Median overall survival:

56.4 vs 43.1 months

Patients Surviving (%)

HR=0.695 (95% CI, 0.57-0.85); P<0.05 70 60 50 40 30 20

VELCADE+MP (n=344)

MP (n=338)

0 0

Kaplan-Meier estimate.

Months

IMPORTANT SAFETY INFORMATION VELCADE Warnings and Precautions

Adverse Reactions

▼ Women should avoid becoming pregnant while being treated with VELCADE. Pregnant women should be apprised of the potential harm to the fetus ▼ Peripheral neuropathy, including severe cases, may occur— manage with dose modification or discontinuation. Patients with pre-existing severe neuropathy should be treated with VELCADE only after careful risk-benefit assessment ▼ Hypotension can occur. Caution should be used when treating patients receiving antihypertensives, those with a history of syncope, and those who are dehydrated ▼ Patients with risk factors for, or existing heart disease, should be closely monitored ▼ Acute diffuse infiltrative pulmonary disease has been reported ▼ Nausea, diarrhea, constipation, and vomiting have occurred and may require use of antiemetic and antidiarrheal medications or fluid replacement ▼ Thrombocytopenia or neutropenia can occur; complete blood counts should be regularly monitored throughout treatment ▼ Tumor Lysis Syndrome, Reversible Posterior Leukoencephalopathy Syndrome, and Acute Hepatic Failure have been reported

Most commonly reported adverse reactions (incidence ≥30%) in clinical studies include asthenic conditions, diarrhea, nausea, constipation, peripheral neuropathy, vomiting, pyrexia, thrombocytopenia, psychiatric disorders, anorexia and decreased appetite, neutropenia, neuralgia, leukopenia, and anemia. Other adverse reactions, including serious adverse reactions, have been reported Please see Brief Summary for VELCADE on next page.

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Conference News: SABCS and ASH The following articles are based on presentations at the CTRC-AACR SABCS held December 6-10, 2011, in San Antonio, Texas, and the 53rd Annual ASH Meeting held December 10-13, 2011, in San Diego, California.

Gene Array Test for Predicting... Continued from cover DCIS treated with local excision with or without adjuvant hormonal therapy. The score can identify low-risk patients who can forgo further treatment, as

well as high-risk patients who require more aggressive therapy; it can also identify intermediate-risk patients, who comprise a small but challenging

group for treatment decisions. Some insurance plans cover the DCIS assay, and Genomic Health has an assistance program to help patients gain reim-

Brief Summary INDICATIONS:

ADVERSE EVENT DATA:

VELCADE® (bortezomib) for Injection is indicated for the treatment of patients with multiple myeloma. VELCADE® (bortezomib) for Injection is indicated for the treatment of patients with mantle cell lymphoma who have received at least 1 prior therapy.

Safety data from phase 2 and 3 studies of single-agent VELCADE 1.3 mg/m2/dose twice weekly for 2 weeks followed by a 10-day rest period in 1163 patients with previously treated multiple myeloma (N=1008, not including the phase 3, VELCADE plus DOXIL® [doxorubicin HCI liposome injection] study) and previously treated mantle cell lymphoma (N=155) were integrated and tabulated. In these studies, the safety profile of VELCADE was similar in patients with multiple myeloma and mantle cell lymphoma.

CONTRAINDICATIONS: VELCADE is contraindicated in patients with hypersensitivity to bortezomib, boron, or mannitol. WARNINGS AND PRECAUTIONS: VELCADE should be administered under the supervision of a physician experienced in the use of antineoplastic therapy. Complete blood counts (CBC) should be monitored frequently during treatment with VELCADE. Peripheral Neuropathy:: VELCADE treatment causes a peripheral neuropathy that is predominantly sensory. However, cases of severe sensory and motor peripheral neuropathy have been reported. Patients with pre-existing symptoms (numbness, pain or a burning feeling in the feet or hands) and/or signs of peripheral neuropathy may experience worsening peripheral neuropathy (including ≥Grade 3) during treatment with VELCADE. Patients should be monitored for symptoms of neuropathy, such as a burning sensation, hyperesthesia, hypoesthesia, paresthesia, discomfort, neuropathic pain or weakness. Patients experiencing new or worsening peripheral neuropathy may require change in the dose and schedule of VELCADE. Following dose adjustments, improvement in or resolution of peripheral neuropathy was reported in 51% of patients with ≥Grade 2 peripheral neuropathy in the relapsed multiple myeloma study. Improvement in or resolution of peripheral neuropathy was reported in 73% of patients who discontinued due to Grade 2 neuropathy or who had ≥Grade 3 peripheral neuropathy in the phase 2 multiple myeloma studies. The long-term outcome of peripheral neuropathy has not been studied in mantle cell lymphoma. Hypotension:: The incidence of hypotension (postural, orthostatic, and hypotension NOS) was 13%. These events are observed throughout therapy. Caution should be used when treating patients with a history of syncope, patients receiving medications known to be associated with hypotension, and patients who are dehydrated. Management of orthostatic/postural hypotension may include adjustment of antihypertensive medications, hydration, and administration of mineralocorticoids and/or sympathomimetics. Cardiac Disorders:: Acute development or exacerbation of congestive heart failure and new onset of decreased left ventricular ejection fraction have been reported, including reports in patients with no risk factors for decreased left ventricular ejection fraction. Patients with risk factors for, or existing heart disease should be closely monitored. In the relapsed multiple myeloma study, the incidence of any treatmentemergent cardiac disorder was 15% and 13% in the VELCADE and dexamethasone groups, respectively. The incidence of heart failure events (acute pulmonary edema, cardiac failure, congestive cardiac failure, cardiogenic shock, pulmonary edema) was similar in the VELCADE and dexamethasone groups, 5% and 4%, respectively. There have been isolated cases of QT-interval prolongation in clinical studies; causality has not been established. Pulmonary Disorders:: There have been reports of acute diffuse infiltrative pulmonary disease of unknown etiology such as pneumonitis, interstitial pneumonia, lung infiltration and Acute Respiratory Distress Syndrome (ARDS) in patients receiving VELCADE. Some of these events have been fatal. In a clinical trial, the first two patients given high-dose cytarabine (2 g/m2 per day) by continuous infusion with daunorubicin and VELCADE for relapsed acute myelogenous leukemia died of ARDS early in the course of therapy. There have been reports of pulmonary hypertension associated with VELCADE administration in the absence of left heart failure or significant pulmonary disease. In the event of new or worsening cardiopulmonary symptoms, a prompt comprehensive diagnostic evaluation should be conducted. Reversible Posterior Leukoencephalopathy Syndrome (RPLS):: There have been reports of RPLS in patients receiving VELCADE. RPLS is a rare, reversible, neurological disorder which can present with seizure, hypertension, headache, lethargy, confusion, blindness, and other visual and neurological disturbances. Brain imaging, preferably MRI (Magnetic Resonance Imaging), is used to confirm the diagnosis. In patients developing RPLS, discontinue VELCADE. The safety of reinitiating VELCADE therapy in patients previously experiencing RPLS is not known. Gastrointestinal Adverse Events:: VELCADE treatment can cause nausea, diarrhea, constipation, and vomiting sometimes requiring use of antiemetic and antidiarrheal medications. Ileus can occur. Fluid and electrolyte replacement should be administered to prevent dehydration. Thrombocytopenia/Neutropenia:: VELCADE is associated with thrombocytopenia and neutropenia that follow a cyclical pattern with nadirs occurring following the last dose of each cycle and typically recovering prior to initiation of the subsequent cycle. The cyclical pattern of platelet and neutrophil decreases and recovery remained consistent over the 8 cycles of twice weekly dosing, and there was no evidence of cumulative thrombocytopenia or neutropenia. The mean platelet count nadir measured was approximately 40% of baseline. The severity of thrombocytopenia was related to pretreatment platelet count. In the relapsed multiple myeloma study, the incidence of significant bleeding events (≥Grade 3) was similar on both the VELCADE (4%) and dexamethasone (5%) arms. Platelet counts should be monitored prior to each dose of VELCADE. Patients experiencing thrombocytopenia may require change in the dose and schedule of VELCADE. There have been reports of gastrointestinal and intracerebral hemorrhage in association with VELCADE. Transfusions may be considered. The incidence of febrile neutropenia was <1%. Tumor Lysis Syndrome:: Because VELCADE is a cytotoxic agent and can rapidly kill malignant cells, the complications of tumor lysis syndrome may occur. Patients at risk of tumor lysis syndrome are those with high tumor burden prior to treatment. These patients should be monitored closely and appropriate precautions taken.

In the integrated analysis, the most commonly reported adverse events were asthenic conditions (including fatigue, malaise, and weakness); (64%), nausea (55%), diarrhea (52%), constipation (41%), peripheral neuropathy NEC (including peripheral sensory neuropathy and peripheral neuropathy aggravated); (39%), thrombocytopenia and appetite decreased (including anorexia); (each 36%), pyrexia (34%), vomiting (33%), anemia (29%), edema (23%), headache, paresthesia and dysesthesia (each 22%), dyspnea (21%), cough and insomnia (each 20%), rash (18%), arthralgia (17%), neutropenia and dizziness (excluding vertigo); (each 17%), pain in limb and abdominal pain (each 15%), bone pain (14%), back pain and hypotension (each 13%), herpes zoster, nasopharyngitis, upper respiratory tract infection, myalgia and pneumonia (each 12%), muscle cramps (11%), and dehydration and anxiety (each 10%). Twenty percent (20%) of patients experienced at least 1 episode of ≥Grade 4 toxicity, most commonly thrombocytopenia (5%) and neutropenia (3%). A total of 50% of patients experienced serious adverse events (SAEs) during the studies. The most commonly reported SAEs included pneumonia (7%), pyrexia (6%), diarrhea (5%), vomiting (4%), and nausea, dehydration, dyspnea and thrombocytopenia (each 3%). In the phase 3 VELCADE + melphalan and prednisone study, the safety profile of VELCADE in combination with melphalan/prednisone is consistent with the known safety profiles of both VELCADE and melphalan/prednisone. The most commonly reported adverse events in this study (VELCADE+melphalan/ prednisone vs melphalan/prednisone) were thrombocytopenia (52% vs 47%), neutropenia (49% vs 46%), nausea (48% vs 28%), peripheral neuropathy (47% vs 5%), diarrhea (46% vs 17%), anemia (43% vs 55%), constipation (37% vs 16%), neuralgia (36% vs 1%), leukopenia (33% vs 30%), vomiting (33% vs 16%), pyrexia (29% vs 19%), fatigue (29% vs 26%), lymphopenia (24% vs 17%), anorexia (23% vs 10%), asthenia (21% vs 18%), cough (21% vs 13%), insomnia (20% vs 13%), edema peripheral (20% vs 10%), rash (19% vs 7%), back pain (17% vs 18%), pneumonia (16% vs 11%), dizziness (16% vs 11%), dyspnea (15% vs 13%), headache (14% vs 10%), pain in extremity (14% vs 9%), abdominal pain (14% vs 7%), paresthesia (13% vs 4%), herpes zoster (13% vs 4%), bronchitis (13% vs 8%), hypokalemia (13% vs 7%), hypertension (13% vs 7%), abdominal pain upper (12% vs 9%), hypotension (12% vs 3%), dyspepsia (11% vs 7%), nasopharyngitis (11% vs 8%), bone pain (11% vs 10%), arthralgia (11% vs 15%) and pruritus (10% vs 5%). DRUG INTERACTIONS: Bortezomib is a substrate of cytochrome P450 enzyme 3A4, 2C19 and 1A2. Co-administration of ketoconazole, a strong CYP3A4 inhibitor, increased the exposure of bortezomib by 35% in 12 patients. Therefore, patients should be closely monitored when given bortezomib in combination with strong CYP3A4 inhibitors (e.g. ketoconazole, ritonavir). Co-administration of omeprazole, a strong inhibitor of CYP2C19, had no effect on the exposure of bortezomib in 17 patients. Co-administration of rifampin, a strong CYP3A4 inducer, is expected to decrease the exposure of bortezomib by at least 45%. Because the drug interaction study (n=6) was not designed to exert the maximum effect of rifampin on bortezomib PK, decreases greater than 45% may occur. Efficacy may be reduced when VELCADE is used in combination with strong CYP3A4 inducers; therefore, concomitant use of strong CYP3A4 inducers is not recommended in patients receiving VELCADE. St. John’s Wort (Hypericum perforatum) m may decrease bortezomib exposure unpredictably and should be avoided. Co-administration of dexamethasone, a weak CYP3A4 inducer, had no effect on the exposure of bortezomib in 7 patients. Co-administration of melphalan-prednisone increased the exposure of bortezomib by 17% in 21 patients. However, this increase is unlikely to be clinically relevant. USE IN SPECIFIC POPULATIONS: Nursing Mothers:: It is not known whether bortezomib 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 VELCADE, a decision should be made whether to discontinue nursing or to discontinue the drug, taking into account the importance of the drug to the mother. Pediatric Use:: The safety and effectiveness of VELCADE in children has not been established. Geriatric Use:: No overall differences in safety or effectiveness were observed between patients ≥age 65 and younger patients receiving VELCADE; but greater sensitivity of some older individuals cannot be ruled out. Patients with Renal Impairment:: The pharmacokinetics of VELCADE are not influenced by the degree of renal impairment. Therefore, dosing adjustments of VELCADE are not necessary for patients with renal insufficiency. Since dialysis may reduce VELCADE concentrations, the drug should be administered after the dialysis procedure. For information concerning dosing of melphalan in patients with renal impairment, see manufacturer’s prescribing information. Patients with Hepatic Impairment:: The exposure of VELCADE is increased in patients with moderate and severe hepatic impairment. Starting dose should be reduced in those patients. Patients with Diabetes:: During clinical trials, hypoglycemia and hyperglycemia were reported in diabetic patients receiving oral hypoglycemics. Patients on oral antidiabetic agents receiving VELCADE treatment may require close monitoring of their blood glucose levels and adjustment of the dose of their antidiabetic medication.

Please see full Prescribing Information for VELCADE at VELCADE.com.

Hepatic Events:: Cases of acute liver failure have been reported in patients receiving multiple concomitant medications and with serious underlying medical conditions. Other reported hepatic events include increases in liver enzymes, hyperbilirubinemia, and hepatitis. Such changes may be reversible upon discontinuation of VELCADE. There is limited re-challenge information in these patients. Hepatic Impairment:: VELCADE is metabolized by liver enzymes. VELCADE exposure is increased in patients with moderate or severe hepatic impairment. These patients should be treated with VELCADE at reduced starting doses and closely monitored for toxicities. Use in Pregnancy: Pregnancy Category D. Women of childbearing potential should avoid becoming pregnant while being treated with VELCADE. Bortezomib administered to rabbits during organogenesis at a dose approximately 0.5 times the clinical dose of 1.3 mg/m2 based on body surface area caused post-implantation loss and a decreased number of live fetuses.

VELCADE, MILLENNIUM and are registered trademarks of Millennium Pharmaceuticals, Inc. Other trademarks are property of their respective owners. Millennium Pharmaceuticals, Inc., Cambridge, MA 02139 Copyright © 2011, Millennium Pharmaceuticals, Inc. All rights reserved. Printed in USA

V-11-0264

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bursement from plans that may not cover the test. “The DCIS score [derived from the multigene RT-PCR assay] can be used to quantify an individual patient’s 10-year risk of developing a recurrence. The score provides independent information on recurrence risk beyond clinical and pathological variables. We are not just reinventing the wheel here,” said lead author Lawrence J. Solin, MD, chair of radiation oncology at Einstein Medical Center in Philadelphia, Pennsylvania. The increased incidence of DCIS is attributed to increased use of screening mammography finding cancers at very early stages. The majority of patients diagnosed with DCIS will not have a recurrence. However, until now there has been no validated method to predict recurrence, so all patients with DCIS typically receive radiation and/or hormonal therapy if they are estrogen receptor positive.

The majority of patients diagnosed with DCIS will not experience a recurrence. The validation study presented at SABCS was based on paraffin-embedded tumor samples from 327 patients enrolled in ECOG 5194, a multi-institutional study of patients with low-, intermediate-, or high-grade DCIS who underwent breast conservation surgery with wide negative margins but did not receive radiation; treatment with tamoxifen was optional. The Oncotype DX DCIS multigene assay was used to classify patients as low, intermediate, or high risk according to prespecified characteristics. Solin noted that about 75% were low risk. The DCIS score was a significant and strong predictor of local recurrence (P = .02) and invasive local recurrence (P = .01) over a 10-year period. The cost of the DCIS test will be similar to that of the Oncotype DX 21-gene assay. Solin said the cost should be offset by the ability to avoid radiation and further treatment in low-risk DCIS. “Treatment selection is not clear for intermediate-risk patients, but this test allows us to provide information on their individual risk level. The numbers of patients in the intermediate-risk group are actually very small. Most patients with DCIS are low risk,” Solin said. ●

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Conference News: SABCS and ASH

Survivors With BRCA Mutations Are at Increased Risk of Contralateral Breast Cancer By Alice Goodman

RCA mutation carriers who have had breast cancer are at increased risk of developing contralateral breast cancer, according to a study presented at the 2011 CTRCAACR San Antonio Breast Cancer Symposium. In fact, women with a BRCA1 or BRCA2 mutation had a greater than 10% risk of developing contralateral breast cancer, and the risk was strongly associated with younger age at diagnosis and a diagnosis of triple-negative (estrogen receptor–negative, progesterone receptor–negative, and HER2negative) breast cancer. “As far as we know, this is the first study to show that subgroups of BRCA1 or BRCA2 carriers have an increased or decreased risk of contralateral breast cancer,” said Alexandra J. van den Broek, MSc, a doctoral candidate at the Netherlands Cancer Institute in Amsterdam.

Women with a BRCA1 or BRCA2 mutation had a greater than 10% risk of developing contralateral breast cancer, and the risk was strongly associated with younger age at diagnosis and a diagnosis of triple-negative breast cancer.

The study included 5061 women who were diagnosed with unilateral, invasive breast cancer at 10 different institutions in the Netherlands. Of these, 211 (4.2%) were carriers of the BRCA1 or BRCA2 mutation. At a median follow-up of 8.4 years, 8.6% of the women developed contralateral breast cancer. The overall 10-year risk for developing contralateral breast cancer was 6%

in noncarriers versus 17.9% in carriers. Among carriers who were diagnosed with their first breast cancer before age 40, the 10-year risk of developing contralateral breast cancer rose to 26%; carriers between the ages of 40 and 50 years at first diagnosis had a 10-year risk of 11.6%. Mutation carriers diagnosed at first with triple-negative breast cancer had a 10-year risk of

developing contralateral breast cancer that reached 18.9%, compared with 11.2% among carriers whose first cancer was not triple-negative. When asked whether knowing their risk of developing contralateral breast cancer might be overwhelming to carriers, who are already anxious over their mutational status, van den Broek said it is crucial to know who is at risk and by how much. In her view, these findings point to the importance of revisiting current guidelines for mutation carriers and incorporating risk factors such as younger age at first diagnosis of breast cancer and a diagnosis of triple-negative breast cancer when considering prophylactic measures and screening. “If these findings are confirmed, it will be possible to personalize the guidelines for these specific subgroups,” she stated. ●

New Look at Discontinued Drug in Older Patients With Acute Myeloid Leukemia

www.TheOncologyNurse.com

©iStockphoto.com/Gene Chutka

dministering gemtuzumab ozogamicin (GO) on a new schedule achieved impressive progression-free survival (PFS) and overall survival (OS) compared with standard chemotherapy in older patients with acute myeloid leukemia (AML) with favorable cytogenetics, according to a phase 3 study presented at the Plenary Session of the 53rd Annual Meeting of the American Society of Hematology (ASH). GO was taken off the market in 2010 due to toxicity concerns and is no longer available in the US. “Research has demonstrated that GO has very potent anti-cancer properties, and with this study, we have identified a dosing regimen that gives patients the therapeutic benefit of the drug without some of the toxicities reported at higher doses,” stated lead author Sylvie Castaigne, MD, professor, department of hematology at Hôpital de Versailles, Versailles, France. “The standard of care has been daunorubicin plus cytarabine for many years. There hasn’t been a new therapeutic option for several decades, and with this research we are encouraged that GO may be able to improve overall outcomes for these AML patients with limited alternatives.” GO is an anti-CD33 antibody conjugated with a toxin; the antibody

binds to the surface of CD33-positive leukemia cells and releases the toxin (ie, calicheamicin) into the leukemia cells. The antibody is specifically targeted to the leukemia cells and theoretically spares toxicity to other cells that do not express CD33. The phase 3, prospective, openlabel, randomized trial enrolled newly diagnosed de novo AML patients aged 50 to 70 years. The new 3,3,3 regimen

(ie, 3 mg/m2 GO IV on days 1, 4, 7) was designed to give lower but repeated doses that might enhance the efficacy of GO and minimize hepatic and hematologic toxicities reported earlier with this antibody. Patients (N = 280) were randomized to arm A (standard daunorubicin plus cytarabine) or arm B (the same chemotherapy plus the GO 3,3,3 regimen). Those who achieved remission on 2 cycles of treatment were further ran-

domized to 2 courses of consolidation therapy with the same treatments. The experimental arm extended event-free survival (EFS) by just under 8 months. At 2 years, median EFS was 11.9 months with standard therapy versus 19.6 months with the addition of GO, a result that was highly significant (P = .0018). The addition of GO also extended OS: median OS was 19.2 months with standard chemotherapy versus 34 months with chemotherapy plus GO (P = .046). Improvement in EFS and OS was observed in patients with favorable cytogenetics, but not in those with unfavorable cytogenetics, Castaigne emphasized. Fatal events occurred in 6.7% in the standard therapy arm versus 8.7% in GO arm. Adverse events of note in the GO arm included prolonged grade 3 thrombocytopenia in 19 patients and sinusoidal obstructive syndrome in 3 patients (2 fatal). No differences were observed between the treatment arms in the rate of severe sepsis or intensive care admission during therapy. This study, and 2 other positive studies of GO reported at ASH will put pressure on Pfizer to reconsider applying for approval for GO. A Pfizer spokesperson said that the company plans to review results of the positive studies presented at ASH. ● —AG

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Conference News: SABCS and ASH

New Preventive Program for Latinas Unveiled By Alice Goodman

n outreach effort aimed at Latina women was unveiled at a poster session during the 2011 CTRC-AACR San Antonio Breast Cancer Symposium (SABCS). The innovation was a novela called “Se Valiente … Son Tus Senos” (Be Brave … They’re Your Breasts) that conveys accessible and personal information for Latina women in an effort to overcome barriers in this community to accessing healthcare. The novela was developed by SHARE (Self-help for Women with Breast or Ovarian Cancer), a peer-group organization for survivors of breast and ovarian cancer. The novela has been distributed to 25,000 people at 478 sites within New York City and 89 other sites in the United States, as well as internationally. Pretest and posttest evaluations show that the novela significantly increases Latina women’s knowledge about breast health, breast cancer,

worse prognosis. Hispanic women had a 20% increased risk of death due to breast cancer compared with non-Hispanic white women. The authors suggested that the mortality difference may be related to increased resistance to chemotherapy in tumors of Latina women. The findings were from the New Mexico Women’s Health Study (NMWHS), conducted from 1992 to 1996. A first primary breast cancer was documented in 692 women, 577 of them with invasive breast cancer. The latter group was followed through 2008 to compare long-term survival differences between Hispanics and nonHispanic whites. Lead author was Kathy Baumgartner, PhD, professor of epidemiology and associate dean at the University of Louisville, Kentucky. Baumgartner said this research is consistent with previous studies. After adjusting for other risk factors, including

age, stage, lymph node involvement, and estrogen receptor status, the risk dropped considerably, suggesting that there may be a biological basis for the difference in breast cancer mortality among Hispanics, Baumgartner said. The adjusted analysis also showed that Hispanic women treated with chemotherapy were 1.5 times more likely to die of breast cancer compared with non-Hispanic whites who received chemotherapy. She commented that the altered response to chemotherapy may be related to a propensity toward developing resistance among Hispanic women. “Some studies have suggested that Hispanic women are more likely to develop estrogen receptor–negative tumors that are resistant to chemotherapy,” Baumgartner stated. No difference in deaths due to other causes was observed between Hispanics and non-Hispanic whites. ●

Management of Lymphoma During Pregnancy Feasible

February 2012 I VOL 5, NO 1

©iStockphoto.com/JoKMedia

lthough management of lymphoma during pregnancy is not well studied, a retrospective review at 10 academic centers in the United States suggests that in selected cases, lymphoma can be treated with minimal maternal and fetal complications, and that treatment can be deferred until after giving birth in patients with low-risk lymphomas. The study was presented at the 53rd Annual Meeting of the American Society of Hematology held December 2011 in San Diego, California. “To our knowledge, this represents one of the largest experiences reported of lymphoma during pregnancy. There is not much published data in the literature to guide us. Therefore, 10 different centers came together to collect our experiences for guidance for not only ourselves, but treating oncologists across the world,” said lead author of this study, Andrew M. Evens, DO, MSc, University of Massachusetts Medical School, Worcester, Massachusetts. “The main point of our study is that the outcomes we found were consistent with non– pregnancy-associated lymphoma outcomes.” In the United States, approximately 3500 new cases of cancer are diagnosed each year in pregnant women. Breast cancer is the most common type, and hematologic malignancies (about 20% of all cases) are the second most common.

Prior to this study, knowledge about lymphoma during pregnancy came primarily from case reports, Evens explained. The retrospective review included 82 evaluable cases of lymphoma in pregnant women over a 13-year period. Treatment of selected cases of localized disease during the second and third trimester was associated with minimal maternal and fetal risk of complications. The data suggest that treatment for lymphoma can be safely deferred until after giving birth in patients with low-risk lymphomas, such as indolent non-Hodgkin lymphoma (NHL), and/or diagnosis late in gestation. Evens said that this approach can achieve survival similar to that of nonpregnant patients with lymphoma.

Almost all of the cases of lymphoma during pregnancy were comanaged with high-risk maternal fetal medicine, with the goal of carrying the fetus to term (beyond 36 weeks’ gestation). In the 82 evaluable patients, median age was 31 years, about 38% were nulliparous, and lymphoma was diagnosed at a median of 24 weeks’ gestation (range, 5-40): 15% during the first trimester, 46% during the second trimester, 35% during the third trimester, and 4% was preexisting. Of the 82 evaluable cases, 43 were NHL and 39 were Hodgkin lymphoma (HL). Median weight gain was 3.1%, which is considered low. Since lymphoma is associated with weight loss, this low weight gain makes sense, Evens noted. Almost two-thirds (63%) of NHL patients had advanced-stage disease (most of them diffuse large Bcell lymphoma), and 46% of those with HL were in advanced stage; 25% of HL patients had stage IIB. Six patients (4 NHL, 2 HL) terminated pregnancy to initiate chemotherapy (5 in the first trimester and 1 in the early second trimester). Chemotherapy was based mainly on cyclophosphamide, doxorubicin, vincristine, and prednisone (CHOP) or rituximab plus CHOP (R-CHOP) for NHL and doxorubicin, bleomycin, vinblastine, and dacarbazine for HL patients. Therapy was deferred in 34% of patients (n=28).

Seventy-two percent of patients had a vaginal delivery. Among 48 patients who received chemotherapy during pregnancy, full-term gestation occurred in 73% (85% delivered at 35 weeks’ gestation or longer). Among 28 patients who deferred chemotherapy, delivery was at a median of 38 weeks, and 86% of pregnancies were carried to full term. Most common preterm complications were induction of labor (45%), pre-eclampsia (8%), spontaneous rupture of membranes (5%), and diabetes mellitus (4%). No difference in events was observed between patients treated during pregnancy and those who deferred treatment. One stillbirth occurred in an NHL patient treated with 1 cycle of R-CHOP. Fetal outcomes were evaluable in 76 live births. No difference was seen in median birth weight between infants of chemotherapy-treated patients and those who deferred therapy. Only 1 fetal malformation was found: microcephaly in an NHL patient treated with 4 cycles of CHOP. For all patients, 3-year progression-free survival (PFS) and overall survival (OS) were 79% and 89%, respectively: for Bcell NHL, 73% and 82%; for T-cell NHL, 50% and 90%; and for HL, 90% and 95%, respectively. Among the 6 patients who terminated pregnancy, 3year PFS and OS were 100%. ● —AG

www.TheOncologyNurse.com

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SANCUSO速 (Granisetron Transdermal System): A recommendation from NCCN1 and ASCO2 In the treatment of CINV, she is now

armed & ready 5 full days of 5-HT3 protection in a single patch3 Visit www.sancuso.com to learn more about the only transdermal antiemetic patch for CINV. Please refer to the important safety information for sunlight warning.

Important safety information SANCUSO速 (Granisetron Transdermal System) is indicated for the prevention of nausea and vomiting in patients receiving moderately and/or highly emetogenic chemotherapy regimens of up to 5 consecutive days duration.4 SANCUSO is contraindicated in patients with known hypersensitivity to granisetron or to any of the components of the patch.4 Granisetron may mask a progressive ileus and/or gastric distention caused by the underlying condition.4 Mild application site reactions have occurred; remove the patch if severe reaction or a generalized skin reaction occurs.4 Patients should avoid direct exposure of application site to natural or artificial sunlight by covering with clothing while wearing the patch and for 10 days after removing it.4 The most common adverse reaction in patients receiving SANCUSO is constipation (5.4%).4 SANCUSO contains granisetron.4 Healthcare professionals should avoid prescribing any additional products that contain granisetron. No clinically relevant drug interactions have been reported in clinical studies with SANCUSO.4

References: 1. National Comprehensive Cancer Network. NCCN Clinical Practice Guidelines in Oncology: Antiemesis. V.1.2012. http://www.nccn.org/professionals/ physician_gls/pdf/antiemesis.pdf. Accessed December 13, 2011. 2. Basch E, Prestrud AA, Hesketh PJ, et al. Antiemetics: American Society of Clinical Oncology Clinical Practice Guideline Update. J Clin Oncol. 2011;29(31):4189-4198. 3. Boccia RV, Gordan LN, Clark G, Howell JD, Grunberg SM; on behalf of the Sancuso Study Group. Efficacy and tolerability of transdermal granisetron for the control of chemotherapy-induced nausea and vomiting associated with moderately and highly emetogenic multi-day chemotherapy: a randomized, double-blind, phase III study. Support Care Cancer. 2011;19(10):1609-1617. 4. SANCUSO [package insert]. Bedminster, NJ: ProStrakan, Inc; 2011.

ONLY 速

Please see brief summary of Prescribing Information on adjacent page.

Keeps them covered

11:23 AM

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Conference News: SABCS and ASH

New Preventive Program for Latinas Unveiled By Alice Goodman

conveys accessible and personal information for Latina women in an effort to overcome barriers in this community to accessing healthcare. The novela was developed by SHARE (Self-help for Women with Breast or Ovarian Cancer), a peer-group organization for survivors of breast and ovarian cancer.

BRIEF SUMMARY OF PRESCRIBING INFORMATION INDICATIONS AND USAGE SANCUSO® (Granisetron Transdermal System) is indicated for the prevention of nausea and vomiting in patients receiving moderately and/or highly emetogenic chemotherapy regimens of up to 5 consecutive days duration. DOSAGE AND ADMINISTRATION The transdermal system (patch) should be applied to clean, dry, intact healthy skin on the upper outer arm. SANCUSO should not be placed on skin that is red, irritated or damaged. Each patch is packed in a pouch and should be applied directly after the pouch has been opened. The patch should not be cut into pieces. Adults Apply a single patch to the upper outer arm a minimum of 24 hours before chemotherapy. The patch may be applied up to a maximum of 48 hours before chemotherapy as appropriate. Remove the patch a minimum of 24 hours after completion of chemotherapy. The patch can be worn for up to 7 days depending on the duration of the chemotherapy regimen. DOSAGE FORMS AND STRENGTHS SANCUSO is a 52 cm2 patch containing 34.3 mg of granisetron. The patch releases 3.1 mg of granisetron per 24 hours for up to 7 days. CONTRAINDICATIONS SANCUSO is contraindicated in patients with known hypersensitivity to granisetron or to any of the components of the patch. WARNINGS AND PRECAUTIONS Gastrointestinal The use of granisetron in patients may mask a progressive ileus and/or gastric distention caused by the underlying condition. Skin Reactions In clinical trials with SANCUSO, application site reactions were reported which were generally mild in intensity and did not lead to discontinuation of use. The incidence of reactions was comparable with placebo. If severe reactions, or a generalized skin reaction occur (e.g. allergic rash, including erythematous, macular, papular rash or pruritus), the patch must be removed. Exposure to Sunlight Granisetron may be affected by direct natural or artificial sunlight. Patients must be advised to cover the patch application site, e.g. with clothing, if there is a risk of exposure to sunlight throughout the period of wear and for 10 days following its removal because of a potential skin reaction. ADVERSE REACTIONS Clinical Trials Experience The safety of SANCUSO was evaluated in a total of 404 patients undergoing chemotherapy who participated in two double-blind, comparator studies with patch treatment durations of up to 7 days. The control groups included a total of 406 patients who received a daily dose of 2 mg oral granisetron, for 1 to 5 days. Adverse reactions considered by the investigators as drug-related occurred in 8.7% (35/404) of patients receiving SANCUSO and 7.1% (29/406) of patients receiving oral granisetron. The most common adverse reaction was constipation that occurred in 5.4% of patients in the SANCUSO group and 3.0% of patients in the oral granisetron group. Table 1 lists the treatment emergent adverse reactions that occurred in at least 3% of patients treated with SANCUSO or oral granisetron.

The novela has been distributed to 25,000 people at 478 sites within New York City and 89 other sites in the United States, as well as internationally. Pretest and posttest evaluations show that the novela significantly increases Latina women’s knowledge about breast health, breast cancer,

Renal Failure or Hepatically-Impaired Patients Although no studies have been performed to investigate the pharmacokinetics of SANCUSO in patients with renal or hepatic impairment, pharmacokinetic information is available for intravenous granisetron. OVERDOSAGE There is no specific antidote for granisetron overdosage. In the case of overdosage, symptomatic treatment should be given. Overdosage of up to 38.5 mg of granisetron hydrochloride, as a single intravenous injection, has been reported without symptoms or only the occurrence of a slight headache. In clinical trials there were no reported cases of overdosage with SANCUSO. HOW SUPPLIED/STORAGE AND HANDLING SANCUSO (Granisetron Transdermal System) is supplied as a 52 cm2 patch containing 34.3 mg of granisetron. Each patch is printed on one side with the words “Granisetron 3.1 mg/24 hours”. Each patch is packaged in a separate sealed foil-lined plastic pouch. SANCUSO is available in packages of 1 (NDC 42747-726-01) patch. Store at 20˚-25˚C (68˚-77˚F); excursions permitted between 15˚-30˚C (59˚-86˚F). [see USP Controlled Room Temperature]. SANCUSO should be stored in the original packaging. PATIENT COUNSELING INFORMATION See FDA-approved patient labeling. Gastrointestinal Because the use of granisetron may mask a progressive ileus and/or gastric distention caused by the underlying condition, patients should be instructed to tell their physician if they have pain or swelling in their abdomen. Skin Reactions Patients should be instructed to remove the patch if they have a severe skin reaction, or a generalized skin reaction (e.g. allergic rash, including erythematous, macular, papular rash or pruritus). When patients remove the patch, they should be instructed to peel it off gently. Exposure to Sunlight Granisetron may be degraded by direct sunlight or exposure to sunlamps. In addition, an in vitro study using Chinese hamster ovary cells suggests that granisetron has the potential for photogenotoxicity. Patients must be advised to cover the patch application site, e.g. with clothing, if there is a risk of exposure to sunlight or sunlamps throughout the period of wear and for 10 days following its removal. FDA-Approved Patient Labeling Rx Only Manufactured by: Aveva Drug Delivery Systems Inc., Miramar FL 33025

Table 1: Incidence of Adverse Reactions in Double-Blind, Active Comparator Controlled Studies in Cancer Patients Receiving Chemotherapy (Events ≥ 3% in either group) Body System Preferred Term

SANCUSO TDS N=404 (%)

Oral granisetron N=406 (%)

5.4

3.0

0.7

3.0

Gastrointestinal disorders Constipation Nervous system disorders Headache

DRUG INTERACTIONS Granisetron does not induce or inhibit the cytochrome P-450 drug-metabolizing enzyme system in vitro. There have been no definitive drug-drug-interaction studies to examine pharmacokinetic or pharmacodynamic interaction with other drugs. However, in humans, granisetron hydrochloride injection has been safely administered with drugs representing benzodiazepines, neuroleptics and anti-ulcer medications commonly prescribed with antiemetic treatments. Granisetron hydrochloride injection also does not appear to interact with emetogenic cancer therapies. In agreement with these data, no clinically relevant drug interactions have been reported in clinical studies with SANCUSO. Because granisetron is metabolized by hepatic cytochrome P-450 drug-metabolizing enzymes (CYP1A1 and CYP3A4), inducers or inhibitors of these enzymes may change the clearance and hence, the half-life of granisetron. In addition, the activity of the cytochrome P-450 subfamily 3A4 (involved in the metabolism of some of the main narcotic analgesic agents) is not modified by granisetron hydrochloride in vitro. In in vitro human microsomal studies, ketoconazole inhibited ring oxidation of granisetron hydrochloride. However, the clinical significance of in vivo pharmacokinetic interactions with ketoconazole is not known. In a human pharmacokinetic study, hepatic enzyme induction with phenobarbital resulted in a 25% increase in total plasma clearance of intravenous granisetron hydrochloride. The clinical significance of this change is not known. USE IN SPECIFIC POPULATIONS Pregnancy Pregnancy Category B Reproduction studies with granisetron hydrochloride have been performed in pregnant rats at intravenous doses up to 9 mg/kg/day (54 mg/m2/day, about 24 times the recommended human dose delivered by the SANCUSO patch, based on body surface area) and oral doses up to 125 mg/m2/day (750 mg/m2/day, about 326 times the recommended human dose with SANCUSO based on body surface area). Reproduction studies have been performed in pregnant rabbits at intravenous doses up to 3 mg/kg/day (36 mg/m2/day, about 16 times the human dose with SANCUSO based on body surface area) and at oral doses up to 32 mg/kg/day (384 mg/m2/ day, about 167 times the human dose with SANCUSO based on body surface area). These studies did not reveal any evidence of impaired fertility or harm to the fetus due to granisetron. There are, however, no adequate and well-controlled studies in pregnant women. Because animal reproduction studies are not always predictive of human response, SANCUSO should be used during pregnancy only if clearly needed. Nursing Mothers It is not known whether granisetron is excreted in human milk. Because many drugs are excreted in human milk, caution should be exercised when SANCUSO is administered to a nursing woman. Pediatric Use Safety and effectiveness of SANCUSO in pediatric patients under 18 years of age have not been established. Geriatric Use Clinical studies of SANCUSO did not include sufficient numbers of subjects aged 65 and over to determine whether they respond differently from younger subjects. Other reported clinical experience has not identified differences in responses between the elderly and younger patients. In general, cautious treatment selection for an elderly patient is prudent because of the greater frequency of decreased hepatic, renal, or cardiac function, and of concomitant disease or other drug therapy.

February 2012 I VOL 5, NO 1

Revised: 08/2008

detection, diagnosis, treatment, and survivorship. The genesis for the novella was the recognition that many Latina women do not undergo screening and are less likely to seek treatment for breast cancer than non-Latinas. “Breast cancer remains a leading cause of death among Latina women, and 5-year survival rates remain lower than those of other groups. Language and cultural barriers, as well as myths and fears, prevent many women from being diagnosed early and receiving adequate treatment. The novela has been shown to have a critical impact on dispelling those myths and providing accurate and relevant information,” said SHARE’s senior director of programs, Ivis Sampayo. [more information is available at www.sharecan cersupport.org] A separate study presented at the 2011 SABCS underscored the fact that Latina women with breast cancer have a worse prognosis. Hispanic women had a 20% increased risk of death due to breast cancer compared with non-Hispanic white women. The authors suggested that the mortality difference may be related to increased resistance to chemotherapy in tumors of Latina women. The findings were from the New Mexico Women’s Health Study (NMWHS), conducted from 1992 to 1996. A first primary breast cancer was documented in 692 women, 577 of them with invasive breast cancer. The latter group was followed through 2008 to compare long-term survival differences between Hispanics and nonHispanic whites. Lead author was Kathy Baumgartner, PhD, professor of epidemiology and associate dean at the University of Louisville, Kentucky. Baumgartner said this research is consistent with previous studies. After adjusting for other risk factors, including age, stage, lymph node involvement, and estrogen receptor status, the risk dropped considerably, suggesting that there may be a biological basis for the difference in breast cancer mortality among Hispanics, Baumgartner said. The adjusted analysis also showed that Hispanic women treated with chemotherapy were 1.5 times more likely to die of breast cancer compared with non-Hispanic whites who received chemotherapy. She commented that the altered response to chemotherapy may be related to a propensity toward developing resistance among Hispanic women. “Some studies have suggested that Hispanic women are more likely to develop estrogen receptor–negative tumors that are resistant to chemotherapy,” Baumgartner stated. No difference in deaths due to other causes was observed between Hispanics and non-Hispanic whites. ●

www.TheOncologyNurse.com

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Your determination to educate patients on how they can benefit from therapy is what makes you a vital part of the treatment team DISCOVER THE MANY WAYS TREANDAÂŽ SUPPORTS NURSES IN THE CONTINUED FIGHT AGAINST CANCER. Patient brochures and treatment diaries t Everything patients need to know about their disease and treatment in an easy-to-read format t Patients can track their progress, blood counts, and report side effects

Cephalon Oncology Reimbursement Expertise (CORE) t A service that helps patients and providers with the reimbursement process and accessing TREANDA CephalonCaresÂŽ Foundation t A program that provides patients who qualify with FDA-approved Cephalon products free of charge Additional disease education tools and useful patient resources We want to hear about your patientsâ&#x20AC;&#x2122; success with TREANDA. Help them share their story today! t From Where I Stand is a program in which patients who have benefitted from treatment with TREANDA share their experiences t 7JTJU XXX 53&"/%" DPN 8IFSF*4UBOE GPS NPSF QSPHSBN JOGPSNBUJPO

Real Patients. Real Passions. Real Practices.

Learn more about all of these resources at www.TREANDA.com. Indications TREANDA is indicated for the treatment of patients with chronic lymphocytic leukemia (CLL). Efficacy relative to first-line therapies other than chlorambucil has not been established. TREANDA is indicated for the treatment of patients with indolent B-cell non-Hodgkinâ&#x20AC;&#x2122;s lymphoma (NHL) that has progressed during or within 6 months of treatment with rituximab or a rituximab-containing regimen. Important Safety Information t Serious adverse reactions, including myelosuppression, infections, infusion reactions and anaphylaxis, tumor lysis syndrome, skin reactions including SJS/TEN, other malignancies, and extravasation, have been associated with TREANDA. Some reactions, such as myelosuppression, infections, and SJS/TEN (when TREANDA was administered concomitantly with allopurinol and other medications known to cause SJS/TEN), have been fatal. Patients should be monitored closely for these reactions and treated promptly if any occur t Adverse reactions may require interventions such as decreasing the dose of TREANDA, or withholding or delaying treatment t TREANDA is contraindicated in patients with a known hypersensitivity to bendamustine or mannitol. Women should be advised to avoid becoming pregnant while using TREANDA t The most common non-hematologic adverse reactions associated with TREANDA (frequency â&#x2030;Ľ15%) are nausea, fatigue, vomiting, diarrhea, pyrexia, constipation, anorexia, cough, headache, weight decreased, dyspnea, rash, and stomatitis. The most common hematologic abnormalities associated with TREANDA (frequency â&#x2030;Ľ15%) are lymphopenia, anemia, leukopenia, thrombocytopenia, and neutropenia

TON_February2011_v9_TON 2/15/12 11:45 AM Page 26

Brief Summary of Prescribing Information INDICATIONS AND USAGE: TREANDA is indicated for the treatment of patients with chronic lymphocytic leukemia (CLL). Efficacy relative to first line therapies other than chlorambucil has not been established. TREANDA for Injection is indicated for the treatment of patients with indolent B-cell non-Hodgkin’s lymphoma (NHL) that has progressed during or within six months of treatment with rituximab or a rituximab-containing regimen. CONTRAINDICATIONS: TREANDA is contraindicated in patients with a known hypersensitivity (eg, anaphylactic and anaphylactoid reactions) to bendamustine or mannitol. [See Warnings and Precautions] WARNINGS AND PRECAUTIONS: Myelosuppression. Patients treated with TREANDA are likely to experience myelosuppression. In the two NHL studies, 98% of patients had Grade 3-4 myelosuppression. Three patients (2%) died from myelosuppression-related adverse reactions; one each from neutropenic sepsis, diffuse alveolar hemorrhage with Grade 3 thrombocytopenia, and pneumonia from an opportunistic infection (CMV). In the event of treatment-related myelosuppression, monitor leukocytes, platelets, hemoglobin (Hgb), and neutrophils closely. In the clinical trials, blood counts were monitored every week initially. Hematologic nadirs were observed predominantly in the third week of therapy. Hematologic nadirs may require dose delays if recovery to the recommended values have not occurred by the first day of the next scheduled cycle. Prior to the initiation of the next cycle of therapy, the ANC should be ≥ 1 x 109/L and the platelet count should be ≥ 75 x 109/L. [See Dosage and Administration]. Infections. Infection, including pneumonia and sepsis, has been reported in patients in clinical trials and in post-marketing reports. Infection has been associated with hospitalization, septic shock and death. Patients with myelosuppression following treatment with TREANDA are more susceptible to infections. Patients with myelosuppression following TREANDA treatment should be advised to contact a physician if they have symptoms or signs of infection. Infusion Reactions and Anaphylaxis. Infusion reactions to TREANDA have occurred commonly in clinical trials. Symptoms include fever, chills, pruritus and rash. In rare instances severe anaphylactic and anaphylactoid reactions have occurred, particularly in the second and subsequent cycles of therapy. Monitor clinically and discontinue drug for severe reactions. Patients should be asked about symptoms suggestive of infusion reactions after their first cycle of therapy. Patients who experienced Grade 3 or worse allergic-type reactions were not typically rechallenged. Measures to prevent severe reactions, including antihistamines, antipyretics and corticosteroids should be considered in subsequent cycles in patients who have previously experienced Grade 1 or 2 infusion reactions. Discontinuation should be considered in patients with Grade 3 or 4 infusion reactions. Tumor Lysis Syndrome. Tumor lysis syndrome associated with TREANDA treatment has been reported in patients in clinical trials and in post-marketing reports. The onset tends to be within the first treatment cycle of TREANDA and, without intervention, may lead to acute renal failure and death. Preventive measures include maintaining adequate volume status, and close monitoring of blood chemistry, particularly potassium and uric acid levels. Allopurinol has also been used during the beginning of TREANDA therapy. However, there may be an increased risk of severe skin toxicity when TREANDA and allopurinol are administered concomitantly. Skin Reactions. A number of skin reactions have been reported in clinical trials and post-marketing safety reports. These events have included rash, toxic skin reactions and bullous exanthema. Some events occurred when TREANDA was given in combination with other anticancer agents, so the precise relationship to TREANDA is uncertain. In a study of TREANDA (90 mg/m2) in combination with rituximab, one case of toxic epidermal necrolysis (TEN) occurred. TEN has been reported for rituximab (see rituximab package insert). Cases of Stevens-Johnson syndrome (SJS) and TEN, some fatal, have been reported when TREANDA was administered concomitantly with allopurinol and other medications known to cause these syndromes. The relationship to TREANDA cannot be determined. Where skin reactions occur, they may be progressive and increase in severity with further treatment. Therefore, patients with skin reactions should be monitored closely. If skin reactions are severe or progressive, TREANDA should be withheld or discontinued. Other Malignancies. There are reports of pre-malignant and malignant diseases that have developed in patients who have been treated with TREANDA, including myelodysplastic syndrome, myeloproliferative disorders, acute myeloid leukemia and bronchial carcinoma. The association with TREANDA therapy has not been determined. Extravasation. There are postmarketing reports of bendamustine extravasations resulting in hospitalizations from erythema, marked swelling, and pain. Precautions should be taken to avoid extravasations, including monitoring of the intravenous infusion site for redness, swelling, pain, infection, and necrosis during and after administration of TREANDA. Use in Pregnancy. TREANDA can cause fetal harm when administered to a pregnant woman. Single intraperitoneal doses of bendamustine in mice and rats administered during organogenesis caused an increase in resorptions, skeletal and visceral malformations, and decreased fetal body weights. ADVERSE REACTIONS: The data described below reflect exposure to TREANDA in 349 patients who participated in an actively-controlled trial (N=153) for the treatment of CLL and two single-arm studies (N=176) for the treatment of indolent B-cell NHL. 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. The following serious adverse reactions have been associated with TREANDA in clinical trials and are discussed in greater detail in other sections [See Warnings and Precautions] of the label: Myelosuppression; Infections; Infusion Reactions and Anaphylaxis; Tumor Lysis Syndrome; Skin Reactions; Other Malignancies. Clinical Trials Experience in CLL. The data described below reflect exposure to TREANDA in 153 patients. TREANDA was studied in an active-controlled trial. The population was 45-77 years of age, 63% male, 100% white, and had treatment naïve CLL. All patients started the study at a dose of 100 mg/m2 intravenously over 30 minutes on days 1 and 2 every 28 days. Adverse reactions were reported according to NCI CTC v.2.0. In the randomized CLL clinical study, non-hematologic adverse reactions (any grade) in the TREANDA group that occurred with a frequency greater than 15% were pyrexia (24%), nausea (20%), and vomiting (16%). Other adverse reactions seen frequently in one or more studies included asthenia, fatigue, malaise, and weakness; dry mouth; somnolence; cough; constipation; headache; mucosal inflammation; and stomatitis. Worsening hypertension was reported in 4 patients treated with TREANDA in the randomized CLL clinical study and none treated with chlorambucil. Three of these 4 adverse reactions were described as a hypertensive crisis and were managed with oral medications and resolved. The most frequent adverse reactions leading to study withdrawal for patients receiving TREANDA were hypersensitivity (2%) and pyrexia (1%). Table 1 contains the treatment emergent adverse reactions, regardless of attribution, that were reported in ≥ 5% of patients in either treatment group in the randomized CLL clinical study. Table 1: Non-Hematologic Adverse Reactions Occurring in Randomized CLL Clinical Study in at Least 5% of Patients Number (%) of patients TREANDA Chlorambucil (N=153) (N=143) System organ class Preferred term All Grades Grade 3/4 All Grades Grade 3/4 Total number of patients with at least 1 adverse reaction 121 (79) 52 (34) 96 (67) 25 (17) Gastrointestinal disorders Nausea 31 (20) 1 (<1) 21 (15) 1 (<1) Vomiting 24 (16) 1 (<1) 9 (6) 0 Diarrhea 14 (9) 2 (1) 5 (3) 0

Table 1: Non-Hematologic Adverse Reactions Occurring in Randomized CLL Clinical Study in at Least 5% of Patients (continued) Number (%) of patients TREANDA Chlorambucil (N=153) (N=143) System organ class Preferred term All Grades Grade 3/4 All Grades Grade 3/4 General disorders and administration site conditions Pyrexia 36 (24) 6 (4) 8 (6) 2 (1) Fatigue 14 (9) 2 (1) 8 (6) 0 Asthenia 13 (8) 0 6 (4) 0 Chills 9 (6) 0 1 (<1) 0 Immune system disorders Hypersensitivity 7 (5) 2 (1) 3 (2) 0 Infections and infestations Nasopharyngitis 10 (7) 0 12 (8) 0 Infection 9 (6) 3 (2) 1 (<1) 1 (<1) Herpes simplex 5 (3) 0 7 (5) 0 Investigations Weight decreased 11 (7) 0 5 (3) 0 Metabolism and nutrition disorders Hyperuricemia 11 (7) 3 (2) 2 (1) 0 Respiratory, thoracic and mediastinal disorders Cough 6 (4) 1 (<1) 7 (5) 1 (<1) Skin and subcutaneous tissue disorders Rash 12 (8) 4 (3) 7 (5) 3 (2) Pruritus 8 (5) 0 2 (1) 0 The Grade 3 and 4 hematology laboratory test values by treatment group in the randomized CLL clinical study are described in Table 2. These findings confirm the myelosuppressive effects seen in patients treated with TREANDA. Red blood cell transfusions were administered to 20% of patients receiving TREANDA compared with 6% of patients receiving chlorambucil. Table 2: Incidence of Hematology Laboratory Abnormalities in Patients Who Received TREANDA or Chlorambucil in the Randomized CLL Clinical Study

Laboratory Abnormality Hemoglobin Decreased Platelets Decreased Leukocytes Decreased Lymphocytes Decreased Neutrophils Decreased

TREANDA (N=150) All Grades Grade 3/4 n (%) n (%) 134 (89) 20 (13) 116 (77) 16 (11) 92 (61) 42 (28) 102 (68) 70 (47) 113 (75) 65 (43)

Chlorambucil (N=141) All Grades Grade 3/4 n (%) n (%) 115 (82) 12 (9) 110 (78) 14 (10) 26 (18) 4 (3) 27 (19) 6 (4) 86 (61) 30 (21)

In the randomized CLL clinical study, 34% of patients had bilirubin elevations, some without associated significant elevations in AST and ALT. Grade 3 or 4 increased bilirubin occurred in 3% of patients. Increases in AST and ALT of Grade 3 or 4 were limited to 1% and 3% of patients, respectively. Patients treated with TREANDA may also have changes in their creatinine levels. If abnormalities are detected, monitoring of these parameters should be continued to ensure that significant deterioration does not occur. Clinical Trials Experience in NHL. The data described below reflect exposure to TREANDA in 176 patients with indolent B-cell NHL treated in two singlearm studies. The population was 31-84 years of age, 60% male, and 40% female. The race distribution was 89% White, 7% Black, 3% Hispanic, 1% other, and <1% Asian. These patients received TREANDA at a dose of 120 mg/m2 intravenously on Days 1 and 2 for up to 8 21-day cycles. The adverse reactions occurring in at least 5% of the NHL patients, regardless of severity, are shown in Table 3. The most common non-hematologic adverse reactions (≥30%) were nausea (75%), fatigue (57%), vomiting (40%), diarrhea (37%) and pyrexia (34%). The most common non-hematologic Grade 3 or 4 adverse reactions (≥5%) were fatigue (11%), febrile neutropenia (6%), and pneumonia, hypokalemia and dehydration, each reported in 5% of patients. Table 3: Non-Hematologic Adverse Reactions Occurring in at Least 5% of NHL Patients Treated With TREANDA by System Organ Class and Preferred Term (N=176) System organ class Preferred term Total number of patients with at least 1 adverse reaction Cardiac disorders Tachycardia Gastrointestinal disorders Nausea Vomiting Diarrhea Constipation Stomatitis Abdominal pain Dyspepsia Gastroesophageal reflux disease Dry mouth Abdominal pain upper Abdominal distension General disorders and administration site conditions Fatigue Pyrexia Chills Edema peripheral Asthenia Chest pain Infusion site pain Pain Catheter site pain

Number (%) of patients* All Grades Grade 3/4 176 (100) 94 (53)

13 (7)

132 (75) 71 (40) 65 (37) 51 (29) 27 (15) 22 (13) 20 (11) 18 (10) 15 (9) 8 (5) 8 (5)

7 (4) 5 (3) 6 (3) 1 (<1) 1 (<1) 2 (1) 0 0 1 (<1) 0 0

101 (57) 59 (34) 24 (14) 23 (13) 19 (11) 11 (6) 11 (6) 10 (6) 8 (5)

19 (11) 3 (2) 0 1 (<1) 4 (2) 1 (<1) 0 0 0

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Table 3: Non-Hematologic Adverse Reactions Occurring in at Least 5% of NHL Patients Treated With TREANDA by System Organ Class and Preferred Term (N=176) (continued) System organ class Number (%) of patients* Preferred term All Grades Grade 3/4 Infections and infestations Herpes zoster 18 (10) 5 (3) Upper respiratory tract infection 18 (10) 0 Urinary tract infection 17 (10) 4 (2) Sinusitis 15 (9) 0 Pneumonia 14 (8) 9 (5) Febrile Neutropenia 11 (6) 11 (6) Oral Candidiasis 11 (6) 2 (1) Nasopharyngitis 11 (6) 0 Investigations Weight decreased 31 (18) 3 (2) Metabolism and nutrition disorders Anorexia 40 (23) 3 (2) Dehydration 24 (14) 8 (5) Decreased appetite 22 (13) 1 (<1) Hypokalemia 15 (9) 9 (5) Musculoskeletal and connective tissue disorders Back pain 25 (14) 5 (3) Arthralgia 11 (6) 0 Pain in extremity 8 (5) 2 (1) Bone pain 8 (5) 0 Nervous system disorders Headache 36 (21) 0 Dizziness 25 (14) 0 Dysgeusia 13 (7) 0 Psychiatric disorders Insomnia 23 (13) 0 Anxiety 14 (8) 1 (<1) Depression 10 (6) 0 Respiratory, thoracic and mediastinal disorders Cough 38 (22) 1 (<1) Dyspnea 28 (16) 3 (2) Pharyngolaryngeal pain 14 (8) 1 (<1) Wheezing 8 (5) 0 Nasal congestion 8 (5) 0 Skin and subcutaneous tissue disorders Rash 28 (16) 1 (<1) Pruritus 11 (6) 0 Dry skin 9 (5) 0 Night sweats 9 (5) 0 Hyperhidrosis 8 (5) 0 Vascular disorders Hypotension 10 (6) 2 (1) *Patients may have reported more than 1 adverse reaction. NOTE: Patients counted only once in each preferred term category and once in each system organ class category. Hematologic toxicities, based on laboratory values and CTC grade, in NHL patients treated in both single arm studies combined are described in Table 4. Clinically important chemistry laboratory values that were new or worsened from baseline and occurred in >1% of patients at grade 3 or 4, in NHL patients treated in both single arm studies combined were hyperglycemia (3%), elevated creatinine (2%), hyponatremia (2%), and hypocalcemia (2%). Table 4: Incidence of Hematology Laboratory Abnormalities in Patients Who Received TREANDA in the NHL Studies Percent of patients All Grades Grade 3/4 99 94 94 56 88 11 86 60 86 25

Hematology Variable Lymphocytes Decreased Leukocytes Decreased Hemoglobin Decreased Neutrophils Decreased Platelets Decreased

TREANDA administration should be delayed in the event of Grade 4 hematologic toxicity or clinically significant ≥ Grade 2 non-hematologic toxicity. Once non-hematologic toxicity has recovered to ≤ Grade 1 and/or the blood counts have improved [Absolute Neutrophil Count (ANC) ≥ 1 x 109/L, platelets ≥ 75 x 109/L], TREANDA can be reinitiated at the discretion of the treating physician. In addition, dose reduction may be warranted. [See Warnings and Precautions] Dose modifications for hematologic toxicity: for Grade 3 or greater toxicity, reduce the dose to 50 mg/m2 on Days 1 and 2 of each cycle; if Grade 3 or greater toxicity recurs, reduce the dose to 25 mg/m2 on Days 1 and 2 of each cycle. Dose modifications for non-hematologic toxicity: for clinically significant Grade 3 or greater toxicity, reduce the dose to 50 mg/m2 on Days 1 and 2 of each cycle. Dose re-escalation in subsequent cycles may be considered at the discretion of the treating physician. Dosing Instructions for NHL. Recommended Dosage: The recommended dose is 120 mg/m2 administered intravenously over 60 minutes on Days 1 and 2 of a 21-day cycle, up to 8 cycles. Dose Delays, Dose Modifications and Reinitiation of Therapy for NHL: TREANDA administration should be delayed in the event of a Grade 4 hematologic toxicity or clinically significant ≥ Grade 2 non-hematologic toxicity. Once non-hematologic toxicity has recovered to ≤ Grade 1 and/or the blood counts have improved [Absolute Neutrophil Count (ANC) ≥ 1 x 109/L, platelets ≥ 75 x 109/L], TREANDA can be reinitiated at the discretion of the treating physician. In addition, dose reduction may be warranted. [See Warnings and Precautions] Dose modifications for hematologic toxicity: for Grade 4 toxicity, reduce the dose to 90 mg/m2 on Days 1 and 2 of each cycle; if Grade 4 toxicity recurs, reduce the dose to 60 mg/m2 on Days 1 and 2 of each cycle. Dose modifications for non-hematologic toxicity: for Grade 3 or greater toxicity, reduce the dose to 90 mg/m2 on Days 1 and 2 of each cycle; if Grade 3 or greater toxicity recurs, reduce the dose to 60 mg/m2 on Days 1 and 2 of each cycle. Reconstitution/Preparation for Intravenous Administration. M D6AE:42==J C64@?DE:EFE6 6249 ,* & G:2= 2D 7@==@HD M >8 ,* & G:2= 55 >$ @7 @?=J Sterile Water for Injection, USP M >8 ,* & G:2= 55 >$ @7 @?=J Sterile Water for Injection, USP. Shake well to yield a clear, colorless to a pale yellow solution with a bendamustine HCl concentration of 5 mg/mL. The lyophilized powder should completely dissolve in 5 minutes. If particulate matter is observed, the reconstituted product should not be used. M D6AE:42==J H:E95C2H E96 G@=F>6 ?66565 7@C E96 C6BF:C65 5@D6 32D65 @? >8 >$ 4@?46?EC2E:@? and immediately transfer to a 500 mL infusion bag of 0.9% Sodium Chloride Injection, USP (normal saline). As an alternative to 0.9% Sodium Chloride Injection, USP (normal saline), a 500 mL infusion bag of 2.5% Dextrose/0.45% Sodium Chloride Injection, USP, may be considered. The resulting final concentration of bendamustine HCl in the infusion bag should be within 0.2–0.6 mg/ mL. The reconstituted solution must be transferred to the infusion bag within 30 minutes of reconstitution. After transferring, thoroughly mix the contents of the infusion bag. The admixture D9@F=5 36 2 4=62C 2?5 4@=@C=6DD E@ D=:89E=J J6==@H D@=FE:@? M -D6 +E6C:=6 /2E6C 7@C "?;64E:@? -+( for reconstitution and then either 0.9% Sodium Chloride Injection, USP, or 2.5% Dextrose/0.45% Sodium Chloride Injection, USP, for dilution, as outlined above. No other diluents have been shown E@ 36 4@>A2E:3=6 M (2C6?E6C2= 5CF8 AC@5F4ED D9@F=5 36 :?DA64E65 G:DF2==J 7@C A2CE:4F=2E6 >2EE6C 2?5 discoloration prior to administration whenever solution and container permit. Any unused solution should be discarded according to institutional procedures for antineoplastics. Admixture Stability. TREANDA contains no antimicrobial preservative. The admixture should be prepared as close as possible to the time of patient administration. Once diluted with either 0.9% Sodium Chloride Injection, USP, or 2.5% Dextrose/0.45% Sodium Chloride Injection, USP, the final admixture is stable for 24 hours when stored refrigerated (2-8°C or 36-47°F) or for 3 hours when stored at room temperature (15-30°C or 59-86°F) and room light. Administration of TREANDA must be completed within this period. DOSAGE FORMS AND STRENGTHS: TREANDA for Injection single-use vial containing either 25 mg or 100 mg of bendamustine HCl as white to off-white lyophilized powder. HOW SUPPLIED/STORAGE AND HANDLING: Safe Handling and Disposal. As with other potentially toxic anticancer agents, care should be exercised in the handling and preparation of solutions prepared from TREANDA. The use of gloves and safety glasses is recommended to avoid exposure in case of breakage of the vial or other accidental spillage. If a solution of TREANDA contacts the skin, wash the skin immediately and thoroughly with soap and water. If TREANDA contacts the mucous membranes, flush thoroughly with water. Procedures for the proper handling and disposal of anticancer drugs should be considered. Several guidelines on the subject have been published. There is no general agreement that all of the procedures recommended in the guidelines are necessary or appropriate. How Supplied. TREANDA (bendamustine hydrochloride) for Injection is supplied in individual cartons as follows: NDC 63459-390-08 TREANDA (bendamustine hydrochloride) for Injection, 25 mg in 8 mL amber single-use vial and NDC 63459-391-20 TREANDA (bendamustine hydrochloride) for Injection, 100 mg in 20 mL amber single-use vial. Storage. TREANDA may be stored up to 25°C (77°F) with excursions permitted up to 30°C (86°F) (see USP Controlled Room Temperature). Retain in original package until time of use to protect from light.

In both studies, serious adverse reactions, regardless of causality, were reported in 37% of patients receiving TREANDA. The most common serious adverse reactions occurring in ≥ 5% of patients were febrile neutropenia and pneumonia. Other important serious adverse reactions reported in clinical trials and/or post-marketing experience were acute renal failure, cardiac failure, hypersensitivity, skin reactions, pulmonary fibrosis, and myelodysplastic syndrome. Serious drug-related adverse reactions reported in clinical trials included myelosuppression, infection, pneumonia, tumor lysis syndrome, and infusion reactions. [See Warnings and Precautions] Adverse reactions occurring less frequently but possibly related to TREANDA treatment were hemolysis, dysgeusia/taste disorder, atypical pneumonia, sepsis, herpes zoster, erythema, dermatitis, and skin necrosis. PostMarketing Experience. The following adverse reactions have been identified during post-approval use of TREANDA. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure: anaphylaxis; and injection or infusion site reactions including pruritus, irritation, pain, and swelling. Skin reactions including SJS and TEN have occurred when TREANDA was administered concomitantly with allopurinol and other medications known to cause these syndromes. [See Warnings and Precautions] OVERDOSAGE: The intravenous LD of bendamustine HCl is 240 mg/m2 in the mouse and rat. Toxicities included sedation, tremor, ataxia, convulsions and respiratory distress. Across all clinical experience, the reported maximum single dose received was 280 mg/m2. Three of four patients treated at this dose showed ECG changes considered dose-limiting at 7 and 21 days post-dosing. These changes included QT prolongation (one patient), sinus tachycardia (one patient), ST and T wave deviations (two patients), and left anterior fascicular block (one patient). Cardiac enzymes and ejection fractions remained normal in all patients. No specific antidote for TREANDA overdose is known. Management of overdosage should include general supportive measures, including monitoring of hematologic parameters and ECGs. 50

DOSAGE AND ADMINISTRATION: Dosing Instructions for CLL. Recommended Dosage: The recommended dose is 100 mg/m2 administered intravenously over 30 minutes on Days 1 and 2 of a 28-day cycle, up to 6 cycles. Dose Delays, Dose Modifications and Reinitiation of Therapy for CLL:

Manufactured by: Pharmachemie B.V. The Netherlands

Manufactured for: Cephalon, Inc. Frazer, PA 19355

TREANDA is a trademark of Cephalon, Inc., or its affiliates. ©2008-2011 Cephalon, Inc., or its affiliates. TRE-2263 (Label Code: 00016287.03) This brief summary is based on TREANDA full Prescribing Information.

TON_February2011_v9_TON 2/15/12 11:45 AM Page 28

Cancer Center Profile Medical City Cancer Resource Center ing in treatment, recognizing and controlling adverse effects of treatment, managing stress, mobilizing and managing resources, and adapting to a life of uncertainty.1 Studies have shown that providing comprehensive consumer information increased patient satisfaction and empowered patients to make the decisions related to their care.2 Newly diagnosed patients often react to hearing the word cancer with much anxiety and disbelief and need much more than information regarding their disease and its management.3 It is imperative that a positive healthcare environment, perceived emotional support, and effective communication with healthcare providers also be included with the delivery of the information.4 These are only a few of the services the Medical City Cancer Resource Center (CRC) provides. History and Development Under the guidance and passion of the Medical City Hospital administration, the CRC project was initiated in 2005. The vision was to provide a central location for cancer patients to receive educational and psychosocial support. Further, it was created to address the need for patients to feel personalized care throughout their cancer treatment, from diagnosis to survivorship. Knowing the difficulties patients face accessing resources, our aim was to create a “home base” for patients where they could receive support within our center while also being navigated to the appropriate resources both within our healthcare facility and in the community. To set up these channels and forge a true cancer support community, collaboration with cancer-related community resources and organizations was needed. When the opportunity arose in 2005 to partner with the American Cancer Society (ACS), it seemed like an ideal pairing. With their valuable volunteer training programs specifically for cancer patient care and their plethora of resources, ACS would become an essential component of the center. The ACS generously donates wigs, postmastectomy bras, and literature. It also provides personal health managers to the CRC and programs such as “Look Good…Feel Better” and “Reach to Recovery.” Our ACS liaison is responsive to our inventory needs, helps with community screenings and education programs, and supports the volunteers and staff as needed. In addition to the partnership with ACS, we have several community groups with giving spirits who donate handcrafted postmastectomy pillows, drain pouches, chemo caps, and wooden angels. The location in the lobby of Medical

February 2012 I VOL 5, NO 1

Volunteer participant at “Ponytail Donations” showing her “ponytail” for children with cancer.

City’s main tower means that the CRC is centrally located and accessible to the inpatient oncology units, chemotherapy infusion suite, oncologists’ offices, and the radiation therapy department. The physical space of the CRC was developed to provide an open atmosphere while also allowing areas for confidential conversations. The architect and interior designer used a natural setting theme with earthy colors, a therapeutic water wall, bamboo stalks, and fresh flowers. The glass outer face of the center allows for transparency, encouraging more hesitant patients to enter. The entry space houses the volunteer’s desk, as well as a seating and research area

Essential to our volunteer team are our ACS-trained “Reach to Recovery” volunteers; they are breast cancer survivors who make visits to the inpatient units...

with 2 computers with open access for visitors. While seated at the computers, patients can peruse a wide variety of educational pamphlets ranging from prevention and lifestyle choices to cutting-edge genetic testing and research trials. The center has a small kitchenette area with a coffee maker and a refrigerator stocked with drinks and snacks for visitors. The granite counter holds light meals offered for special events and support groups. For staff

Continued from cover

meetings, support groups, and educational seminars, our conference room holds up to 20 people and has a variety of layout options. Beyond the entryway are a “meditation area” with lounge chairs and a Zen sand garden and fountain. This area provides a respite for patients, who are welcome to enjoy the facilities at any point during their treatment journey. Two small back rooms include a private consultation space with more educational materials and an office for the CRC coordinator. Since its inception, the CRC has grown tremendously through strategic marketing with physicians’ offices, inpatient units, and the community. We advertise all of our cancer screenings and educational programs in the local newspapers, on the Medical City Web page, on Facebook, and in flyers and posters. This marketing allows us to expand the patient population exposed to the center, as well as our Medical City Cancer Program. In addition, community events also reach out to family members and friends of cancer patients, who are then able to carry our message to their networks. CRC Staff Our team works synergistically toward addressing all of the needs of our patients, with administrators providing the framework and marketing, and trained volunteers providing a helping hand and spending time one-on-one with patients. The core care team at the CRC is composed of a coordinator, a part-time registered nurse, and generous volunteers. Members of the core team meet with newly diagnosed cancer patients and their families and provide educational and emotional support. Jan Tichenor, RN, MSN, CNS, OCN, is available as a liaison to the center and provides consultation with physicians, social workers, and other interdisciplinary professionals in developing a plan of care that includes connections with outside community cancer resources to best meet the needs of the individual. The CRC Coordinator addresses the administrative needs of the center. This includes coordinating CRC and community outreach events and screenings, ensuring mailings and reminders are sent in a timely fashion, ordering educational literature, and maintaining correspondence with the ACS and other community resources. Volunteers who have attended the ACS CRC all-day training session are an integral part of the center. With a volunteer team composed entirely of cancer survivors, patients entering the center are given intensive support from another individual who identifies with their struggles. Essential to our volun-

teer team are our ACS-trained “Reach to Recovery” volunteers; they are breast cancer survivors who make visits to the inpatient units of the hospital and provide comprehensive educational materials and postsurgical exercises for patients who have undergone recent breast cancer surgery. In addition, we have a wide array of referrals and partners, including a genetic counselor who is available to patients with a strong family history of cancer, and a progressive cancer research center with access to all phases of cancer treatment clinical trials. Comprehensive Cancer Support We are fortunate to be able to provide our services free of charge. Upon entering the center, the patient is greeted by a volunteer and offered a snack or beverage. They can choose to take advantage of the center’s computers for guided research on a topic or opt for a personal meeting with a volunteer or staff member. During this time, the needs of the patient are evaluated and educational and support resources provided. The session can span from several minutes to an hour, depending on the amount of personal attention the patient requires. There are several channels through which a patient or caregiver might go when visiting our center. Many patients enter with a recent diagnosis of cancer. In this case, they may be offered a consultation with our Oncology Clinical Nurse Specialist, as well as given a personal health manager notebook for medical paperwork and literature specific to their cancer type. In addition, they may be given a calendar of cancer events, as well as a referral to one of our support groups. Patients are also offered wigs and caps if they do not have the financial resources to purchase one of their own. In some instances we may also make referrals to genetic counseling, psychological counseling, financial aid programs, discounted hotels, and outside ACS support groups that are pertinent and more convenient for the patient. Our community programs include support groups, educational seminars, and cancer prevention and awareness events. Support groups meet 3 times a month and currently address breast, prostate, and gynecologic cancers. For each meeting, the CRC Coordinator arranges for a community expert to speak on a relevant topic in his or her field. Recent topics have included “Using Your Head to Take Care of Your Heart” provided by a cardiologist, and “Acupuncture” by a practitioner of Chinese medicine. Larger events have included our “Medical City Goes Pink” for breast cancer awareness month and

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Cancer Center Profile â&#x20AC;&#x153;Ponytail Donations,â&#x20AC;? for which volunteer hairdressers from the community came to the CRC to assist volunteers who donated their hair for wigs for children with cancer. Awareness Screenings and educational events allow the CRC to further its goal of expanding awareness and supporting prevention efforts. Each month, the CRC targets a type of cancer to highlight and often creates an event centered on education of that cancer. For example, during colon cancer awareness month, March, we hold a colon cancer screening with an educational lunch program by one of our colorectal surgeons. During the free screening open to the community in March 2011, we distributed 73 fecal immunochemical occult blood kits; of the 38 returned, 2 tests had positive findings. In addition to the event itself, a research study was conducted to gauge participantsâ&#x20AC;&#x2122; awareness and knowledge of colon cancer and how to prevent it. Since its inception, the CRC has participated in free screenings for skin, colon, breast, and prostate cancers. These screenings can include anyone from the community and often draw many Medical City employees as well for their own personal screenings.

ulation. We continue to do this through community outreach events, support groups, and screenings. Along these lines, we hope to develop a strong survivorship program to ease the transition from treatment-centered care to survivorship care. We hope to address this with psychosocial programs and followup to ensure that patients are following through with their posttreatment clini-

cal protocols and experiencing a smooth integration back into daily life. The dynamic nature of the CRC ensures that it will continue to expand and find new ways of improving the lives of patients and their families. Through continued community events, screenings, and research, we anticipate that the CRC will remain the premier cancer resource center of north Texas. â&#x2014;?

References 1. Eddleman J, Warren C. Cancer resource center: a setting for patient empowerment. Cancer Pract. 1994;2:371-378. 2. Sutherland G, Dpsych LH, White V, et al. How does a cancer education program impact on people with cancer and their family and friends? J Cancer Educ. 2008;23:126-132. 3. Saca-Hazboun H. Empowering patients with knowledge. An update on trends in patient education. ONS Connect. 2007;5:8-13. 4. Lehto RH. Identifying primary concerns in patients newly diagnosed with lung cancer. Oncol Nurs Forum. 2011;38:440-447.

A Clinical Trial to Evaluate an Investigational Compound (ipilimumab) GPS NFUBTUBUJD QSPTUBUF DBODFS JO QBUJFOUT XIP IBWF GBJMFE IPSNPOBM UIFSBQZ We are now enrolling subjects who meet the following key criteria:

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Collaborative Support The CRC at Medical City Hospital has become a comprehensive support community where patients are able to access all of their nonclinical needs under one roof. The strategic development of the center has ensured that every piece of our operation has been developed with patient satisfaction as the primary goal. In doing so, it has also brought the cancer departments of the hospital together. Through the support groups and community events, the CRC has fostered a collaborative atmosphere with physiciansâ&#x20AC;&#x2122; offices and hospital administrators. Doctors appreciate that the CRC provides their patients with care outside of their offices but does not navigate them away from Medical City. Although the CRC has grown exponentially since its inception, we are always pushing for greater visibility of the center to reach a wider patient pop-

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NCT01057810 or CA184-095

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February 2012 I VOL 5, NO 1

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Breast Cancer

Eribulin Associated With Less Neuropathy Than Ixabepilone in a Prospective, Randomized Study By Caroline Helwick

n a randomized phase 2 study of metastatic breast cancer patients, peripheral neuropathy (PN) was less likely to occur in patients receiving eribulin mesylate than with ixabepilone. “Peripheral neuropathy is a big problem in the treatment of breast cancer. Across the spectrum, patients have it, and we don’t know how to treat it,” said Linda T. Vahdat, MD, of Weill Cornell Medical College in New York, who presented the study at the 2011 CTRCAACR San Antonio Breast Cancer Symposium (Poster P519-02). “If we want to be able to identify patients at risk for peripheral neuropathy and develop strate- Figure. Waterfall graphs of percent change in summed longest diameter of target lesions from baseline to nadir in patients receivgies to manage it we need to ing a) eribulin or b) ixabepilone according to RECIST (ITT population) characterize it better. This trial Figure courtesy of Prash Krishna, MBBS, MRCS. was conceived and started after the close of the EMBRACE trial. It gave us the opportunity to get a better lone as single agents on an every-3-week “We found the incidence of neuropaIn addition, safety end points, handle on how eribulin performed from schedule; the mean number of treatment thy was about 13% lower with eribulin,” including objective response rate and the perspective of side effects. The end- cycles was 6.2 in the eribulin group and Vahdat reported. PN of any grade progression-free survival, based on point was the incidence of neuropathy.” occurred in 31% of the eribulin group Response Evaluation Criteria in EMBRACE demonstrated that and 44% of the ixabepilone group. Solid Tumors, showed greater reduceribulin treatment significantly im- PN was less likely to Grade 3/4 PN occurred in 10% versus tion in the longest diameter of target proved median overall survival by 2.5 20%, respectively. The difference numer- lesions (ie, reducing tumor size) with months compared with standard treat- occur in patients ically favored eribulin, though it was not eribulin (~80%) compared with ments in heavily pretreated metastatic receiving eribulin statistically significant, she added. ixabepilone (~70%) from baseline to breast cancer patients. The overall inci- mesylate than with “Most importantly,” she said, “the nadir, as well as faster rate of change dence of PN in eribulin-treated patients median time to the onset of treatment- with eribulin, as shown in the was 35% and was mostly mild; grade 3 ixabepilone. emergent neuropathy was longer in the Figure. was seen in 8% and grade 4 in <1%. eribulin group: 36 weeks versus only Vahdat acknowledged that if The current study prospectively evaluabout 12 weeks with ixabepilone. By ixabepilone were given weekly, as it ated PN in 101 heavily pretreated 4.8 in the ixabepilone group. Almost cycle 4, only 24% of patients receiving often is, the incidence of PN would metastatic breast cancer patients who one-third of patients in each arm had eribulin had developed neuropathy, com- be lower. The study followed the were randomized to eribulin or ixabepi- received at least 6 prior agents. pared to 44% receiving ixabepilone.” FDA-approved dosing schedule. ●

Highest Risk of Discontinuing Endocrine Therapy Found Among Women With Symptoms From Previous Chemotherapy or Radiation for Breast Cancer By Alice Goodman

quality-of-life analysis of the large randomized NCIC MA.27 trial shows that symptoms of endocrine therapy can be severe and have a negative effect on quality of life. The study also found that women with side effects from previous chemotherapy or radiotherapy before they start taking

February 2012 I VOL 5, NO 1

endocrine therapy are at higher risk for early discontinuation. The most frequent symptoms of aromatase inhibitors are joint pain and hot flashes. For tamoxifen, the most frequent symptoms are hot flashes and vaginal dryness. Many women with breast cancer stop taking hormonal ther-

apy even though it is known to prevent or delay recurrence. The study sought to examine quality of life in women taking aromatase inhibitors and reasons for treatment discontinuation. “Treatment-related symptoms were comparable between anastrozole and exemestane. The frequency of side

effects [from these two aromatase inhibitors] reported by patients was much higher than toxicity reported in clinical trials, and the percentage of moderate-to-severe symptoms was also much higher in patient reports than physician reports of adverse events. We found that symptom burden [of

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Breast Cancer endocrine therapy] negatively affects quality of life,” said Lynne I. Wagner, MD, Northwestern University in Chicago, Illinois, who presented these results at the 2011 CTRC-AACR San Antonio Breast Cancer Symposium. “Another major finding of this study was that women who have side effects from previous cancer treatment before initiating aromatase inhibitor therapy are at high risk for early discontinuation. These women may benefit from monitoring adherence and helping them to manage their side effects,” Wagner told listeners.

Median age was 66 years; most of the women were Caucasian and had good performance status, and 25% to 30% had received prior chemotherapy.

MA.27 was a large, prospective Eastern Cooperative Oncology Group (ECOG)-sponsored clinical trial that enrolled postmenopausal women with primary estrogen receptor–positive early breast cancer and randomized them to 5 years of treatment with 2 different aromatase inhibitors: anastrozole or exemestane. The original study showed that both drugs had comparable anticancer effects on recurrence or new primary breast tumor. The quality-of-life analysis was based on 686 women who provided selfreported outcomes on symptoms using the 46-item PRO-FACT instrument—a disease-specific tool to evaluate side effects. Quality of life was assessed at baseline and again at 3, 6, 12, and 24 months following the initiation of endocrine therapy and included women who stopped taking hormonal therapy over the course of the trial. Median age was 66 years; most of the women were Caucasian and had good performance status, and 25% to 30% had received prior chemotherapy. The women reported the following new symptoms on endocrine therapy: joint pain (55%), weight gain (55%), hot flashes (40%), decreased libido (30%), breast sensitivity (42%), night sweats (28%), and mood swings (22%). The most common new symptoms were also the most common moderate-tosevere symptoms, Wagner explained. The only difference between the two hormonal therapies was in moderate-tosevere fatigue: 15% of the anastrozole group versus 24% of those who received exemestane.

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Early discontinuation of hormonal therapy occurred in 10% by month 24 and 36% by 4.1 years. The prevalence of joint pain was not associated with discontinuation of hormonal therapy. Factors significantly related to early discontinuation were side effects at baseline from previous chemotherapy and radiotherapy, and the number of other medications patients were taking.

Commenting on this study, Patricia Ganz, MD, University of California Jonsson Comprehensive Cancer Center, Los Angeles, said that the strengths of this study were its size and that a diseasespecific instrument was used to evaluate quality of life. “The rates of new joint pain remain high and are no different between the two treatment arms. Hot flashes are also

a problem. The higher rate of baseline symptoms affected discontinuation, showing that prior therapies can influence the degree of being bothered by new side effects and coming off of therapy. Uncontrolled symptoms can impact quality of life, and we need to focus on managing symptoms so that women who can benefit from hormonal therapy continue to take it,” Ganz said. ●

“Quality care is everyone’s business.” Beth Faiman, PhD(c), MSN, APRN-BC, AOCN Nurse Practitioner, Multiple Myeloma Program Cleveland Clinic Taussig Cancer Institute Cleveland, OH

Value-Based Care in Myeloma !&%0!,- !2 &/-%0! %(.!,0%!1( *!,-*! .%0!- ,!& .! .) )-. +/ &%.3 ( !-- %--/!*! % & -! .%)(- "), -! &%(% % (0 ( ! *, .% ! (/,-!- ( *$ ,' %-.- 1%&& &-) ") /- )( .$! /(%+/! $ &&!(#!%( .$! ' ( #!'!(. )" '/&.%*&! '3!&)'

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February 2012 I VOL 5, NO 1

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Warm and Hearty Lentils By Karen Connelly, RD, CSO ake the chill out of winter with the nutrient- tent commonly found in animal proteins. According to packed goodness of lentils. These tiny members the CDC, colon cancer is the second leading cause of of the legume family may be small in size but are cancer death in the United States, and a majority of big on nutrition. Lentils are loaded with vitamins, min- colorectal cancer cases arise in adenomatous polyps. erals, fiber, and protein. They also contain antioxidants Results from a recent research study show that conand phytonutrients—naturally occurring plant com- sumption of legumes at least 3 times per week reduced pounds that help prevent damage to cells throughout the risk of developing colorectal polyps by 33%.1 The the body. Lentils are so versatile that they can be made higher consumption of cooked green vegetables, dried into a variety of different dishes, from appetizers and fruit, legumes, and brown rice was associated with a decreased risk of colorectal polyps.1 Modifying the diet side dishes to main meals and desserts. Lentils have been cultivated for centuries. They are can have a profound impact on reducing the risk of thought to be one of the first agricultural crops in the developing colorectal cancer. Another study looked at the impact of legumes on the world. They are still a staple development of several other food for many cultures around Lentils are so versatile types of cancer and showed the world. Lentils, along with that a higher intake of legumes dried peas and garbanzo beans, that they can be made decreased the risk of upper are known as legumes or pulses. into a variety of different digestive tract cancers, as well They grow in pods that contain and either 1 or 2 lentil seeds. These dishes, from appetizers as stomach, colorectal, kidney cancers.2 More reseeds can be round, oval, or and side dishes to main search is needed to determine heart-shaped and are sold the exact impact that lentils whole or split into halves. meals and desserts. and other legumes have on Lentils come in a variety of colreducing the risk of cancer. ors, with brown and green being the most popular, but they can also be found in Specific populations may also benefit from increased lentil and legume intake, as evidenced by the results of black, yellow, red, and orange. The nutritional benefits of lentils lend themselves to a study examining the effect of legume intake on the the prevention and management of a number of med- development of colorectal adenomas in Africanical conditions. Lentils can help improve heart health Americans. The study showed that consumption of by lowering cholesterol levels as well as improve legumes such as lentils, dried beans, and split peas was glycemic control in diabetes. There are also studies to associated with a reduced risk of formation and growth support their role in reducing the risk of certain types of of adenomas.3 The incidence of colorectal cancer is cancer. Another important function of lentils is in higher in African-American men and women, accordweight management because of their low fat, complex ing to the 2007 CDC cancer incidence rates report.4 carbohydrate, and high protein content. The nutrition- Based on these statistics, the results of this study and al profile of lentils makes them an essential part of a others that show a positive impact of increased intake healthy diet and an asset in helping to improve the of fruits, vegetables, grains, and legumes on cancer prevention is powerful information that can be used to quality of one’s diet. A common theme in the prevention of cancer and in help specific populations reduce their risk of cancer by the dietary recommendations proposed in survivorship making targeted dietary changes. Obesity, diabetes, and cardiovascular disease are is to move toward a plant-based diet. Lentils are an important part of this diet plan as they offer the vita- also among the most common health conditions that mins and minerals, fiber, and phytochemicals most plague Americans. Lentils and other legumes are the often found in vegetables and also the rich protein con- perfect food to help manage these conditions. The high fiber content makes the lentil ideal for improving cholesterol levels, regulating blood sugars, and ensuring satiety and calorie control. Lentils contain both Ms Connelly is a Registered insoluble fiber, the type that helps maintain bowel Dietitian and Certified Specialist in Oncology Nutrition at the regularity, and soluble fiber, the type that helps Steeplechase Cancer Center in remove impurities from the body. The lower fat conSomerville, New Jersey. As tent of lentils makes them a smart substitution for a part of her responsibilities, she higher-fat animal protein. The high-quality protein provides nutrition counseling, and complex carbohydrates found in lentils are group classes, and monthly responsible for their satiating property. Encouraging cooking classes for patients patients to make 1 meal per week meatless is a great and families. way to help them reach their fruit and vegetable goals.

February 2012 I VOL 5, NO 1

The USDA makes it easy for people to track the quality of their diet by using the ChooseMyPlate.gov Web site.5 This Web site allows people to keep track of what they are consuming and if they are consuming the recommended amounts of each food group. The American Institute for Cancer Research also encourages a plant-based diet in which two-thirds or more of the plate consists of vegetables, fruits, grains, and legumes and one-third or less of animal protein.6 These tools allow patients to make gradual, sustaining lifestyle and dietary changes that can greatly enhance their overall health. Arming patients with diet education and empowering them with the tools they can use to make these changes in order to produce a positive impact on their health is indispensable to their cancer journey. Whether they are green, brown, red, orange, or black, lentils provide a substantial nutrient profile in such a pint-sized package. A 1-cup serving of lentils provides approximately 18 g of protein, 16 g of fiber, less than 2 g of fat, and a minimal amount of sodium. Lentils are also an excellent source of potassium, magnesium, phosphorus, and folate, and a good source of calcium, iron, zinc, vitamin C, and B vitamins, with the exception of vitamin B12. Unlike dried beans, lentils do not need to be presoaked prior to use. Before cooking, rinse them under cold water in a strainer to remove any debris that may have gotten mixed in with the lentils during packaging. When cooking lentils, it is best if you add the lentils once the water is boiling, as this will make them easier to digest. They can be bought in bulk, prepackaged, or canned. If lentils are bought in bulk, be sure the store has adequate turnover and the lentils are fresh. Canned lentils retain their nutritional value, making them a good alternative for a quick addition to any meal. Many grocery stores now carry a number of different varieties of lentils. The availability of lentils and other legumes in grocery stores and not just specialty stores is making it easier for health professionals to encourage patients to increase their intake of these healthy foods and for patients to be able to do so successfully. Hopefully this is turning the tide to accessibility and healthier eating habits for all people. ● References 1. Tantamango YM, Knutsen SF, Beeson WL, et al. Foods and food groups associated with the incidence of colorectal polyps: the Adventist Health Study. Nutr Cancer. 2011;63:565-572. 2. Aune D, De Stefani E, Ronco A, et al. Legume intake and the risk of cancer: a multisite case-control study in Uruguay. Cancer Causes Control. 2009;20:1605-1615. 3. Agurs-Collins T, Smoot D, Afful J, et al. Legume intake and reduced colorectal adenoma risk in African-Americans. J Natl Black Nurses Assoc. 2006;17:6-12. 4. Colorectal (colon) cancer incidence rates. Centers for Disease Control and Prevention Web site. www.cdc.gov/features/dsColorectalCancer/. Accessed January 20, 2012. 5. ChooseMyPlate.gov. United States Department of Agriculture Web site. www.choosemyplate.gov/. Accessed January 20, 2012. 6. The New American Plate. American Institute for Cancer Research Web site. www.aicr.org/new-american-plate/. Accessed January 20, 2012.

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Karen

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Recipes â&#x2013; Mediterranean White Bean and Lentil Salad Ingredients Â˝ cup white beans (rinsed and soaked overnight) Â˝ cup brown lentils (rinsed and soaked overnight) 2 cups low-sodium vegetable stock 4 sprigs parsley, chopped 1 medium tomato, diced Â˝ medium cucumber, diced 1 medium red pepper, diced Âź cup carrots, shredded

â&#x2013; Brown Lentil Hummus

2 scallions Â˝ cup green olives, chopped 1 tablespoon fresh dill, chopped Âź cup raisins Â˝ cup chickpeas Âź cup lemon juice Âž cup olive oil

1. Cook white beans in low-sodium vegetable stock until tender. 2. Cook lentils in low-sodium vegetable stock until tender. 3. Let beans cool. 4. Toss together with remaining ingredients.

ÂŠiStockphoto.com/Alasdair Thomson

Nutritional Information Yield: 12 servings 170 calories, 6 g total fat, 0 mg cholesterol, 5 g dietary fiber, 110 mg sodium, 7 g protein

Newsletter Series

YOUR QUESTIONS ANSWERED

Ingredients 5 cups of water â&#x2026;&#x201D; cup dried brown lentils 3 (6-inch) whole wheat pitas, each cut into 8 wedges Cooking spray Âź teaspoon ground coriander Âž teaspoon salt, divided 1Â˝ tablespoons fresh lemon juice 1Â˝ tablespoons tahini (sesame seed paste) Âź teaspoon hot pepper sauce 2 garlic cloves 1 tablespoon chopped fresh cilantro

1. Preheat oven to 425Â°F 2. Bring water and lentils to a boil in a medium saucepan. Cover, reduce heat, and simmer for 20 minutes or until tender. Drain and rinse with cold water; drain. 3. Arrange pita wedges in a single layer on a baking sheet; coat pita wedges with cooking spray. Sprinkle evenly with coriander and Âź teaspoon salt. Bake pita wedges at 425Â°F for 10 minutes or until golden brown. 4. Combine cooked lentils, remaining Â˝ teaspoon salt, lemon juice, tahini, hot pepper sauce, and garlic in a food processor; process until smooth. Spoon mixture into a bowl; cover and chill. Sprinkle lentil mixture with cilantro. Serve with pita crisps. Nutritional Information Serving size: about 2Â˝ tablespoons lentil mixture and 2 pita crisps Yield: 12 servings 91 calories, 1.5 g fat, 0.2 g saturated fat, 0.5 g monounsaturated fat, 0.7 g polyunsaturated fat, 4.7 g protein, 15.7 g carbohydrate, 3.7 g fiber, 0 mg cholesterol, 1.6 mg iron, 235 mg sodium, 12 mg calcium

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Editor in Chief

Sagar Lonial, MD

Stephanie A. Gregory, MD

Associate Professor of Hematology and Oncology Emory University School of Medicine

The Elodia Kehm Chair of Hematology Professor of Medicine Director, Section of Hematology Rush University Medical Center/Rush University

Topics include: â&#x20AC;˘ Newly Diagnosed Patients â&#x20AC;˘ Maintenance Therapy â&#x20AC;˘ Transplant-Eligible Patients â&#x20AC;˘ Retreatment â&#x20AC;˘ Transplant-Ineligible Patients â&#x20AC;˘ Cytogenetics â&#x20AC;˘ Side-Effect Management â&#x20AC;˘ Bone Health

Topics include: â&#x20AC;˘ Hodgkin Lymphoma â&#x20AC;˘ Follicular Lymphoma â&#x20AC;˘ Mantle Cell Lymphoma â&#x20AC;˘ Waldenstromâ&#x20AC;&#x2122;s Macroglobulinemia â&#x20AC;˘ Diffuse Large B-Cell Lymphoma â&#x20AC;˘ T-Cell Lymphoma

This activity is supported by an educational grant from Millennium Pharmaceuticals, Inc.

This activity is supported by educational grant from Cephalon Oncology, Millennium Pharmaceuticals, Inc., and Seattle Genetics, Inc.

Target Audience These activities were developed for physicians, nurses, and pharmacists.

Accreditation This activity has been approved for 1.0 AMA PRA Category 1 Creditâ&#x201E;˘ (a total of 14.0 credit hours will be issued for completion of all activities). Nursing and Pharmacy credit hours will also be provided. For complete learning objectives and accreditation information, please refer to each activity. This activity is jointly sponsored by Global Education Group and Medical Learning Institute, Inc. Coordination for this activity provided by Center of Excellence Media, LLC.

For information about the physician accreditation of this activity, please contact Global at 303-395-1782 or inquire@globaleducationgroup.com. COEAsize40611MM

February 2012 I VOL 5, NO 1

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Multiple Myeloma

The Health Burden of Multiple Myeloma: Subcutaneous Bortezomib a New, Convenient Route of Administration Option By Rhonda Williams

n 2011, the American Cancer Society projected there would be 20,520 cases of newly diagnosed multiple myeloma (MM) and 10,610 deaths from the disease that year.1 MM is an incurable hematologic cancer marked by great heterogeneity in terms of its biology and clinical course. Morbidity and survival rates vary widely, even in the age of novel, molecularly based targeted therapies. Many factors account for the differences in prognoses among patients with MM, including genomic aberrations in the plasma cells of the myeloma neoplasm. Survival outcomes range from <1 year in patients with aggressive disease to >10 years in those with indolent disease.2 A variety of patient-, disease-, and therapy-related characteristics have been identified to predict the disease course and outcome among patients with MM. Evaluation of prognostic factors and risk stratification is important to define appropriate treatment strategies, compare therapeutic outcomes, and predict survival among patients.2 The Approach to Therapy in Multiple Myeloma Use of the proteasome inhibitor bortezomib (Velcade), the immunomodulato-

SC administration of bortezomib 1.3 mg/m2 twice weekly significantly reduced the incidence of peripheral neuropathy compared with IV administration at the same dose and schedule, with no deleterious effect on efficacy.

ry agents lenalidomide (Revlimid) and thalidomide (Thalomid), and bisphosphonates such as zoledronic acid (Zometa) and pamidronate (Aredia) has revolutionized the management of patients with MM. These therapies, however, are all associated with potentially serious side effects, which can negatively affect a patientâ&#x20AC;&#x2122;s quality of life. The majority of preferred regimens for initial therapy are 3-drug combinations, although some 2-drug combinations are also recommended in the current guidelines from the National Comprehensive Cancer Network, because these multidrug regimens are associated with the best response rates.3

Table 1 Summary of Efficacy Analyses in the Relapsed MM Study of Bortezomib SC Versus IV5 Intent-to-Treat Population

Bortezomib SC (n = 148)

Bortezomib IV (n = 74)

63 (43)

31 (42)

Primary end point Response rate at 4 cycles ORR (CR + PR), n (%) Ratio of response rates (95% CI) CR, n (%) PR, n (%) nCR, n (%)

1.01 (0.73, 1.40) 11 (7) 52 (35) 9 (6)

6 (8) 25 (34) 4 (5)

ORR (CR + PR), n (%) CR, n (%) PR, n (%)

78 (53) 17 (11) 61 (41)

38 (51) 9 (12) 29 (39)

nCR, n (%)

14 (9)

7 (9)

Median time to progression, months

10.4

9.4

Median progression-free survival, months

10.2

8.0

1-year overall survival, %*

72.6

76.7

Secondary end points Response rate at 8 cycles

*Median duration of follow-up is 11.8 months. CI, confidence interval; CR, complete response; MM, multiple myeloma; nCR, near-complete response; ORR, overall response rate; PR, partial response; SC, subcutaneous.

February 2012 I VOL 5, NO 1

New Treatment Option The proteasome is an enzyme complex that exists in all cells and plays an important role in degrading proteins that control the cell cycle and cellular processes. By blocking the proteasome, bortezomib disrupts biologic pathways related to the growth and survival of cancer cells.4 Bortezomib was approved by the FDA in 2003 for IV injection for the treatment of patients with MM who had received at least 2 previous therapies and had demonstrated disease progression on their last therapy.4 In 2008, the FDA approved an expanded indication for bortezomib for the first-line treatment of patients with previously untreated MM. The approval was based on data from the VISTA trial, which compared the addition of bortezomib to melphalan plus prednisone (MP) versus MP without bortezomib (ie, control group) in 682 patients with newly diagnosed MM. At a median follow-up of 16.3 months, the addition of bortezomib to the MP regimen resulted in significantly improved outcomes, including improved response rates, increased time to disease progression, overall survival (OS), and progressionfree survival.5 The trial was stopped early and patients in the control group were permitted to cross over to the bortez omib regimen. In December 2011, results of 5-year median follow-up of the VISTA trial confirmed a >13-month OS advantage of the bortezomib plus MP regimen for patients with previously untreated MM. Bortezomib is also indicated for the treatment of patients with mantle cell lymphoma who have received at least 1 previous therapy.5 In January 2012, the FDA approved a new route of administration for bortezomib. The new subcutaneous (SC)

form of bortezomib for injection offers patients an easier mode of administration, with a safety profile comparable to the IV form but with significantly reduced peripheral neuropathy (6% vs 16%, respectively),5 providing patients with MM a new option for route of administration. Clinical Pharmacology of Bortezomib

Mechanism of Action Bortezomib is a reversible inhibitor of the chymotrypsin-like activity of the 26S proteasome in mammalian cells; the 26S proteasome degrades ubiquitinated proteins. The ubiquitin-proteasome pathway plays an essential role in regulating the intracellular concentration of specific proteins, thereby maintaining homeostasis within cells. Inhibition of this pathway can therefore affect multiple signaling cascades within the cell and can lead to cell death.5 Pharmacodynamics After twice-weekly administration of bortezomib 1 mg/m2 and 1.3 mg/m2, the maximum inhibition of 20S proteasome activity, relative to baseline, occurred 5 minutes after drug administration.5 Pharmacokinetics After IV administration of bortezomib 1 mg/m2 and 1.3 mg/m2 in 24 patients with MM, the maximum plasma concentrations (Cmax) of bortezomib were 57 ng/mL and 112 ng/mL, respectively. The mean elimination half-life of bortezomib with multiple dosing ranged from 40 to 193 hours after administration of the 1 mg/m2 dose and 76 to 108 hours after administration of the 1.3 mg/m2 dose. After an IV or a bolus SC injection of a 1.3 mg/m2 dose in patients with MM, the total systemic exposure with a repeat dose administration was equivalent for the SC and the IV routes of administration. The Cmax after SC administration (20.4 ng/mL) was lower than that after IV administration (223 ng/mL).5 In vitro studies suggest that bortez omib is primarily oxidatively metabolized via the cytochrome P450 enzymes 3A4, 2C19, and 1A2.5 Phase 3 Clinical Trials: SC Versus IV Bortezomib The FDA approval of SC bortezomib was based on a randomized, open-label,

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Multiple Myeloma phase 3, noninferiority trial that compared the efficacy and safety of SC versus IV administration of bortezomib in patients with relapsed MM. A total of 222 bortezomib-naive patients were randomly assigned, in a 2:1 ratio, to receive bortezomib 1.3 mg/m2 by either SC injection (n = 148) or IV infusion (n = 74) for 8 cycles. Patients were stratified according to the number of lines of previous therapy they had received (1 previous line vs >1 previous line of therapy) and stage of disease, using International Staging System (ISS) stage I, II, or III.5 The primary study end point was to demonstrate noninferiority of singleagent SC bortezomib with respect to overall response rate (ORR)—complete response (CR) plus partial response (PR). In this study, noninferiority was defined as retaining at least 60% of the ORR relative to single-agent IV bor tezomib after 4 cycles of therapy.5 Patients who did not obtain an optimal response (less than CR) to treatment with bortezomib alone after 4 cycles were allowed to receive oral dexamethasone 20 mg daily on the day of and day after bortezomib administration (n = 82 in the SC treatment group; n = 39 in the IV treatment group). Patients with baseline grade ≥2 peripheral neuropathy or neuropathic pain, or platelet counts <50,000/μL, were excluded from trial participation. A total of 218 patients were evaluable for response.5

Table 2 Most Common Adverse Events (≥10%) in the Relapsed MM Study of Bortezomib SC Versus IV5 Bortezomib SC (n =147)* toxicity MedDRA System Organ Class MedDRA preferred term

Total n (%)

grade 3

grade ≥4

n (%)

Bortezomib IV (n = 74)* toxicity grade 3

grade ≥4

n (%)

Total n (%)

n (%)

Blood and lymphatic system disorders Anemia

53 (36)

14 (10)

4 (3)

26 (35)

6 (8)

Leukopenia

29 (20)

9 (6)

16 (22)

4 (5)

1 (1)

Neutropenia

42 (29)

22 (15)

4 (3)

20 (27)

10 (14)

3 (4)

Thrombocytopenia 52 (35) Gastrointestinal disorders

12 (8)

7 (5)

27 (36)

8 (11)

6 (8)

Abdominal pain

5 (3)

1 (1)

8 (11)

Abdominal pain upper

3 (2)

8 (11)

Constipation

21 (14)

1 (1)

11 (15)

1 (1)

Diarrhea

35 (24)

2 (1)

1 (1)

27 (36)

3 (4)

1 (1)

Nausea

27 (18)

14 (19)

Vomiting

17 (12)

3 (2)

12 (16)

1 (1)

General disorders and administration site conditions Asthenia Fatigue

23 (16) 17 (12)

3 (2) 3 (2)

0 0

14 (19) 15 (20)

4 (5) 3 (4)

0 0

Pyrexia

28 (19)

12 (16)

16 (11)

2 (1)

7 (9)

1 (1)

22 (15)

2 (3)

1 (1)

7 (9)

Infections and infestations Herpes zoster Investigations Weight decreased

Metabolism and nutrition disorders Decreased appetite

14 (10)

Musculoskeletal and connective tissue disorders Back pain Pain in extremity

The primary study end point was to demonstrate noninferiority of singleagent SC bortezomib with respect to overall response rate.

21 (14)

1 (1)

8 (11)

1 (1)

8 (5)

1 (1)

8 (11)

2 (3)

0 5 (3)

0 0

8 (11) 17 (23)

0 7 (9)

0 0

56 (38)

8 (5)

1 (1)

39 (53)

11 (15)

1 (1)

18 (12)

8 (11)

Nervous system disorders Headache 5 (3) Neuralgia 35 (24) Peripheral neuropathies NEC† Psychiatric disorders Insomnia

Respiratory, thoracic, and mediastinal disorders Dyspnea The baseline demographic and other characteristics of the 2 treatment groups were similar. The median patient age was approximately 64 years (range, 38-88 years), and the majority of patients were male (SC, 50%; IV, 64%). The primary type of myeloma was immunoglobulin G. ISS stage I/II/III was 27%, 41%, and 32%, respectively, with both SC and IV routes of administration. The Karnofsky performance status score was ≤70 in 22% of SC-treated patients and 16% of IV-treated patients. Creatinine clearance was 67.5 mL/min in the SC group and 73 mL/min in the IV group. The median years from diagnosis were 2.68 years and 2.93 years in the SC and IV groups, respectively. The

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11 (7)

2 (1)

9 (12)

2 (3)

14 (10)

3 (2)

3 (4)

Vascular disorders Hypertension

*Safety population: 147 patients in the SC treatment and 74 patients in the IV treatment who received at least 1 dose of study medication. † Represents MedDRA high-level term. MedDRA, Medical Dictionary for Regulatory Affairs; NEC, not elsewhere classified; SC, subcutaneous.

proportion of patients with >1 prior line of therapy was 38% with SC treatment versus 35% with IV treatment.5 This study met its primary objective (noninferiority) that treatment with single-agent SC bortezomib retains at least 60% of the ORR after 4 cycles versus IV bortezomib (Table 1).5 Safety Profile: Reduced Peripheral Neuropathy With SC Administration The safety data reported herein are

from the randomized, open-label study that compared the SC administration of bortezomib with IV administration of bortezomib at the recommended dose of 1.3 mg/m2 in 222 patients with relapsed MM. Overall, the safety data were similar between the SC and IV treatment groups (Table 2), but with significant differences in some adverse events (AEs) favoring the SC form of bortezomib. Differences of ≥5% between the

2 groups favoring the SC administration were reported for neuralgia (3% SC vs 9% IV), peripheral neuropathy grade ≥3 (6% SC vs 16% IV) and all grades (38% vs 53%), and thrombocytopenia (13% SC vs 19% IV).5 In the SC treatment group, local reactions, primarily redness, were reported in 6% of patients; 2 patients (1%) experienced local reactions that were considered severe (1 case of pruritus and 1 case of redness). These reac-

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Multiple Myeloma tions resolved in a median of 6 days. Local reaction led to study discontinuation in 1 patient and reduction in dose concentration in 1 patient.5 Dose reductions associated with drug-related AEs were reported in 31% of patients in the SC group compared with 43% of patients in the IV group. The most common AEs leading to dose reduction included sensory peripheral neuropathy (17% SC vs 31% IV) and neuralgia (11% SC vs 19% IV).5 Warnings and Precautions Associated With Bortezomib

Peripheral Neuropathy Peripheral neuropathy has long been recognized as a problem, because it is frequently associated with both MM and its treatment. The peripheral neuropathy associated with bortezomib use is primarily sensory; however, cases of severe sensory and motor peripheral neuropathy have been reported with use of the agent. Patients with preexisting symptoms such as numbness, pain, or a burning sensation in the feet or hands, and/or signs of peripheral neuropathy, may experience worsening of peripheral neuropathy, including grade ≥3, during treatment with bortezomib.5 A paradigm shift regarding bortezomib use currently exists, with recent data suggesting that changing the mode of administration or dosing schedule can substantially impact the incidence of neuropathy. The results of a phase 3 study by Moreau and colleagues that included patients with relapsed MM who had received 1 to 3 previous lines of therapy showed that SC administration of bortezomib 1.3 mg/m2 twice weekly significantly reduced the incidence of peripheral neuropathy compared with IV administration at the same dose and schedule, with no deleterious effect on efficacy.6 The protocol of this study provided for a robust comparison of the 2 routes of administration, since it specified 4 cycles of single-agent bortezomib with the addition of oral dexamethasone 20 mg to enhance response at the end of cycle 4 in patients who achieved a suboptimal response.6 In this trial, the incidence of grade ≥2 peripheral neuropathy was 24% in patients who received SC bortezomib and 41% in those who received IV bortezomib.5,6 Also in this trial, grade ≥3 peripheral neuropathy occurred in 6% of patients in the SC treatment group and 16% of those in the IV treatment group.5,6 When initiating bortezomib therapy, SC administration may be considered for patients with preexisting peripheral neuropathy or those who are at high risk for developing peripheral neuropathy. In patients with preexisting, severe peripheral neuropathy, the risk-benefit

February 2012 I VOL 5, NO 1

Table 3 Recommended Dose Modification for Bortezomib-Related Neuropathic Pain and/or Peripheral Sensory or Motor Neuropathy5 Severity of Peripheral Neuropathy Modification of Dose and Regimen Signs and Symptoms* Grade 1 (asymptomatic; loss of deep No action tendon reflexes or paresthesia) without pain or loss of function Grade 1 with pain or grade 2 (moderate Reduce bortezomib to 1 mg/m2 symptoms; limiting instrumental activities of daily living [ADL])† Grade 2 with pain or grade 3 (severe symptoms; limiting self-care ADL)‡

Grade 4 (life-threatening consequences; urgent intervention indicated)

Withhold bortezomib therapy until toxicity resolves; when toxicity resolves reinitiate with a reduced dose of bortezomib at 0.7 mg/m2 once weekly Discontinue bortezomib

*Grading is based on NCI Common Terminology Criteria for Adverse Events (CTCAE) v4.0. † Instrumental ADL refers to preparing meals, shopping for groceries or clothes, using telephone, managing money. ‡ Self-care ADL refers to bathing, dressing and undressing, feeding self, using the toilet, taking medications, and not bedridden.

should be carefully assessed prior to beginning bortezomib therapy.5 Prevention rather than treatment is the best approach to use when addressing bortezomib-related neuropathy. One advantage of bortezomib is that most episodes of grade 3/4 neuropathy can be prevented by closely adhering to the algorithm for dose modification and interruption provided in the prescribing information (Table 3). By following these recommendations, the severity of peripheral neuropathy can usually be decreased to grade 1 or 2, and in many cases, patients may resume bortezomib therapy.5

Prevention rather than treatment is the best approach to use when addressing bortezomibrelated neuropathy.

Hypotension The incidence of hypotension, which included postural hypotension, orthostatic hypotension, and hypotension not otherwise specified, reported with the use of bortezomib was 13%. These events occurred throughout treatment. Caution should be used when administering bortezomib to patients with a history of syncope, those receiving medications known to be associated with hypotension (eg, antihypertensive agents), and persons who are dehydrated.5

Cardiac Disorders Exacerbation or acute development of congestive heart failure and new onset of decreased left ventricular ejection fraction (LVEF) have been reported in patients receiving treatment with bortezomib, including those with no known risk factors for decreased LVEF. Thus, patients at risk for the development of heart disease or those with a history of existing heart disease should be monitored closely.5 Pulmonary Disorders Reports of acute diffuse infiltrative pulmonary disease of unknown etiology, such as pneumonitis, interstitial pneumonia, acute respiratory distress syndrome, and lung infiltration, have been noted among patients receiving treatment with bortezomib.5 Reversible Posterior Leukoencephalopathy Syndrome Reversible posterior leukoencephalopathy syndrome (RPLS), a rare, reversible neurologic disorder that can present with seizure, hypertension, lethargy, headache, blindness, confusion, and other visual and neurologic disturbances, has been reported in patients receiving bortezomib therapy. Bortezomib should be discontinued in patients who develop RPLS that has been confirmed by brain imaging, preferably MRI.5 Gastrointestinal Events Nausea, diarrhea, constipation, and vomiting, at times requiring the use of antiemetic therapy and antidiarrheal agents, have been reported in patients receiving bortezomib. In order to prevent dehydration, fluid and electrolyte replacement should be administered to these patients.5

Thrombocytopenia and Neutropenia Bortezomib is associated with the development of thrombocytopenia and neutropenia that follows a cyclical pattern, with nadirs that generally occur following the last dose of each cycle and typically recover prior to initiation of the next cycle of therapy. This cyclical pattern remained consistent over 8 cycles of twice-weekly therapy, with no evidence of cumulative thrombocytopenia or neutropenia observed. In patients experiencing thrombocytopenia, platelet counts should be monitored prior to the administration of each dose; an adjustment in dose and/or schedule may be required. There have been reports of gastrointestinal and intracerebral hemorrhage associated with the use of bortezomib.5 Tumor Lysis Syndrome Tumor lysis syndrome may occur with the use of bortezomib because the agent is cytotoxic and can rapidly kill malignant cells. Patients with a high tumor burden prior to therapy may be at a higher risk for the development of tumor lysis syndrome.5 Hepatic Events Acute liver failure has occurred in bortezomib-treated patients receiving multiple concomitant medications and in those with serious underlying medical conditions. Other hepatic events reported with the use of bortezomib include elevations in liver enzymes, hyperbilirubinemia, and hepatitis.5 Hepatic Impairment Because bortezomib is metabolized by the liver, exposure is increased in patients with moderate or severe hepatic impairment. Therefore, such patients should be started on reduced doses of bortezomib and closely monitored for the development of toxicities.5 Use in Pregnancy Women of childbearing potential should avoid becoming pregnant while being treated with bortezomib.5 Dosing Bortezomib is for IV or SC administration only and should not be administered by any other route. The recommended starting dose of bortezomib is 1.3 mg/m2 for both SC and IV forms of administration. Because each route of administration has a different reconstituted concentration, caution should be used when calculating the volume of drug to be administered. With IV administration, the recommended concentration of bortezomib is 1 mg/mL; with SC administration, the recommended concentration of bortezomib is 2.5 mg/mL.5

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The Oncology Nurse-APN/PA is pleased to announce the Second Annual Oncology Nurse Excellence award sponsored by TREANDA.

Who Will Be the

ONE?

The Oncology Nurse Excellence Award Winner The Oncology Nurse-APN/PA Nurse Excellence award will recognize an oncology nurse nominated by his/her peers for an outstanding contribution to oncology nursing practice, patient care, research, or education in 2011. The four leading nominees will be profiled in the April issue of The Oncology Nurse-APN/PA. Readers will have an opportunity to vote for the winner online at www.TheOncologyNurse.com/award or by visiting The Oncology Nurse-APN/PA booth at the 2012 ONS Congress. The winner will be announced in the June issue of The Oncology Nurse-APN/PA.

TREANDA is manufactured by Cephalon, Inc., a wholly owned subsidiary of Teva Pharmaceutical Industries Ltd.

Nomination forms are available at

www.TheOncologyNurse.com/award

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Multiple Myeloma Dosage in Patients With Previously Untreated MM In patients with previously untreated MM, bortezomib is administered in combination with oral melphalan and oral prednisone for a total of nine 6week treatment cycles. In cycles 1 through 4, bortezomib is administered twice weekly (on days 1, 4, 8, 11, 22, 25, 29, and 32). In cycles 5 through 9, bortezomib is administered once weekly (on days 1, 8, 22, and 29). At least 72 hours should elapse between consecutive doses of bortezomib.5 Dosage in Patients With Relapsed MM or Mantle Cell Lymphoma In patients with relapsed MM or mantle cell lymphoma, bortezomib 1.3 mg/m2 per dose is administered twice weekly for 2 weeks (on days 1, 4, 8, and 11), followed by a 10-day rest period (days 12 through 21). For extended therapy of more than 8 cycles, bortezomib may be administered according to the standard schedule or on a maintenance, once-weekly schedule for 4 weeks (days 1, 8, 15, and 22), followed by a 13-day rest period.5

is used, the site for each injection (thigh or abdomen) should be rotated. New injections should be given at least 1 inch from an old site and never into areas where the site is tender, bruised, erythematous, or indurated.5 If local injection site reactions occur after SC bortezomib administration, a less concentrated bortezomib solution (1 mg/mL instead of 2.5 mg/mL) may be used for SC administration.

Alternatively, the IV route of administration may be considered.5 Conclusion MM is an incurable hematologic cancer with great clinical burden. The use of bortezomib, and lenalidomide and thalidomide, as well as zoledronic acid and pamidronate, has revolutionized the management of patients with MM. These therapies, however, are all associ-

PROVENGEÂ® (sipuleucel-T) Suspension for Intravenous Infusion

Rx Only

BRIEF SUMMARY â&#x20AC;&#x201D; See full Prescribing Information for complete product information

INDICATIONS AND USAGE: PROVENGEÂ® (sipuleucel-T) is an autologous cellular immunotherapy indicated for the treatment of asymptomatic or minimally symptomatic metastatic castrate resistant (hormone refractory) prostate cancer. DOSAGE AND ADMINISTRATION Å&#x2DC; For Autologous Use Only. Å&#x2DC; 7KH UHFRPPHQGHG FRXUVH RI WKHUDS\ IRU 3529(1*( LV FRPSOHWH GRVHV JLYHQ DW DSSUR[LPDWHO\ ZHHN LQWHUYDOV Å&#x2DC; 3UHPHGLFDWH SDWLHQWV ZLWK RUDO DFHWDPLQRSKHQ DQG DQ DQWLKLVWDPLQH VXFK DV diphenhydramine. Å&#x2DC; %HIRUH LQIXVLRQ FRQÅµUP WKDW WKH SDWLHQWÅ&#x2018;V LGHQWLW\ PDWFKHV WKH SDWLHQW LGHQWLÅµHUV RQ the infusion bag. Å&#x2DC; Do Not Initiate Infusion of Expired Product. Å&#x2DC; ,QIXVH 3529(1*( LQWUDYHQRXVO\ RYHU D SHULRG RI DSSUR[LPDWHO\ PLQXWHV Do Not Use a Cell Filter. Å&#x2DC; ,QWHUUXSW RU VORZ LQIXVLRQ DV QHFHVVDU\ IRU DFXWH LQIXVLRQ UHDFWLRQV GHSHQGLQJ RQ WKH VHYHULW\ RI WKH UHDFWLRQ (See Dosage and Administration [2] of full Prescribing Information.) CONTRAINDICATIONS: None. WARNINGS AND PRECAUTIONS Å&#x2DC; PROVENGE is intended solely for autologous use.

Peripheral neuropathy has long been recognized as a problem, because it is frequently associated with both MM and its treatment.

Å&#x2DC; Acute infusion reactions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ÅµUVW LQIXVLRQ DQG GHFUHDVHG WR following the third infusion. Some (1.2%) patients in the PROVENGE group were KRVSLWDOL]HG ZLWKLQ GD\ RI LQIXVLRQ IRU PDQDJHPHQW RI DFXWH LQIXVLRQ UHDFWLRQV 1R *UDGH RU DFXWH LQIXVLRQ UHDFWLRQV ZHUH UHSRUWHG LQ SDWLHQWV LQ WKH PROVENGE group. &ORVHO\ PRQLWRU SDWLHQWV ZLWK FDUGLDF RU SXOPRQDU\ FRQGLWLRQV ,Q WKH HYHQW RI DQ DFXWH LQIXVLRQ UHDFWLRQ WKH LQIXVLRQ UDWH PD\ EH GHFUHDVHG RU WKH LQIXVLRQ VWRSSHG GHSHQGLQJ RQ WKH VHYHULW\ RI WKH UHDFWLRQ $SSURSULDWH PHGLFDO WKHUDS\ VKRXOG EH administered as needed.

Dose Modifications A patientâ&#x20AC;&#x2122;s platelet count should be â&#x2030;¥70 Â¥ 109/L and his or her absolute neutrophil count should be â&#x2030;¥1.0 Â¥ 109/L before receiving any cycle of therapy with bortezomib in combination with melphalan and prednisone. All nonhematologic toxicities should have resolved to grade 1 or to baseline level.5 Dose modification guidelines for patients with relapsed MM or mantle cell lymphoma state that bortezomib therapy should be withheld at the onset of any grade 3 nonhematologic or grade 4 hematologic toxicities excluding neuropathy, which is discussed separately. Once the symptoms of the toxicity have resolved, bortez omib therapy may be reinitiated at a 25% reduced dose.5 Administration Precautions When the SC route of administration

February 2012 I VOL 5, NO 1

Å&#x2DC; Handling Precautions for Control of Infectious Disease. PROVENGE is not URXWLQHO\ WHVWHG IRU WUDQVPLVVLEOH LQIHFWLRXV GLVHDVHV 7KHUHIRUH SDWLHQW leukapheresis material and PROVENGE may carry the risk of transmitting infectious GLVHDVHV WR KHDOWK FDUH SURIHVVLRQDOV KDQGOLQJ WKH SURGXFW 8QLYHUVDO SUHFDXWLRQV should be followed. Å&#x2DC; Concomitant Chemotherapy or Immunosuppressive Therapy. Use of either FKHPRWKHUDS\ RU LPPXQRVXSSUHVVLYH DJHQWV VXFK DV V\VWHPLF FRUWLFRVWHURLGV JLYHQ FRQFXUUHQWO\ ZLWK WKH OHXNDSKHUHVLV SURFHGXUH RU 3529(1*( KDV QRW EHHQ VWXGLHG 3529(1*( LV GHVLJQHG WR VWLPXODWH WKH LPPXQH V\VWHP DQG FRQFXUUHQW XVH RI LPPXQRVXSSUHVVLYH DJHQWV PD\ DOWHU WKH HIÅµFDF\ DQG RU VDIHW\ RI 3529(1*( 7KHUHIRUH SDWLHQWV VKRXOG EH FDUHIXOO\ HYDOXDWHG WR GHWHUPLQH ZKHWKHU LW LV PHGLFDOO\ DSSURSULDWH WR UHGXFH RU GLVFRQWLQXH LPPXQRVXSSUHVVLYH DJHQWV SULRU WR WUHDWPHQW with PROVENGE. Å&#x2DC; Product Safety Testing. PROVENGE is released for infusion based on the microbial DQG VWHULOLW\ UHVXOWV IURP VHYHUDO WHVWV PLFURELDO FRQWDPLQDWLRQ GHWHUPLQDWLRQ E\ *UDP VWDLQ HQGRWR[LQ FRQWHQW DQG LQ SURFHVV VWHULOLW\ ZLWK D GD\ LQFXEDWLRQ WR GHWHUPLQH DEVHQFH RI PLFURELDO JURZWK 7KH ÅµQDO GD\ LQFXEDWLRQ VWHULOLW\ WHVW UHVXOWV DUH QRW DYDLODEOH DW WKH WLPH RI LQIXVLRQ ,I WKH VWHULOLW\ UHVXOWV EHFRPH SRVLWLYH IRU PLFURELDO FRQWDPLQDWLRQ DIWHU 3529(1*( KDV EHHQ DSSURYHG IRU LQIXVLRQ Dendreon will notify the treating physician. Dendreon will attempt to identify the PLFURRUJDQLVP SHUIRUP DQWLELRWLF VHQVLWLYLW\ WHVWLQJ RQ UHFRYHUHG PLFURRUJDQLVPV and communicate the results to the treating physician. Dendreon may request additional information from the physician in order to determine the source of contamination. (See Warnings and Precautions [5] of full Prescribing Information.) ADVERSE REACTIONS %HFDXVH FOLQLFDO WULDOV DUH FRQGXFWHG XQGHU ZLGHO\ YDU\LQJ FRQGLWLRQV DGYHUVH UHDFWLRQ UDWHV REVHUYHG LQ WKH FOLQLFDO WULDOV RI D GUXJ FDQQRW EH GLUHFWO\ FRPSDUHG WR UDWHV LQ WKH FOLQLFDO WULDOV RI DQRWKHU GUXJ DQG PD\ QRW UHÅ¶HFW WKH UDWHV REVHUYHG LQ SUDFWLFH

ated with potentially serious side effects. A 3-drug combination therapy is the preferred approach to treatment, but some 2-drug combinations are also recommended in current guidelines. Peripheral neuropathy has long been recognized as a problem, because it is frequently associated with both MM and its treatment. A paradigm shift regarding bortezomib use has emerged, with recent data suggesting that chang-

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Any Adverse Event Chills Fatigue )HYHU %DFN SDLQ Nausea Joint ache Headache Citrate toxicity Paresthesia Vomiting $QHPLD Constipation Pain Paresthesia oral Pain in extremity 'L]]LQHVV Muscle ache $VWKHQLD Diarrhea ,QÅ¶XHQ]D OLNH LOOQHVV Musculoskeletal pain Dyspnea Edema peripheral Hot flush Hematuria Muscle spasms

Control* (N = 303)

All Grades n (%)

Grade 3-5 n (%)

All Grades n (%)

591 (98.3)

247 (41.1)

186 (30.9)

7 (1.2)

291 (96.0)

Grade 3-5 n (%) 97 (32.0)

(Table 1 continued on next page.)

www.TheOncologyNurse.com

TON_February2011_v9_TON 2/15/12 2:06 PM Page 39

Multiple Myeloma ing the mode of administration or dosing schedule can substantially impact the incidence of neuropathy. â&#x2014;? References 1. American Cancer Society. Cancer Facts & Figures 2011. Atlanta, GA: American Cancer Society; 2011. 2. Munshi NC, Anderson AC, Bergsagel PL, et al; for 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;117:46964700.

3. National Comprehensive Cancer Network (NCCN). NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelinesâ&#x201E;˘). Multiple Myeloma, Version 1. 2012. www.nccn.org. Accessed February 5, 2012. 4. CenterWatch. Drug information. Velcade (bortezomib). www.centerwatch.com/druginformation/fdaapprovals/drug-details.aspx?DrugID=830. Accessed February 5, 2012. 5. Velcade prescribing information. Cambridge, MA: Millennium Pharmaceuticals, Inc; 2012. 6. 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.

Did You Know?

Prospective data from the Nursesâ&#x20AC;&#x2122; Health Study indicate that drinking at least 4 cups of coffee daily is associated with a lower risk of endometrial cancer. Researchers speculate that the link may be related to the role of caffeine, which has been reported to lower the levels of estrogen and insulin. â&#x20AC;&#x201C; Cancer Epidemiol Biomarkers Prev. 2011;20:2487-2495.

Table 1 Incidence of Adverse Events Occurring in â&#x2030;Ľ5% of Patients Randomized to PROVENGE PROVENGE (N = 601)

Hypertension $QRUH[LD %RQH SDLQ Upper respiratory tract infection ,QVRPQLD Musculoskeletal chest pain Cough Neck pain Weight decreased Urinary tract infection Rash Sweating Tremor

Control* (N = 303)

All Grades n (%)

Grade 3-5 n (%)

All Grades n (%)

Grade 3-5 n (%)

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Cerebrovascular Events. ,Q FRQWUROOHG FOLQLFDO WULDOV FHUHEURYDVFXODU HYHQWV LQFOXGLQJ KHPRUUKDJLF DQG LVFKHPLF VWURNHV ZHUH UHSRUWHG LQ RI SDWLHQWV LQ WKH 3529(1*( JURXS FRPSDUHG ZLWK RI SDWLHQWV LQ WKH FRQWURO JURXS (See Adverse Reactions [6] of full Prescribing Information.)

To report SUSPECTED ADVERSE REACTIONS, contact Dendreon Corporation at 1-877-336-3736 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch.

Dendreon Corporation Seattle, Washington 98101

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www.TheOncologyNurse.com

February 2012 I VOL 5, NO 1

TON_February2011_v9_TON 2/15/12 11:47 AM Page 40

In asymptomatic or minimally symptomatic metastatic castrate resistant prostate cancer

Before, Frank's immune cells could barely recognize a prostate cancer cell.

Now, they are focused on it.

PROVENGE is the first in a new class of therapy that is designed to activate a patient’s own antigen-presenting cells to stimulate an immune response against prostate cancer.

« Extends median survival beyond 2 years—25.8 months compared with 21.7 months for patients in the control* group (P=.032) « Reduction in risk of death—22.5% (HR=0.775, 95% CI: 0.614, 0.979) « Therapy completed in 3 cycles—3 infusions, at approximately 2-week intervals† « Most common adverse events are primarily mild or moderate— chills, fatigue, fever, back pain, nausea, joint ache, and headache *

Control was nonactivated, autologous, peripheral blood mononuclear cells. The dosing interval ranged from 1 to 15 weeks in controlled clinical trials.

†

INDICATION: PROVENGE® (sipuleucel-T) is an autologous cellular immunotherapy indicated for the treatment of asymptomatic or minimally symptomatic metastatic castrate resistant (hormone refractory) prostate cancer. IMPORTANT SAFETY INFORMATION: PROVENGE is intended solely for autologous use and is not routinely tested for transmissible infectious diseases. In controlled clinical trials, serious adverse events reported in the PROVENGE group include acute infusion reactions (occurring within 1 day of infusion) and cerebrovascular events. Severe (Grade 3) acute infusion reactions were reported in 3.5% of patients in the PROVENGE group. Reactions included chills, fever, fatigue, asthenia, dyspnea, hypoxia, bronchospasm, dizziness, headache, hypertension, muscle ache, nausea, and vomiting. No Grade 4 or 5 acute infusion reactions were reported in patients in the PROVENGE group. The most common adverse events (incidence ≥15%) reported in the PROVENGE group are chills, fatigue, fever, back pain, nausea, joint ache, and headache. Please see Brief Summary of full Prescribing Information on the adjacent page.

www.PROVENGE.com

Stimulate a Response