MARCH 2012, VOL 5, NO 2 by The Oncology Nurse

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MARCH 2012

www.TheOncologyNurse.com

VOL 5, NO 2

GENETIC COUNSELING

CANCER CENTER PROFILE

USC Norris Comprehensive Cancer Center A Comprehensive Approach to Treatment of Colorectal Cancers

Genetic Discrimination: What Oncology Nurses Need to Know About GINA and Health Insurance By Cristi Radford, MS, CGC Sarasota Memorial Health Care System, Sarasota, Florida Anya Prince, Esq Cancer Legal Resource Center, Los Angeles, California

ear of genetic discrimination is often a stated barrier to referral to genetic counseling services and to willingness to undergo genetic testing.1,2 As a result, when the Genetic Infor mation Nondiscrimination Act (GINA) was signed almost 4 years ago by

President George W. Bush, many felt that this would be the panacea for individuals concerned about discrimination. GINA was the first federal legislation providing protections against genetic discrimination by health insurers and employers. While GINA has granted Continued on page 14

THE PATIENT’S VOICE Tina Soo, Karen Julien, and Taline Khoukaz (left to right), GI nurse practitioners at the University of Southern California Norris Comprehensive Cancer Center.

he University of Southern California (USC) Norris Comprehensive Cancer Center is part of the Keck School of Medicine and is designated by the National Cancer Institute as one of the nation’s 40 comprehensive cancer centers. Located in Los Angeles, the USC Norris Comprehensive Cancer Center serves as a regional and national resource for cancer treatment, research, prevention, and education. The staff at the cancer center includes approximately 200 basic and population scientists, physicians from the faculty of the USC Keck School of Medicine, and members of several USC professional schools/departments and the College of Letters, Arts and Sciences.

Continued on page 24

What Doctors Can Learn From Nurses By MMA

“Are you crazy, yet?” I heard a voice floating through the early morning air. I stirred out of my sleep, turned my head to the source of the voice, and mumbled, “Not any more than usual.” After a moment, though, as I tried to focus despite the tumor sitting on my optic nerve, which left my vision blurred, I realized the question came from the

doctor assigned to see me during my inhospital chemotherapy sessions. I knew that if I did not snap into reality quickly despite the fact that it was only 7:30 AM and I had been kept up most of the night with nausea, he would simply ask me if everything was alright and literally sprint out my door. So, remembering through the blur that I had important questions I Continued on page 34

NEWS BRIEFS

Bone Biomarker Identified for Metastatic Prostate Cancer By Alice Goodman

new quantitative imaging bone biomarker has been identified that can assess response and is prognostic for survival in men with metastatic castration-resistant prostate cancer (mCRPC). Called the bone scintigraphy index (BSI), it represents the first quantitative imaging biomarker in prostate cancer. In a head-to-head comparison, the BSI

was superior to PSA (prostate-specific antigen)—the traditional method—in assessing response to therapy and prognosticating for survival after 3 and 6 months on therapy for mCRPC, according to a study published online ahead of print in the Journal of Clinical Oncology on January 9, 2012. Michael Morris, MD, Memorial Sloan-Kettering Cancer

INSIDE Supportive and palliative Care . . . . . . . . . . . . . . . .

Assessing Pain in a Geriatric Oncology Population Side effeCt ManageMent

Long-term Implications of Oophorectomy BaSal Cell CarCinoMa

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Vismodegib: A New Treatment Option for Basal Cell Carcinoma

perSonalized MediCine in onCology . . . . . . . . . . . . . . . . . . . .

BreaSt CanCer

Crizotinib Miracle: A Nursing Perspective ..............

28 28

BOLERO-2: Practice-Changing Results With Exemestane Plus Everolimus in Advanced Breast Cancer leukeMiaS

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Minimal Residual Disease to Monitor Therapy in Acute Leukemia

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VELCADE and Millennium are registered trademarks of Millennium Pharmaceuticals, Inc. Other trademarks are property of their respective owners. Millennium Pharmaceuticals, Inc., Cambridge, MA 02139 *The VELCADE Reimbursement Assistance Program does not file claims or appeal claims for callers, nor can it guarantee that you will be successful in obtaining reimbursement

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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, PhD(c), MSN, APRNBC, 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

www.TheOncologyNurse.com

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

March 2012 I VOL 5, NO 2

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From the Editor

ith this issue of The Oncology Nurse-APN/PA (TON), we cover everything from issues related to genetic discrimination to how a patient feels about her interaction with a doctor. Cristi Radford and Anya Prince provide specific information about the 2008 Genetic Information Nondiscrimination Act so oncology nurses can help their patients navigate Beth Faiman, PhD(c), MSN, APRN-BC, AOCN the concerns about their medical Editor-in-Chief records and health insurance coverage. In the Patient’s Voice article, MMA tells us about how she feels when a doctor asks her if she’s “crazy yet,” giving us all insight into how our actions as healthcare providers are perceived by patients. We hope to provide you with more perspectives from MMA as she journeys through her cancer treatment, which at this point includes a stem cell transplant in the near future. MMA would like

PUBLISHING STAFF Senior Vice President, Sales & Marketing Philip Pawelko phil@greenhillhc.com Publisher John W. Hennessy john@greenhillhc.com Director, Client Services Joe Chanley joe@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

to remain anonymous, but we welcome her contributions to TON. March is national colorectal cancer awareness month. To acknowledge this, Noteworthy Numbers focuses on the statistics of this disease, which is the second leading cause of cancer-related death in the United States. Our Cancer Center Profile this month is an interview with Taline Khoukaz, an oncology nurse specializing in colorectal cancer at the USC Norris Comprehensive Cancer Center in Los Angeles. Taline tells us about the changes she’s seen in the field and makes it clear that she likes chocolate! Please note Tara Rich’s article discussing the “crizotinib miracle,” which demonstrates some of the promise that personalized medicine can bring to oncology care. Be sure to visit our Web site, www.TheOncology Nurse.com. You’ll find a delicious quinoa recipe from Karen Connelly, and you can respond to this month’s Reader Poll about genetic discrimination. Let us know your thoughts about The Patient’s Voice—we want to hear your reactions to MMA’s experience. And, as always, let us know what topics you want to see covered in TON. ●

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241 Forsgate Drive, Suite 205C Monroe Twp, NJ 08831 The Oncology Nurse-APN/PA®, ISSN 1944-9798 (print); ISSN 1944-9801 (online) is published 11 times a year by Green Hill Healthcare Communications, LLC, 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. BPA Worldwide membership applied for April 2011.

March 2012 I VOL 5, NO 2

Drug Shortage Actions On February 21, 2012, the FDA announced a series of actions to deal with the severe shortages of Doxil (doxorubicin hydrochloride liposome injection; Janssen Research & Development, LLC) and preservative-free formulations of methotrexate. Doxorubicin is used to treat patients with ovarian cancer, multiple myeloma, and Kaposi’s sarcoma when first-line therapies have failed. Methotrexate is an antimetabolite used in both adults and children for the treatment of osteosarcoma, acute lymphoid leukemia, and lung cancer. It is also used to treat adults with gestational trophoblastic tumors, meningeal leukemia, breast cancer, head and neck cancer, advanced mycosis fungoides, and advanced non-Hodgkin lymphomas. Doxorubicin Hydrochloride Liposome Injection Janssen, the sole supplier of Doxil in the United States, reported that the shortage is a result of manufacturing issues at its contracted manufacturer, Ben Venue Laboratories, which voluntarily suspended production on November 19, 2011, after problems occurred at its manufacturing facility in Bedford, Ohio. A Janssen spokeswoman stated there was “unplanned downtime due to equipment failure” at the facility. The facility had been cited by regulators for manufacturing deficiencies. To increase the supplies of doxorubicin, the FDA is allowing the temporary importation and distribution of Lipodox. The FDA’s action is limited to Sun Pharma Global FZE and its authorized distributor, Caraco Pharmaceutical Laboratories Ltd—no other entities will be allowed to import or distribute doxorubicin. Sun Pharma’s Lipodox contains the same active ingredient

and concentration as the doxorubicin hydrochloride liposome injection manufactured in the US (Doxil). Lipodox is manufactured at an FDA-inspected facility in India, and Caraco Pharmaceutical Laboratories is working with FDA to make Lipodox available to wholesalers in the US. The FDA stated Sun Pharma Global’s Lipodox remains unapproved for marketing in the US. According to the FDA, “Temporary importation of foreign drugs is considered in rare cases when a shortage of an approved critical US drug exists and the shortage cannot be resolved by manufacturers of the approved drug in the immediate future.”

Preservative-Free Methotrexate The FDA has approved a preservative-free methotrexate generic drug manufactured by APP Pharmaceuticals after a prioritized review. APP has a generic drug already approved by the FDA, and the approval for preservative-free methotrexate was based on a supplemental application. The pharmaceutical companies that manufacture methotrexate slowed or stopped manufacturing for a variety of reasons, citing increased demand and manufacturing delays. Ben Venue Laboratories, one of the suppliers of the preservative-free formulation of methotrexate, voluntarily shut down production and distribution at its Ohio facility for issues related to maintenance and requalification of equipment. After confirming the safety of the already-manufactured preservative-free methotrexate, the FDA worked with Ben Venue to release its supply of the product. This supply is available for emergency distribution while APP and other manufacturers work to increase the production of preservative-free methotrexate. ●

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. 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

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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_March2012_v8_TON 3/15/12 11:02 AM Page 9

ADCETRIS is the firs first fir st appr appro approved oved CD30directed direct dir ected antibody-drug cconjugat conjugate 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 is an ADC designed tto o ttarget arget ccells ells expressing e xpressing CD301

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.

003557_sgn35_adc_ton_fa1.indd 2

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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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Continue tr treatment eatment until a maximum of 16 cy cycles, cles, disease pr progression progr ogression or unac unacceptable ceptable ttoxicity oxicity1 mg/kg g administered only as an IV infusion over Recommended dose is 1.8 mg/k 30 minutes every 3 weeks1 • Patients who have experienced a prior infusion-related reaction should be premedicated for subsequent infusions1 • Complete blood counts 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 GP.. 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. 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 Colorectal cancer is the second leading cause of cancer-related deaths in the United States among men and women. As we recognize colorectal cancer awareness month, let’s examine the statistics.

Overall, the lifetime risk of developing colorectal cancer is approximately 1 in 20 (5.1%), and the risk is slightly lower for women than men.

The risk of developing colorectal cancer increases with age. More than 90% of cases develop in people aged 50 or older.

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

It is estimated there will be 103,170 new cases of colon cancer and 40,290 new cases of rectal cancer in the US in 2012.

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%). 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.

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%.

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.

Renal impairment The kidney is a route of excretion for MMAE. The influence of renal impairment on the pharmacokinetics of MMAE has not been determined. 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 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.

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%).

www.TheOncologyNurse.com

The death rate from colorectal cancer has been declining over the past 20 years. If patients aged 50 years and older were screened regularly, as many as 60% of colorectal cancer deaths could be prevented. Between 2003 and 2007, approximately 66,000 colorectal cancer cases were prevented and 32,000 lives were saved (compared with 2002). Half of the prevented cases and deaths were avoided as a result of colorectal cancer screening.

Hepatic impairment

Use in pregnancy

Adverse reactions

As of 2010, 1 in 3 adults between the ages of 50 and 75 were not up-todate with recommended colorectal cancer screening.

Effect of ADCETRIS on other drugs

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 disease is expected to cause approximately 51,690 deaths during 2012 (26,470 in men and 25,220 in women).

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. 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.

From 2004 to 2008, 75 years was the median age at death for patients with cancer of the colon and rectum.

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

From 2004 to 2008, the average age at the time of colorectal cancer diagnosis was approximately 70 years. Today, there are more than 1 million colorectal cancer survivors in the US. Sources: www.cdc.gov/features/colorec talawareness/; www.cancer.org/Cancer/ ColonandRectumCancer/Detailed Guide/colorectal-cancer-key-statistics; http://seer.cancer.gov/statfacts/html/col orect.html#incidence-mortality; www. cancer.net/patient/Cancer+Types/ Colorectal+Cancer?sectionTitle= Statistics.

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Genetic Counseling Genetic Discrimination: What Oncology Nurses Need to Know... Continued from cover many important protections, the law is only as good as its interpretation and enforcement. This is especially true in the oncology setting. Oncology nurses interact with patients at all stages of the genetic testing process: prior to being identified as at-risk for a hereditary cancer syndrome, during genetic counseling and testing, and after being diagnosed with a hereditary cancer syndrome. Therefore, it is important for oncology nurses to have a basic understanding of GINA as it applies to patients in the various stages of identification. Not only can oncology nurses help minimize misconceptions about genetic discrimination, they can also assist patients in being proactive after undergoing cancer genetic testing to fully maximize the protections GINA provides. Overview of GINA GINA was signed into law on May 21, 2008.3 It is a federal law and as such provides a basic level of protection for all Americans. It prohibits health insurers and employers from discriminating against individuals on the basis of genetic information. It also prohibits these actors from collecting genetic information except in limited circumstances discussed below. Some states have provisions for genetic discrimination that are more protective than GINA.4 In such situations, entities must comply with GINA and the more protective state laws. The definition of genetic information in GINA is not limited to genetic test results. It is defined broadly and includes family medical history, genetic test results, participation in genetic research, and use of genetic services.5 GINA does not apply to Tricare, the Veterans Health Administration, the Indian Health Service, or the Federal Employees Health Benefits Program. However, many of these programs have protections similar to GINA. Although GINA does provide protection for the majority of individuals against genetic discrimination for health insurance and employment, it is important to note that GINA does not apply to life, long-term care, or disability insurance. The only circumstance under which a health insurance company can request genetic information is when trying to determine if a procedure is medically necessary. For example, if a patient is seeking to undergo prophylactic surgery, the insurance company can gather information about genetic test results and family history to determine if that is a necessary procedure. The insurance company does not have to cover the procedure, but it cannot use the genetic information to raise rates, cancel a policy, or otherwise discriminate. Under GINA, if it is reasonable for an employ-

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Anya Prince, Esq

er or insurance company to expect that genetic information could be gathered in a request for medical records, the collection request must explicitly state that genetic information should not be provided. If healthcare professionals or patients do not comply with the notice by handing over genetic information, then insurance companies will not have violated the law by receiving genetic information.

information includes use of genetic services, such as genetic counseling. Thus, a health insurer or employer cannot discriminate against an individual based on undergoing genetic counseling. Therefore, you can encourage Samantha to meet with a genetics provider to obtain additional information. It is the responsibility of the individual providing the genetic counseling to discuss state and federal laws as they apply to genetic testing in more detail. As Samantha has expressed that her concern is loss of health insurance with a positive test result, educating her about the benefits of genetic counseling may not be enough. To encourage her to attend the appointment, you can reassure her that under GINA a health insurer cannot use the results of a genetic test to discriminate. Additionally, she may not be aware that her test results may have implications in her current treatment and future medical management, as well as medical management for her family members. Her actual risk of genetic discrimination is most likely

Applying Knowledge to Clinical Practice

Scenario 1: Patient is considering genetic services Samantha is a 38-year-old female recently diagnosed with breast cancer. Additionally, she has a family history of numerous cancers. She was previously referred for genetic counseling, and you notice she did not keep her appointment. When you inquire about the reason, she responds, “If I have a positive genetic test, I will lose my health insurance.” How can you encourage Samantha to undergo genetic counseling? Genetic counseling is a multifaceted

GINA was signed into law on May 21, 2008. It is a federal law and as such provides a basic level of protection for all Americans.

process. One component of the process is empowering patients to make an informed decision regarding genetic testing. Therefore, undergoing genetic counseling does not translate into automatic genetic testing. The practitioner providing the genetic counseling will discuss the benefits, limitations, and risks of genetic testing. Additionally, he or she will discuss current legislation regarding genetic discrimination.6,7 Under GINA, the definition of genetic

much less than the chance she would have an additional cancer if she tested positive. In the unlikely situation that Samantha has an insurance plan that does not fall under GINA’s protections, she would need to look at state laws to see if her plan is covered under them or look to the rules of the plan itself. For example, the Federal Employees Health Benefits Program has rules against genetic discrimination that are similar to many aspects of GINA.

Scenario 2: Patient has been identified as having a hereditary cancer syndrome John is a 40-year-old male who was found to have over 50 adenomatous polyps on a screening colonoscopy. Due to numerous adenomatous colonic polyps, he underwent a colectomy and was found to have an additional 83 adenomatous polyps. Genetic testing revealed a mutation in the APC gene and confirmed a diagnosis of familial adenomatous polyposis. You receive a request for medical records from his insurance company as it is reviewing the claim to determine if colectomy was indicated. What should you do? One of the most notable parts of GINA is prohibition of both health insurers and employers gaining access to an individual’s genetic information. Discriminatory intent can often be difficult to prove, and this provision helps ensure that a person cannot discriminate, even subconsciously, against the individual. However, the provision is only completely effective if these companies truly do not get the information. Medical records are rife with genetic information, including family history and genetic test results. Therefore, in order to ensure full protection of the law, healthcare providers and individuals with hereditary cancer syndromes should be aware of how medical records are handled. If healthcare professionals receive a medical records request, they should be sure to redact the genetic information of a patient to help ensure the full protection of the law. This includes redaction not just of genetic test results but also of family medical history, use of genetic services, and participation in genetic research. However, manifested diseases are not included in the definition of genetic information. In John’s case, the presence of the adenomatous polyps would not be redacted because those are manifest in the patient. However, any information about family members who have had cancer in the past or John’s APC gene mutation should not be passed to the insurance company. As the person receiving the request for medical records, you should make sure to remove information about John’s APC test results, family history, genetic counseling services, and/or participation in genetic research. If you send this information and the insurance company stated this information should not be included, then John may not be fully protected under GINA. Tabatha is a 58-year-old female diagnosed with colorectal cancer at age 56. She has a germline mutation in the MSH2 gene and, thus, a diagnosis of Lynch syndrome. Tabatha is worried about what her diagnosis means for her children. Additionally, she

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Genetic Counseling confides that she doesn’t think they should be tested for the MSH2 mutation because she is worried that they won’t be able to get life insurance. Under GINA, the medical history of family members cannot be used by health insurers to discriminate against an individual. This fact is important to mention to patients such as Tabatha, who are worried about their children’s well-being. If Tabatha’s children are applying for health insurance, they do not need to disclose their mother’s colorectal or MSH2 diagnosis on the application. If the health insurer somehow gets information about the colorectal cancer or MSH2 mutation, they cannot use this information to change premium amounts, deny coverage, change benefits, or otherwise discriminate. GINA does not apply to life, longterm care, and disability insurance. Therefore, Tabatha’s concerns about her children’s ability to get life insurance may be well-founded; however, this depends on where her children are trying to get insurance. Life, long-term care, and disability insurances are regulated at the state level, and the extent of protection varies greatly among the states. As Tabatha’s nurse, you can point her to resources that can help her determine how her children are protected across state lines. It is important

Life, long-term care, and disability insurances are regulated at the state level, and the extent of protection varies greatly among the states.

to keep in mind that not only the protections but also the definition of genetic information may vary among state laws. For example, Connecticut has no state-level protections for these insurances, while Vermont prohibits insurers from basing a policy of insurance on genetic test results. Additionally, some states, such as California, define genetic information broadly to include family history, while others include only genetic test results in the definition. Oncology nurses should inform patients such as Tabatha that these laws may vary but be clear that this is an area where there may be gaps in the law. Despite possible gaps, overall, you can encourage Tabatha to have her children undergo genetic counseling. The definition of genetic information in many state laws regarding life, disability, and long-term care insurance

only includes information about genetic test results, not family history. Therefore, if the insurer wants to take genetic predispositions into account for enrollment, they unfortunately probably already have the information through family medical history. Therefore, additional information from a genetic test may not change the outcome of insurance, but it can greatly assist medical treatment options. In fact, a negative test result may even help an individual get these insurances despite a family history of a disease. Take-Home Messages • Under GINA, the definition of genetic information includes genetic counseling, family medical history, and genetic test results. Thus, a health insurer cannot discriminate against an individual based on undergoing genetic counseling, their

family’s manifested diseases (such as cancer), or genetic test results • Medical records are rife with genetic information. When receiving a request for medical records, providers should make sure to remove information on genetic test results, family medical history, use of genetic services, and participation in genetic research to ensure that their patients have the fullest protections of the law • GINA does not apply to life, longterm care, and disability insurance. However, state laws may provide some protection. Providers should know where to direct patients for additional information ● References 1. Ader T, Susswein LR, Callanan NP, et al. Attitudes and practice of genetic counselors regarding anonymous testing for BRCA1/2. J Genet Couns. 2009;18:606-617. 2. Nedelcu R, Blazer K, Schwerin B, et al. Genetic discrimination: the clinician perspective. Clin Genet. 2004;66:311-317. 3. GINA§101. Genetic Information Nondiscrimination Act, H. R. 493, 110th Congress of United States of America. 2008. 4. State laws on genetic privacy. www.councilforrespon siblegenetics.org/geneticprivacy/map_statelaw.html. Accessed February 15, 2012. 5. GINA overview. www.ginahelp.org/. Accessed February 15, 2012. 6. American Society of Clinical Oncology. Statement of the American Society of Clinical Oncology: genetic testing for cancer susceptibility. J Clin Oncol. 1996;14:1730-1736. 7. American College of Obstetricians and Gynecologists. Hereditary breast and ovarian syndrome. ACOG Practice Bulletin. Number 103, April 2009.

Reader Poll ©iStockphoto.com/Nathan Maxfield

Have patients talked to you about the issue of genetic discrimination?

Go to www.TheOncologyNurse.com to cast your vote and add your comments. Please tell us what you think and what your patients are saying. www.TheOncologyNurse.com

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NOW APPROVED FOR SUBCUTANEOUS ADMINISTRATION

Subcutaneous VELCADE Demonstrated Efficacy Consistent With IV for the Primary Endpoint RESPONSE RATES† IN RELAPSED MULTIPLE MYELOMA (MM): SUBCUTANEOUS AND IV AT 12 WEEKS (AFTER 4 CYCLES) Single-agent VELCADE® (bortezomib)

AT 24 WEEKS (AFTER 8 CYCLES) VELCADE±dexamethasone

53% 51%

43% 42%

11% 12%

7% 8% ORR Primary Endpoint

SC (n=148) IV (n=74)

ORR

▼ The study met its primary non-inferiority objective that single-agent subcutaneous VELCADE retained at least 60% of the overall response rate after 4 cycles relative to single-agent IV VELCADE SUBCUTANEOUS VS IV TRIAL: a non-inferiority, phase 3, randomized (2:1), open-label trial compared the efficacy and safety of VELCADE administered subcutaneously (n=148) with VELCADE administered intravenously (n=74) in patients with relapsed MM. The primary endpoint was overall response rate at 4 cycles. Secondary endpoints included response rate at 8 cycles, median TTP and PFS (months), 1-year overall survival (OS), and safety. *INDICATIONS: VELCADE is indicated for the treatment of patients with multiple myeloma. VELCADE is indicated for the treatment of patients with mantle cell lymphoma who have received at least 1 prior therapy. †

Responses were based on criteria established by the European Group for Blood and Marrow Transplantation.1

VELCADE IMPORTANT SAFETY INFORMATION CONTRAINDICATIONS VELCADE is contraindicated in patients with hypersensitivity to bortezomib, boron, or mannitol. VELCADE is contraindicated for intrathecal administration.

WARNINGS, PRECAUTIONS AND DRUG INTERACTIONS ▼ Peripheral neuropathy, including severe cases, may occur – manage with dose modification or discontinuation. Patients with preexisting severe neuropathy should be treated with VELCADE only after careful risk-benefit assessment ▼ Hypotension can occur. Use caution when treating patients receiving antihypertensives, those with a history of syncope, and those who are dehydrated ▼ Closely monitor patients with risk factors for, or existing heart disease ▼ 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

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IN ALL INDICATIONS*

Difference in Incidence of Peripheral Neuropathy With Subcutaneous VELCADE PERIPHERAL NEUROPATHY (PN) IN RELAPSED MM: SUBCUTANEOUS AND IV GRADE ≥3

SC (n=147) IV (n=74)

16% ALL GRADES

38% 53% ▼ Starting VELCADE® (bortezomib) subcutaneously may be considered for patients with preexisting PN or patients at high risk for PN. Patients with preexisting severe neuropathy should be treated with VELCADE only after careful risk-benefit assessment ▼ Treatment with VELCADE may cause PN that is predominantly sensory. However, cases of severe sensory and motor PN have been reported. 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 PN during therapy with VELCADE may require a decrease in the dose, a less-dose-intense schedule, or discontinuation. Please see full Prescribing Information for dose modification guidelines for PN

WARNINGS, PRECAUTIONS AND DRUG INTERACTIONS CONTINUED ▼ Women should avoid becoming pregnant while being treated with VELCADE. Pregnant women should be apprised of the potential harm to the fetus ▼ Closely monitor patients receiving VELCADE in combination with strong CYP3A4 inhibitors. Concomitant use of strong CYP3A4 inducers is not recommended

ADVERSE REACTIONS 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. For Patient Assistance Information or Reimbursement Assistance, call 1-866-VELCADE (835-2233), Option 2, or visit VELCADEHCP.com Reference: 1. 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(5):431-440.

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News Briefs Bone Biomarker Identified for Metastatic Prostate Cancer Center, New York City, was senior author of the paper. Bone scintigraphy is an older technology that images bone but not the cancerous lesions themselves. It shows the effect on the bone surrounding the metastasis, and, as such, is considered an imperfect tool on its own.

BSI is a method of expressing the tumor burden in bone as a percent of the total skeletal mass based on reference man skeletal masses. The study included 88 men enrolled in 4 different clinical trials who had bone scintigraphy done at baseline, 3 months, and 6 months on therapy.

Continued from cover

The percent change in BSI from baseline to 3 and 6 months was prognostic for survival. Doubling of the BSI was associated with an almost 2-fold increase in risk of death. When compared head-to-head with PSA, change in PSA from baseline was not prognostic for survival.

“BSI tells us about response to therapy and survival. When the BSI goes up, survival is shorter, and when it goes down, survival will be longer,” Morris explained. He and his colleagues are developing a computer-generated BSI that will have wide applicability. At present, the BSI is computed manually. ●

Brief Summary INDICATIONS: 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.

CONTRAINDICATIONS: VELCADE is contraindicated in patients with hypersensitivity to bortezomib, boron, or mannitol. VELCADE is contraindicated for intrathecal administration.

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. In the Phase 3 relapsed multiple myeloma trial comparing VELCADE subcutaneous vs. intravenous the incidence of Grade ≥ 2 peripheral neuropathy events was 24% for subcutaneous and 41% for intravenous. Grade ≥ 3 peripheral neuropathy occurred in 6% of patients in the subcutaneous treatment group, compared with 16% in the intravenous treatment group. Starting VELCADE subcutaneously may be considered for patients with pre-existing or at high risk of peripheral neuropathy. Patients experiencing new or worsening peripheral neuropathy during VELCADE therapy may benefit from a decrease in the dose and/or a less dose-intense schedule. In the single agent phase 3 relapsed multiple myeloma study of VELCADE vs. Dexamethasone 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 of VELCADE vs. dexamethasone, the incidence of any treatment-emergent 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

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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 of VELCADE vs. dexamethasone, 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. 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: Bortezomib is metabolized by liver enzymes. Bortezomib 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. (continued)

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News Briefs

Chronic Kidney Disease and Risk of Kidney Cancer

n patients with chronic kidney disease (CKD), decreasing glomerular filtration rate (GFR) is associated with increased risk of kidney and urothelial cancer in a step-wise fashion, according to a large community-based study. An adjusted multivariate analysis found a 2-

fold increase in risk of renal cancer and a substantially increased risk of urothelial cancer at GFR <30 mL/min/1.73 m2. The study was presented at the 2012 ASCO Genitourinary Cancers Symposium, held February 2-4 in San Francisco, California.

Use in Pregnancy: Pregnancy Category D. Women of childbearing potential should avoid becoming pregnant while being treated with VELCADE (bortezomib). 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.

ADVERSE EVENT DATA: Safety data from phase 2 and 3 studies of single-agent VELCADE 1.3 mg/m2/dose administered intravenously 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. 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 in previously untreated multiple myeloma, the safety profile of VELCADE administered intravenously 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%). In the phase 3 VELCADE subcutaneous vs. intravenous study in relapsed multiple myeloma, safety data were similar between the two treatment groups. The most commonly reported adverse events in this study were peripheral neuropathy NEC (38% vs 53%), anemia (36% vs 35%), thrombocytopenia (35% vs 36%), neutropenia (29% vs 27%), diarrhea (24% vs 36%), neuralgia (24% vs 23%), leukopenia (20% vs 22%), pyrexia (19% vs 16%), nausea (18% vs 19%), asthenia (16% vs 19%), weight decreased (15% vs 3%), constipation (14% vs 15%), back pain (14% vs 11%), fatigue (12% vs 20%), vomiting (12% vs 16%), insomnia (12% vs 11%), herpes zoster (11% vs 9%), decreased appetite (10% vs 9%), hypertension (10% vs 4%), dyspnea (7% vs 12%), pain in extremities (5% vs 11%), abdominal pain and headache (each 3% vs 11%), abdominal pain upper (2% vs 11%). The incidence of serious adverse events was similar for the subcutaneous treatment group (36%) and the intravenous treatment group (35%). The most commonly reported SAEs

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“Our study found an increased risk of renal and urothelial cancer with lower GFR rates. This suggests that estimated GFR may play a role in identifying patients with CKD at higher risk of these cancers. We need to assess whether there is a clinical benefit for targeted cancer

were pneumonia (6%) and pyrexia (3%) in the subcutaneous treatment group and pneumonia (7%), diarrhea (4%), peripheral sensory neuropathy (3%) and renal failure (3%) in the intravenous treatment group.

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 (bortezomib) 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) 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.

About 11.5% of people in the United States have CKD or proteinuria, and 13.5 million Americans have stage 3 CKD

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, VELCADE 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 bortezomib 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 VELCADEHCP.com.

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 © 2012, Millennium Pharmaceuticals, Inc. All rights reserved. Printed in USA

screenings in this population,” stated William Thomas Lowrance, MD, Huntsman Cancer Institute, University of Utah, who presented the study. The association between dialysis patients with end-stage renal disease (ESRD) and kidney cancer is well established, with a 3 to 4 times greater risk of kidney cancer. The link between CKD and kidney cancer has been less well studied, Lowrance noted. About 11.5% of people in the United States have CKD or proteinuria, and 13.5 million Americans have stage 3 CKD or worse. CKD is an independent risk factor for death, cardiovascular events, and hospitalization. About 65,000 new cases of kidney cancer and about 75,000 new cases of urothelial cancer are reported each year. These diseases pose a major health concern.

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or worse.

Using the SEER (Surveillance, Epidemiology, and End Results) registry to capture data from 2000 through 2008, Lowrance and colleagues analyzed Kaiser Permanente members of their renal registry, excluding members with preexisting cancer or ESRD. Just under 1.2 million adults were included, with a median follow-up of 5.3 years. During that time, more than 76,000 had a new cancer diagnosis. Median age was 55 years, and median age increased with decreasing GFR. Increase in comorbidities was associated with decreasing GFR. The crude rate of renal cancer increased in a step-wise fashion as GFR decreased. The same was true for urothelial cancers. In a multivariate analysis adjusted for confounding factors, these results persisted for kidney and urothelial cancers, but no association was seen with breast, lung, colorectal, or prostate cancer. Lowrance said that one limitation of this study is potential selection bias, since subjects with worse renal function may be followed more closely. Also, there was no adjustment for severity of comorbidities or dosages of medication. “More study is needed to elucidate the mechanism by which decreased GFR may play a role in development of kidney and urothelial cancers,” he said. ● —AG

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News Briefs

Protocol-Ineligible Patients With Metastatic Renal Cell Carcinoma Fare Worse Than Those Eligible for Clinical Trials

“Many patients in everyday © ASCO/Todd Buchanan 2012.

atients with metastatic renal cell carcinoma (mRCC) who do not meet eligibility criteria for clinical trials have worse outcomes on targeted therapy compared with eligible patients. In fact, extrapolating results of clinical trials to ineligible patients leads to inferior response rates (RRs), progression-free survival (PFS), and overall survival (OS). “Many patients in everyday practice do not meet eligibility for clinical trials, yet they receive the same targeted therapies as those in clinical trials. Our study shows that ineligible patients have worse outcomes and 1.5 times greater risk of death on the same therapies compared with eligible patients. These findings suggest that these discrepancies should be taken into account when we consider using protocol therapies in protocol-ineligible patients. We need to temper our enthusiasm,” said lead author Daniel Yick Chin Heng, MD, Tom Baker

practice do not meet eligibility for clinical trials, yet they receive the same targeted therapies as those in clinical trials.” —Daniel Yick Chin Heng, MD

Cancer Centre, University of Calgary, Alberta, Canada. Heng presented the study results at the 2012 ASCO Genitourinary Cancers Symposium. The study included 894 ineligible patients and 1182 eligible patients with mRCC consecutively treated with VEGF-targeted therapy at 17 international cancer centers. Patients were deemed ineligible retrospectively

according to common exclusion criteria for clinical trials. All other patients were assumed to be eligible. Patients received a variety of antiVEGF tyrosine kinase inhibitors, including sunitinib, sorafenib, bevacizumab, pazopanib, and axitinib. The most common exclusion criteria were Karnofsky performance status <70% (13.4%), nonclear cell histology

(11.2%), brain metastasis (8.3%), and hemoglobin 9 g/dL (7.4%). Patients in the ineligible group were much more likely to be poor risk, and fewer had undergone nephrectomy compared with eligible patients. Overall response rate was 27%. RR was 34% in favorable-risk patients, 28% in intermediate-risk patients, and 19% in poor-risk patients. RRs were uniformly lower in ineligible patients than eligible patients for every risk category. Median PFS was 8.6 months for eligible patients and 5.2 for ineligible patients (P <.0001); median PFS when these drugs were used as second-line therapy was 4.4 months and 3.2 months, respectively (P = .0074). Median OS was 28.8 months versus 14.5 months, respectively (P <.0001). “Specific trials should be undertaken to address the needs of protocol-ineligible patients and assess overall survival,” he said. ● —AG

Colonoscopy With Polypectomy Saves Lives

olonoscopy screening and removal of adenomatous polyps reduced the risk of colorectal cancer death by 53% in a recent study reported in the New England Journal of Medicine (2012;366:687-696). According to the authors, the findings demonstrate that adenomas identified and removed at colonoscopy are clinically important, because they have the potential to develop into carcinomas. Colorectal cancer is common, with an expected 143,000 new cases and 51,000 deaths due to colorectal cancer in the United States this year. Although polypectomy via colonoscopy has been shown to prevent the development of colorectal cancer, the longterm cancer-specific mortality among people who have had adenomatous polyps removed via colonoscopy is not well studied. Study subjects (N = 2602) were participants in the National Polyp Study who had adenomatous polyps removed during colonoscopy. The National Polyp Study was a randomized trial of subjects referred for colonoscopy between 1980 and 1990 because of positive findings on a barium enema test, sigmoidoscopy, fecal occult blood tests, or other tests, or because they

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had symptoms or a family history of colon cancer. Subjects were followed for a median of 16 years, with a maximum follow-up of 23 years. Among the 2602 patients with adenomas removed during the study, after a median follow-up of 15.8 years, 1246

The cancer mortality rate of the adenoma cohort was also compared with a group of 773 participants in the National Polyp Study who had been found to have nonadenomatous polyps on initial colonoscopy. Over the first 10 years after the index colonoscopy, the

Colorectal cancer is common, with an expected 143,000 new cases and 51,000 deaths due to colorectal cancer in the United States this year.

study subjects (48%) died, including 12 deaths due to colorectal cancer. Using data from the SEER (Surveillance, Epidemiology, and End Results) registry, the authors determined the expected number of deaths in the general population among people matched for age, sex, and race. The estimated percentage of cumulative deaths from colorectal cancer in the general population over 20 years was 1.5%, compared with a cumulative mortality of 0.8% in the adenoma cohort treated with polypectomy.

mortality rate was 0.15% in the nonadenomatous polyp group versus 0.19% in those with adenomas. These findings show that the risk of mortality due to colorectal cancer was similar between patients with adenomas removed at first colonoscopy and those with nonadenomatous polyps removed at that time. The authors used a model to estimate mortality if the adenomas had not been removed and no intervention had interfered with the natural history of adenomas developing into carcinoma.

“The model showed an even larger reduction in mortality [after] polypectomy than the comparison with the SEER incidence-based mortality rates,” noted lead author Ann Zauber, PhD, Memorial Sloan-Kettering Cancer Center, New York City. For colonoscopy to be effective, adults who are candidates must comply with screening guidelines. But several studies have shown poor compliance in the United States, as well as a general reluctance to undergo colonoscopy. The compliance problem is not limited to the US. In the same issue of the New England Journal of Medicine, a study from Spain found that only 24.6% of adults offered colonoscopy agreed to undergo the test. ● —AG

Did You Know? Diabetes is associated with an increased risk of colon and rectal cancers, even in studies that controlled for the common risk factors of smoking, obesity, and exercise. —Am J Gastroenterol. 2011;106:1911-1921.

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News Briefs

Vemurafenib Extends Survival in Patients With BRAF-Positive Metastatic Melanoma

onger follow-up of a phase 2 trial shows that vemurafenib (Zelboraf) extends overall survival (OS) for patients with BRAF-positive metastatic melanoma. Median OS was 16 months, compared with the median OS of 6 to 10 months typically reported for advanced melanoma (N Engl J Med. 2012;366:707-714). First reports from the phase 2 trial showed that vemurafenib induced meaningful responses in a significant number of BRAF-positive patients, but the study was not long enough to show an effect on OS at the time those results were presented. The latest data are an update on the effect of the drug on survival.

sun sensitivity, alopecia, and fatigue. Twenty-six percent developed cutaneous squamous cell carcinoma, which was treated with surgical excision. Vemurafenib has also been studied in a phase 3 trial. An interim analysis showed that vemurafenib achieved a

significant improvement in both progression-free survival and OS versus chemotherapy. The phase 2 trial is the first to confirm the durability of response. Vemurafenib is approved for metastatic melanoma in the United States, Europe, and elsewhere. ● —AG

Did You Know?

A recent study showed that people with systemic lupus erythematosus may be at increased risk for potentially viral-related malignancies, especially those cancers associated with the human papilloma virus. —Arthritis Rheum. 2011;63:3032-3037.

“This study shows that vemurafenib changes the natural history of the disease. …the drug is having a very big impact and this changes the way we treat

Nurse & Patient Navigator Association

metastatic melanoma.” —Antoni Ribas, MD

Best Practices A selection of member-submitted best practices for others to learn from and comment on.

Continuing Education About 50% of patients with advanced melanoma are BRAF-positive. “This study shows that vemurafenib changes the natural history of the disease. These results tell us that the drug is having a very big impact and this changes the way we treat metastatic melanoma,” said coprincipal investigator, Antoni Ribas, MD, UCLA Jonsson Comprehensive Cancer Center, Los Angeles, California. Jeffrey Sosman, MD, Vanderbilt-Ingram Cancer Center, Nashville, Tennessee, was coprincipal investigator as well. The study enrolled 132 patients with stage IV BRAF-positive melanoma previously treated with at least 1 systemic therapy. The rate of partial response was 47%, and complete response was 6%. Overall response rate was 53% in these advanced patients. The majority of patients had at least 1 adverse event that was attributed to vemurafenib. The most common adverse events were arthralgia, rash,

www.TheOncologyNurse.com

Learn how to advance your understanding of the complexities of cancer care through our live, online, and printed educational activities.

Networking Opportunities Coordinated events throughout the year both in person and online to help you connect with members and leaders.

Community Resources A collection of resources to help you and your patients better navigate their cancer treatment.

Expert Opinion Blogs Thought-provoking articles from the leaders in navigation and survivorship on various subject areas.

Publications Subscriptions to the Journal of Oncology Navigation & Survivorship® and The Oncology Nurse®-APN/PA.

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Supportive and Palliative Care

Assessing Pain in a Geriatric Oncology Population By Rachelle Rodriguez, MS, ARNP, AOCNP University of South Florida, College of Nursing, Tampa, Florida

ain is a frequent and pervasive problem for older persons with cancer, affecting approximately 80% of this population.1 Treating older adults with cancer can be complex because of the presence of comorbid conditions that may impact chronic pain.2 Once pain is identified and the cause is known, it is sometimes necessary to target specific pain mechanisms.3 Hence, a comprehensive assessment of each individual patient is essential in order to identify all of the conditions contributing to pain. Older persons with cancer also experience pain directly related to disease or treatment modalities, such as radiation therapy or surgery. Cancer-related chronic pain is not limited to those who are receiving end-of-life care but may be present in patients for whom cure or control of the underlying cancer is the treatment goal. With continuing advances in cancer treatment, patients can be expected to live longer, thus requiring ongoing extended pain management. Despite the many advances in pain management over the past few decades, and the numerous guidelines and evidenced-based measures available to physicians and practitioners for treating cancer-related pain, undertreatment of pain in cancer patients continues to be a problem.4 Assessment It is through a thorough pain assessment that clinicians can understand how to help their patients. Since pain is subjective and there is no objective way to measure it, a satisfactory method of pain assessment is the foundation needed to properly control pain in older patients with cancer.

Methods of Pain Assessment When it comes to assessing pain intensity, there are many different scales available that have proven to be valid. In a cross-sectional multicenter study of 240 advanced cancer patients with pain, background pain and current pain intensity were assessed using a 6point verbal rating scale as well as an 11-point (0-10) numeric rating scale. During this study, the numeric rating scale was shown to be most consistent and reproducible, suggesting that during cancer pain exacerbations, patients use numeric rating scales more appropriately and effectively.5 According to Herr and colleagues, older adults, particularly those with cognitive impairment, tend to prefer vertical rather

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description of the pain; any aggravating and alleviating factors; any other associated symptoms; and any current or past treatments and why these were started or stopped and by whom. It is important to obtain a complete history and physical so that polypharmacy can be avoided. At the end of the assessment, a pain diagnosis and an individualized pain treatment plan should be established, based on mutually agreed upon goals.8

Rachelle Rodriguez, MS, ARNP, AOCNP

than horizontal scales.6 Whenever pain is assessed, no matter which scale is used, it is important to ensure that the scale is well understood by the clinician who is presenting the scale to the patient.

Pain Assessment in Older Adults A study reviewing emergency department records of older adult patients found that 34% had no objective assessment of pain documented.7 Pain assessment and reassessment are essential to managing and treating pain appropriately; however, such reassessments are often lacking. When a patient is able to self-report, simply using a pain scale to determine pain intensity is not the completion of pain assessment. One obstacle in this population is the inability of older adults to self-report with accuracy.

It is through a thorough pain assessment that clinicians can understand how to help their patients. Pain Assessment in Individuals With Cancer Thorough pain assessment is done by both the nurse and the clinician to determine all aspects of the patient’s pain. As self-report is the standard of care, this assessment is obtained from the patient. It is important for clinicians to determine the location and intensity of the pain; whether the pain interferes with daily activities; the timing (onset, duration, course, persistent or intermittent), quality, and

Treatment of Chronic Cancer Pain Many studies on the treatment of pain specifically related to older adults with cancer pain have been conducted. For example, one cross-sectional study in 2004 by the National Nursing Home Society of 1174 nursing homes in the United States examined pain prevalence, pain treatment, and associated factors in 303 older residents assigned to a hospice specialty unit. Of these residents, 11.4% had a cancer diagnosis, 36.63% had experienced pain in the past 7 days, and of those with observed or reported pain, 86.4% had received analgesics, with 65.5% receiving an opiate preparation. While it is clear that residents with pain are receiving some pharmacologic intervention, the lack of pain medication in the prior 24-hour period suggests the potential for inadequate pain control overall.9 With the knowledge that 45% to 80% of nursing home residents endure substantial pain, it is disconcerting to know that these medications are not being provided to clients on a more regular basis.2 These studies highlight the need for more diligent assessment and reassessment of pain to ensure that patients’ pain is continually addressed and managed. Nonpharmacologic treatments for cancer pain are also available; however, there are fewer rigorous clinical trials investigating the use and effectiveness of nonpharmacologic therapies in managing cancer pain, and these treatments need additional research before recommendations for practice can be made. The Cancer Health Empowerment for Living without Pain (Ca-HELP) study was a randomized trial sponsored by the American Cancer Society that was completed in Sacramento, California. This study included 265 cancer patients with pain of at least moderate severity who were randomly assigned to receive either educationally enhanced usual care (EUC) or tailored education and coaching (TEC), to demonstrate that a brief, tailored patient activation intervention

may promote better cancer pain care and outcomes.10 This study showed that TEC, compared with EUC, resulted in improved pain communication self-efficacy and temporary improvement in pain-related impairment, but no im provement in the pain severity itself.11 A quasi-experimental, comparative study in 187 ambulatory-care cancer patients tested an educational intervention called “Passport to Comfort,” which focused on reducing barriers to pain and fatigue management through educational sessions. To be included, patients with breast, lung, colon, or prostate cancers had to report pain and/or fatigue of at least 4 or greater on an 11-point (0-10) numeric scale. The intervention, which included 4 educational sessions, was shown to be effective in both reducing patient barriers to pain and fatigue management as well as increasing patient knowledge regarding pain and fatigue.12 When treating chronic cancer pain, we should continue to explore educational interventions in the older adult population, as these might be beneficial to our patients. Barriers to Cancer Pain Management There are numerous barriers to treating pain in older adults, including that they are more tolerant of pain, that they cannot tolerate the use of opioids for cancer pain, and that they experience less pain and/or are less sensitive to pain.13 Also, it is a common misconception that older adults with decreased cognitive function experience less pain or are completely unaware of pain. In a cross-sectional, correlational study, Allen and colleagues explored the associations between pain and cognitive function among cancer patients and their family caregivers.14 What they found was that, contrary to expectations, patients with cognitive impairment reported more intense pain than did patients with intact cognitive function. Barriers that can be common to all adults have been documented well in the literature. Patients’ beliefs and actions lead to underreporting and thus undertreatment of pain. Some patients are reluctant to report pain because they are fearful of side effects from pain medications; they feel pain control is not a realistic goal; they do not want to distract their physicians from continuing to treat their cancer; or they might feel that the pain means their disease is progressing. Physicians and practitioners face barriers as well. These include fail-

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Supportive and Palliative Care ing to adequately assess pain or recognize barriers the patient is experiencing; lack of knowledge regarding treatment options for pain or side effects; and not understanding key concepts such as addiction, tolerance, dosing, and communication.12 Implications for Research and Nursing Practice There is a gap in the literature in regard to pain control in long-term cancer cases. More research is needed to determine how much more effective an interdisciplinary team is at not only managing but also assessing pain in cancer patients. More research is also needed specifically related to chronic cancer pain and how often practitioners are assessing this pain in both inpatient and outpatient settings. Nurses are also vital in the assessment of pain, and this is a core competency that must be mastered in all clinical settings. Individualized, comprehensive, continued assessment allows the nurse to relay vital information to the clinician regarding the patient, which is why it is so important that nurses receive continued education on pain assessment and that there be continued research to determine best nursing practices for assessment in various settings. When patients are confronted with a diagnosis of cancer, they are fearful of the future and what life now holds for them. Despite practitionersâ&#x20AC;&#x2122; best attempts to reassure patients and answer their questions, patients cannot help but think they are about to embark on a long painful road. As practitioners, we must not only reassure patients that there are options for pain treatment but also ensure that thorough assessment and reassessment of pain continues and is integrated into all aspects of care. In order to give patients the best possible pain control, it is important to continue to implement evidence-based treatment protocols and utilize guidelines for pain, specific not only to cancer patients but also to the older adult. This is a special population, one that will have special psychological needs and will, in many circumstances, be dealing with this diagnosis for the rest of their life, thus requiring ongoing long-term management of pain. â&#x2014;? References 1. Rao A, Cohen HJ. Symptom management in the elderly cancer patient: fatigue, pain, and depression. J Natl Cancer Inst Monogr. 2004;32:150-157. 2. Miaskowski C. Effective management of pain in older adults with cancer. Oncol Nurs Forum. 2010; 37(suppl):5-6. 3. American Geriatrics Society Panel on Pharmacological Management of Persistent Pain in Older Persons. Pharmacological management of persistent pain in older persons. J Am Geriatr Soc. 2009;57:1331-1346. 4. Deandrea S, Montanari M, Moja L, et al. Prevalence of undertreatment in cancer pain: a review of published literature. Ann Oncol. 2008;19:1985-1991. 5. Brunelli C, Zecca E, Martini C, et al. Comparison of numerical and verbal rating scales to measure pain

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Pain. Version 2.2011. www.nccn.org/professionals/ exacerbations in patients with chronic cancer pain. physician_gls/PDF/pain.pdf. Accessed September 6, Health Qual Life Outcomes. 2010;22:42. 2011. 6. Herr K, Spratt KF, Garand L, et al. Evaluation of the 9. Hanlon JT, Perera S, Sevick MA, et al. Pain and its Iowa pain thermometer and other selected pain intentreatment in older nursing home hospice/palliative sity scales in younger and older adult cohorts using care residents. J Am Med Dir Assoc. 2010;11:579-583. controlled clinical pain: a preliminary study. Pain Med. 10. Kravitz RL, Tancredi DJ, Street RL Jr, et al. Cancer 2007;8:585-600. Health Empowerment for Living without Pain (Ca7. Herr K, Titler M. Acute pain assessment and pharHELP): study design and rationale for a tailored edumacological management practices for the older adult cation and coaching intervention to enhance care of with a hip fracture: review of ED trends. J Emerg Nurs. cancer-related pain. BMC Cancer. 2009;9:319. 2009;35:312-320. 11. Kravitz RL, Tancredi DJ, Grennan T, et al. Cancer 8. National Comprehensive Cancer Network. NCCN Health Empowerment for Living without Pain (CaClinical Practice Guidelines in Oncology: Adult Cancer

HELP): effects of a tailored education and coaching intervention on pain and impairment. Pain. 2011; 152:1572-1582. 12. Borneman T, Koczywas M, Sun VC, et al. Reducing patient barriers to pain and fatigue management. J Pain Symptom Manage. 2010;39:486-501. 13. Miaskowski C, Cleary J, Burney R, et al. Guideline for the Management of Cancer Pain in Adults and Children. 3rd ed. Glenview, IL: American Pain Society; 2005. 14. Allen RS, Haley WE, Small BJ, et al. Pain reports by older hospice cancer patients and family caregivers: the role of cognitive functioning. Gerontologist. 2002;42:507-514.

â&#x20AC;&#x153;Quality care is everyoneâ&#x20AC;&#x2122;s business.â&#x20AC;? 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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Cancer Center Profile USC Norris Comprehensive Cancer Center The USC Norris CompreDepartment, we have 4 GI hensive Cancer Center prooncologists and 3 nurse vides patient care through practitioners. The multidisinpatient and outpatient serciplinary group consists of vices at several affiliated hosspecialized colorectal surpitals (USC Norris Cancer geons, hepatobiliary surHospital, Children’s Hospital geons, radiation oncoloLos Angeles, USC Unigists, a patient advocate, an versity Hospital, and Los ostomy nurse, dietitians, Angeles County + USC and genetic counselors. Medical Center) and outpaWorking as a team, we Taline Khoukaz, NP, tient clinics. provide effective and MSN, ACNP-C Taline Khoukaz, NP, MSN, seamless outcomes for our ACNP-C, works in the patients. In addition, our Gastrointestinal Oncology Program at delegated social worker provides emothe USC Norris Comprehensive Cancer tional support for patients and their Center. She answered our questions family members and assists in making about colorectal cancer care and working appropriate referrals to home services. as part of a multidisciplinary team. What types of outreach programs for As an oncology nurse specializing in colon cancer management is the USC colorectal cancer, can you describe Norris Cancer Center involved in? your interaction with the multidisciplinary team at USC Norris Compre- TK: Every year in the month of March, hensive Cancer Center and how it which is colorectal cancer awareness month, we at USC celebrate with our relates to patient outcomes? patients at a reception. Throughout the Taline Khoukaz (TK): At USC year, we provide lectures to patient Norris Comprehensive Oncology advocacy groups and wellness commu-

Continued from cover

nities, write blogs on a colon cancer Web site, and post to a novel biomarker-driven Web site called CollabRx (www.collabrx.com/) that we created.

Can you describe the role of genetic counseling as part of your patients’ care? TK: The genetic counselor is an integral part of our team, seeing all patients who may have any kind of genetic predisposition based on their age, pathology, or family history of cancer. She works closely with us to develop screening guidelines for patients with familial adenomatous or hereditary nonpolyposis colorectal cancer.

What are you most excited about in the field of colorectal cancer? TK: I have been an oncology nurse practitioner for over 11 years. Since I have been in this field, we have had 4 new agents, including targeted agents, approved by the FDA for the treatment of colon cancer. Patients have been living years past the survival statistics given

to them for stage IV colon cancer. At USC, we are very proud to be on the forefront on individualized chemotherapy. Our patients are screened for mutations in Kras, Braf, PI3K, and Nras, and gene expression levels of TS, ERCC-1, EGFR, VEGF, and VEGFR, which will guide us to select the most effective therapy for our patients.

What inspired you to become an oncology nurse? TK: Initially, I did not consider becoming an oncology nurse. I used to work as an RN in the ICU, and then interviewed for a neurosurgical nurse practitioner job. By chance, I was offered an oncology nurse practitioner position instead. After much debate with myself, I decided I would try it and see how I felt. Immediately, I was drawn to this patient population and their fight to live! I have found this to be a most rewarding job—with its share of tears. The patients and their families are always showing their gratitude with hugs, kisses, and, at times, with chocolates! ●

Side Effect Management

Long-term Implications of Oophorectomy By Alice Goodman

ophorectomy in younger women leads to decreased bone mineral density (BMD) and a higher prevalence of arthritis, according to a study reported at the 2011 CTRCAACR San Antonio Breast Cancer Symposium. An estimated 300,000 women undergo oophorectomy each year in the United States for a variety of reasons. Women at high risk of breast cancer are recommended to have their ovaries removed at a younger age, and removal of the ovaries is often done together with hysterectomy, which is performed for several benign conditions, including fibroid tumors, explained lead author Anne Marie McCarthy, PhD, Johns Hopkins Bloomberg School of Public Health and Sidney Kimmel Com prehensive Cancer Center in Baltimore, Maryland. She and her colleagues wanted to explore the effect of oophorectomy at a younger age on bone health. “To our knowledge, this has not been reported before. Our study suggests that women who undergo oophorectomy at a younger age may have significant bone loss and may develop arthritis.

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These women should have their BMD closely monitored to prevent the development of osteoporosis. Longitudinal studies are needed to assess bone loss over time and the incidence of arthritis in women who undergo oophorectomy,” she told listeners.

An estimated 300,000 women undergo oophorectomy each year in the United States.

The study was based on data from the third National Health and Nutrition Examination Survey (NHANES III) from 1988 to 1994. This study focused on women aged 40 years and older who answered detailed questionnaires that included questions about diagnosis of arthritis and BMD test results. Total hysterectomy and removal of ovaries was performed in 98% of the oophorectomy

group. The BMD analysis included 3660 women and the arthritis analysis included 4039 women. Oophorectomy was performed in 560 women for a variety of reasons, excluding cancer surgery; the remaining women had intact ovaries. Low BMD was defined as BMD >2.0 standard deviations below the mean. Among women who had never used hormone replacement therapy (HRT), those who had an oophorectomy before the age of 45 were more than twice as likely as those with intact ovaries to have low BMD. The odds of arthritis were similar with and without HRT. Low BMD was reported in 28.8% of the oophorectomy group younger than 45 years, in 26% of those who had an oophorectomy after reaching 45 years, and in 23.3% of those with intact ovaries. Arthritis was diagnosed in 47.9% of younger women with oophorectomy, 41.5% of women older than 45 with oophorectomy, and 32% of those with intact ovaries. When HRT was excluded, the rates of low BMD in these 3 groups, respectively, were 50.7%, 33%, and 22.9%. The rates of arthritis in non-HRT users were 54%, 50.5%, and

28.7%, respectively. A multivariate analysis adjusted for age, race, smoking, alcohol, body mass index, parity, maternal history of osteoporosis, osteoporosis treatment, physical activity, calcium, and vitamin D found that age <45 at the time of oophorectomy was the strongest predictor for low BMD in the total study population. When HRT users were excluded, oophorectomy at a younger age remained a significant predictor of low BMD. The odds of arthritis were similar with and without HRT in those who had oophorectomy, with younger women being twice as likely to get a diagnosis of arthritis as those with intact ovaries. McCarthy speculated that the explanation for an increased risk of arthritis found in this study might be related to deleterious effects on the joints and cartilage occurring with estrogen deprivation. Future studies by these investigators will address pre- and post-oophorectomy effects on BMD and arthritis. These studies will involve collaboration with basic scientists, McCarthy said, noting that she is an epidemiologist. ●

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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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Basal Cell Carcinoma

Vismodegib: A New Treatment Option for Basal Cell Carcinoma By Rhonda Williams

asal cell carcinoma (BCC) and squamous cell carcinoma (SCC), commonly referred to as nonmelanoma skin cancers (NMSCs), are the most common types of cancers in the United States. These 2 cancers account for approximately 2 million cases of skin cancer annually.1 BCC is approximately 4 to 5 times more common than SCC.2 Although rarely metastatic, BCC and SCC can cause substantial local destruction involving extensive areas of soft tissue, cartilage, and bone, as well as disfigurement. It is estimated that the cost of treating these NMSCs in the Medicare population exceeds $400 million annually.3

The Management of BCC The goal of primary treatment for BCC of the skin is curing the tumor. Surgical approaches are the most common treatment and offer the most effective method for achieving cure for this condition; however, considerations related to preserving function; preservation, restoration, or physical appearance; and patient preference all may lead to the choice of radiation therapy as the primary treatment to achieve optimal overall results.4 For patients who have low-risk, superficial BCC, or for those in whom surgery or radiation is contraindicated or unfeasible, topical therapies or vigorous cryotherapy may be considered, although the cure rate with these options may be lower. In addition, for patients at high risk for multiple primary skin tumors, increased surveillance and prophylactic measures may be indicated.4 Postoperative radiation has been widely accepted as a valuable approach for high-risk patients to reduce the rate of recurrence. Adjuvant radiotherapy is recommended by the National Comprehensive Cancer Network panel for any NMSC that shows evidence of substantial perineural involvement; that is, involvement of more than a few small or large nerves.4 All patients with BCC of the trunk and extremities who have undergone lymph node dissection should be considered for adjuvant radiation therapy; despite resection followed by radiation therapy, patients at high risk often experience locoregional recurrence and distant metastasis. The behavior of cutaneous BCC is characteristically indolent, but it rarely metastasizes to distant areas. When the disease does metastasize to distant sites, systemic therapy is indicated.4

March 2012 I VOL 5, NO 2

Table 1 Objective Response Rate With Vismodegib: Efficacy in Evaluable Patients6 Metastatic BCC (n = 33)

Locally advanced BCC (n = 63)

10 (30.3)

27 (42.9)

15.6-48.2

30.5-56.0

0 (0)

13 (20.6)

Partial response

10 (30.3)

14 (22.2)

Median response duration, months

7.6

5.6-nonestimable

5.7-9.7

Response Objective response rate, N (%)* 95% CI Complete response

95% CI

*Confirmed by independent review facility. BCC indicates basal cell carcinoma; CI, confidence interval.

A New Treatment Option for Advanced Disease Extensive research has led to advances in the understanding of the genetics of NMSCs.5 Among these advances, an understanding of the role of the sonic hedgehog pathway has played a pivotal role in understanding the pathogenesis of BCCs. We now know that mutations in PTCH, the patched gene located on chromosome 9q that codes for the sonic hedgehog receptor, are the underlying cause of nevoid BCC syndrome. These mutations are also common in sporadic BCCs. In addition, specific mutations in the tumor suppressor gene p53 appear to be involved in the development of NMSCs.5

The ORR was 30.3% in patients with metastatic BCC and 42.9% in patients with locally advanced BCC.

On January 30, 2012, the FDA approved vismodegib (Erivedge), a hedgehog pathway inhibitor, for the treatment of BCC in adults with locally advanced or metastatic disease who are not candidates for surgery or radiotherapy. The FDA used its priority review process for the approval of vismodegib; this approval was based on the results of an international, open-label, single-arm trial that evaluated the efficacy and safety of vis-

modegib in 104 patients with locally advanced or metastatic BCC. The approval of vismodegib represents the first approved therapy for patients with locally advanced or metastatic BCC whose disease was not amenable to surgery or radiation therapy, which are the standard treatments for this serious condition. In addition, vismodegib’s oral formulation may be viewed as more convenient for patients and may increase patient adherence to therapy. Some type of assistance program may be necessary to increase patients’ ability to obtain the drug. Clinical Pharmacology and Pharmacokinetics Vismodegib binds to and inhibits smoothened, a transmembrane protein involved in hedgehog signal transduction.6 Vismodegib is eliminated via multiple pathways, but it is predominantly excreted unchanged. Inhibition of the cytochrome (CY) P450 is not predicted to alter vismodegib’s systemic exposure, because steady-state plasma concentrations of vismodegib were observed in patients enrolled in vismodegib’s clinical trials who were being treated concomitantly with CYP3A4 inducers or CYP3A4 inhibitors.6 The results of in vitro studies indicate that vismodegib is a substrate of the efflux transporter P-glycoprotein; therefore, when vismodegib is coadministered with drugs that inhibit Pglycoprotein, such as clarithromycin, erythromycin, and azithromycin, systemic exposure to vismodegib and the incidence of adverse events may be increased.6 Drugs that alter the pH of the upper gastrointestinal tract may alter the sol-

ubility of vismodegib and reduce its bioavailability, but no formal studies have been conducted to evaluate the effect of gastric pH-altering drugs on the systemic exposure of vismodegib. Therefore, if vismodegib is coadministered with proton pump inhibitors, H2receptor antagonists, or antacids, the systemic exposure of vismodegib may be decreased, and the effect of vismodegib on efficacy is unknown.6 The single-dose bioavailability of vismodegib is 31.8%. The systemic exposure of vismodegib is not affected by food; therefore, vismodegib may be taken with or without food. The volume of distribution of vismodegib ranges from 16.4 L to 26.6 L. The plasma protein binding of the drug in patients is >99%. The primary route of elimination of vismodegib and its metabolites is hepatic, with 82% of the dose administered recovered in the feces and 4.4% recovered in urine. The vismodegib estimated elimination halflife is 4 days after continuous oncedaily dosing and 12 days after administration of a single dose.6 Clinical Trial Evidence and Efficacy The efficacy and safety of vismodegib was evaluated in an international, singlearm, open-label trial of 104 patients with metastatic BCC (n = 33) or with locally advanced BCC (n = 71). Enrolled patients with locally advanced BCC had to have lesions that recurred after radiotherapy, unless radiotherapy was contraindicated or inappropriate (ie, Gorlin syndrome, limitations because of the location of the tumor, or in cases where the lesion was unresectable or when surgical resection would result in substantial deformity). Patients received vismodegib 150 mg/day orally until disease progression or unacceptable toxicity occurred. The primary efficacy outcome of this study was determination of objective response rate (ORR), which was assessed by an independent review facility. In the cohort of patients with metastatic BCC, tumor response was evaluated using the Response Evaluation Criteria in Solid Tumors (RECIST) Version 1.0. In the cohort of patients with locally advanced BCC, evaluation of tumor response included measurement of externally assessable tumor (including scarring) and assessment for ulceration in photographs, radiographic assessment of target lesions when appropriate, and tumor biopsy.6 Of the 104 patients enrolled in this study, 96 patients were evaluable for

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Basal Cell Carcinoma ORR: 33 patients in the metastatic BCC cohort and 63 patients in the locally advanced BCC cohort. The median age of all patients evaluable for efficacy was 62 years; 46% of patients were aged ≥65 years. Of the patients in the metastatic BCC cohort, 97% of patients had received previous therapies, including surgery (97%), radiotherapy (58%), and systemic therapies (30%). Among the patients with locally advanced BCC, 94% had previous therapies, including surgery (89%), radiotherapy (27%), and systemic/topical therapies (11%).6 The ORR was 30.3% in patients with metastatic BCC and 42.9% in patients with locally advanced BCC. There were no complete responses in the metastatic BCC cohort compared with 20.6% of patients in the locally advanced BCC cohort who had a complete response. The median duration of response in the metastatic and the locally advanced BCC cohorts was 7.6 months.6 Table 1 outlines the response rates in both cohorts.

Table 2 Adverse Reactions Occurring in ≥10% of Patients With Advanced BCC6

Safety Profile When vismodegib monotherapy was administered at daily oral doses of ≥150 mg in 4 open-label, uncontrolled, dose-ranging or fixed singledose clinical trials enrolling a total of 138 patients with advanced BCC, the most common adverse reactions (≥10% of patients) included muscle spasms, alopecia, dysgeusia, and others, as shown in Table 2. Furthermore, 3 of 10 premenopausal women developed amenorrhea while being treated with vismodegib. In addition, treatment-emergent grade 3 laboratory abnormalities were observed in 11 patients in clinical trials; 6 (4%) patients experienced hyponatremia, 2 (1%) patients experienced hypokalemia, and azotemia was reported in 3 (2%) patients.6 The safety and effectiveness of vismodegib has not been established in patients with renal or hepatic impairment. In addition, clinical trials of vismodegib did not include sufficient numbers of patients aged ≥65 years to establish whether this patient population responded differently to vismodegib than younger patients. The safety and effectiveness of vismodegib have not been established in pediatric patients.6 Warnings and Precautions Associated With Vismodegib

Black Box Warning: Embryo-Fetal Death and Severe Birth Defects Vismodegib can result in severe birth defects or embryo-fetal death. Vismodegib is embryotoxic and teratogenic in animals. Teratogenic effects with this medication included severe

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MedDRA Preferred Term

All Patients With Advanced BCC (N = 138) All grades,* N (%)

Grade 3, N (%)

Grade 4, N (%)

42 (30.4)

1 (0.7)

–

Diarrhea

40 (29)

1 (0.7)

–

Constipation

29 (21)

–

19 (13.8)

–

55 (39.9)

7 (5.1)

1 (0.7)

62 (44.9)

10 (7.2)

–

35 (25.4)

3 (2.2)

–

Gastrointestinal disorders Nausea

Vomiting

General disorders and administration site conditions Fatigue Investigations Weight loss Metabolism and nutrition disorders Decreased appetite

Musculoskeletal and connective tissue disorders Muscle spasms

99 (71.7)

5 (3.6)

–

Arthralgias

22 (15.9)

1 (0.7)

–

Dysgeusia

76 (55.1)

–

Ageusia

15 (10.9)

–

88 (63.8)

–

Nervous system disorders

Skin and subcutaneous disorders Alopecia

*Grading according to NCI-CTCAE v3.0. BCC indicates basal cell carcinoma; MedDRA, Medical Dictionary for Regulatory Activities; NCI-CTCAE v3.0, National Cancer Institute Cancer Therapy Evaluation Program, Common Terminology Criteria for Adverse Events, Version 3.0.

midline defects, missing digits, and other irreversible malformation. In rats at maternal exposures lower than human exposures of the recommended dose (150 mg/day), vismodegib was teratogenic, embryotoxic, and fetotoxic. Malformations in rats included craniofacial anomalies, open perineum, and absent or fused digits. Fetal retardation and variations were also observed. Pregnancy status should be verified before initiation of treatment with vismodegib. Both male and female patients should be made aware of these risks. Female patients should be advised of the need for contraception, and male patients should be advised of the potential risk to the fetus of vismodegib exposure through semen. Patients should be advised to notify their healthcare provider immediately if they suspect that they or their female partner may be pregnant. Patients exposed to vismodegib during pregnancy, either directly or through seminal fluid, should be encouraged to participate in the vismodegib pregnancy pharmacovigilance program.6

Blood Donation Patients should be advised not to donate blood or blood products while receiving vismodegib and for at least 7

months after the last dose of vismodegib is received.6 Dosing The recommended dose of vismodegib is 150 mg orally once daily until evidence of disease progression exists or until unacceptable toxicity is noted. If a dose of vismodegib is missed, the dose should not be made up. Dosing should resume with the next scheduled dose.6 Vismodegib may be taken with or without food. The capsule should be taken whole and not be opened or crushed. Vismodegib is not available at local drugstores and is only distributed through specialty pharmacies. Conclusion Vismodegib, a hedgehog pathway inhibitor, was approved by the FDA earlier this year for the treatment of BCC in adults with locally advanced or metastatic disease who are not candidates for surgery or radiotherapy. This approval, which was done under the FDA’s priority review process, was based on the results of an international, open-label, single-arm trial that evaluated the efficacy and safety of vismodegib in 104 patients with locally advanced or metastatic BCC.

Vismodegib is the first FDA-approved agent for the treatment of this serious condition. Although BCC is usually curable if lesions are contained to a small area of skin, in rare cases the lesions can become disfiguring, invade surrounding tissue, and/or metastasize. In these instances of advanced BCC, the disease cannot be effectively managed with surgery or radiation, the standard treatments for this common skin cancer. This recent approval of vismodegib fills a gap and an unmet need in the treatment paradigm of this serious condition. ● References 1. American Cancer Society. Cancer Facts & Figures 2011. Atlanta, GA: American Cancer Society; 2011. www.cancer.org/acs/groups/content/@epidemiology surveilance/documents/document/acspc-029771.pdf. Accessed February 17, 2012. 2. Miller SJ, Alam M, Andersen J, et al. Basal cell and squamous cell skin cancers. J Natl Compr Cancer Netw. 2010;8:836-864. 3. Mudigonda T, Pearce DJ, Yentzer BA, et al. The economic impact of non-melanoma skin cancer: a review. J Natl Compr Canc Netw. 2010;8:888-896. 4. National Comprehensive Cancer Network (NCCN). NCCN Clinical Practice Guidelines in Oncology: Basal Cell and Squamous Cell Skin Cancers. Version 1.2012. www.nccn.org/professionals/physi cian_gls/pdf/nmsc.pdf. Accessed February 3, 2012. 5. Benjamin CL, Melnikova VO, Ananthaswamy HN. P53 protein and pathogenesis of melanoma and nonmelanoma skin cancer. Adv Exp Med Biol. 2008; 624:265-282. 6. Erivedge [prescribing information]. South San Francisco, CA: Genentech, Inc; 2012.

March 2012 I VOL 5, NO 2

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Personalized Medicine in Oncology: Lung Cancer

Crizotinib Miracle: A Nursing Perspective By Tara L. Rich, MSN, RN, CNP Taussig Cancer Institute, Cleveland Clinic, Ohio

or every nurse there is a crizotinib. Upon initial patient who you will evaluation, his tissue was never forget; the details sent for epidermal growth of that story will not blur over factor receptor and time. In the developing era of EML4-ALK testing, but personalized medicine, there is due to the urgent nature that one patient whose story I of his symptoms, the deciwill not easily forget. It is the sion was made to start story of a 24-year-old male standard platinum doumedical student who presentblet chemotherapy. This ed for initial consultation the is when I first met him— Tara L. Rich, MSN, same week that crizotinib was he was sitting in the RN, CNP approved by the FDA for the chemo chair waiting for treatment of anaplastic lymtreatment to start. He was phoma kinase (ALK)-positive non– quickly becoming symptomatic and was small cell lung cancer. admitted to the hospital that day for This young never smoker was blissful- evaluation. Over the course of the next ly unaware of the recent advances in couple days he acutely developed a periidentifying the echinoderm microtubule- cardial effusion that tamponaded, associated protein-like 4 (EML4)-ALK requiring emergent bedside pericardiooncogene and the associated response to centesis. He proceeded to develop pul-

monary emboli, atrial fibrillation, and pleural effusions requiring bilateral chest tubes. The second day he was in the ICU we received the news that his tumor was ALK positive. He was too sick to understand the news, and his family was too scared to understand the possible utility of this information. Our patient assistance team worked feverishly with the pharmaceutical company and his insurance company since the drug was brand new. Twenty-four hours later he was taking crizotinib. His response was immediate and miraculous. He was discharged home 20 days later; he walked out of the hospital without any assistance or medical equipment. Within 1 month of leaving the hospital he had resumed his normal activities of weekend outings and visiting his friends from med school. I remember the day he

called the office to inquire whether he was allowed to have a beer, a once typical social activity for a 24-year-old student. We all smiled with relief, knowing that without crizotinib the outcome would not have been the same. He continues to do well and has become actively involved in educating people about lung cancer and crizotinib. Speaking to the public has given him a purpose and focus while he decides whether to continue with medical school. As a nurse practitioner, being able to witness the life-altering effects of crizotinib reminds me of the progress that is being made each day in cancer research. We hope that these advances in genomic testing and targeted agents continue to provide patients not only with individualized care but with increased treatment options. ●

Breast Cancer

BOLERO-2: Practice-Changing Results With Exemestane Plus Everolimus in Advanced Breast Cancer By Alice Goodman

pdated results of the phase 3 BOLERO-2 trial demonstrated that adding everolimus to hormonal therapy extends progressionfree survival (PFS) in hormone receptor–positive (HR+) metastatic breast cancer that progressed on hormonal therapy with anastrozole or letrozole. The positive outcomes observed in this study suggest that everolimus plus exemestane will be a new option for postmenopausal metastatic HR+ breast cancer. First results of this study, called BOLERO-2, were presented in September 2011 at ECCO/ESMO/ESTRO. Updated results with additional followup, presented at the 2011 CTRCAACR San Antonio Breast Cancer Symposium, confirm the PFS benefit of adding everolimus to exemestane in this group of women. Overall survival data are not yet mature. “We believe these results underline that everolimus is the first agent to significantly enhance the efficacy of hormonal therapy in patients with HR+ breast cancer. The addition of everolimus in advanced breast cancer could represent a paradigm shift in the management of this patient popula-

March 2012 I VOL 5, NO 2

tion,” stated Gabriel N. Hortobagyi, MD, professor of medicine and director of the Multidisciplinary Breast Cancer Research Program at the University of Texas MD Anderson Cancer Center in Houston, Texas.

Everolimus is an mTOR inhibitor. This pathway is activated in hormoneresistant advanced breast cancer.

“Endocrine therapy is the treatment of choice for the majority of breast cancers that express the estrogen receptor, which represents about 75% of patients over age 50. The standard is to use multiple endocrine regimens in sequence to get multiple mileage. But the sad truth is that after a few months of suppression of tumor cells on one

agent, tumor cells become smarter and resistant and we need to change agents,” Hortobagyi explained. Everolimus is an mTOR inhibitor. This pathway is activated in hormoneresistant advanced breast cancer. Phase 2 clinical trials of everolimus monotherapy and in combination with endocrine therapy were encouraging in advanced HR+ breast cancer, Hortobagyi explained. Positive results of phase 2 trials with everolimus added to hormonal therapy led to the strategy tested in BOLERO-2, he said. BOLERO-2 was a prospective, double-blind, placebo-controlled, phase 3 trial. The study population included 724 postmenopausal women with HR+ metastatic breast cancer with disease progression on previous hormonal therapy (ie, resistance). Patients were randomized 2:1 to exemestane plus everolimus (n = 485) versus exemestane plus placebo (n = 279). Baseline demographics and disease characteristics were similar between the arms. At baseline, median age was 62 years, 56% had visceral metastases, and 84% had documented benefit from previous endocrine therapy with letrozole or anastrozole (100%),

tamoxifen (48%), fulvestrant (16%), and chemotherapy for advanced disease (25%). Sixty percent had excellent performance status. The study population reflects a variety of ethnic groups, he said. At a median follow-up of 12.5 months, median PFS was 7.4 months for the combination versus 3.2 months for exemestane plus placebo. The percentage of patients who experienced clinical benefit (complete response, partial response, stable disease, amount of pain, and overall benefit of the drug) was almost double in the combination arm: 50.5% for the combination versus 25.5% for exemestane plus placebo. The combination of exemestane plus everolimus was well tolerated, Hortobagyi told listeners. The most common grade 3 or higher adverse events for the combination versus exemestane plus placebo, respectively, were stomatitis (8% vs 1%), anemia (7% vs 1%), hyperglycemia (5% vs <1%), dyspnea (4% vs 1%), and fatigue (4% vs 1%). Adverse events were manageable with dose delays or dose reductions. Quality of life was almost identical in both arms of the study. ●

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Leukemias

Minimal Residual Disease to Monitor Therapy in Acute Leukemia By Sally Blair, MD; Elaine Coustan-Smith, MS; Dario Campana, MD, PhD Department of Pediatrics, Yong Loo Lin School of Medicine, National University of Singapore

-7,396

104 105 0

-7,396

-517

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104 105

-7,396

104 105

CD34

-517

104 105 103

-517

CD10

103

104 105

reatment response in patients Methods to Measure MRD monitoring of MRD with a sensitivity of tial monitoring may be informative.6-8 In with acute leukemia is tradition- Leukemic cells have several distinguish- at least 0.001%.5 Ig and TCR genes are addition to gene fusions, NPM1 gene ally measured by searching for ing features that can be used to track rarely rearranged in AML and therefore mutations, when present, can be used as leukemic cells that persist during them during chemotherapy. ALL cells their contribution to the range of poten- targets for MRD studies.9 Leukemic cells can also be identified chemotherapy. This is done by screening have unique clonal rearrangement of the tial targets is negligible.3 Another feature that can be used to by the expression of unique combinasmears of bone marrow aspirates and genes encoding immunoglobulin (Ig) peripheral blood samples using light and T-cell receptor (TCR) proteins that distinguish leukemic from normal cells tions of cell markers that are best detectmicroscopy, striving to identify leukemic can be identified in the majority of consists of chromosomal abnormalities ed with monoclonal antibodies and flow cases.3 The leukemia-spe- and their resulting gene fusions.3 Fusion cytometry (Figure).10 The most current cells by their morphologic feacific rearrangements are transcripts, such as BCR-ABL1, MLL- flow cytometers allow the detection of 8 tures. However, leukemic cells elucidated in each patient AFF1, TCF3-PBX1, and ETV6-RUNX1 or more markers. Leukemia-associated in most cases closely resemat diagnosis, and specific in ALL, and RUNX1-RUNX1T1, immunophenotypes are identified at ble normal bone marrow and primers are synthesized and CBFB-MYH11, and PML-RARA in diagnosis in each patient by comparing blood cells: acute lymphoblasthen incorporated into a AML can be used as targets for amplifi- the cell marker profile of leukemic blasts tic leukemia (ALL) lympolymerase chain reaction cation.2,3 Real-time PCR provides the to that of reference bone marrow samples phoblasts can be confused (PCR) assay. After deter- most accurate way to measure their lev- from healthy donors and from patients with normal immature lymmining the optimal condi- els. Overall, up to one-third during and after chemotherphoid cells and activated tions of the assay, these are of patients with ALL or apy or transplant.10 If a suffilymphocytes; acute myeloid cient number of cells are applied to follow-up sam- AML have leukemic cells leukemia (AML) myelo analyzed (eg, 100,000 ples to monitor MRD. with genetic abnormalities blasts are similar to normal Sally Blair, MD mononuclear cells per antiPCR analysis of Ig and that currently can be perimmature myeloid cells. body combination), flow TCR genes allows for the formed as routine assays in Hence, the identification of cytometry has a routine senleukemic cells among normal cells is a routine detection of 1 leukemic cell in molecular pathology laborasitivity of detection of difficult task even for an experienced 10,000 to 100,000 normal cells.3 In a tories, allowing the detection 0.01% in ALL.10 Among hematopathologist, and the cutoff to study by the AIEOP-BFM ALL group, of 1 leukemic cell in 1000 to 2143 patients with B-lindefine leukemia remission is therefore only 305 of the 3341 (9.1%) diagnostic 100,000 normal bone mareage ALL enrolled on 9900 rather lax; at most centers it is 5%. samples examined either lacked suitable row cells.2,3 Abnormal fusion series treatment protocols of However, patients with <5% leukemic gene rearrangements for PCR analysis or transcripts may persist long blasts in the bone marrow and in com- had rearrangements with sequences not into clinical remission. Elaine Coustan-Smith, the Children’s Oncology MS Group, a test with the sensiplete remission by this criterion may still sufficiently distinct to reach a sensitivity Therefore, positive results, 4 tivity of at least 0.01% on have a large total number of residual of 0.01%. In a study performed at St. particularly at low levels, are Jude Children’s Research Hospital, 475 difficult to interpret for some of the day 29 could be performed in 92% of leukemic cells (potentially up to 1010). Measuring treatment response of 539 (88.1%) bone marrow samples fusion transcripts such as ETV6- patients.11 In the St. Jude Total XV study, more accurately is important because from patients with newly diagnosed B- RUNX1, RUNX1-RUNX1T1, and MRD could be monitored by flow the degree of initial leukemia cytore- lineage ALL had clonal antigen receptor CBFB-MYH11 as they often do not indi- cytometry with a 0.01% sensitivity in Continued on page 30 duction is strongly associated with gene rearrangements suitable for PCR cate a higher risk of relapse, but sequenrisk of subsequent relapse. It is well known that patients who have a poor ALL AML response to remission induction therDiagnosis Follow-up Diagnosis Follow-up apy and fail to achieve morphologic remission have a high risk of relapse. 0.4% Pt. 3 0.3% Pt. 1 However, with contemporary therapy, the majority of patients with ALL and AML do achieve complete remission as defined by the above criterion, yet a substantial number subsequently relapse. The hypothesis underlying 103 104 105 103 104 105 0 0 103 104 105 0 103 104 105 0 studies of minimal residual disease -208 -208 -206 -206 (MRD), which denotes leukemia not <0.1% Pt. 4 Pt. 2 detectable by conventional morpho<0.01% logic analysis, is that among “good responders” there may be substantial heterogeneity in residual leukemia burden that is unappreciated by morphologic analysis. Studies reported during the past 2 decades are in line 103 104 105 0 103 104 105 0 103 104 105 103 104 105 0 0 -208 -206 -208 -206 with this hypothesis, and the progCD7 CD58 nostic importance of MRD has been demonstrated unequivocally.1,2 ThereFigure. Detection of MRD by flow cytometry. Flow cytometric dot plots show results obtained in bone marrow samples fore, the more stringent definition of from 4 patients (2 with ALL and 2 with AML) at diagnosis and during chemotherapy. Each axis indicates intensity of remission provided by MRD assays is expression of the markers used; the dashes areas enclose signals from leukemic cells. The percentage of MRD in each progressively replacing that defined follow-up sample is shown. by morphologic analysis.

March 2012 I VOL 5, NO 2

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Leukemias Minimal Residual Disease to Monitor Therapy in Acute Leukemia Continued from page 29 482 of 492 patients (98%).12 In AML, distinctive markers can also be identified in most patients, although in approximately 40% of patients the routine sensitivity that can be achieved is not higher than 1 in 1000, a consequence of partial overlap between the phenotype of leukemic cells and those of normal hematopoietic cells.13 In the studies performed in the St. Jude AML02 trial, we found immunophenotypes suitable for MRD studies with a sensitivity of at least 0.1% in 200 of 210 (95%) patients.13 The number of antibody combinations used to identify leukemic cells, the stability of the markers targeted, and the skill of the investigator interpreting the results are key to the reliability of MRD monitoring by flow cytometry.

Table Main Properties of MRD Assays in Acute Leukemia PCR Ig/TCR Genes

MRD Assay PCR Fusion Transcripts

Flow Cytometry

Use in ALL

Yes (~90%)

Yes (~40%)

Yes (>95%)

Use in AML

Yes (~40%)

Yes (95%)

0.01%-0.001%

0.01% (ALL); 0.1%-0.01% (AML)

Potential for wide availability?

Yes

Specific expertise in MRD required?

Yes

Analysis of diagnostic sample required?

Yes

Property

Sensitivity

AML showed that MRD detected in the first bone marrow obtained after induction treatment was highly predictive of relapse.29 Others reported that the rate of decrease in cells expressing aberrant immunophenotypes during treatment was significantly and independently related to treatment outcome.30 More recently, Maurillo and colleagues31 reported that levels of MRD after consolidation therapy were particularly informative: MRD-negative patients had a significantly better outcome, regardless of whether they underwent autologous or allogeneic stem cell transplantation. Practical Considerations for the Clinical Application of MRD In patients with ALL, MRD results obtained by PCR amplification of Ig and TCR genes or by flow cytometry are generally concordant when MRD is present at levels of ≥0.01%.32,33 Each method has unique strengths (Table).10 Flow cytometry is more likely to be readily available as it is routinely used for leukemia profiling for diagnostic purposes. For studies at early time points during therapy, such as on day 15, flow cytometry has an edge over PCR because the development of a PCR assay currently requires more than 2 weeks. By contrast, the higher sensitivity of PCR can be advantageous for studies at the end of therapy or after transplant, where it may uncover MRD undetectable by flow cytometry. PCR has often been said to be more expensive, but many variables must be factored into this calculation including equipment

Development of Yes No No* Prognostic Significance patient-specific of MRD in ALL assay? Many studies have demonstrated the MRD positivity Yes No Yes clinical significance of MRD monitoring strongly correlated in children and adolescents with ALL. with outcome? MRD tests performed during the early phases of treatment appear to be particu*The best markers for each patient should be selected at diagnosis. larly informative and often outweigh the prognostic impact of clinical and biological features previously associated with enrolled in the Total XIII study, those MRD positive had a 4.8 times higher risk treatment outcome (reviewed in with early leukemia cell clearance (ie, of relapse than those who were MRD Campana1). For example, a recently MRD <0.01% on day 19 of treatment; negative and that MRD was the reported study of 3184 B-lineage ALL 46%) had a 5-year cumulative incidence strongest prognostic factor among the patients enrolled in the AIEOP-BFM of relapse of 6.0% ± 3.4%.19 Likewise, in variables considered.25 Likewise, a study ALL 2000 protocol showed that MRD the AIEOP-BFM ALL 2000 study, performed in the St. Jude Children’s measurements by PCR amplification of patients with MRD <0.01% on day 33 Research Hospital AML97 cohort antigen-receptor gene rearrangements (42%) had a 5-year event-free survival of showed that the mean 2-year survival estimates for patients with MRD positivon days 33 and 78 of treatment were 92.3% ± 0.9%.14 It is also clinically useful to monitor ity (≥0.1%) after induction therapy was superior to previous stratification criteria based on leukocyte count, age, early MRD in children and adolescents with response to prednisone, and genetic sub- first-relapse ALL who achieve a second type.14 Other recent studies also pointed remission,20 and in those undergoing MRD is most commonly tested in bone marrow to the predictive value of MRD for oth- allogeneic hematopoietic stem cell transerwise homogeneous subgroups of plantation, as the level of MRD before aspirates, as the bone marrow is the site where patients, such as infants,15 those with T- transplant is associated with risk of leukemic cells grow and are typically found in ALL,16 and those with specific genetic relapse posttransplant.21,22 Finally, conabnormalities.17 Another study from the vincing evidence is emerging that MRD higher proportions. same group measured MRD by flow is clinically important in adult patients cytometry on day 15 of treatment in 815 with ALL. In studies by the German patients and found a strong Multicenter Study Group correlation between higher for Adult Acute Lymph- 33%, compared with 72% for those with costs, consumables, and staff support. In MRD levels and subsequent oblastic Leukemia, MRD lower levels or no detectable MRD; our experience, the costs of the 2 methrelapse.18 A high level of on days 11 and 24 of treat- MRD was also the strongest predictor of ods are similar. Both assays must be perMRD (ie, ≥1%) at the end of ment predicted outcome outcome in this cohort.26 Subsequent formed in laboratories with proven remission induction predicts in adult patients with “ studies in children with AML consoli- expertise; therefore the type of expert a particularly poor outcome, standard-risk” ALL,23 and dated these early findings.27,28 In the St. laboratory available to a cancer center or sequential studies of MRD Jude AML02 study, we used MRD to cooperative group may ultimately be the and it remained an unfavorwere also informative.24 guide treatment schedule and intensity. decisive factor in selecting the method to able predictor of outcome in Other studies also demon- Patients with MRD ≥1% at the end of be used to monitor MRD in ALL. Flow the St. Jude Total XV study strated the predictive value remission induction therapy were classi- cytometry is the only method that can (the only independent adof MRD in different sub- fied as high risk and offered transplant; study MRD in most patients with AML. verse predictor together with Dario Campana, groups of adult ALL patients with MRD 0.1% to <1% Studies of MRD by PCR amplification of CNS3 status), despite MRDMD, PhD (reviewed in Campana1). received gemtuzumab ozogamicin and, if fusion transcripts are also an option, but based treatment intensifica12 MRD persisted, became candidates for they are obviously limited to specific tion. Conversely, patients who attain MRD <0.01% early during Prognostic Significance transplant. MRD remained a predictive leukemic subtypes and are generally used therapy have excellent chances to of MRD in AML prognostic factor, although patients with on an ad hoc basis. remain in continuous complete remis- In an early study, Children’s Oncology lower levels of MRD (0.1%-<1%) MRD is most commonly tested in sion with contemporary postremission Group investigators showed that chil- appeared to benefit from this strategy.13 bone marrow aspirates, as the bone marEarly studies in adult patients with row is the site where leukemic cells grow therapy. In our early study with patients dren with AML in remission who were

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Leukemias and are typically found in higher proportions. Some studies examined the potential for using peripheral blood instead. It was found that in patients with T-lineage ALL, MRD levels in peripheral blood were similar to those in bone marrow.34,35 Interestingly, this was also the case in patients with T-cell lymphoblastic lymphoma.36 Thus, in patients with T-cell malignancies, sequential MRD testing can be performed in blood. In patients with B-lineage ALL, early MRD measurements in peripheral blood (eg, on day 8) may be clinically informative.11 The clinical significance of MRD and its use for treatment stratification depends on protocol design. Therefore there is considerable variability in the time points during treatment at which MRD studies are performed and in the levels of MRD considered to be most informative. The current COG AALL08B1 protocol for children with B-lineage ALL includes MRD measurements in peripheral blood on day 8 of treatment and in bone marrow at the end of remission induction therapy (day 29), and the cutoff levels used to assign risk are 1% and 0.01%, respectively. In the Dana-Farber Cancer Institute study 0501 for childhood ALL, the MRD threshold of 0.001% at the end of remission induction therapy (day 28) is used for risk assignment. In the St. Jude Children’s Research Hospital Total XVI study, MRD levels on day 15 and day 42 are used for treatment assignment. Patients with MRD of ≥1% on day 15 receive intensified remission induction therapy; further intensification is reserved for patients with ≥5% leukemic cells. Patients with MRD <0.01% on day 15 receive a slightly less intensive reinduction therapy and lower cumulative doses of anthracycline. Patients with standard-risk ALL who have MRD of ≥0.01% on day 42 are reclassified as high-risk; patients with MRD ≥1% are eligible for allogeneic transplant in first remission. For patients with AML, MRD is typically measured after each block of chemotherapy, as well as before and after transplant. In the current St. Jude AML08 study for children and adolescents with AML, 0.1% is the threshold used to define MRD positivity, while levels of MRD ≥1% indicate high-risk AML. The prevalence of MRD varies among different genetic subtypes of ALL and AML.1,12,13,37,38 Other presenting features that have been shown to be associated with MRD are gene profiles of leukemic cells,39,40 and germline- or leukemia-associated gene polymorphisms.41 These associations raise the question whether MRD studies can be replaced by these presenting features. However, in virtually all correlative studies performed to date, MRD was an independent prognostic factor, and it could dissect subgroups

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Clinical studies have shown that MRD results can be applied to most patients with ALL and AML and can be delivered in a timely fashion.

of patients with different outcomes among those with apparently identical leukemia subtype. In addition to measuring initial response to chemotherapy, MRD assays have many other uses in the management of patients with acute leukemia. For patients who achieve MRD-negative status after remission induction therapy, conversion to MRD positivity alerts of the possibility of relapse; a subsequent increase in MRD levels usually indicates impending relapse. Therefore, such a finding can give a head start in the preparation for salvage therapy and/or transplant. Because levels of MRD before transplant are strongly related to the success of the procedure, it is increasingly common to attempt to reduce them with chemotherapy before initiating the transplant conditioning, although evidence that this practice is effective is not yet available. MRD measurements can also be used to guide intervention posttransplant, such as reduction of immunosuppression, administration of donor lymphocyte infusions, or preparation for a second transplant.

routine diagnostic laboratory assays but, overall, are not significantly more expensive than high-complexity tests, such as cytogenetics or molecular pathology. Moreover, when one considers the potential benefits of avoiding undertreatment and relapse, or overtreatment and its sequelae, the cost of MRD testing is fully justified as it can ultimately reduce the cost of patient care. Regardless, current MRD assays remain too expensive and complex for many centers to implement. Thus, the potential benefits of careful leukemia monitoring are limited to a minority of patients. The approach of having reference centers performing the tests in the context of multicenter studies can help in this regard, as it saves costly and time-consuming setup and standardization efforts in peripheral centers while ensuring an expert sample processing and analysis. Ultimately, however, it would be desirable to make MRD

The clinical significance of MRD and its use for

The Future of MRD Studies Evidence for the prognostic importance of MRD in both ALL and AML is solid. One could argue that the collective data supporting the clinical use of MRD are considerably more compelling than those provided in the past in support of established parameters widely used for risk stratification. Moreover, as discussed in this article, MRD testing has multiple applications during the course of treatment that go beyond prognostication. Clinical studies have shown that MRD results can be applied to most patients with ALL and AML and can be delivered in a timely fashion.12,13 Some believe that, with time, MRD studies may become obsolete in the context of the ever-increasing knowledge of the biology and genetics of leukemic cells, but we think it unlikely as MRD measurements reflect the composite influence of multiple factors, such as drug dosage, drug interaction, pharmacokinetic and pharmacogenomic variable, and compliance with the scheduled treatment plan, which cannot be captured by examining the leukemic cells alone. Methods to study MRD are continually being refined.42 MRD studies can be relatively expensive in relation to other

treatment stratification depends on protocol design.

testing simpler and less expensive. To this end, we developed a simplified flow cytometric assay to study MRD in patients with B-lineage ALL during remission induction therapy.43 When applied to samples collected on day 19 of treatment, the results of the simplified assay correlated well with those of the more complex flow cytometric assay and those of PCR amplification of antigenreceptor genes. This assay is currently being used in international protocols to identify patients with good initial response to therapy who are then offered a low-intensity, low-toxicity treatment regimen, an approach that has produced encouraging preliminary results. It is sometimes disputed that only a few leukemic cells have long-term repopulating capacity (“leukemia stem cells”) and that current MRD assays cannot determine whether the signals detected originate from these or more differentiat-

ed cells incapable of driving relapse. This is a rather controversial topic. Evidence that such “stem cells,” defined as leukemic subsets that preferentially grow in immunodeficient mice, also have a growth advantage in humans is lacking. Data indicating that such subsets are more resistant to chemotherapy are less than compelling. In any case, the strong correlation between MRD levels and relapse indicates that MRD positivity should be interpreted as evidence for the persistence of leukemic cells that are resistant to further chemotherapy and are capable of driving the recurrence of clinically overt disease. Besides their use in clinical management, MRD studies are likely to be used more often as a surrogate marker to measure the effectiveness of novel antileukemic therapies. For example, MRD levels during and at the end of remission induction therapy can be used to develop a stopping rule when comparing the efficacy of a new remission induction regimen in relation to that of its predecessor. In addition, MRD testing could be used to quickly determine whether a new agent exerts significant antileukemic effects in vivo, thus sparing the need for lengthy trials with ineffective agents. ● References 1. Campana D. Minimal residual disease in acute lymphoblastic leukemia. Hematology Am Soc Hematol Educ Program. 2010;2010:7-12. 2. Shook D, Coustan-Smith E, Ribeiro RC, et al. Minimal residual disease quantitation in acute myeloid leukemia. Clin Lymphoma Myeloma. 2009;9(suppl 3): S281-S285. 3. Brüggemann M, Schrauder A, Raff T, et al. Standardized MRD quantification in European ALL trials: proceedings of the Second International Symposium on MRD assessment in Kiel, Germany, 18-20 September 2008. Leukemia. 2010;24:521-535. 4. Flohr T, Schrauder A, Cazzaniga G, et al. Minimal residual disease-directed risk stratification using real-time quantitative PCR analysis of immunoglobulin and T-cell receptor gene rearrangements in the international multicenter trial AIEOP-BFM ALL 2000 for childhood acute lymphoblastic leukemia. Leukemia. 2008;22:771-782. 5. Stow P, Key L, Chen X, et al. Clinical significance of low levels of minimal residual disease at the end of remission induction therapy in childhood acute lymphoblastic leukemia. Blood. 2010;115:4657-4663. 6. Zelent A, Greaves M, Enver T. Role of the TELAML1 fusion gene in the molecular pathogenesis of childhood acute lymphoblastic leukaemia. Oncogene. 2004;23:4275-4283. 7. Lane S, Saal R, Mollee P, et al. A >or=1 log rise in RQPCR transcript levels defines molecular relapse in core binding factor acute myeloid leukemia and predicts subsequent morphologic relapse. Leuk Lymphoma. 2008;49:517-523. 8. Corbacioglu A, Scholl C, Schlenk RF, et al. Prognostic impact of minimal residual disease in CBFB-MYH11-positive acute myeloid leukemia. J Clin Oncol. 2010;28:3724-3729. 9. Krönke J, Schlenk RF, Jensen KO, et al. Monitoring of minimal residual disease in NPM1-mutated acute myeloid leukemia: a study from the German-Austrian acute myeloid leukemia study group. J Clin Oncol. 2011;29:2709-2716. 10. Coustan-Smith E, Campana D. Immunologic minimal residual disease detection in acute lymphoblastic leukemia: a comparative approach to molecular testing. Best Pract Res Clin Haematol. 2010;23:347-358. 11. Borowitz MJ, Devidas M, Hunger SP, et al. Clinical significance of minimal residual disease in childhood acute lymphoblastic leukemia and its relationship to other prognostic factors. a Children’s Oncology Group study. Blood. 2008;111:5477-5485. 12. Pui CH, Campana D, Pei D, et al. Treating childhood acute lymphoblastic leukemia without cranial irradiation. N Engl J Med. 2009;360:2730-2741.

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Leukemias Minimal Residual Disease to Monitor Therapy in Acute Leukemia Continued from page 31 13. Rubnitz JE, Inaba H, Dahl G, et al. Minimal residual 16. Schrappe M, Valsecchi MG, Bartram CR, et al. Late disease-directed therapy for childhood acute myeloid MRD response determines relapse risk overall and in subleukaemia: results of the AML02 multicentre trial. Lancet sets of childhood T-cell ALL: results of the AIEOP-BFMOncol. 2010;11:543-552. ALL 2000 study. Blood. 2011;118:2077-2084. 14. Conter V, Bartram CR, Valsecchi MG, et al. 17. Attarbaschi A, Mann G, Panzer-GrĂźmayer R, et Molecular response to treatment redefines all prognosal. Minimal residual disease values discriminate tic factors in children and adolescents with B-cell prebetween low and high relapse risk in children with Bcursor acute lymphoblastic leukemia: results in 3184 cell precursor acute lymphoblastic leukemia and an patients of the AIEOP-BFM ALL 2000 study. Blood. intrachromosomal amplification of chromosome 21: 2010;115:3206-3214. the Austrian and German acute lymphoblastic 15. Van der Velden VH, Corral L, Valsecchi MG, et al. leukemia Berlin-Frankfurt-Munster (ALL-BFM) trials. Prognostic significance of minimal residual disease in J Clin Oncol. 2008;26:3046-3050. infants with acute lymphoblastic leukemia treated within 18. Basso G, Veltroni M, Valsecchi MG, et al. Risk of relapse of childhood acute lymphoblastic leukemia is prethe Interfant-99 protocol. Leukemia. 2009;23:1073-1079.

dicted by flow cytometric measurement of residual disease on day 15 bone marrow. J Clin Oncol. 2009;27:5168-5174. 19. Coustan-Smith E, Sancho J, Behm FG, et al. Prognostic importance of measuring early clearance of leukemic cells by flow cytometry in childhood acute lymphoblastic leukemia. Blood. 2002;100:52-58. 20. Raetz EA, Borowitz MJ, Devidas M, et al. Reinduction platform for children with first marrow relapse of acute lymphoblastic leukemia: A Childrenâ&#x20AC;&#x2122;s Oncology Group Study. J Clin Oncol. 2008;26:3971-3978. 21. Bader P, Kreyenberg H, Henze GH, et al. Prognostic value of minimal residual disease quantification before allogeneic stem-cell transplantation in relapsed childhood acute lymphoblastic leukemia: the ALL-REZ BFM

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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

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Study Group. J Clin Oncol. 2009;27:377-384. 22. Leung W, Campana D, Yang J, et al. High success rate of hematopoietic cell transplantation regardless of donor source in children with very high-risk leukemia. Blood. 2011;118:223-230. 23. Bruggemann M, Raff T, Flohr T, et al; German Multicenter Study Group for Adult Acute Lymphoblastic Leukemia. Clinical significance of minimal residual disease quantification in adult patients with standard-risk acute lymphoblastic leukemia. Blood. 2006;107:1116-1123. 24. Raff T, GĂśkbuget N, LĂźschen S, et al; GMALL Study Group. Molecular relapse in adult standard-risk ALL patients detected by prospective MRD monitoring during and after maintenance treatment: data from the GMALL 06/99 and 07/03 trials. Blood. 2007;109:910-915. 25. Sievers EL, Lange BJ, Buckley JD, et al. Prediction of relapse of pediatric acute myeloid leukemia by use of multidimensional flow cytometry. J Natl Cancer Inst. 1996;88:1483-1488. 26. Coustan-Smith E, Ribeiro RC, Rubnitz JE, et al. Clinical significance of residual disease during treatment in childhood acute myeloid leukemia. Br J Haematol. 2003;123:243-252. 27. MRD-AML-BFM Study Group; Langebrake C, Creutzig U, Dworzak M, et al. Residual disease monitoring in childhood acute myeloid leukemia by multiparameter flow cytometry: the MRD-AML-BFM Study Group. J Clin Oncol. 2006;24:3686-3692. 28. van der Velden VH, van der Sluijs-Geling A, Gibson BE, et al. Clinical significance of flowcytometric minimal residual disease detection in pediatric acute myeloid leukemia patients treated according to the DCOG ANLL97/MRC AML12 protocol. Leukemia. 2010;24: 1599-1606. 29. San Miguel JF, Vidriales MB, Lopez-Berges C, et al. Early immunophenotypical evaluation of minimal residual disease in acute myeloid leukemia identifies different patient risk groups and may contribute to postinduction treatment stratification. Blood. 2001;98:1746-1751. 30. Kern W, Voskova D, Schoch C, et al. Determination of relapse risk based on assessment of minimal residual disease during complete remission by multiparameter flow cytometry in unselected patients with acute myeloid leukemia. Blood. 2004;104:3078-3085. 31. Maurillo L, Buccisano F, Del Principe MI, et al. Toward optimization of postremission therapy for residual disease-positive patients with acute myeloid leukemia. J Clin Oncol. 2008;26:4944-4951. 32. Neale GA, Coustan-Smith E, Stow P, et al. Comparative analysis of flow cytometry and polymerase chain reaction for the detection of minimal residual disease in childhood acute lymphoblastic leukemia. Leukemia. 2004;18:934-938. 33. Kerst G, Kreyenberg H, Roth C, et al. Concurrent detection of minimal residual disease (MRD) in childhood acute lymphoblastic leukaemia by flow cytometry and real-time PCR. Br J Haematol. 2005;128:774-782. 34. Coustan-Smith E, Sancho J, Hancock ML, et al. Use of peripheral blood instead of bone marrow to monitor residual disease in children with acute lymphoblastic leukemia. Blood. 2002;100:2399-2402. 35. van der Velden V, Jacobs DC, Wijkhuijs AJ, et al. Minimal residual disease levels in bone marrow and peripheral blood are comparable in children with T cell acute lymphoblastic leukemia (ALL), but not in precursor-B-ALL. Leukemia. 2002;16:1432-1436. 36. Coustan-Smith E, Sandlund JT, Perkins SL, et al. Minimal disseminated disease in childhood T-cell lymphoblastic lymphoma: a report from the childrenâ&#x20AC;&#x2122;s oncology group. J Clin Oncol. 2009;27:3533-3539. 37. Coustan-Smith E, Mullighan CG, Onciu M, et al. Early T-cell precursor leukaemia: a subtype of very highrisk acute lymphoblastic leukaemia. Lancet Oncol. 2009;10:147-156. 38. Mullighan CG, Su X, Zhang J, et al; Childrenâ&#x20AC;&#x2122;s Oncology Group. Deletion of IKZF1 and prognosis in acute lymphoblastic leukemia. N Engl J Med. 2009;360:470-480. 39. Cario G, Stanulla M, Fine BM, et al. Distinct gene expression profiles determine molecular treatment response in childhood acute lymphoblastic leukemia. Blood. 2005;105:821-826. 40. Flotho C, Coustan-Smith E, Pei D, et al. A set of genes that regulate cell proliferation predicts treatment outcome in childhood acute lymphoblastic leukemia. Blood. 2007;110:1271-1277. 41. Yang JJ, Cheng C, Yang W, et al. Genome-wide interrogation of germline genetic variation associated with treatment response in childhood acute lymphoblastic leukemia. JAMA. 2009;301:393-403. 42. Coustan-Smith E, Song G, Clark C, et al. New markers for minimal residual disease detection in acute lymphoblastic leukemia. Blood. 2011;117:6267-6276. 43. Coustan-Smith E, Ribeiro RC, Stow P, et al. A simplified flow cytometric assay identifies children with acute lymphoblastic leukemia who have a superior clinical outcome. Blood. 2006;108:97-102.

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Quintessential Quinoa

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By Karen Connelly, RD, CSO uinoa, the ancient “grain” of the Andes, culti- cells from damage by free radicals that are created from vated for over 7000 years, has transitioned such things as smoking and pollution, as well as the byitself into our present-day kitchens and the products of normal metabolism. Free radical damage is title of a modern-day superfood. The Incas believed associated with an increased risk of many chronic disquinoa to be a sacred food and referred to the “grain” as eases. Vitamin E is a strong antioxidant that can protect the “mother seed.” Many years later, this superfood cells against free radicals, and quinoa is an ideal food would make its way to the United States, where its pop- choice to add to your menu to increase your intake of ularity continues to grow as its numerous nutritional this important vitamin. Quinoa is also a good source of B vitamins such as thiamin, folic acid, and riboflavin, benefits are spotlighted. How do you say that strange name? Quinoa, or and it provides about 15% of your daily recommended “keen-wah” as is it properly pronounced, will have a few amount of iron.2 Add a food item that is high in vitapeople looking twice and asking, “Are you sure that is min C such as tomatoes, broccoli, or peppers to cooked quinoa to help improve the body’s absorption of planthow you say that?” Quinoa is often referred to as a grain but is actually the based non-heme iron. Diet and lifestyle changes seed of a plant. It belongs to may help to reduce the risk of the same plant family as beets, The excellent protein certain types of cancer. In parchard, and spinach. Quinoa ticular, increasing fiber-rich cooks up just like a grain, so it content, vitamin and foods in the diet may help to is often grouped in this categoreduce the risk of colorectal ry. One distinguishing quality mineral profile, as well cancer.4 Quinoa is an excelof quinoa is that it is a complete protein. It is unusual for a as impressive antioxidant lent source of fiber, providing 5 grams of fiber per 1-cup servplant food to provide all the and phytonutrient activity ing.2 Incorporating fiber-rich essential amino acids that our foods from a variety of differbodies cannot make on their make it an exceptional ent food groups enhances the own. This makes quinoa a fanprotective effect against cantastic protein source for vegfood choice. cer and other chronic diseases. ans, vegetarians, and those It is not well understood at looking to replace an animal protein meal with a plant-based protein meal. One of the this time if the protective benefit lies solely within the amino acids in high concentration in quinoa is lysine. fiber content or if it is how the fiber content of a particThis amino acid is particularly important in tissue ular food interacts with the other naturally occurring growth, tissue repair, and collagen formation. Due to this compounds that helps to reduce the risk of disease. By including quinoa in your everyday menu, you benefit, quinoa is a good choice for anyone going through chemotherapy, radiation, or postsurgical recov- will also be receiving a serving of whole grain. The 2010 Dietary Guidelines for Americans recommends ery to help the body heal and generate new cells. In addition to the superior protein content of quinoa, that all Americans make half or more of the grains it is also abundant in a variety of vitamins and miner- they consume be whole grains—about 3 to 5 servings als, as well as naturally occurring compounds such as of whole grain per day. A half-cup serving of quinoa polyphenols, phytosterols, and flavonoids with possible provides 1 serving of whole grain. The Whole Grains nutraceutical benefits.1 Quinoa is a good source of mag- Council is an invaluable resource to help people nesium, manganese, folate, phosphorus, and potassi- identify whole grain foods and understand their health um.2 The minerals present in quinoa work as cofactors benefits, as well as to provide health professionals with in antioxidant enzymes.3 Antioxidants help to protect scientific studies supporting the health benefits of whole grains. The Whole Grains Council also developed the Whole Grain Stamp found on many food products in your local supermarket. This stamp identiMs Connelly is a Registered Dietitian and Certified Specialist fies a food item as whole grain and tells consumers in Oncology Nutrition at the exactly how much whole grain it contains. The Whole Steeplechase Cancer Center in Grain Stamp and the wealth of information on their Somerville, New Jersey. As Web site help take the mystery out of eating healthy.5 part of her responsibilities, she Quinoa is so versatile it can become a part of your provides nutrition counseling, regular diet from breakfast to dessert. It can be made group classes, and monthly into savory or sweet dishes. Cooked quinoa is smooth cooking classes for patients and fluffy yet slightly chewy with a nutty flavor. It is and families. similar to couscous and rice, so it is easy to substitute

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quinoa in these recipes. Quinoa can also be used as a hot cereal in the morning—just add the toppings you would typically add to oatmeal, and you will have a nutrient-packed breakfast. The quinoa seed is tiny and round. The yellow seed is the most common variety, but it also comes in red, black, pink, orange, and purple. Quinoa is also gluten free, making it a superb, highly nutritious choice for people with celiac disease or anyone with a wheat allergy or intolerance. Before cooking quinoa, the seeds need to be rinsed to remove the soapy saponins that will give the seed a bitter taste if not removed. Commercial brands of quinoa are sometimes sold prerinsed, but it is still good to rinse these seeds one more time before cooking. Quinoa is the tiny “grain” with a funny name that packs a huge nutritional punch. The advantages of adding quinoa to your diet are numerous. The excellent protein content, vitamin and mineral profile, as well as impressive antioxidant and phytonutrient activity make it an exceptional food choice to incorporate into the diet. Quinoa is low in fat and is cholesterol free, another added bonus. This is a food item that I regularly recommend people introduce into their diet. It is a great choice for people on active chemotherapy and radiation treatment because of its mild flavor and the ability to adjust it to their particular taste, while at the same time providing more nutrition than plain white rice or pasta. It is also perfect for those patients who have completed treatment and are looking to improve the quality of their diet or perhaps move toward a plant-based diet. Quinoa is a perfect food for people to start this new journey. It is not an intimidating grain or so strange that it may discourage some from making a change to a healthier way of eating. Another recommendation is to encourage people to go their local health food stores or supermarkets and look for prepared quinoa or whole grain salads in the deli section to give them an idea of what these grains should look and taste like once they make it on their own. Making small changes is ultimately what will motivate most people into following a healthier diet and overall healthier lifestyle; quinoa can be that first stepping-stone. ● References 1. Abugoch James LE. Quinoa (Chenopodium quinoa Willd.): composition, chemistry, nutritional, and functional properties. Adv Food Nutr Res. 2009;58:1-31. 2. US Department of Agriculture. Quinoa, cooked. Nutrition Fact Information. http://ndb.nal.usda.gov/ndb/foods/show/6430. Accessed February 25, 2012. 3. Vega-Galvez A, Miranda M, Vergara J, et al. Nutrition facts and functional potential of quinoa (Chenopodium quinoa willd.), an ancient Andean grain: a review. J Sci Food Agric. 2010;90:2541-2547. 4. Chan AT, Giovannucci EL. Primary prevention of colorectal cancer. Gastroenterology. 2010;138:2029-2043. 5. Whole Grains Council. Identifying whole grain products. www.whole grainscouncil.org. Accessed February 25, 2012.

Visit www.TheOncologyNurse.com for Karen’s quinoa recipe.

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The Patientâ&#x20AC;&#x2122;s Voice What Doctors Can Learn From Nurses Continued from cover needed answered (What did it mean that I had a high platelet count? When would I know if this round of chemotherapy worked? What alternatives existed if it did not?), I fuddled around until I found the button on my electronic bed, pushed it, and waited until the small, humming motor slowly raised my head so I could carry on a decent conversation. â&#x20AC;&#x153;Oh, good morning, Dr F,â&#x20AC;? I said. â&#x20AC;&#x153;Why would I be crazy?â&#x20AC;? â&#x20AC;&#x153;The steroids we are giving you will make you crazy!â&#x20AC;? he stated forcefully.

â&#x20AC;&#x153;Hi, Ms M,â&#x20AC;? she (in this case) would gently say to me as I drifted in and out of sleep interrupted by nausea, exhaustion, blurry vision, and confusion. â&#x20AC;&#x153;I am just here to see if you need more medicineâ&#x20AC;Śâ&#x20AC;? or â&#x20AC;&#x153;I am just here to let you know that someone is aroundâ&#x20AC;Śâ&#x20AC;? or â&#x20AC;&#x153;I am just here to answer any questions you may haveâ&#x20AC;Śâ&#x20AC;? or â&#x20AC;&#x153;I am just here to check

up on youâ&#x20AC;Śâ&#x20AC;? or â&#x20AC;&#x153;I am just here.â&#x20AC;Śâ&#x20AC;? Yes, Dr F, use my name! Talk to me in a calm voice (you already know I am somewhat disoriented because of the time of day and the characteristics of my illness). Tell me what you want from me or have to offer me. Do not be sarcastic. Do not speak loudly when you see me lying with my eyes closed.

PROVENGEÂŽ (sipuleucel-T) Suspension for Intravenous Infusion

Rx Only

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

INDICATIONS AND USAGE: PROVENGEÂŽ (sipuleucel-T) is an autologous cellular immunotherapy indicated for the treatment of asymptomatic or minimally symptomatic metastatic castrate resistant (hormone refractory) prostate cancer.

Tell me what you want from me or have to offer me. Do not be sarcastic. Do not speak loudly when you see me lying with my eyes closed.

DOSAGE AND ADMINISTRATION Ĺ&#x2DC; For Autologous Use Only. Ĺ&#x2DC; 7KH UHFRPPHQGHG FRXUVH RI WKHUDS\ IRU 3529(1*( LV FRPSOHWH GRVHV JLYHQ DW DSSUR[LPDWHO\ ZHHN LQWHUYDOV Ĺ&#x2DC; 3UHPHGLFDWH SDWLHQWV ZLWK RUDO DFHWDPLQRSKHQ DQG DQ DQWLKLVWDPLQH VXFK DV diphenhydramine. Ĺ&#x2DC; %HIRUH LQIXVLRQ FRQĹľUP WKDW WKH SDWLHQWĹ&#x2018;V LGHQWLW\ PDWFKHV WKH SDWLHQW LGHQWLĹľHUV RQ the infusion bag. Ĺ&#x2DC; Do Not Initiate Infusion of Expired Product. Ĺ&#x2DC; ,QIXVH 3529(1*( LQWUDYHQRXVO\ RYHU D SHULRG RI DSSUR[LPDWHO\ PLQXWHV Do Not Use a Cell Filter. Ĺ&#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.)

Dr F represents an entire cadre of doctors who could learn from the nurses who surround them how to approach a real, live patient. Certainly, I understand the hierarchy in the hospital. I understand that many demands seemingly much more important than visiting me, or any other patient, clutter the days of doctors. I understand what a nurse explained to me: the doctors give the orders and the nurses carry them out; the doctor comes up with the treatment plan, the nurse applies it and comforts the patient through it; the doctor does a round on the floor at given intervals, while the nurse actually works on the floor, spending his/her days with patients. However, in my mind, none of that gives the doctor a right to be curt, sarcastic, and disorienting in his/her interaction with me! So how would I suggest to Dr F that he enter a patientâ&#x20AC;&#x2122;s room, even if it is 7:30 in the morning, and the patient has gotten literally no sleep after a difficult night? The same way the nurses did all during the night!

Did You Know?

Prospective data from a recent study link the long-term use of non-aspirin nonsteroidal antiinflammatory drugs to increased risk for renal cell carcinoma. The use of acetaminophen and aspirin was not associated with the risk for renal cell carcinoma. â&#x20AC;&#x201D;Arch Intern Med. 2011;171:1487-1493.

March 2012 I VOL 5, NO 2

CONTRAINDICATIONS: None. WARNINGS AND PRECAUTIONS Ĺ&#x2DC; PROVENGE is intended solely for autologous use. Ĺ&#x2DC; Acute infusion reactions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ĹľUVW 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. Ĺ&#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. Ĺ&#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 HIĹľFDF\ 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. Ĺ&#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 ĹľQDO 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 UHĹśHFW WKH UDWHV REVHUYHG LQ SUDFWLFH

Do not ask me disorienting questions. In short, Dr F, act like a nurse around me! It would do both of us a world of good in your job as a doctor! â&#x2014;? MMA is undergoing treatment for cancer. She wishes to use her initials.

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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 ,QĹśXHQ]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_March2012_v8_TON 3/15/12 12:30 PM Page 35

Reader Survey

Should everyone be required to purchase health insurance? In the February issue, we published an editorial from the Wall Street Journal about the requirement under the federal 2010 Patient Protection and Affordable Care Act that everyone have health insurance. This aspect of the act is scheduled to take effect in 2014, but there are legal challenges working their way through the courts.

We asked our online reading community about this subject, and here are the results: â&#x20AC;˘ 64% said people should be required to purchase health insurance â&#x20AC;˘ 36% didnâ&#x20AC;&#x2122;t think people should be required to purchase health insurance

Our thanks to all who participated in this survey. If you want to participate in this monthâ&#x20AC;&#x2122;s survey, see page 15 for details.

www.TheOncologyNurse.com 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 (%)

&RQWURO ZDV QRQ DFWLYDWHG DXWRORJRXV SHULSKHUDO EORRG PRQRQXFOHDU FHOOV

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

References: 1. Kantoff PW, Higano CS, Shore ND, et al; for the IMPACT Study Investigators. Sipuleucel-T immunotherapy for castration-resistant prostate cancer. N Engl J Med. 2010;363:411-422. 2. PROVENGE [package insert]. Dendreon Corporation; June 2011. 3. NCCN Clinical Practice Guidelines in Oncology: Prostate Cancer. V.4.2011. National Comprehensive Cancer Network Web site. www.nccn.org. Accessed October 24, 2011.

k 'HQGUHRQ &RUSRUDWLRQ $OO ULJKWV UHVHUYHG )HEUXDU\ 3ULQWHG LQ WKH 8 6 $ 'HQGUHRQ WKH 'HQGUHRQ ORJR DQG PROVENGE are registered trademarks of Dendreon Corporation. P-A-11.10-073.02(b)

www.TheOncologyNurse.com

March 2012 I VOL 5, NO 2

TON_March2012_v8_TON 3/15/12 11:05 AM Page 36

IN ADVANCED PROSTATE CANCER...

PROVENGE ACTIVATE THE POWER OF THE IMMUNE SYSTEM. EXTEND SURVIVAL.

Resting T cell

PROVENGE

PROVENGE-activated T cell

Activated T cell attacks prostate cancer

Prostate cancer cell

s PROVENGE extends median survival beyond 2 years1 s Only 1.5% of patients treated with PROVENGE in the pivotal trial discontinued treatment due to adverse events2 — The most common adverse events in PROVENGE trials were chills, fatigue, fever, back pain, nausea, joint ache, and headache2 s PROVENGE is the first and only FDA-approved immunotherapy for advanced prostate cancer s The NCCN recommends PROVENGE as a first-line treatment for men with asymptomatic or minimally symptomatic metastatic castrate resistant prostate cancer (NCCN Category 1 recommendation)3 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 were chills, fatigue, fever, back pain, nausea, joint ache, and headache. For more information on PROVENGE, please see Brief Summary of Prescribing Information on adjacent page.

5392_Onc_Nurse_APN-PA_L1.indd 1

www.PROVENGE.com

2/21/12 2:32 PM