TON January 2015 Vol 8 No 1

January 2015

www.TheOncologyNurse.com

Vol 8, No 1

Lung Cancers and Stigma: Perception or Reality?

Cancer Center Profile

University of Washington Medical Center

Caroline Kornhauser, Sarah Quinlan, Nian Hu, Christin Washington, Dawn Zador, and Carolyn Messner

“Who can I blame? I am 67 years old and have been a heavy smoker all my life. I have lived with chronic obstructive pulmonary disease, and was just diagnosed with lung cancer. I made my bed and now I have to sleep in it.”

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his patient vignette portrays the self-blame, suffering, and personal pain that a diagnosis of lung cancer may precipitate in patients who smoked cigarettes for a significant part of their life. Lung cancers are the leading cause of cancer deaths in the United States.1 “Lung cancer is classified as small cell (14%) or non small cell (84%) for the purposes of treatment.

Based on type and stage of cancer, as well as specific molecular characteristics

Diana Su (left), a recently hired oncology nurse, and Sandra Elliott, a nurse recruiter at the University of Washington Medical Center.

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he University of Washington (UW) Medical Center in Seattle is a leading academic medical center, with specialties in cardiac care, cancer care and stem-cell transplantation, obstetrics (including high-risk neonatal intensive care), orthopedic care, and solid organ transplantation. U.S. News & World Report ranks UW Medical Center as the top hospital in the metropolitan Seattle area and in Washington state, and the center is ranked seventh in the nation for its cancer care.

UW Medical Center partners with the Seattle Cancer Care Alliance to Continued on page 7

Conference News

Highlights from ASH and SABCS Alice Goodman

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he annual meetings of the American Society of Hematology (ASH) and the San Antonio Breast Cancer Symposium (SABCS) took place in December 2014, attracting US and international oncologists interested in the latest research on basic science and clinical medicine. Below is a selection of highlights from these meetings.

ASH Announces Second Choosing Wisely List ASH announced its second list of 5 commonly used tests, treatments, and procedures in hematology that physicians and patients should discuss before routine use. This Choosing Wisely list adds to the first list of 5 practices that the society released in 2013 as part of

the Choosing Wisely campaign, an initiative of the American Board of Internal Medicine (ABIM) Foundation that intends to spark conversations between patients and physicians about the risks and benefits of certain procedures.1 ASH’s new Choosing Wisely recommenContinued on page 8

of cancer cells, treatments include surgery, radiation therapy, chemotherapy and targeted therapies.”1 However, oncology professionals often do not have the resources to address the psychosocial distress of this population.

This article describes the stigma that may be associated with a lung cancer diagnosis and its impact on body image, self-perception, and coping. Also explored are ways in which this stigma may be alleviated by the multidisciplinary Continued on page 12

Sunrise, Sunset: Swiftly Go the Years Peggy Barton, RN, BSBA; Sue Mahoney-Stombaugh, CNP; and Bahu Shaikh, MD, FACP; Toledo Clinic, OH

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any experienced oncology nurses who are retiring or approaching retirement possess knowledge about oncology patient care that comes from years of experience. They have seen a transition from general oncology to specialties in bone marrow transplant, genetics, hematology, medical oncology, palliative care and hospice, radiation oncology, as well as site-specific and surgical oncology. What used to be a limited number of treatment resources has exploded to multiple new

inside 11 Best Practices Shift Work, Sleep Deprivation, and Cancer Risk 7 Electronic Health Records 1 Epic: Electronic Health Records Company 18 Palliative Care

Palliative Care Sells Itself 9 Side Effects Management 1

Novel Agent Effective for the Management of Cachexia

© 2015 Green Hill Healthcare Communications, LLC

methodologies, many of which are based on specific tumor markers. How does a practice ensure that the knowledge, skills, and abilities of its senior nursing staff are transferred to newer nurses joining the practice?

Background

The Toledo Clinic is a multispecialty physician organization, of which oncology is one of its specialties. The practice was established in the 1960s, when the first medical oncologist was recruited to Continued on page 10

Continuing Education

0 Non–Small-Cell Lung Cancer 2 Latest Treatment Advances for Individualized Care of NSCLC 30 Colorectal Cancer

Latest Treatment Advances for Individualized Care of CRC

Take a bite out of G-CSF acquisition costs*

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

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

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

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

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

GRANIX is another option in short-acting G-CSF therapy TM

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

» Safety was evaluated in 3 Phase III clinical trials1

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

» Potential for tumor growth stimulatory effects on malignant cells: The granulocyte colonystimulating factor (G-CSF) receptor, through which GRANIX acts, has been found on tumor cell lines.

The possibility that GRANIX acts as a growth factor for any tumor type, including myeloid malignancies and myelodysplasia, diseases for which GRANIX is not approved, cannot be excluded.

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

Please see brief summary of Full Prescribing Information on adjacent page.

For more information, visit GRANIXhcp.com.

Reference: 1. GRANIX TM (tbo-filgrastim) Injection Prescribing Information. North Wales, PA: Teva Pharmaceuticals; 2013.

©2014 Cephalon, Inc., a wholly-owned subsidiary of Teva Pharmaceutical Industries Ltd. GRANIX is a trademark of Teva Pharmaceutical Industries Ltd. All rights reserved. GRX-40138 January 2014.

FDA update Jakafi Gets New Indication for Use in Patients with Polycythemia Vera

with PV whose disease was resistant to or who were intolerant of hydroxyurea. The composite end point was durable hemat­ The FDA approved ruxolitinib (Jakafi; ocrit control and spleen volume reducIncyte Corporation) for the treatment of tion, and a durable hematocrit control patients with polycythemia vera (PV) that obviated the need for regular phlewho have had an inadequate response botomy. Patients were randomized to to or are intolerant of hydroxyurea. The ruxolitinib 10 mg twice daily (N = 110) FDA approval was based on Protocol or to best available care (N = 112).

CINC424B2301, a multicenter, open-­ Ruxolitinib was superior to best availlabel, active-control trial of 222 patients able therapy in durable hematocrit con-

BRIEF SUMMARY OF PRESCRIBING INFORMATION FOR GRANIX™ (tbo-filgrastim) Injection, for subcutaneous use SEE PACKAGE INSERT FOR FULL PRESCRIBING INFORMATION 1 INDICATIONS AND USAGE GRANIX is indicated to reduce the duration of severe neutropenia in patients with non-myeloid malignancies receiving myelosuppressive anti-cancer drugs associated with a clinically significant incidence of febrile neutropenia.

4 CONTRAINDICATIONS None.

5 WARNINGS AND PRECAUTIONS 5.1 Splenic Rupture Splenic rupture, including fatal cases, can occur following administration of human granulocyte colony-stimulating factors. In patients who report upper abdominal or shoulder pain after receiving GRANIX, discontinue GRANIX and evaluate for an enlarged spleen or splenic rupture.

5.2 Acute Respiratory Distress Syndrome (ARDS) Acute respiratory distress syndrome (ARDS) can occur in patients receiving human granulocyte colony-stimulating factors. Evaluate patients who develop fever and lung infiltrates or respiratory distress after receiving GRANIX, for ARDS. Discontinue GRANIX in patients with ARDS. 5.3 Allergic Reactions Serious allergic reactions including anaphylaxis can occur in patients receiving human granulocyte colony-stimulating factors. Reactions can occur on initial exposure. The administration of antihistamines‚ steroids‚ bronchodilators‚ and/or epinephrine may reduce the severity of the reactions. Permanently discontinue GRANIX in patients with serious allergic reactions. Do not administer GRANIX to patients with a history of serious allergic reactions to filgrastim or pegfilgrastim.

5.4 Use in Patients with Sickle Cell Disease Severe and sometimes fatal sickle cell crises can occur in patients with sickle cell disease receiving human granulocyte colony-stimulating factors. Consider the potential risks and benefits prior to the administration of human granulocyte colony-stimulating factors in patients with sickle cell disease.

Discontinue GRANIX in patients undergoing a sickle cell crisis.

5.5 Potential for Tumor Growth Stimulatory Effects on Malignant Cells The granulocyte colony-stimulating factor (G-CSF) receptor through which GRANIX acts has been found on tumor cell lines. The possibility that GRANIX acts as a growth factor for any tumor type, including myeloid malignancies and myelodysplasia, diseases for which GRANIX is not approved, cannot be excluded.

6 ADVERSE REACTIONS The following potential serious adverse reactions are discussed in greater detail in other sections of the labeling: • Splenic Rupture [see Warnings and Precautions (5.1)] • Acute Respiratory Distress Syndrome [see Warnings and Precautions (5.2)] • Serious Allergic Reactions [see Warnings and Precautions (5.3)] • Use in Patients with Sickle Cell Disease [see Warnings and Precautions (5.4)] • Potential for Tumor Growth Stimulatory Effects on Malignant Cells [see Warnings and Precautions (5.5)] The most common treatment-emergent adverse reaction that occurred at an incidence of at least 1% or greater in patients treated with GRANIX at the recommended dose and was numerically two times more frequent than in the placebo group was bone pain.

6.1 Clinical Trials Experience Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in clinical practice.

GRANIX clinical trials safety data are based upon the results of three randomized clinical trials in patients receiving myeloablative chemotherapy for breast cancer (N=348), lung cancer (N=240) and non-Hodgkin’s lymphoma (N=92). In the breast cancer study, 99% of patients were female, the median age was 50 years, and 86% of patients were Caucasian. In the lung cancer study, 80% of patients were male, the median age was 58 years, and 95% of patients were Caucasian. In the non-Hodgkin’s lymphoma study, 52% of patients were male, the median age was 55 years, and 88% of patients were Caucasian. In all three studies a placebo (Cycle 1 of the breast cancer study only) or a non-US-approved filgrastim product were used as controls. Both GRANIX and the non-US-approved filgrastim product were administered at 5 mcg/kg subcutaneously once daily beginning one day after chemotherapy for at least five days and continued to a maximum of 14 days or until an ANC of ≥10,000 x 106/L after nadir was reached.

GRX-40189_6.75x8.875_DIGITAL_Island_Brief Summary.indd 1

trol and in spleen volume reduction at week 32 (21% vs 1%; P <.001) and at week 48 (19% vs 1%; P <.001), as well as in a relatively high rate (55%) of durable hematocrit control at week 48.

The most common hematologic adverse reactions (incidence >20%) through week 32 were thrombocytopenia and anemia. The most common nonhematologic adverse events (incidence >10%) were headache, abdomi-

Bone pain was the most frequent treatment-emergent adverse reaction that occurred in at least 1% or greater in patients treated with GRANIX at the recommended dose and was numerically two times more frequent than in the placebo group. The overall incidence of bone pain in Cycle 1 of treatment was 3.4% (3.4% GRANIX, 1.4% placebo, 7.5% non-US-approved filgrastim product).

Leukocytosis In clinical studies, leukocytosis (WBC counts > 100,000 x 106/L) was observed in less than 1% patients with non-myeloid malignancies receiving GRANIX. No complications attributable to leukocytosis were reported in clinical studies.

6.2 Immunogenicity As with all therapeutic proteins, there is a potential for immunogenicity. The incidence of antibody development in patients receiving GRANIX has not been adequately determined.

7 DRUG INTERACTIONS No formal drug interaction studies between GRANIX and other drugs have been performed.

Drugs which may potentiate the release of neutrophils‚ such as lithium‚ should be used with caution.

Increased hematopoietic activity of the bone marrow in response to growth factor therapy has been associated with transient positive bone imaging changes. This should be considered when interpreting bone-imaging results.

8 USE IN SPECIFIC POPULATIONS 8.1 Pregnancy Pregnancy Category C There are no adequate and well-controlled studies of GRANIX in pregnant women. In an embryofetal developmental study, treatment of pregnant rabbits with tbo-filgrastim resulted in adverse embryofetal findings, including increased spontaneous abortion and fetal malformations at a maternally toxic dose. GRANIX should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus.

In the embryofetal developmental study, pregnant rabbits were administered subcutaneous doses of tbo-filgrastim during the period of organogenesis at 1, 10 and 100 mcg/kg/day. Increased abortions were evident in rabbits treated with tbo-filgrastim at 100 mcg/kg/day. This dose was maternally toxic as demonstrated by reduced body weight. Other embryofetal findings at this dose level consisted of post-implantation loss‚ decrease in mean live litter size and fetal weight, and fetal malformations such as malformed hindlimbs and cleft palate. The dose of 100 mcg/kg/day corresponds to a systemic exposure (AUC0-24) of approximately 50-90 times the exposures observed in patients treated with the clinical tbo-filgrastim dose of 5 mcg/kg/day.

8.3 Nursing Mothers It is not known whether tbo-filgrastim is secreted in human milk. Because many drugs are excreted in human milk, caution should be exercised when GRANIX is administered to a nursing woman. Other recombinant G-CSF products are poorly secreted in breast milk and G-CSF is not orally absorbed by neonates.

8.4 Pediatric Use The safety and effectiveness of GRANIX in pediatric patients have not been established.

8.5 Geriatric Use Among 677 cancer patients enrolled in clinical trials of GRANIX, a total of 111 patients were 65 years of age and older. No overall differences in safety or effectiveness were observed between patients age 65 and older and younger patients.

8.6 Renal Impairment The safety and efficacy of GRANIX have not been studied in patients with moderate or severe renal impairment. No dose adjustment is recommended for patients with mild renal impairment.

8.7 Hepatic Impairment The safety and efficacy of GRANIX have not been studied in patients with hepatic impairment.

10 OVERDOSAGE No case of overdose has been reported. ©2013 Cephalon, Inc., a wholly owned subsidiary of Teva Pharmaceutical Industries Ltd. All rights reserved.

GRANIX is a trademark of Teva Pharmaceutical Industries Ltd. Manufactured by: Distributed by: Sicor Biotech UAB Teva Pharmaceuticals USA, Inc. Vilnius, Lithuania North Wales, PA 19454 U.S. License No. 1803 Product of Israel GRX-40189 January 2014 This brief summary is based on TBO-003 GRANIX full Prescribing Information.

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nal pain, diarrhea, dizziness, fatigue, pruritus, dyspnea, and muscle spasms.

Overall, 4% of patients discontinued therapy with ruxolitinib because of adverse events. (December 14, 2014)

Cyramza Approved in Combination with Docetaxel for Metastatic NSCLC

Ramucirumab (Cyramza; Eli Lilly) received a new indication for use in combination with docetaxel for the treatment of patients with metastatic non–small-cell lung cancer (NSCLC) whose disease is progressing with or after platinum-based chemotherapy. In patients with EGFR or ALK mutations, disease progression should be considered for treatment with an FDA-approved medication for these genetic mutations before administering ramucirumab. Earlier in the year, the FDA approved ramucirumab alone and in combination with paclitaxel for the treatment of patients with advanced gastric or gastroesophageal junction (GEJ) adenocarcinoma after disease progression while using firstline therapy.

The approval of ramucirumab in combination with docetaxel for patients with NSCLC was based on results of the multicenter, double-blind, placebo-­controlled study of 1253 patients with previously treated metastatic NSCLC that showed improved overall survival (OS). Patients were randomized to ramucirumab in combination with docetaxel on day 1 of a 21-day cycle (N = 628) or to placebo plus docetaxel (N = 625). The median OS was 10.5 months in the ramucirumab plus docetaxel arm and 9.1 months in the placebo plus docetaxel arm, a significant difference (hazard ratio [HR], 0.86; 95% confidence interval [CI], 0.75-0.98; P = .024). Progression-free survival (PFS) was also significantly longer with ramucirumab than with placebo (HR, 0.76; 95% CI, 0.68-0.86; P <.001).

Among 1245 patients who received at least 1 dose of ramucirumab plus docetaxel, the most frequent adverse reactions (incidence ≥30%) were neutropenia, fatigue/asthenia, and stomatitis/ mucosal inflammation. The most common serious adverse reactions with the active combination were febrile neutropenia (14%), pneumonia (6%), and neutropenia (5%). (December 12, 2014)

Cyramza plus Paclitaxel for Advanced Gastric Cancer After Chemotherapy

The FDA approved ramucirumab (Cyramza; Eli Lilly) in combination with paclitaxel for patients with advanced or metastatic gastric cancer or with GEJ adenocarcinoma whose cancer has progressed while receiving or Continued on page 11

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january 2015 I VOL 8, NO 1

www.TheOncologyNurse.com

From The Editor This issue of The Oncology Nurse-APN/PA (TON), our first of the new year, features a selection of insightful topics that we hope you will find useful when caring for patients with cancer.

In this issue, we share highlights from the 2014 American Society of Hematology (ASH) annual meeting and the 2014 San Antonio Breast Beth Faiman, PhD, Cancer Symposium (SABCS).

APRN-BC, AOCN During the ASH meeting, a Editor-in-Chief second list of 5 practices to question was announced as part of the society’s participation in the American Board of Internal Medicine Foundation’s Choose Wisely campaign. In addition, results from a trial on the use of pediatric regimens for adolescents and young adults with acute lymphoblastic leukemia are discussed, as are those from a trial studying the role of tinzaparin in reducing the risk of recurrent venous thromboembolism in patients with active cancer. From SABCS, results are shared from a trial exploring the role of dietary fat and its impact on mortality in patients with hormone-negative breast cancer, as are those from a trial studying the effectiveness of capecitabine in elderly pa-

tients with moderate- to high-risk early-stage breast cancer.

We also feature an article that explores the stigmas associated with a diagnosis of lung cancer. The connection between smoking and lung cancer, how this connection contributes to stigmas associated with the disease, and the effects of this stigma on research funding, access to care, and patients’ psychological states are discussed. The article also includes steps to help overcome the stigma, as well as the role of the oncology nurse in supporting patients who are diagnosed with lung cancer.

Be sure to also read an inspiring profile of the University of Washington Medical Center, as well as a compelling article on the potential impact of shift work and sleep deprivation on the human body. “There is a very strong link between shift work and lack of sleep, and fewer hours of sleep can translate to a higher risk for obesity and disease,” said Eva S. Schernhammer, MD, DrPH, who recently spoke on the topic.

Finally, discover how one clinic developed a process to ensure that its nursing team received ongoing learning opportunities and how the transfer of knowledge was facilitated from retiring staff to newly hired nurses. Also in this issue, lung cancer screening, electronic health records, the benefits of palliative care, and the management of cancer-related cachexia are explored.

Thank you for your continued support of TON, and best wishes for a healthy and happy 2015! n

PUBLISHING STAFF Vice President/Group Publisher Russell Hennessy rhennessy@the-lynx-group.com Vice President/Director of Sales & Marketing Joe Chanley jchanley@the-lynx-group.com Director, Client Services Dave Dempsey ddempsey@the-lynx-group.com Editorial Director Kristin Siyahian ksiyahian@the-lynx-group.com Managing Editor Kristen Olafson kolafson@the-lynx-group.com Copyeditors Mollie Friedman Peggy Roeske Production Manager Melissa Lawlor

The Lynx Group President/CEO Brian Tyburski Chief Operating Officer Pam Rattananont Ferris Vice President of Finance Andrea Kelly Human Resources Jennine Leale

Reader Poll Do you have a process in place to provide onsite continuing education to staff members? o Yes In their article “Sunrise, Sunset: Swiftly Go the Years,” the authors discuss steps taken at their clinic to provide convenient, ongoing learning opportunities for the nursing team as well as ensure the transfer of knowledge from veteran team members to newly hired nurses. Orientation efforts, mentorship arrangements, and efforts to

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integrate continuing education programs into clinic activities are discussed. Do you have a process in place to provide continuing education to staff members? Let us know how your clinic or practice setting ensures the transfer of knowledge from long-standing team members to those who are newly hired.

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

The Oncology Nurse-APN/PA®, ISSN 1944-9798 (print); ISSN 1944-9801 (online) is published 6 times a year by Green Hill Healthcare Communications, LLC, 1249 South River Road, Suite 202A, Cranbury, NJ 08512. Telephone: 732.656.7935. Fax: 732.656.7938. Copyright © 2015 by Green Hill Health­care Com­munications, LLC. All rights reserved. The Oncology Nurse-APN/PA® logo is a registered trademark of Green Hill Healthcare Communications, LLC. No part of this publication may be reproduced or transmitted in any form or by any means now or hereafter known, electronic or mechanical, including photocopy, recording, or any informational storage and retrieval system, without written permission from the Publisher. Printed in the United States of America.

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

It is the responsibility of the treating physician or other healthcare professional, relying on independent experience and knowledge of the patient, to determine drug dosages and the best treatment for the patient. Every effort has been made to check generic and trade names, and to verify dosages. The ultimate responsibility, however, lies with the prescribing physician. Please convey any errors to the Editorial Director.

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Director, Strategy & Program Development John Welz Director, Quality Control Barbara Marino Quality Control Assistant Theresa Salerno Director, Production & Manufacturing Alaina Pede Director, Creative & Design Robyn Jacobs Creative & Design Assistants Lora LaRocca Wayne Williams Director, Digital Media Anthony Romano Jr Digital Media Specialist Charles Easton IV Web Content Manager Anthony Trevean Digital Programmer Michael Amundsen Meeting & Events Planner Linda Mezzacappa Senior Project Managers Alyson Bruni Jini Gopalaswamy Project Manager Deanna Martinez Project Coordinator Mike Kodada IT Manager Kashif Javaid Administrative Team Leaders Rachael Baranoski Allison Ingram Administrative Assistant Amanda Hedman Office Coordinator Robert Sorensen

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january 2015 I VOL 8, NO 1

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Editorial Board EDITOR-IN-CHIEF

Beth Faiman,

PhD, APRN-BC, AOCN

Cleveland Clinic Taussig Cancer Institute Cleveland, OH

Cassandra J. Hammond, RN, MSN, CRNP

Avid Education Partners, LLC Sharpsburg, MD

Catherine Bishop,

Shannon Hazen,

Johns Hopkins Kimmel Cancer Center/Sibley Infusion Washington, DC

Charlotte, NC

DNP, NP, AOCNP

Deena Damsky Dell, RN-BC, MSN,

RN, BSN, OCN

Taline Khoukaz, MSN, ACNP-C

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

Wendye DiSalvo,

Sandra E. Kurtin,

DNP, APRN, AOCN Genentech New London, NH

RN, MS, AOCN, ANP-C

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

Pharmacy John F. Aforismo,

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

Gary Shelton,

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

City of Hope National Medical Center Duarte, CA

John Theurer Cancer Center Hackensack University Medical Center Hackensack, NJ

Constance Engelking, RN,

Kena C. Miller,

Jacqueline Marie Toia, RN, MS,

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

Millennium Pharmaceuticals, Inc Boston, MA

Northwestern University Myeloma Program Chicago, IL

Patricia Molinelli,

Pamela Hallquist Viale, RN, MS,

Amy Ford, RN, Quintiles Dallas, TX

MS, RN, APN-C, AOCNS

Somerset Medical Center Somerville, NJ

RD, CSO

Patient Advocacy Peg Ford

BSN

Joseph D. Tariman,

BSN, OCN

Nutrition Karen Connelly,

Lori Stover, RN,

Ann McNeill,

MS, CNS, OCN

RJ Health Systems International, LLC Wethersfield, CT

Somerset Medical Center Somerville, NJ

Denice Economou,

RN, MSN, ARNP-BC

BSc Pharm, RPh, FASCP

NYU Clinical Cancer Center New York, NY

Western Pennsylvania Cancer Institute Pittsburgh, PA

RN, MSN, APN

PhD, RN, AOCN

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

Arizona Cancer Center Tucson, AZ

RN, MN, CNS, AOCN

Rita Wickham,

RN, DNS

John Theurer Cancer Center Hackensack University Medical Center Hackensack, NJ

Fox Chase Cancer Center Philadelphia, PA

AOCN, LNC

Melinda G. Oberleitner,

PhD, ANP-BC DePaul University Chicago, IL

Ovarian Cancer Alliance of San Diego San Diego, CA

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

DNP

CS, ANP, AOCN Saratoga, CA

Genetic Counseling Cristi Radford, MS, CGC

Invitae Atlanta, GA

Managed Care and Pharmaceutical Management Burt Zweigenhaft, BS

Onco360/OncoMed New York, NY

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

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

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january 2015 I VOL 8, NO 1

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

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

Connie Visovsky,

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

Isabell Castellano, RN

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

Jeanne Westphal, RN Meeker Memorial Hospital Litchfield, MN

www.TheOncologyNurse.com

Cancer Center profile

University of Washington Medical Center provide integrated care for oncology patients. The multidisciplinary team includes medical oncologists, surgical oncologists, radiation oncologists, radiologists, pathologists, clinical pharmacists, nurses, nutritionists, and other healthcare professionals with specialized training.

The hospital has 450 licensed beds and more than 4000 employees. In 2012, the medical center reported 17,900 admissions, 23,400 emergency department visits, 300,000 clinic visits, and 15,000 surgery cases.

The Oncology Nurse-APN/PA spoke with Sandra Elliott, one of two nurse recruiters at UW Medical Center, about her role in finding and hiring nurses to fill the various vacancies that arise.

Describe your job.

Sandra Elliott (SE): I have an awesome job. I have the privilege of recruiting nurses to work at one of the top hospitals in the United States. I recruit for staff nurses, nurse practitioners, and nurse managers.

Applicants find us through our online presence. I also attend national conferences, such as the Oncology Nursing Society Annual Congress, to let nurses know about the opportunities in Seattle. While most nurses don’t attend conferences to look for a job, I love this opportunity to meet nurses and find out if they are interested or if they know other nurses who may want to work in Seattle.

Continued from the cover

positions. There is a shortage of nurses and nurse practitioners in some specialty areas, and recruitment is very competitive. For example, it is hard to find neonatal ICU nurse practitioners.

In cancer, we have 4 oncology inpatient units and must recruit both locally and nationally to attract top-notch staff.

For new graduates, we provide a residency program for training to become an oncology nurse. We also have study groups to obtain oncology certification.

Sandra Elliott

Why is your hospital a good place to work?

SE: We were the first hospital in the world to receive the Magnet designation from the American Nurses Credentialing Center, and we were the first hospital to receive a fifth redesignation.

Our nurses are highly educated and receive ongoing education. The nurses have autonomy and work in a collegial environment. Our hospital is known for providing excellent patient care. We provide excellent benefits for our staff, including insurance coverage for family members and a work/life balance. This makes UW Medical Center a wonderful place to work.

What are your biggest challenges?

SE: My biggest challenge is finding highly skilled nurses to fill available

“There is a shortage of nurses and nurse practitioners in some specialty areas, and recruitment is very competitive.”

—Sandra Elliott, nurse recruiter

What is your biggest reward?

SE: I get a lot of satisfaction from finding the right applicant for a specific position. I interview applicants first, and then they interview with the manager. It always makes me happy when it is obvious that the applicant is a good fit for the unit.

How did you become a nurse recruiter?

SE: I have a broad-based human resources (HR) background, and I have worked at UW for many years. When

http://www.uwmedicine.org

an opening came up as a nurse recruiter, I applied for it. This is my favorite job, as I have the opportunity to partner with managers I have known for many years. It is really satisfying to see people you hire continue to grow and be rewarded for providing excellent patient care.

What advice would you give to someone who wanted to be a nurse recruiter?

SE: I would say it is important to work in a lot of different HR and customer services environments and to understand the healthcare environment.

Also, build relationships with managers, and try to understand their needs.

What would you be doing if you won the lottery?

SE: I would travel around the United States and then all over the world. n

Take action: get YOUR cancer center profiled!

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

Contact editorial@greenhillhc.com for information.

www.TheOncologyNurse.com

january 2015 I VOL 8, NO 1

7

© American Society of Hematology. All rights reserved.

Photo Courtesy © SABCS/Todd Buchanan 2012

© American Society of Hematology. All rights reserved.

Conference News

ASH Announces Second Choosing Wisely List dations include the following2: • Do not treat with an anticoagulant for >3 months in a patient with a first Lisa Hicks, MD venous thromboembolism occurring in the setting of a major transient risk factor • Do not routinely transfuse patients with sickle-cell disease for chronic anemia or uncomplicated pain crisis without an appropriate clinical indication • Do not perform baseline or routine surveillance computed tomography scans in patients with asymptomatic, early-stage chronic lymphocytic leukemia • Do not test or treat for suspected heparin-induced thrombocytopenia

(HIT) in patients with a low pretest probability of HIT • Do not treat patients with immune thrombocytopenic purpura in the absence of bleeding or a very low platelet count.

“Unnecessary treatments or tests not only add waste to the healthcare system, but in some cases, they also expose our patients to a risk of harm,” said Lisa Hicks, MD, of St. Michael’s Hospital and the University of Toronto, Ontario, Canada, and chair of the ASH Choosing Wisely Task Force.

“ASH developed its second Choosing Wisely list to help hematologists manage the utilization and delivery of patient care resources, and ASH encourages hematologists to consider these recommendations in all facets of their work including patient care, teaching, innovation, and research.”

Continued from the cover

The guiding principle for the practices included in Choosing Wisely is to do no harm. Other principles guiding

“Unnecessary treatments or tests not only add waste to the healthcare system, but in some cases, they also expose our patients to a risk of harm.”

—Lisa Hicks, MD ASH’s choices for the lists include strength of evidence, aggregate cost, frequency, making recommendations within the purview of hematology, and potential impact in the field.3

Since the launch of the Choosing Wisely campaign in April 2012, more than 100 national and state medical specialty societies, regional health collaborative organizations, and consumer partners have joined this initiative aimed at providing appropriate care to patients.4 Consumer Reports has joined the effort, spreading the word to patients all over the country to stimulate discussions between physicians and patients about these and other practices. n

References

1. Choosing wisely: an initiative of the ABIM Foundation. www.ChoosingWisely.org. Accessed January 15, 2015.

2. American Society of Hematology. The ASH Choosing Wisely List. www.hematology.org/Clinicians/Guide lines-Quality/502.aspx. Accessed January 15, 2015.

3. Choosing wisely: an initiative of the ABIM Foundation. Lists. www.choosingwisely.org/doctor-patient-lists/.

Accessed January 15, 2015.

4. Choosing wisely: an initiative of the ABIM Foundation. Partners. www.choosingwisely.org/partners. Accessed January 15, 2015.

Dietary Fat Intake Studied in Patients with Early-Stage Breast Cancer Women who limited their intake of dietary fat for 5 years after being diagnosed with early-stage breast Rowan T. cancer signifiChlebowski, MD, PhD cantly reduced the mortality rate from all causes at 15 years of follow-up; this occurred specifically in women with hormone-unrelated cancer. No long-term effect of dietary fat reduction on mortality was observed in women with hormone receptor–positive breast cancer. The study was presented at the 2014 SABCS. “These findings with respect to long-term influence of dietary lifestyle intervention on overall survival are mixed, but of potential importance,” said lead author Rowan T. Chlebow­

ski, MD, PhD, Los Angeles Biomedical Research Institute at Harbor-UCLA Medical Center.

“These findings with respect to long-term influence of dietary lifestyle intervention on overall survival are mixed, but of potential importance.”

—Rowan T. Chlebowski, MD, PhD At 15 years, the overall mortality rate was lower in the dietary intervention group in the overall analysis compared with those in the control group, but the difference between the groups did not

reach statistical significance (13.6% vs 17%, respectively). An exploratory analysis found a 36% reduction in mortality rates of women with estrogen receptor–negative breast cancer who lowered their dietary fat intake.

The Women’s Intervention Nutrition Study enrolled 2437 women with early-stage breast cancer who were treated with standard care at 39 centers in the United States. Ages at enrollment were between 48 and 79 years.

Of this group, 1597 had estrogen receptor–positive breast cancer, 478 had estrogen receptor–negative breast cancer, and 362 had estrogen receptor–negative/progesterone receptor– negative breast cancer. Within the first 6 months following diagnosis, women were randomized to a dietary fat intervention (N = 975) or control group (N = 1642).

In the intervention group, centrally

trained dietitians counseled women for 8 biweekly individual sessions on how to implement a low-fat diet.

Women were then contacted by dietitians every 3 months for 5 years.

Women assigned to the dietary intervention group kept written records of their fat/gram intake. At 5 years, calorie intake was 8.9% lower in the intervention group, and these women lost about 6 pounds when compared with the control group.

Dr Chlebowski noted that human epidermal growth factor receptor 2 status was not assessed at the time this study was being conducted, but suggested that women with triple-negative breast cancer (estrogen receptor–negative/progesterone receptor–negative/ and HER2-negative status) may also benefit from dietary fat reduction. In general, lowering dietary fat is a good idea for general health, he added. n

Tinzaparin Is Safe and Effective in Reducing Risk for Recurrent Venous Thromboembolism Tinzaparin, a low­-molecular­weight heparin (LMWH), reduced the risk of recurrent veAgnes Lee, MD nous thromboembolism (VTE) in patients with active cancer, lowered the risk of symptomatic deep vein thrombosis (DVT), and did not increase the risk of major bleeding despite full-dose use in the randomized,

8

january 2015 I VOL 8, NO 1

open-label CATCH study reported at the 2014 annual meeting of ASH by Agnes Lee, MD, University of British Columbia, Vancouver, Canada.

“Thrombosis is a common, deadly, and costly complication of cancer.

Some tumors place patients at higher risk, including pancreatic, lung, co­ lorectal, gastrointestinal, and brain cancer. As the largest randomized, controlled trial on the treatment of thrombosis among cancer patients, this

“Thrombosis is a common, deadly, and costly complication of cancer.”

—Agnes Lee, MD study reinforces clinical guidelines supporting the use of LMWH instead of warfarin to prevent recurrent blood clots,” said Dr Lee. Patients with cancer are at increased

risk for VTE and DVT, which present major challenges for treatment, balancing the risks of bleeding with the benefits of blood clot dissolution. Current guidelines recommend the use of LMWH to reduce the risk of clotting—however, this recommendation was based on a single trial. Given the lack of confirmatory trials or trials of different medications, warfarin is commonly used as an anticoagulant in cancer patients.

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Conference News

Photo Courtesy © SABCS/Todd Buchanan 2012

© American Society of Hematology. All rights reserved.

CATCH enrolled 900 cancer patients with DVT or pulmonary embolism at 165 different centers around the world to evaluate the efficacy and safety of tinzaparin versus warfarin.

Patients were randomized to receive tinzaparin once daily for 6 months, or

tinzaparin once daily for 5 to 10 days followed by 6 months of warfarin.

During treatment, 31 patients (6.9%) experienced recurrent VTE on tinzaparin versus 45 (10%) of the patients treated with warfarin, representing a 35% reduction in the risk of re-

current VTE. However, this difference was not statistically significant.

Tinzaparin reduced the risk of symptomatic DVT by 52% compared with the warfarin arm, and this difference was statistically significant (P = .04).

Tinzaparin also reduced clinically rele-

vant nonmajor bleeding (11% vs 16%, respectively; P = .03).

“This study validates the superiority of LMWH,” Dr Lee said. “Although LMWH is much more expensive than warfarin, there is no need for continual monitoring as there is with warfarin.” n

Pediatric Regimens the New Standard for Adolescents and Young Adults with ALL Early results of the large, prospective intergroup trial, C10403, demon­ Wendy Stock, MD strate that a pediatric-inspired regimen improves event­ -free survival (EFS) and overall survival (OS) in adolescents and young adults (AYAs) with acute lymphoblastic leukemia (ALL). Many smaller studies have shown that AYAs have improved outcomes on pediatric regimens, but this is the first large data set to validate this practice. Two-year EFS was 66%, and 2-year OS was 78%.

“These results are a major improvement compared with 34% and 39%, respectively, in historical controls. This is a clear opportunity to improve care in AYAs with ALL,” said lead author Wendy Stock, MD, University of Chicago Medical Center in Ilinois.

The study showed that the presence

of a BCR-ABL1–like signature and aberrant CRLF2 expression were associated with worse EFS and OS; patients without these features had excellent EFS and OS, Dr Stock told listeners at the 2014 annual meeting of ASH. The intergroup C10403 trial was undertaken by cooperative groups in North America to evaluate treatment with a pediatric intensive regimen delivered by adult hematologists/oncologists. Dr Stock presented the main results of the trial. Additional analysis of adherence and outcomes based on psychosocial factors will be presented in the future.

From 2007 to 2012, 296 AYA patients with ALL were treated. Median age was 24 years; 75% were white, 10% were African American, and 15% were Hispanic/Latino. Seventy-six percent had B-precursor ALL, and 24% had T-precursor ALL. Thirty-two percent of patients had a body mass index of ≥30, and 7% were morbidly obese.

The backbone of the pediatric­ EFS was similar regardless of ageinspired regimen included intensified group or precursor B- or T-lineage. OS glucocorticoid, vincristine, and aspara- was significantly worse in obese paginase, and more maintenance therapy. tients, and significantly improved in patients with undetectable minimal residual disease (MRD).

“These results are a Dr Stock and colleagues are planning to propose a successive US intermajor improvement group trial that should begin in 2015. compared with 34% The plans include use of the molecular signature of the disease to stratify paand 39%, respectively, tients and the addition of either a in historical controls. novel antibody or tyrosine kinase inhibitor to eradicate MRD and improve This is a clear outcomes.

“This is a phenomenal achieveopportunity to improve ment,” said Yoav Messinger, MD, a care in AYAs with ALL.” pediatric oncologist at Children’s Hos—Wendy Stock, MD pitals and Clinics of Minnesota in Minneapolis, and chairman of the sesThe regimen included remission induc- sion where these data were presented. tion and consolidation, interim mainte- “We have been waiting for a long time nance, delayed intensification, and for these data, which put what we alprolonged maintenance—2 years in ready know into a formalized protocol women, and 3 years in men. on a large-scale basis.” n

Single-Agent Capecitabine Fails to Improve Outcomes in Elderly Patients with Breast Cancer Adjuvant therapy with cape­ citabine plus ibandronate does not improve outcomes Gunter von Minckwitz, MD compared with ibandronate alone in elderly patients with moderate­to­high-risk early­-stage breast cancer in the ICE (Ibandronate With or Without Capecitabine in Elderly Patients With Early Breast Cancer) study. Toxic effects of anthracyclines and taxanes would improve outcomes. The women included in this trial were not candidates for conventional chemotherapy with taxanes and anthracyclines. The hope was that an oral therapy free of the side effects of combination chemotherapy could improve outcomes.

Lead author of ICE, Gunter von Minckwitz, MD, University of Frankfurt, Germany, and chairman of the

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German Breast Group, said that capecitabine is frequently used in elderly patients who cannot tolerate the side effects of conventional chemotherapy—but these findings no longer support that practice.

“These results, together with results of CALGB 49907, strongly support the use of combination chemotherapy in elderly patients.”

—Gunter von Minckwitz, MD Three-year invasive disease-free survival (DFS) was 85.4% for those who received the capecitabine/ibandronate treatment arm versus 84.3% in the

ibandronate arm; 5-year invasive DFS was 78.8% versus 75%, respectively.

ICE was a prospective, randomized, multicenter trial that enrolled 1380 patients with node-positive or highrisk node-negative early breast cancer.

Women aged ≥65 years were randomized in a 1:1 ratio to capecitabine plus ibandronate or ibandronate alone for 2 years of treatment. At the time the study was initiated, ibandronate was thought to have a protective effect against breast cancer.

Mean age was 71 years, and about 25% were aged 75 years or older. About 10% had a Charlson Comorbidity Index score of 2. One third of patients were receiving ≥3 medications for comorbidities. About 14% had triple-negative breast cancer, about 80% had hormone receptor–positive breast cancer, and about 70% were on aromatase inhibitors only.

Interestingly, ibandronate did not

prevent bone-related events in this study. Fractures, surgery, and new os­ teoporosis—excluding bone metastases­ —occurred in 25% of the patients in the capecitabine/ibandronate group versus 24.7% receiving ibandronate alone. It did not make a difference whether ibandronate was given intravenously (about 35%) or orally (about 65%). Results of treatment were similar across all subgroups.

“These results, together with results of CALGB 49907, strongly support the use of combination chemotherapy in elderly patients,” Dr von Minckwitz said. CALGB 49907 compared capeci­ tabine versus combination chemotherapy in elderly women and found that combination chemotherapy was superior and could be given to patients with a reasonable life expectancy.

“A patient has to be really unfit [for me to] not give her chemotherapy,” he added. n

january 2015 I VOL 8, NO 1

9

Best Practices

Sunrise, Sunset: Swiftly Go the Years Toledo, and grew with the addition of new partners who specialized in both medical oncology and hematology.

Today, the practice has 6 locations in Ohio and Michigan, with 8 physicians, 9 nurse practitioners, and approximately 79 employees—including 17 registered nurses—staffing the offices.

Its founding members have retired, but the group continues to expand.

Today, several senior partners in the clinic are approaching retirement, some are in the middle of their careers, and new partners have joined. The practice recognizes a need to provide the new partners with a mentoring process that provides historical perspective and practical knowledge. The mentor can help in the transition from student to practicing physician.

As more experienced nurses and nurse practitioners prepared for retirement, the need for role development was identified. With an explosion of new advances in diagnosis and treatment, newer nurses need a longer learning curve. We asked ourselves these questions: How does a practice ensure that its new nurses understand and appreciate the history of the practice, and how are ongoing learning opportunities provided for the nursing staff, especially in an era where there are competing priorities for nurses’ time?

Orientation

The process of educating new nursing staff has evolved over time. Today, the orientation program has been revised and extended to a minimum of 6 months, and includes mentorship and continuing education (CE) programs.

Time is spent providing an orientation to the Toledo Clinic, as well as to overall practice operations. New registered nurses take a biotherapy/chemotherapy course online offered through the Oncology Nursing Society (ONS; www.

ONS.org/online-courses). Because the practice is also very involved in clinical research, newly hired nurses complete a human protection course through the National Institutes of Health Office of Extramural Research (https://phrp.nih training.com).

During the first few months, orientation is designed around the practice’s policies and procedures, electronic medical record system, chemotherapy order writing process, and documentation of patient assessment and treatment. Time is also spent with the practice administrator learning about the history of the practice. As with new physicians, understanding the practice’s goals, mission, and contributions to the community is important.

Implementation of the new nurse

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january 2015 I VOL 8, NO 1

training program has changed the schedule on the practice’s end. Formalized CE and pharmaceutical programs have been integrated into quarterly nursing meetings. In the past year, an event approved for nurses to earn CE units (CEUs) was also added.

In-house education programs should be customized to fit the needs of the nursing staff and the practice.

Mentorship

New nurses are assigned a mentor who is responsible for initiating an orientation checklist (Table) that includes activities from the office observation period to the responsibilities related to chemotherapy administration and patient care in the infusion room. When the mentor completes the checklist, the nurse can begin taking patients independently, but the mentor and other experienced nurses remain available to answer questions.

As nurses transition from orientation, they can continue their relationship with the mentor, or, if necessary, another nurse in the office. Experienced nurses are paid a differential because of the importance of their role in the orientation of the newer staff. Mentors are active participants in the initial orientation, and they complete the orientation checklist as well as a 90-day evaluation. Emphasis is also placed on chemotherapy safety, with mentors providing an assessment of skills and direct observation of performance in the mixing room.

Continuing Education Program

The practice has nursing personnel from all of its locations, including nursing staff and licensed nursing practitioners, attend quarterly meetings. Clinical topics are provided by one of the

Continued from the cover

physicians, nurse practitioners, or nurses who brings back information from the national ONS meeting. However, none of these meetings have provided approved CEUs, which was an identified need. The agenda also includes updates on new drugs, legislative and reimbursement changes, as well as topics of interest, including practice updates, inventory management, safety topics, electronic medical record and documentation requirements, new drugs and updates from pharmaceutical representatives, as well as updates on quality initiatives, including depression screening.

To become a provider of approved nursing CEUs in Ohio, the Ohio Nurses Association (ONA) requires the following: • A clearly defined unit or department responsible for nursing CE • A nurse planner who meets the ONA’s specific qualifications • The organization to be functioning for at least 6 months, using accreditation criteria and the Ohio Board of Nursing’s rules, during which time at least 3 separate activities of at least 60 minutes in length must have been planned, approved by the ONA, implemented, and evaluated • The practice to submit a form and the required fees showing intent to apply as an accredited CE provider.

One of our nurse practitioners accepted responsibility for the role of nurse planner, and the practice has now received a preliminary CEU provider designation. Our first planned activity was a review of oncology drugs of the past, present, and future, which was presented by an oncology pharmacist. The objectives of the review were to state the mechanism, administration, and clinical pearls related to older, traditional chemotherapeutic agents, and to list a variety of targeted anticancer agents and explain their administration and common adverse effects.

The nurses who attended this session and completed an evaluation received 1.0 contact hour of CEUs. The first

Table Sample Nurse Orientation Checklist Front-desk operations

Yes No N/A

Schedule chemotherapy appointments utilizing appropriate cycle process Comments: Ensure appropriate laboratory tests/x-rays are ordered before upcoming visits, as required by treatment plan/protocol Comments: Chemotherapy orders Review order and demonstrate understanding of dosing and administration requirements; clarify with physician as necessary Comments: Complete dose calculations properly within 24 hours of receipt of order Comments: N/A indicates not applicable.

Yes No N/A

program was well-received by the staff, and evaluations will be used to develop future presentations. Assessment of the evaluations showed that nurses appreciated the pharmacist’s knowledge of chemotherapy and presentation of the information in a manner that enhanced their understanding of oncology drugs.

Several individuals requested that the pharmacist attend the quarterly in­ service meetings to review treatment regimens on an ongoing basis.

Based on the evaluations, programs are being developed on chronic lymphocytic leukemia, neuroendocrine tumors, genetic tests, and palliative care.

A physician will provide clinical information on the topic and a nurse practitioner will provide nursing care–specific information.

Discussion

Developing an in-house nursing CEU program is beneficial to the practice. It demonstrates the practice’s commitment to CE and to staff development. For individual nurses, the program provides necessary information that is not readily available to them, and is an effective way for the practice to ensure nursing personnel have the information needed to care for patients.

Other benefits include meeting the needs of busy nursing personnel, saving staff time, and minimizing travel time and expense.

In-house education programs should be customized to fit the needs of the nursing staff and the practice, which will keep doctors and nurses in tune with each other. The programs should provide the staff with updated information as changes occur and should provide a forum for responding to problems, issues, regulations, and new trends in a timely manner. These programs can offer an opportunity for knowledge transfer from experienced nurses to newer nurses, and can provide potential recruits with a reason to join the practice.

Conclusions

Using the above approach, our practice has developed a program to prepare for the sunset of retiring nurses and the sunrise of new nurses who will care for patients over the next decades. Orientation and mentorship programs allow newly hired nurses to learn about our clinic, including an overall understanding of processes, administrative procedures, the clinic’s role in the community, and expectations for the clinical care of patients. Educational programs and approved CE programs allow nurses to earn CEUs while maintaining clinical competency and helping to meet the practice’s clinical standards. n

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Best Practices

Shift Work, Sleep Deprivation, and Cancer Risk Meg Barbor

“T

here is a very strong link between shift work and lack of sleep, and fewer hours of sleep can translate to a higher risk for obesity and disease,” according to Eva S. Schernhammer, MD, DrPH, who spoke at the recent American Association for Cancer Research International Conference on Frontiers in Cancer Prevention Research.1 In the Nurses’ Health Study 2 (NHS2), it was found that nurses who had “ever” worked rotating night shifts had a 20% increased risk of sleeping fewer than 7 hours per night on average, compared with 0 nurses who had “never” worked night shifts. The risk for decreased sleep was even higher among nurses who worked permanent night shifts.

There is evidence that obesity is significantly more common among people with shift work experience, according to data collected from more than 20 epidemiologic studies. Further, Schernhammer said, the NHS2 found that among 107,663 women, each 5-year increase in rotating shift work translated to a gain of 0.45 kg in weight.

Impact on the Circadian System

“Up to 15 million Americans work alternative shifts, but shift work is not the only factor contributing to the reduction in sleep hours among many Americans,” said Schernhammer, Associate Professor of Medicine at Harvard Medical School in Boston, MA. Frequent flyers and city dwellers are other typically night-active cohorts who

regularly expose themselves to external light at night, potentially impacting their circadian systems. According to the World Health Organization cancer mortality database, the most industrialized, or most lit-up, areas of the world have the highest cancer rates.

“Furthermore, we don’t know yet how PCs, tablets, and TV right before bed affect the circadian system,” Schernhammer added.

When sleeping and eating are not aligned with the body’s internal clock, changes in appetite and metabolism can occur, which can lead to weight gain, she explained. People who go to bed late and sleep late eat more calories in the evening, eat more fast food and fewer fruits and vegetables, and weigh more than people who go to sleep early and wake up early.

“The circadian system is an internal clock that works on its own but can be affected by external light,” said Schernhammer. It controls a number of functions besides waking and sleeping activity in the body, including temperature, hormones, immune system, and gene activity and expression.

The Mismatch Between Internal and External Clocks

Chronotype, which is determined by the individual’s internal clock system, categorizes people by whether they have a little more or a little less than a 24-hour rhythm. Those with a rhythm more than 24 hours are colloquially referred to as “night owls”; those with

less are called “morning larks.” The most frequently used measure for chronotype is the Morningness-Eveningness Questionnaire, which measures whether a person’s peak alertness is in the morning, the evening, or in between. “Young individuals tend to fall into evening types, and as they get older they fall into morning types,” Schernhammer noted.

Schernhammer further referenced a 2012 study by Hansen and Lassen,2 which used a more refined definition of circadian disruption and found that women with morning preference who work night shifts have a higher breast cancer risk than evening types. This underlines the need for better assessment of chronotype, she stressed.

“Evidence so far from the NHS suggests that the women in the study encounter higher cancer risks, in particular breast cancer and more recently lung cancer.”

“Evidence so far from the NHS suggests that the women in the study encounter higher cancer risks, in particular breast cancer and more recently lung cancer,” she said. The evidence also suggests that the longer the duration of night work among nurses in the study, the higher their risk for cancer.

Moving forward, “more refined exposure assessments that take into account external as well as internal clocks will likely enable us to more finely delineate chronic disease risk, including that of cancer,” said Schernhammer. “Future prevention strategies and work schedules likely ought to target a reduction in mismatch between biological (internal) and social (external) time.” n

— Eva S. Schernhammer, MD, DrPH Both chronotype (internal) and shift work (external) affect the circadian system. “There is clearly some type of interaction between chronotype and shift workers. Evening types fare better working night shifts because their attitudes are high compared to intermediate types and morning types,” Schernhammer explained. “When you put an evening type on a shift schedule, it’s as if they are working according to their internal clock.”

Translating to Disease Risk

References

1. Schernhammer ES. Sleep, shift work, obesity, and cancer risk. Presented at: 13th Annual American Association for Cancer Research International Conference on Frontiers in Cancer Prevention Research; September 28-October 1, 2014; New Orleans, LA. 2. Hansen J, Lassen CF. Nested case-control study of night shift work and breast cancer risk among women in the Danish military. Occup Environ Med. 2012;69: 551-556.

FDA update Cyramza plus Paclitaxel for Advanced... Continued from page 4

after fluoropyrimidine- or platinum-containing chemotherapy. In April, ramucirumab was approved as monotherapy for advanced or metastatic gastric cancer or GEJ adenocarcinoma.

This new approval was based on the RAINBOW study, a phase 3 clinical trial that compared ramucirumab plus paclitaxel versus placebo plus paclitaxel. Ramucirumab plus paclitaxel significantly extended median OS at 9.6 months compared with 7.4 months (P = .017) with placebo plus paclitaxel. Furthermore, ramucirumab plus paclitaxel significantly delayed disease progression: the PFS was 4.4 months with the active combination versus 2.9 months (P <.001) with placebo plus paclitaxel.

Overall, 28% of patients responded to ramucirumab plus paclitaxel versus 16% with placebo plus paclitaxel (P <.001).

The FDA approved this new therapy with a boxed warning regarding the risk for bleeding, including severe and sometimes fatal hemorrhaging. Ramucirumab injection should be permanently discontinued in patients with severe bleeding.

The most common adverse reactions in the trial with the active combination and ≥2% higher than in the placebo group were fatigue, neutropenia, diarrhea, and epistaxis. The most common serious adverse events with ramuciru­ mab plus paclitaxel were neutro­penia (3.7%) and febrile neutropenia (2.4%); furthermore, 19% of patients receiving the active combination had to receive granulocyte colony-stimulating factors.

(November 5, 2014)

Blincyto First Immunotherapy Approved for B-Cell Acute Lymphoblastic Leukemia

The FDA approved blinatumomab

(Blincyto; Amgen) for the treatment of patients with relapsed or refractory Philadelphia chromosome (Ph)-negative precursor B-cell acute lymphoblastic leukemia (ALL), a rare and rapidly growing form of ALL. Blinatumomab is intended for use in patients with B-cell ALL. Blinatumomab is the first immunotherapy approved by the FDA for patients with leukemia. The drug acts as a connector between the CD19 protein (which is found on the surface of most B-cell lymphoblasts) and the CD3 protein found on T-cell lymphocytes, using the body’s T-cells to destroy the leukemia cells.

The FDA had initially granted this drug a breakthrough therapy designation, and applied its priority review and accelerated approval program to approve the drug 5 months ahead of the scheduled date. Blinatumomab has an orphan drug designation. The FDA is now requiring the manufacturer to con-

duct a new clinical trial to show a survival benefit with blinatumomab in patients with relapsed or refractory Ph-negative precursor B-cell ALL. The approval was based on the safety and efficacy of blinatumomab in a clinical trial of 185 adults with Ph-negative relapsed or refractory precursor B-cell ALL. All patients received an infusion of blinatumomab for at least 4 weeks.

The results showed a 32% complete remission rate lasting approximately 6.7 months. The trial was not designed to show improvement in survival.

Blinatumomab is associated with significant risks, including cytokine release syndrome, encephalopathy, and nervous system adverse events. The most common side effects reported were pyrexia, headache, peripheral edema, febrile neutropenia, nausea, hypokalemia, fatigue, constipation, diarrhea, and tremor.

Blinatumomab was approved with a Continued on page 15

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january 2015 I VOL 8, NO 1

11

Lung Cancer

Lung Cancers and Stigma: Perception or Reality? Continued from the cover

Caroline Kornhauser, MPH, Education Outreach Coordinator, CancerCare

Sarah Quinlan, Senior Education Technical and Marketing Coordinator, CancerCare

oncology team, with particular emphasis on the important role oncology nurses play in the care of these patients.

Recognizing Stigma

Because smoking has been identified as a risk factor in lung cancer, the disease is often viewed one-dimensionally.2 Many people associate lung cancer with smoking, believing that patients with lung cancer caused their illness through their lifestyle choices and behaviors. This view may lead to bias against these patients. In addition, the stigma of lung cancer is often internalized by patients and translates to feelings of shame, fear, and guilt.3 Some healthcare professionals unintentionally fall prey to this bias, contributing to their patients’ stigmati­ zation. The widespread belief that smoking is the sole cause of lung cancer with the blame placed on the individual may obfuscate the suffering of people living with lung cancer.

The Physical Effects of Smoking

Patients with lung cancer face increased discrimination as a result of the physical effects of smoking. Nonsmokers may be judgmental of lung cancer patients. The physical signs of smoking, including coughing, the lingering scent of smoke, and stained teeth, are often considered repulsive by nonsmokers.

This perception is compounded by the media’s antismoking campaigns. Although the goal of the media is to deter people from smoking, an unanticipated consequence is to further stigmatize patients with lung cancer.

Unfounded Nature of the Lung Cancer Stigma

The many causes of lung cancer There is a proved correlation between smoking and lung cancer, but the causes of lung cancer are complex and manifold. An estimated 15% of people diagnosed with lung cancer have never smoked,4 and a total of 60% of patients are people who have either never smoked or quit years ago.5 Among

Nian Hu, Prep for Prep, Freshman, Harvard Class of 2018

cancer patients, there is a divide between the smokers and the never-smokers. Frequently, never-­smokers wish not to be associated with smokers. They view themselves as having an unfair diagnosis and feel compelled to defend themselves when confronted with the stigma of lung cancer.2,6 Lung cancer has been linked to environmental factors, including exposure to radon, asbestos, and other toxins.

Exposure to radon is the second leading cause of developing lung cancer. “Genetic susceptibility plays a contributing role; especially in those who develop lung cancer at a younger age.”1 In education programs for the public about lung cancer, it is vital to include that there is a complex network of factors leading to a lung cancer diagnosis.

Smoking before the health risks were known The stigma of smoking unfairly at­ tributes blame to those who have lung cancer for allegedly self-inflicting their disease. Cigarette smoking became increasingly popular in the 1960s. At that time, people living in the United States were somewhat unaware of the long-term health risks of smoking.

Only relatively recently has the public been made aware of the health risks associated with tobacco use.

Today, many people living with lung cancer are those who smoked at a time when smoking was not only accepted but was also considered chic and cool.2 Some of these individuals have since quit, but many live with the long-term effects of their prior lifestyle.

Because of the addictive nature of tobacco, once people begin smoking, many find it difficult, if not impossible, to quit.7 Smoking is an extremely powerful addiction that is difficult to overcome because the nicotine creates a physical dependence in the smoker.8

Lung Cancer Impact and Stigma

The physical and psychosocial impact of lung cancer stigma People living with lung cancer may

Christin Washington, Prep for Prep 9, Sophomore, Amherst College 2017

Dawn Zador, Senior Education Program Manager, CancerCare

experience changes in their activities of daily living (ADLs). Lung cancer and its treatment may cause shortness of breath, fatigue, loss of strength, and treatment-related side effects. In addition to dealing with the physical limitations of lung cancer, patients may experience psychosocial challenges regarding their self-image and body image, often compounded by the stigma of the disease.

The physical changes that arise from lung cancer and its treatment are noticeable not only to patients with cancer but to their social network as well.

These restrictions in ADLs and physical functioning are daily reminders of their cancer.

Transformations in one’s physical self, such as weight loss, changes in one’s voice, and coughing and wheezing, can result in changes in perception of body image. For many lung cancer patients, difficulties in adapting to these changes can be amplified by the stigma of lung cancer. Changes, from appearance to feelings and thoughts, can have unexpected consequences on body image and self-perception. As suggested

by Fingeret and colleagues, “It would be ideal to discuss body image with every patient during each encounter but given the infeasibility of this goal, it is impor­ tant to focus on patients whose disease or treatment causes significant self-perceived changes in physical appearance or function.”9 Living with lung cancer brings changes in self-perception not only through physical and psychosocial alterations but also through the stigma associated with the disease. Low self­esteem may often lead to sadness, depression, social withdrawal, and distress.

For the oncology nurse, understanding the impact lung cancer may have on patients’ body image and self-esteem is important in helping patients access needed psychosocial support programs and services.

The psychological impact of lung cancer stigma In addition to lowered self-esteem and body image challenges, those living

Carolyn Messner, DSW, OSW-C, LCSW-R, Director of Education and Training, CancerCare

with lung cancer often face increased psychological challenges, especially if, as mentioned, the stigma of lung cancer has been internalized. Roughly 33% of lung cancer survivors have a negative view of themselves and may feel responsible for their diagnosis, which may lead to higher levels of guilt, shame, anxiety, and depression. Approximately 25% of all patients with lung cancer experience clinical depression at some point during their cancer trajectory.10 Oncology nurses are at the forefront of administering oncology care and support. They are often delivering bedside care at the point of diagnosis or during different phases of patients’ treatment.

It is vital for oncology nurses to recognize these symptoms of sadness and depression in their patients and to understand that patients’ feelings of shame, guilt, and embarrassment are intertwined with their quality of life.

Access to treatment for lung cancer patients People living with lung cancer and experiencing its stigma often do not report symptoms and delay seeking treatment and help. Reluctance to seek medical intervention has significant consequences. When medical help is sought early, there are significantly greater treatment options with potential for improved prognosis and survival outcomes.

The incidence and death rates for lung cancer have been declining in part due to changes in “patterns of smoking uptake and cessation.”1 Subsets of patients with lung cancer are benefiting from the novel treatment approaches that have recently been developed.11 Decreasing delays in early detection may also improve survival.

Impact on funding for lung cancer research The stigma of lung cancer not only impacts the well-being of patients but also influences federal and private funding. Lung cancer funding and research lag far behind those of other cancers in spite of its being the leading cause of Continued on page 14

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Lung Cancer

Lung Cancers and Stigma: Perception... cancer deaths. Many have attributed this disparity to the stigma of lung cancer, the “blame-the-victim” attitude that results in limited funding for lung cancer research. This stigma has been acknowledged by medical professionals, advocacy groups, scholars, and the media. While there is recognition of the existence of stigma for lung cancer patients, research evaluating its impact is limited.2 Statistics show that the National Cancer Institute and the Department of Defense spend far less on lung cancer research compared with other cancers.

More information is needed to assess the impact that stigma generates in order to eradicate its detrimental bias toward research funding for lung cancer.4 Less grant money is available for lung cancer patients compared with other types of cancer. The fact that more funding and resources exist for so many other types of cancers exacerbates the lack of resources available for patients with lung cancer.2 Oncology nurses and other members of the healthcare team need to become advocates to promote increased funding for lung cancer research and the development of resources for these patients and their caregivers.

Overcoming the Stigma

Educating the public One way of overcoming stigma is through increasing awareness and education. Education about the complex factors that may lead to a diagnosis of lung cancer, including environmental risks, genetics, and lifestyle, is needed to reduce the harmful psychological and physical effects of the associated stigma.

Understanding the psychosocial sequelae that the stigma of lung cancer places on patients and their caregivers is an important step toward eliminating bias among healthcare professionals who are much needed to advocate for these patients and their caregivers.

Gaining support of public figures and prestigious institutions The stigma of lung cancer is amplified by inadequate support from public figures and institutions. Though the lung cancer cause has been championed by such celebrities as Dana Reeve and S. Epatha Merkerson, support has been on a smaller scale. In contrast, AIDS was extremely stigmatized until many Hollywood celebrities began speaking out. Breast cancer stigma was diminished when Betty Ford came forward with her diagnosis in 1974,4 followed years later by Nancy Reagan. In both cases, having multiple, vocal celebrity endorsements boosted the public profile of these diseases and encouraged sup-

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january 2015 I VOL 8, NO 1

port, greater awareness, and increased federal research spending.

In addition, smoking is becoming much less common in the public sphere. Workplaces and restaurants in the United States and globally are increasingly becoming smoke-free environments due to advocacy groups.

Elected officials, for example, former Mayor Michael Bloomberg of New York City, extended smoke-free environments to include public spaces, parks, and beaches. These are efforts to reduce exposure to secondhand smoke and discourage smoking.

Advocacy for lung cancer faces a tougher battle. With higher mortality rates, few patients and their family members are able to stay the course as long-term lung cancer advocates. In addition to family members, oncology nurses, and other members of the healthcare team and their institutions must fill these gaps, and become strong lung cancer advocates, ensuring that patients receive high-quality and compassionate care.

Using the Internet for health communication Patients with stigmatized illnesses such as lung cancer may avoid seeking medical attention or health education.12 Too often, lung cancer is diagnosed in its later stages. Information and education are imperative in receiving stateof-the-art medical care for people living with lung cancer. Understanding what symptoms to look for and what questions to ask, and maintaining open lines of communication with family, friends, and healthcare professionals contribute to timely treatment and decreased feelings of stigmatization.

The Internet can be a useful tool for health education and outreach. A national survey conducted in 2005 compared people with a self-reported stigmatized condition with people having at least one other chronic illness. The survey found that the respondents with stigmatized illnesses were significantly more likely to use the Internet for health information research, to have communicated with clinicians about their condition through the Internet, and to have increased utilization of health information based on information found on the Internet. The results from this study suggest that the Internet is a valuable health communication and education tool for those who are affected by stigmatized illnesses.12 Oncology nurses can take the lead in providing patients and their loved ones with reliable and credible websites to obtain information. Below is a list of reliable and well-vetted websites for

Continued from page 12

patients, their caregivers, friends, and healthcare professionals.

Support Programs/Resources

The stigma of lung cancer can have an adverse psychosocial impact on patients and their caregivers. One way to cope with lung cancer is to take advantage of support programs and resources.

These support programs are provided by general cancer organizations, lung cancer–specific organizations, and hospital settings.

The role of lung cancer support groups The organizations on this list provide important information about free support groups, counseling, educational programs, publications, financial assistance, and other services. The information and resources these organizations offer help connect people to a community of patients with lung cancer and healthcare professionals.

Fostering communication within a community of lung cancer patients is another method of overcoming the stigma. Support groups provide psychosocial support for people living with lung cancer and are a wonderful way for people to share their experiences. Promoting an environment where people feel comfortable and safe communicat-

Lung cancer–specific organizations:

• Free to Breathe – www.freeto breathe.org • Lung Cancer Alliance – www. lungcanceralliance.org • LungCancer.org – www.lung cancer.org • LUNGevity Foundation – www. lungevity.org

General cancer organizations:

• American Cancer Society – www.cancer.org • American Society of Clinical Oncology – www.cancer.net • CancerCare – www.cancercare.org • Cancer Support Community – www.cancersupportcommunity.org • LIVESTRONG Foundation – www.livestrong.org • National Cancer Institute – www.cancer.gov • National Coalition for Cancer Survivorship (NCCS) – www. canceradvocacy.org • NeedyMeds – www.needymeds.org • Oncology Nursing Society – www.ons.org • The LGBT Cancer Project – www.lgbtcancer.org

ing their worries helps to break the cycle of silence that people living with lung cancer experience.

More lung cancer support groups are needed, as these resources are not widely available for patients. Often, patients with lung cancer attend support groups for other types of cancers.

But these meetings may not be as effective, as cancer is specific to location of the disease.2 Despite the positive role of support groups, participation of patients with lung cancer in available groups remains low.

According to a study done in 2010, low attendance may be due to disparities between patients and facilitators about support program logistics—including preferred location, type of facilitator, and content.13 For instance, the study found that patients with lung cancer preferred programs held in hospitals, whereas facilitators preferred groups in a community setting. Patients preferred facilitation by trained health professionals, whereas facilitators preferred volunteers. Patients preferred the focus of the group to be on providing cancer information rather than providing emotional support, whereas facilitators preferred the opposite. These differences may explain the poor attendance at existing support groups by lung cancer patients. Other factors that pose additional barriers to attending on-site support programs include the rigors of travel, the costs of travel, parking concerns, fatigue, family or partner obligations, and child care.

To encourage participation, support groups need to be tailored to the needs of patients and their caregivers. Increasingly, groups are being offered as telephone support groups or online groups to facilitate participation and overcome the physical barriers and costs of travel to attend on-site groups. If groups are held at hospitals or in community settings, it is recommended that a brief needs assessment be conducted to determine the preferences of patients and caregivers for the site or location of the group, its frequency, as well as the focus of the group as psychoeducational or support or both.

The Important Role of the Oncology Nurse

Oncology nurses provide important and enduring support for patients. Oncology nurses not only have greater interaction with the patient than any other member of the oncology team, they are often the patient’s first line of support. Oncology nurses are in a critical position to provide the necessary psychosocial support patients living with lung cancer need.

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Lung Cancer

Below are some tips and suggestions that oncology nurses can use in helping patients with lung cancer cope with their diagnosis.

Nonjudgmental approach to lung cancer patients It is first and foremost essential for oncology nurses to debunk any bias they may have toward patients with lung cancer. It is important for oncology nurses to understand that stigma toward this population exists, but is unfounded: there are many mechanisms for developing lung cancer, and smoking, for those individuals who smoke, is a highly addictive habit and difficult to quit. It is also important for nurses to recognize that the stigma associated with lung cancer may be hurtful for patients living with lung cancer.

Smoking cessation programs Even after a diagnosis of lung cancer, it is possible to improve survival rates and quality of life by ending tobacco use. Smoking cessation programs play a key role in helping patients with lung cancer achieve these goals. According to one study, although there are many effective treatments available to help smokers quit, persistent efforts through repeated contacts are necessary to achieve long-term cessation.

Oncology nurses interact with patients frequently enough to engage in these necessary “repeated contacts.”14 Due to their frequency of contact with patients, oncology nurses play an essential role in the identification of and intervention with patients strug-

Smoking cessation programs: American Cancer Society – 800227-2345 National Cancer Institute, Free Help to Quit Smoking Smoking Quitline – 877-44U-Quit (877-448-7848) Smokefree.gov – www.smokefree.gov

State quit lines: Quit for Life – 866-784-8454 State Quit Line – 800-Quit-Now (800-784-8669) gling with tobacco dependence after their diagnosis. It is crucial for oncology nurses to take advantage of their unique position to try to help lung cancer patients stop smoking. There are many smoking cessation programs available to help lung cancer patients who wish to stop smoking.

Helping lung cancer patients cope Oncology nurses also play a key role in discussing quality of life with lung cancer patients. Nurses may focus on treatment and disease management, but it is important for oncology nurses to listen to patients’ concerns. In this way, nurses can help promote patients’ psychosocial adaptation to their diagnosis. Nurses’ supportive, nonjudgmental listening may lessen patients’ feelings of isolation. By empathic listening, oncology nurses may help patients with their worries. Oncology nurses can also help patients cope by

providing educational materials, exploring life stories, discussing personal relationships, suggesting spiritual resources, and helping patients consider treatment and palliative care choices.

These discussions afford vital psychological support for patients who have been newly diagnosed with or are living with lung cancer.15 Fostering communication In conclusion, it is imperative for oncology nurses to help patients with lung cancer overcome the stigma of this disease. As mentioned previously, patients with lung cancer often believe they caused their own cancers, leading to a negative self-image and psychosocial difficulties. It is therefore essential for oncology nurses to foster an en­ vironment of open communication among themselves and with patients and to discuss issues such as cancer causation as well as the patient’s feelings of guilt, shame, depression, and anxiety.16 Addressing the stigma of lung cancer is essential for those living with the disease. Through communication, education, and strategic campaigns, public opinion can be molded.

Changes in public perception and the psychosocial burden placed on the individual begin in the hospital room with the oncology nurse. n

References

1. American Cancer Society. Cancer Facts & Figures 2014. Atlanta, GA: American Cancer Society; 2014.

2. Conlon A, Gilbert D, Aldredge P. Stacked stigma: oncology social workers’ perceptions of the lung cancer experience. J Psychosoc Oncol. 2010;28(1):98-115.

3. Else-Quest NM, LoConte NK, Schiller JH, et al.

Perceived stigma, self-blame and adjustment among lung, breast and prostate cancer patients. Psychol Health.

2009;24(8):949-964.

4. Huber B. Stigma of ‘smoker’s disease’ stifles fight against No. 1 killer, lung cancer. FairWarning. www. fairwarning.org/2012/11/stigma-of-smokers-diseasestifles-fight-against-no-1-killer-lung-cancer/. Published November 1, 2012. Accessed December 29, 2014.

5. Thomas S. Huffman couple fights lung cancer stigma, pushes for awareness. Atascocita Observer. www.your houstonnews.com/atascocita/news/huffman-couplefights-lung-cancer-stigma-pushes-for-awareness/article_ 3ebfbe2a-ea13-55a0-a08d-b6e28330f494.html. Published November 3, 2012. Updated November 7, 2012.

Accessed December 29, 2014.

6. Schiller J, Goodman A. The stigma of lung cancer: never-smokers: a growing trend. Medscape Oncology. www.medscape.com/viewarticle/807904_4. Published July 18, 2013. Accessed December 29, 2014.

7. Schiller J, Goodman A. Are lung cancer patients to blame for their disease? Medscape Oncology. www.med scape.com/viewarticle/807904_1. Published July 18, 2013.

Accessed December 29, 2014.

8. Cessation. American Legacy Foundation. www.legacy forhealth.org/our-issues/cessation. Accessed December 29, 2014.

9. Fingeret MC, Teo I, Epner DE. Managing body image difficulties of adult patients: lessons from available research. Cancer. 2014;120(5):633-641.

10. Eldridge L. Lung cancer: the bias, the stigma, the shame, blame and guilt. www.lungcancerfoundation.org/ 2013/06/lung-cancer-the-bias-the-stigma-the-shameblame­-and-guilt/. Published June 24, 2013. Accessed December 29, 2014.

11. Cooley ME, Lynch J, Fox K, et al. Lung cancer. In: Holland JC, Breitbart WS, Jacobsen PB, et al, eds. Psycho-Oncology. New York, NY: Oxford University Press; 2010:chapter 20.

12. Berger M, Wagner TH, Baker LC. Internet use and stigmatized illness. Soc Sci Med. 2005;61(8):1821-1827.

13. Devitt B, Hatton A, Baravelli C, et al. What should a support program for people with lung cancer look like?

Differing attitudes of patients and support group facilitators. J Thorac Oncol. 2010;5(8):1227-1232.

14. Cooley ME, Sipples RL, Murphy M, et al. Smoking cessation and lung cancer: oncology nurses can make a difference. Semin Oncol Nurs. 2008;24(1):16-26.

15. Vondrasek J, Cody J. Nurses Key in Helping New Cancer Patients Overcome Fears. Michigan State University Today. http://msutoday.msu.edu/news/2012/nurses­key-in-helping-new-cancer-patients-overcome-fears/.

Published February 28, 2012. Accessed December 29, 2014.

16. LoConte NK, Else-Quest NM, Eickhoff J, et al.

Assessment of guilt and shame in patients with nonsmall-cell lung cancer compared with patients with breast and prostate cancer. Clin Lung Cancer. 2008; 9(3):171-178.

FDA update Blincyto First Immunotherapy Approved... Continued from page 11 Risk Evaluation and Mitigation Strategy (REMS) program to inform healthcare providers about the serious risks associated with this medication. The product information also carries a boxed warning to alert providers of the risks and serious side effects associated with the use of blinatumomab. (December 3, 2014)

Avastin plus Chemotherapy for Platinum-Resistant Gynecologic Cancers

The FDA approved a new indication for bevacizumab solution (Avastin; Genentech) to be used in combination with paclitaxel, pegylated liposomal doxorubicin, or topotecan for the treatment of patients with platinum-resistant, recurrent epithelial ovarian, fallo-

pian tube, or primary peritoneal cancer.

The approval is based on the results of the AURELIA study, an international, randomized trial with investigator-assessed PFS. AURELIA compared bevacizumab plus chemotherapy versus chemotherapy alone. Overall, 179 patients were randomized to bevaciz­ umab plus chemotherapy and 182 patients received chemotherapy alone with 1 of the 3 chemotherapies.

Treatment continued until disease progression, unacceptable toxicity, and/or consent withdrawal. All the patients had received ≤2 previous chemotherapy regimens, had ECOG performance status of 0 to 2, and had disease recurrence within <6 months of the platinum-based therapy.

Bevacizumab plus chemotherapy had a significant PFS improvement compared with chemotherapy alone (HR,

0.38; 95% CI, 0.30-0.49; P <.001), with a median PFS of 6.8 months versus 3.4 months, respectively; however, the OS was not significantly different, with a median OS of 16.6 months versus 13.3 months, respectively (HR, 0.89; 95% CI, 0.69-1.14).

The most common adverse reactions (≥15%) with bevacizumab plus chemotherapy were neutropenia, peripheral sensory neuropathy, and hypertension.

Gastrointestinal perforations were reported in 1.7% of patients who received bevacizumab. (November 14, 2014)

FDA Approves Nivolumab for Advanced Melanoma

The US Food and Drug Administration (FDA) recently approved nivolu­ mab (Opdivo; Bristol-Myers Squibb Company), a human programmed death

receptor-1 blocking antibody, for the treatment of patients with unresectable or metastatic melanoma that no longer responds to ipilimumab. The drug was also approved for the treatment of patients with melanoma with a BRAF V600 mutation that no longer responds to ipilimumab and BRAF inhibitor therapy.

The FDA accelerated its approval of nivolumab based on interim data from the CheckMate 037 phase 3 trial showing a 32% (N = 38) objective response rate (ORR) in the first 120 patients who received the drug. This response lasted for >6 months in approximately one third of the patients. The 32% ORR (95% confidence interval, 23, 41) was based on data from 4 patients (3%) who achieved a complete response and 34 patients (28%) who Continued on page 19

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january 2015 I VOL 8, NO 1

15

lung cancer screening

Effective Lung Cancer Screening Meg Barbo

“T

here’s a lot we don’t know about lung cancer screening,” according to Denise Aberle, MD, who spoke at the recent American Association for Cancer Research International Conference on Frontiers in Cancer Prevention Research. However, certain measures can be taken to lower false-positive and overdiagnosis rates, lessen costs, ameliorate patient suffering, and correctly identify screening cohorts, she asserted.

Who Should Be Screened?

The National Lung Screening Trial (NLST) recommends lung cancer screening for adults aged 55 to 74 years who have at least a 30 pack-year smoking history and currently smoke or have quit within the past 15 years. The US Preventive Services Task Force (USPSTF) has the same screening criteria, but has made revisions based on the Cancer Intervention and Surveillance Modeling Network (CISNET) models that are funded by the National Cancer Institute; they have extended the screening period up to individuals aged 80 years and do not recommend screening for individuals who have not smoked within the past 15 years.

The CISNET models that informed the USPSTF recommendations consist of 5 different consortiums, each having independent models for lung cancer, explained Aberle, vice chair of research and a professor in the Department of Radiological Science and professor of bioengineering at the University of California, Los Angeles. “When they looked across these 5 models they found a mortality reduction of anywhere from 8% to

Key Points he NLST recommends lung T cancer screening for adults aged 55-74 years with a smoking history of ≥30 pack-years who currently smoke or have quit within the past 15 years he false-positivity rate was T one of the major limitations of the NLST verscreening results in O unnecessary imaging, radiation exposure, and biopsies and the potential complications and additional costs lthough some lung tumors A will grow over time, others will regress, and there is insufficient knowledge about lung cancer to support screening decisions

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24%. About half who went through screening had early-stage disease, and it is estimated that up to 500 per 100,000 lung cancer deaths across the population could be averted with the gain in life years,” she said.

“I understand the terms of overdiagnosis, and I understand the concept of overdiagnosis; I think where I stumble is when I look at the notion of overdiagnosis in the individual patient setting.”

—Denise Aberle, MD “Many others have recommended that we use risk prediction models to try to better hone in on those individuals who should be screened,” said Aberle.

Their premise is that we determine a threshold below which individuals will not be screened, and that doing so will improve on the existing NLST criteria.

However, “using these risk predictors practically can be somewhat problematic,” she added.

When Is It Overdiagnosis?

“I understand the terms of overdiagnosis, and I understand the concept of overdiagnosis; I think where I stumble is when I look at the notion of overdiagnosis in the individual patient setting,” said Aberle. Questions concerning overdiagnosis are constantly raised, she noted. “But the only question for which there is a resounding answer is ‘we cannot assume a linear growth model.’”

“Some of these cancers are going to get worse over time, even over long periods of time. Some of these cancers are going to stay just the way they were.

Some of these lesions may actually regress,” she noted. “We just don’t know enough and I think it makes it challenging to make these kinds of decisions in the individual patient setting.”

Next Steps in Screening

Aberle stated that it will behoove

society to measure risk in individuals who are screened, redefine actionable nodules to lower false positives, maintain low radiation doses using current multidetector scanners, track smoking cessation efforts and rates, and collect the data via screening centers.

“Only in that way will we begin to understand what risk-to-benefit ratios are in the population setting and how we can maximize cost effectiveness,” she said.

“There’s a lot we don’t know about lung cancer screening; I personally find that exciting because I want to be able to help answer some of those questions,” she added. n

Reference

Aberle DR. Lung cancer screening: from efficacy to effectiveness. Presented at: 13th Annual American Association for Cancer Research International Conference on Frontiers in Cancer Prevention Research; September 28-October 1, 2014; New Orleans, LA.

have you ever wanted to write an article for TON ?

What Can Be Done About False-Positivity Rates?

The false-positivity rate was one of the major limitations of the NLST, said Aberle. Consequences of this in a screening setting include additional unnecessary imaging and radiation exposure, unnecessary biopsies and the complications of those biopsies, unnecessary anxiety, and additional cost, she explained.

According to Aberle, if we look only at the published data from the NLST and stratify the nodules that factored into positive screens over each of the screening intervals, we can see that nodules that were ≤6 mm amounted to more than half of positive screenings but were responsible for less than 1% of lung cancers overall; if we look at increasing nodule size, the positive predictive value goes up so that the larger the nodule, the more likely it is that the person has cancer.

“This gives us a clue that size is important and might help us determine whether or not a screen is significant,” she suggested. “If we look at small nodules, 4-5 mm, we see that if we did nothing with those nodules but simply saw them one year later, we would suffer trivial effects with respect to the ability to diagnose lung cancer.”

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

Contact editorial@greenhillhc.com for information. www.TheOncologyNurse.com

Electronic Health Records

Epic: Electronic Health Records Company Sharon Gentry, RN, MSN, AOCN, CBCN

O

ver the past several years, there has been a huge increase in the use of electronic charting. First, there were electronic medical records, which are digital versions of a patient’s chart used mostly for healthcare professionals in a certain office, clinic, or hospital. Advantages over paper charts were the ability to track data over a period of time, monitor patients from visit to visit with charts and graphs, identify patients for screenings, and enrich the quality of care. The disadvantage was that a clinician in one care area might not have access to the digital chart—for example, a radiation therapist in one department would not have access to the patient’s digital record in medical oncology.

Then, electronic health records (EHRs) expanded beyond this and included information from all authorized healthcare professionals involved in the patient’s care. According to CMS.gov, this electronic chart “may include all of the key administrative clinical data relevant to that person’s care under a particular provider, including demographics, progress notes, problems, medications, vital signs, past medical history, immunizations, laboratory data, and radiology reports. The EHR automates access to information and has the potential to streamline the clinician’s workflow. The EHR also has the ability to support other care-related activities directly or indirectly through various interfaces, including evidence-based decision support, quality management, and outcomes reporting.” This digitalized version follows the patient from primary care, specialized care, hospital, and through the patient’s life.

EHR: A Navigator’s Perspective

One EHR company that was being implemented in many of the systems that navigators are embedded is Epic.

At the Fourth Annual Academy of Oncology Nurse & Patient Navigators Conference in 2013, a session on oncology medical homes initiated an audience discussion on the role of the navigator in the EHR arena, especially with Epic. Feedback from participants requesting more information on this allowed Lisa Delpizzo, RN, and Danielle Guillama, RN-BSN, OCN, of the Reading Health System, PA, to share a session on “An EPIC Presentation: A Patient’s Navigation Journey” at the Fifth Annual Academy of Oncology Nurse & Patient Navigators Conference in 2014. It provided a walk through the system from a navigator perspective, and allowed navigators who were implementing Epic in their future practice

to understand what to expect. With more navigators exposed to EHRs, there was not the deluge of questions from the audience this year, but several participants shared that they would like to understand more about the system.

Because Epic is designed individually for each healthcare system, a group of navigators (clinical and lay) were asked to share their experiences to help fellow navigators who were coming online next, which was like navigators navigating other navigators. The first questions posed to the group were, “Did you have any input into the design for navigation? Did anyone from Epic spend time with you to understand your role and workflow?”

that Epic’s staff understood their needs, but when Epic went live, things were not as they had been explained. “They did spend time with us, but I don’t think that what they designed goes along with our workflow.” Many navigators explained that they were placed in an inpatient chart, and their needs, as well as the majority of their patient encounters, are in the outpatient world. Epic did continue to address the work issues during the optimization phase.

The lay navigators reported not having a role in providing input about the design of Epic’s installation, nor did anyone from the team ask about the lay navigator role. Lay navigators reported that their training was “read-only,” be-

“Make friends with your Epic team in any way you can, and remember that the majority of the time they are not healthcare workers, so you need to be clear about why your needs are not being met, and try not to get frustrated when they don’t always understand the reason behind their logic not working for you.”

—Danielle Guillama, RN-BSN, OCN The nurse navigators reported that meetings where they provided input regarding their needs, which were used to customize Epic for their role, were held during the design phase. Epic met with the nurses on several occasions to discuss workflow and what would work best in daily practice. The development of the design (meetings) was done sporadically and changed several times to fit the needs of the role. Some navigators said that most of what they asked for in implementation, Epic said it could not do.

The number 1 item that navigators requested that Epic could not deliver was a good calendar tool. The following are some of the comments from navigators: • “There is no calendar of patients who we need to see that we can print off on a daily basis. I would like to have a running list of patients that we can add to a work list that automatically pops up when we sign into Epic. I had to go back to a paper calendar.”

• “It would also be nice if there was a good way of making a daily schedule for nurse navigators.”

• “If I could use Epic to track patients I work with and have automated triggers to follow up, that would be a useful tool.”

The majority of navigators thought

cause they are not expected to chart.

The nurse navigators see this as a barrier in care, because the help with finances, transportation, etc, is critical in navigation. The lay navigators are sharing information with the providers (ie, the clinicians) directly, not in Epic. Nurse navigators described taking classes with the lay navigators and were surprised when they looked for their notes and discovered they did not go “live” with the rest of the team. One navigator talked about the duplication of work to set up patient transportation when Epic went live, because no one told the nurse navigators that the lay navigators would not be charting in the system.

The second question revolved around charting: “Where do you chart, and what type of note do you select?” This question was asked because the note is identifiable by its title—progress note, care coordination, telephone encounter, office visit, and so on.

The majority of nurse navigators chart under an outpatient setting documentation at their cancer center or outpatient infusion center, and they primarily use the documentation tool to identify the phone, medical oncology, radiation oncology, or inpatient encounter. Some navigators described having to change the context of chart-

ing as they document patients in an inpatient setting (hospital admission) using an ancillary note, changing back for outpatient charting using a care coordination note, and changing to a care coordination department and using a care coordination note when charting at the imaging facility. As a result of the multiple department identities, a suggestion of having a nurse navigation department to cover inpatients and outpatients has not been successful at this point, but is being requested at the next system update. Also, a nurse navigator reported, “Recently we have started incorporating transition of care notes for patients who have recently been discharged from the inpatient service and will be following up in our outpatient clinic. We also use an initial coordination note for new patient visits and a follow-up visit coordination note. We make a telephone call to all new patients when they are scheduled within 24 hours and document that as an initial contact note.”

The third question was regarding the navigators’ likes and dislikes of the EHR system. All agreed that the pattern was consistent. The patient’s continuum of care across the span of the inpatient and outpatient realms, as well as back information on a timeline, could be viewed without having to contact other providers to obtain history or information in other parts of the patient’s care. Physicians find it very positive that they can see what is happening with the patient and the navigator. The navigators like being able to see notes from the providers throughout the system, and that people can see what the navigator has accomplished. It was described as “better communication for all—nurse, MD, SW—involved in care.” The navigators could reinforce teaching and the plan of care for the patient. The lay navigators found it helpful to have access to Epic to get demographic information about patients.

The major dislike was the lack of a calendar tool, as previously discussed, and the system makes it difficult to see what information has been scanned into a patient’s chart. Because many patients may come from outside the healthcare system, their information is under another tab of care (ie, media), and does not automatically flow into the note section where information is easily reviewed. In addition, navigators did not find it easy to correct charting errors.

The final question was for “pearls of wisdom” to be shared with other navigators. Ms Guillama noted, “Working Continued on page 18

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palliative care

Palliative Care Sells Itself Chase Doyle

E

arly integration of palliative care into oncology programs improves quality of life for patients and caregivers, increases prognostic understanding, and demonstrates survival benefits while substantially reducing costs, according to an interview conducted at the Association of Community Cancer Centers 2014 National Oncology Conference.

In the interview, Joseph Greer, PhD, a clinical psychologist who was instrumental in developing the cancer outcomes research program at the Massachusetts General Hospital Cancer Center, discussed findings from a study of patients with metastatic non–small-cell lung cancer. In the study, overseen by Greer, patients receiving palliative care at the time of diagnosis (with continuous contact in the outpatient setting every month) showed a survival benefit of 2.5 months and a savings of $117 per patient per day over the course of the disease.

Greer emphasized the importance of palliative care—even without the unexpected benefits of survival and cost. “This trial showed wonderful outcomes for patients,” he said. “They had improved quality of life, lower rates of depression… and their sense of whether their cancer was curable was more accurate….The fact that these patients were living better really makes a huge difference.”

Also interviewed at the meeting was Brian Bell, MD, a physician who specializes in hospice and palliative care at the Spartanburg Regional Healthcare System in South Carolina. Bell distinguished palliative care from traditional therapy for its communal character.

“We work as a team,” he said. “We offer

“We offer care that can’t be provided simply from a doctor or a nurse practitioner….No one person can singlehandedly deliver the type of multidimensional care our patients need.”

—Joseph Greer, PhD care that can’t be provided simply from a doctor or a nurse practitioner—we have social workers with PhDs and chaplains, too….No one person can single-handedly deliver the type of multidimensional care our patients need.”

Credibility Is Key

Both doctors stressed the importance

of building a relationship with patients early in their treatment and the need to establish credibility.

“We love to see our patients early on,” said Bell. “We’re seeing them more at the time of the diagnosis, especially for the advanced cancers.”

“One of the toughest situations is the crisis moment,” Greer concurred, “so the benefit of the early palliative care is that you have a chance to know patients when they’re fairly stable and doing well and know what they care about in their lives, and you’ve established that credibility.”

Just as integral to this relationship-building is the location of care— away from the hospital’s often hectic milieu. “The home visit is impor­ tant,” said Bell. “When you’re in the hospital, it’s a stressful place to be.

When you go to somebody’s home… they’re much more comfortable. You’re on their turf. And I think that relationship goes much better. The dynamic changes.”

If end-of-life care is not done well, it’s not just the patient who suffers.

There are ramifications for family members, too, including posttraumatic stress disorder. “It’s critical that caregivers receive the support they need,” urged Bell, “because after the patient

dies, they still have to live with all the things that happened.”

Finally, according to both doctors, the early integration of palliative care is criti-

“Once you start s­ eeing their patients, your value comes across very quickly….Once you’re embedded, palliative care sells itself.”

—Brian Bell, MD cal not just for patients and caregivers but for clinicians as well. “We had to learn how to integrate with the other clinicians because many oncologists feel that this is their job,” said Greer. “And I have to say, in terms of symptom management and illness understanding and treatment decision making, that it is their job. We look at it as a comanagement model.”

Although palliative care physicians may experience some initial reluctance from oncologists, Greer concluded with the following words of encouragement: “Once you start seeing their patients, your value comes across very quickly….

Once you’re embedded, palliative care sells itself.” n

Epic: Electronic Health Records... Continued from page 17 with your fellow navigators and having an Epic builder who understands your needs and is responsive will make your Epic life easier. Make friends with your Epic team in any way you can, and remember that the majority of the time they are not healthcare workers, so you need to be clear about why your needs are not being met, and try not to get frustrated when they don’t always understand the reason behind their logic not working for you. When the system is not working the way it should be, let someone know that sooner rather than later. It will make a huge difference in the level of frustration that you have, and working on a resolution will help others avoid making mistakes or not having the information they need. Finally, you must make the effort to learn what the system can do and cannot do, and try to recognize that past experience is good but no system is perfect or can make miracles happen.”

Becki Swanson, RN, BSN, MSHA, OCN, Executive Director, Oncology Service Line, CHI Health, shared some comments from her navigators: • “You need to have your list of when,

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where, and how long you see that patient ready for the builder. We had the builders shadow the navigators while they worked so that it helped them know how to build the program.

It was built with key things the navigators have to chart so reports can be run easily.”

• “Make sure they understand your work process so it can be developed to be user-friendly for you. As we found out, our department is unique in how we work with patients.”

Tips to Navigators

One bit of advice revolves around the MyChart portal of Epic. MyChart gives patients controlled access to the same Epic medical records their doctors use, which can be accessed by computer or mobile app. With this portal, patients can get notification of upcoming appointments, view test results, fill out visit questionnaires, schedule appointments, as well as other secure patient or healthcare provider interactions. An example was that Ms Smith was coming in to get her cancer diagnosis for the first time this after-

noon. The primary care wanted her to see a certain surgeon and medical oncologist. If the appointment was scheduled previous to Ms Smith getting her diagnosis, and if she was a MyChart user, Ms Smith would get a notice that she had an upcoming visit with a surgeon and medical oncologist before getting her diagnosis. There are ways to delay the notification of appointments, but the whole healthcare team must be aware of the need.

Epic is one of many EHR systems that navigators will encounter. As navigators, an electronic record is not something we have incorporated into the way we see patients—a change over time. It comes as a sudden transition and requires us to work in a different way. The comments from others who have traveled the journey will be invaluable for those getting ready to face this transformation of care. Navigators do work in different ways in each healthcare system, and I wish an Epic person had spent 1 week with our navigators understanding how we work with patients and other healthcare professionals.

Maybe the concept of “walking in the patient’s shoes” or “seeing the world of healthcare through the patient’s eyes” would apply for EHR staff walking and seeing with the navigation team. The documentation of the lay navigator needs to start along with the nurse navigator. The veteran EHR users say there are bugs to work out in any electronic system, and that will come with time and usage. Just as navigators learn as they are setting up their navigation care, it takes time and feedback from the ones affected by change to make a better system of care.

Acknowledgments

I wish to thank Pamela Goetz, Oncology Survivorship Coordinator, Johns Hopkins Medicine, Sibley Memorial Hospital, Washington, DC; Danielle Guillama, RN-BSN, OCN, Oncology Nurse Navigator, McGlinn Cancer Institute, Reading Health System, readinghealth.org; Becki Swanson, RN, BSN, MSHA, OCN, Executive Director, Oncology Service Line, CHIHealth. com; and their respective teams for their contributions to this article. n

www.TheOncologyNurse.com

side effects management

Novel Agent Effective for the Management of Cancer-Related Cachexia Phoebe Starr

C

ancer-related cachexia is a debilitating condition that has had no effective treatment thus far.

Its symptoms include loss of lean body mass, as well as muscle wasting and loss of appetite.

A pair of pivotal international phase 3 studies suggest that the investigational oral drug anamorelin hydrochloride can increase lean body mass, achieve weight gain, and improve quality of life (QOL). This drug is the first to hold promise for improving all of these aspects of cancer-related cachexia.

“Cachexia is one of the most troubling symptoms of cancer for patients and their families. This is a very exciting study. For the first time in more than a decade, a drug is effective in treating cachexia. This will significantly change how we think about cancer­related cachexia and how we treat patients with cancer,” said study coauthor David Currow, MD, of Flinders University in Adelaide, Australia.

Treatment with anamorelin may enable patients to continue with their cancer treatment, he said. Currow discussed these results at a press conference during the 2014 Congress of the European Society for Medical Oncology.

Jennifer Temel, MD, of the Dana­ Farber Cancer Institute in Boston, MA, presented the results in an oral session at the congress. “Cancer-related cachexia­anorexia causes progressive functional impairment, inactivity, and can negatively impact prognosis. Current treatment options have limited efficacy and potential risks, especially in patients with cachexia,” Temel told listeners.

Anamorelin is a first-in-class, orally administered ghrelin receptor agonist.

Release of ghrelin stimulates multiple pathways that regulate body weight, lean body mass, appetite, and metabolism.

ROMANA 1 (N = 484) and ROMANA 2 (N = 495) were identically designed phase 3 studies, representing the largest phase 3 trials conducted to date to assess the safety and efficacy of anamorelin in patients with cachexia.

creases was highly significant in both trials (P < .0001 for all comparisons).

The study failed to show an improvement in handgrip strength, which was a coprimary end point.

QOL (a secondary end point) was

“Cachexia is one of the most troubling symptoms of cancer for patients and their families. This is a very exciting study. For the first time in more than a decade, a drug is effective in treating cachexia. This will significantly change how we think about cancer-related cachexia and how we treat patients with cancer.”

—David Currow, MD Patients with stage III or IV unresectable non–small-cell lung cancer and cancer-related cachexia were randomized 2:1 to receive either anamorelin or placebo for 12 weeks. All patients enrolled in the trials had a life expectancy of >4 months.

For study purposes, cachexia was defined as ≥5% weight loss within the past 6 months or a body mass index <20 kg/m2. At the end of 12 weeks, patients had the option to continue on anamorelin for an additional 12 weeks, and those results (ROMANA 3) will be presented at a later date.

Temel noted that the studies had broad inclusion criteria. Patients could be on chemotherapy, maintenance chemotherapy, or no chemotherapy.

In both ROMANA 1 and ROMANA 2, patients randomized to placebo continued to lose weight and lean body mass over the 12-week study period, whereas those randomized to anamorelin gained weight and lean body mass.

The difference between the 2 groups for lean body mass and body weight in-

assessed, in part, by the Functional Assessment of Anorexia/Cachexia Therapy (FAACT) questionnaire, which looks at patient symptoms and concerns related to anorexia-cachexia, including appetite, early satiety, and general health. In both trials, a significant difference was observed between the 2 treatment arms on the FAACT anorexia/cachexia domain at all time points, favoring anamorelin treatment over placebo. Results for QOL in this domain were slightly more robust for ROMANA 1 (P = .0012) than for ROMANA 2 (P = .0150). Patients were followed for 1 year for survival.

Rates of toxicity related to anamo­ relin were low. The most common adverse events included nausea, hyperglycemia, and a few cases of diabetes.

“These are incredibly exciting results.

The benefits are consistent. Up until now you couldn’t change lean body mass in patients with cancer-related cachexia. This therapy has the potential to affect cancer therapy across all treatment centers,” Currow said.

platin plus paclitaxel. The primary objectives in this trial are ORR and overall survival. The study is ongoing but no longer recruiting patients.

The most common adverse reaction reported among patients receiving the study drug was rash (21%). Grade 3/4 adverse reactions occurred in 42% of the patients receiving the study drug.

The most frequent of these—reported in 2% to <5% of patients receiving the study drug—were abdominal pain, hyponatremia, increased aspartate

aminotransferase, and increased lipase.

The FDA granted breakthrough therapy designation, priority review, and orphan product designation for nivolumab because (1) preliminary clinical evidence demonstrated that the drug may offer a substantial improvement over available therapies; (2) the drug has the potential to be a significant improvement in safety or effectiveness in the treatment of a serious condition; and (3) the drug is intended to treat a rare disease, respectively.

Key Points ancer-related cachexia is a C debilitating condition associated with loss of lean body mass, muscle wasting, and loss of appetite here are currently no T effective treatments for the symptoms of cachexia he investigational drug T anamorelin, a first-in-class, orally administered ghrelin receptor agonist, has shown promising results for this condition I n this new study, anamorelin was associated with “exciting results,” in affecting lean body mass in patients with cancerrelated cachexia, and was associated with low toxicity

The formal discussant of this trial, Florian Scotté, MD, of Georges Pompidou European Hospital in Paris, France, commended the authors on a well­ designed study for a condition with few good treatment options.

He pointed out that other studies of new agents have had disappointing results. “I look forward to hearing the long-term follow-up on these patients.

This is a difficult problem, and we have to pay full attention to this, working with a multidisciplinary approach,” Scotté said. n

Reference

Temel J, Currow D, Fearon K, et al. Anamorelin for the treatment of cancer anorexia-cachexia in NSCLC: results from the phase 3 studies ROMANA 1 and 2. Presented at: 2014 Congress of the European Society for Medical Oncology; September 26-30, 2014; Madrid, Spain. Abstract 1483O_PR.

FDA update FDA Approves Nivolumab for Advanced... Continued from page 15

achieved a partial response.

Efficacy of the drug was evaluated during a planned, interim, single-arm analysis of data from the phase 3, randomized, open-label CheckMate 037 trial. A total of 268 patients received the 3-mg/kg intravenous dose every 2 weeks; patients in the comparator arm (N = 102) received an investigator’s choice of chemotherapy: single-agent dacarbazine or a combination of carbo-

www.TheOncologyNurse.com

“Opdivo is the seventh new melanoma drug approved by the FDA since 2011,” said Richard Pazdur, MD, Director of the Office of Hematology and Oncology Products in the FDA’s Center for Drug Evaluation and Research.

“The continued development and approval of novel therapies based on our increasing understanding of tumor immunology and molecular pathways are changing the treatment paradigm for serious and life-threatening diseases.”

(December 22, 2014) n

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CONTINUING EDUCATION

Faculty Perspectives

JANUARY 2015 • VOLUME 6 • NUMBER 1

™

LATEST TREATMENT ADVANCES FOR INDIVIDUALIZED CARE OF NSCLC PUBLISHING STAFF Group Director, Sales & Marketing John W. Hennessy john@greenhillhc.com Editorial Director Susan A. Berry susan@coexm.com Senior Copyeditor BJ Hansen Copyeditors Dana Delibovi Rosemary Hansen The Lynx Group President/CEO Brian Tyburski Chief Operating Officer Pam Rattananont Ferris Vice President of Finance Andrea Kelly Human Resources Jennine Leale

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

Associate Director, Content Strategy & Development John Welz Director, Quality Control Barbara Marino Quality Control Assistant Theresa Salerno Director, Production & Manufacturing Alaina Pede Director, Creative & Design Robyn Jacobs Creative & Design Assistant Lora LaRocca Director, Digital Media Anthony Romano

FACULTY Roy S. Herbst, MD, PhD Chief of Medical Oncology Professor, Medicine and Pharmacology Yale Comprehensive Cancer Center New Haven, CT

Jr Digital Media Specialist Charles Easton IV Web Content Manager Anthony Trevean Digital Programmer Michael Amundsen Meeting & Events Planner Linda Sangenito Senior Project Managers Alyson Bruni Jini Gopalaswamy

Marianne Davies, RN, MSN, ACNP, AOCN Smilow Cancer Hospital Yale School of Nursing Greenwich, CT

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Project Manager Deanna Martinez Project Coordinator Mike Kodada IT Manager Kashif Javaid

This activity is jointly provided by Global Education Group and Center of Excellence Media, LLC.

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Supported by an educational grant from Boehringer Ingelheim.

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FACULTY PERSPECTIVES Target Audience This activity is directed toward medical and surgical oncologists, advanced practice oncology nurses, research nurses, and clinical oncology pharmacists involved in the personalized management of patients with solid tumors, and interested in the use of molecular biomarkers to help optimize patient care.

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

Educational Objectives After completing this activity, the participant should be better able to: • Assess emerging data from ASCO 2014 and ESMO 2014 on the discovery of molecular biomarkers and their impact on the management of patients with solid tumors • Discuss the advances from ASCO 2014 and ESMO 2014 on the personalized therapy for patients with solid tumors • Outline the practical aspects of integrating molecular biomarkers and emerging targeted agents into everyday clinical practice in the personalized treatment of cancer patients Faculty Roy S. Herbst, MD, PhD Chief of Medical Oncology Professor, Medicine and Pharmacology Yale Comprehensive Cancer Center, New Haven, CT Marianne Davies, RN, MSN, ACNP, AOCN Smilow Cancer Hospital Yale School of Nursing, Greenwich, CT James T. Kenney, Jr, RPh, MBA Pharmacy Operations Manager Harvard Pilgrim Health Care, Wellesley, MA Term of Offering Estimated time to complete activity: 1.0 hour Date of initial release: December 24, 2014 Valid for CME/CPE/CE credit through: December 24, 2015 Physician Accreditation Statement This activity has been planned and implemented in accordance with the Essential Areas and Policies of the Accreditation Council for Continuing Medical Education (ACCME) through the joint providership of Global Education Group (Global) and Center of Excellence Media, LLC. Global is accredited by the ACCME to provide continuing medical education for physicians.

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Updates from ASCO 2014 and ESMO 2014 INTRODUCTION The past decade has witnessed the emergence of targeted therapies in non–small-cell lung cancer (NSCLC), representing a huge paradigm shift in the management of this disease. These advances have been spurred by an improved understanding of the pathobiology of NSCLC, which has led to the molecular characterization of distinct NSCLC subtypes and the development of rational therapeutic agents specific to these subtypes. The presence of epidermal growth factor receptor (EGFR) mutations, which promote an oncogenic phenotype, defines one NSCLC subtype that is exquisitely sensitive to EGFR-tyrosine kinase inhibitor (TKI) therapy. Anaplastic lymphoma kinase (ALK)–positive NSCLC is another molecular subtype that is sensitive to treatment with ALK inhibitors. Unfortunately, many patients inevitably progress on EGFR-TKI and ALK inhibitor therapy. Responding to the urgent need for novel therapeutic improvements, current clinical research efforts are focused on evaluating EGFR-TKIs in combination with other active agents, novel agents directed toward common EGFR resistance mutations, ALK inhibitors in the first-line setting, and novel ALK inhibitors for use in the ALK inhibitor–resistant disease setting. In addition, several novel agents directed toward rational molecular targets, such as mutational variants of the human epidermal growth factor receptor 2 (HER2) and BRAF genes, as well as immunotherapy with vaccines and inhibitors of immune checkpoint regulators, are being evaluated in patients with NSCLC. Results of key clinical trials in EGFR- and ALK-positive NSCLC were reported at the 50th Annual Meeting of the American Society of Clinical Oncology (ASCO), held in Chicago, Illinois, May 30-June 3, 2014, and at the 39th European Society for Medical Oncology (ESMO) Congress, held in Madrid, Spain, September 26-30, 2014. This supplement will provide an overview of these data, as well as key take-home messages from Roy S. Herbst, MD, PhD, Yale Comprehensive Cancer Center; Marianne Davies, RN, MSN, ACNP, AOCN, Smilow Cancer Hospital, Yale School of Nursing; and James T. Kenney, Jr, RPh, MBA, Harvard Pilgrim Health Care.

EGFR-TKI THERAPY IN EGFR MUTATION–POSITIVE NSCLC

EGFR-sensitizing mutations are detected in approximately 10% of all NSCLCs in the Caucasian patient population and at higher rates in the Asian population.1 Several randomized trials have demonstrated significant prolongation of progression-free survival (PFS) with first-line EGFR-TKI

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therapy (erlotinib or gefitinib) compared with chemotherapy in EGFR mutation–positive advanced NSCLC.2-5 Based on these pivotal results, erlotinib and gefitinib are currently indicated as first-line therapy for patients with advanced NSCLC harboring EGFR-sensitizing mutations.1 The prolongation in PFS with EGFR-TKIs is suboptimal, however, and acquired

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CONTINUING EDUCATION resistance to these agents is common.6 Moreover, the role played by EGFRTKI therapy in early-stage EGFR mutation–positive NSCLC is currently unknown; only limited clinical trial data evaluating EGFR-TKIs in the adjuvant setting or in EGFR mutation–positive disease are available.

The National Cancer Institute of Canada Clinical Trials Group (NCIC) BR19 randomized trial, which evaluated adjuvant gefitinib versus placebo in 503 patients with completely resected NSCLC, was closed prematurely because of futility, since no differences in disease-free survival (DFS) and overall survival (OS) were observed in the unselected, and EGFR wild-type (WT) or EGFR mutation–positive patient populations, albeit in only 15 patients in the EGFR mutation–positive cohort.7 The SWOG (Southwest Oncology Group) S0023 trial was initiated in 2001 to compare adjuvant gefitinib versus placebo in unresectable patients with stage IIIA or IIIB NSCLC following concurrent chemotherapy and radiation therapy; however, this trial was also stopped early.8 Unplanned analysis did not show a PFS benefit for patients treated with gefitinib versus placebo8; no information was available on EGFR-mutation status.

Single-Arm Phase 2 Trial of Adjuvant Erlotinib in EGFR Mutation– Positive NSCLC A retrospective study revealed that TKIs may prolong DFS in patients with EGFR mutation–positive tumors.9 In 286 patients with EGFR-positive mutations, treatment with adjuvant erlotinib or gefitinib was associated with a 57% reduced risk for recurrence or death (hazard ratio [HR], 0.43; P = .001) and a trend toward improved OS.9 At ASCO 2014, Pennell and colleagues presented the results of the single-arm, multicenter, phase 2 SELECT trial, which is prospectively evaluating the efficacy of adjuvant erlotinib in patients with EGFR mutation–positive NSCLC.10 Patients enrolled in the trial had surgically resected stage IA-IIIA NSCLC harboring a TKI-sensitizing EGFR mutation and had completed routine adjuvant chemotherapy and/or radiotherapy. Eligible patients were treated with erlotinib 150 mg/day for 2 years. Of the 100 patients enrolled at 7 sites, 89 participants have reached the 2-year follow-up at the time of this analysis. The safety profile was typical of erlotinib, with no grade 4/5 adverse events (AEs) reported and 1 case of grade 2 pulmonary fibrosis.

Dose reductions to 100 mg/day were required in 40% of patients, whereas 2 dose reductions to 50 mg/day were needed in 16% of patients. Overall, 69% of patients completed at least 22 months of erlotinib treatment.10

The use of targeted therapies has provided true benefit to select patients with NSCLC. It is imperative that all patients are screened for the most common mutations and are educated about the implications of the results.

After a median follow-up of 3 years, the 2-year DFS for the total cohort was 90% (97%, 73%, and 92% in patients with stage 1, stage 2, and stage 3 disease, respectively).10 At the time of this report, median DFS and OS had not been reached. A total of 24 patients showed evidence of disease recurrence; 22 of the cases occurred after stopping erlotinib, with a median time to recurrence of 12 months, indicating that patients may benefit from longer duration of adjuvant treatment. Of those who experienced disease recurrence, 15 patients (63%) underwent repeat biopsy and only 1 case of a EGFR T790M mutation was detected; 17 (71%) of recurrent patients were retreated with erlotinib. Currently, 10 patients remain on erlotinib therapy, with treatment ranging from 2 to 42 months, suggesting that patients continue to be sensitive to EGFR-TKIs after first disease recurrence.10 Perspectives The results of the SELECT trial are intriguing and suggest a possible use for EGFR-TKIs in the adjuvant setting. However, this experience is only a singlearm study and larger randomized studies will be needed to more fully answer this question.

-Roy S. Herbst, MD, PhD

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The use of targeted therapies has provided true benefit to select patients with NSCLC. It is imperative that all patients are screened for the most common mutations and are educated about the implications of the results. The SELECT trial highlights the benefit of continued therapy with the orally administered TKI erlotinib. However, providers must remain vigilant in assessing for specific toxicities associated with this agent. As shown in this trial, >50 % of patients required a dose reduction. However, I think that with proper dose adjustment and successful management of toxicities, patients can benefit from an extended course of this therapy.

-Marianne Davies, RN, MSN, ACNP, AOCN The concept of personalized medicine has real application in the treatment of cancer, and health plans are challenged with the task of managing multiple complex and expensive diagnostics and the appropriate drug therapies targeted for specific cancers. The SELECT trial demonstrates the value of targeted adjuvant treatment with erlotinib for NSCLC and the potential for improved outcomes over the standard of care. A key challenge for health plans will be the appropriate targeting of patients to ensure that the best drug treatment regimen is applied to the ideal population in order to achieve favorable clinical outcomes.

-James T. Kenney, Jr, RPh, MBA

Exploratory Analysis of Adjuvant Erlotinib versus Placebo in an EGFR Mutation–Positive Subgroup The RADIANT trial also assessed the role played by erlotinib as adjuvant therapy in patients with EGFR-expressing (immunohistochemistry+ and/or fluorescence in situ hybridization [FISH]+) completely resected stage IB-IIIA NSCLC. In this trial, 973 patients who had undergone complete surgical resection and randomization to either erlotinib or no platinum-based doublet chemotherapy went on to a second 2:1 randomization, at which time they received erlotinib 150 mg/day (n = 623) or placebo (n = 350) for up to 2 years.11 The trial, however, failed to meet the primary end point of prolonged DFS (HR, 0.9; P = .3). Subsequently, a prospectively specified subgroup analysis was conducted to evaluate the efficacy of adjuvant erlotinib therapy in the subgroup of patients with EGFR mutation–positive NSCLC. Shepherd and colleagues presented the results of this exploratory subgroup analysis of the RADIANT trial at ASCO 2014.11 In the current analysis, 161 (17%) of the 973 patients randomized to the RADIANT trial had mutations (exon 19 deletion: 55%; exon 21 L858R: 45%).11 Although the treatment arms were well balanced with respect to gender, age, ethnicity, smoking history, tumor histology, EGFR FISHpositivity, and mutation type, patients in the erlotinib group had received less chemotherapy and had lower-stage disease, whereas those in the placebo group had smaller tumors.

The median duration of treatment was 21.2 months with erlotinib and 21.9 months with placebo. Patients who received adjuvant erlotinib therapy achieved a longer DFS compared with those who received placebo (median: 46.4 months vs 28.5 months, respectively; P = .039); this was not statistically significant, however, because of the hierarchal testing procedure. The DFS effects were reproduced using an exploratory multivariate Cox model after adjusting for other prognostic variables (HR, 0.60; P = .046).11 A lower percentage of erlotinib-treated patients compared with patients receiving placebo relapsed (34.3% vs 52.5%, respectively). Notably, there was a higher incidence of brain relapses (40.0% vs 12.9%, respectively) and a lower incidence of bone relapses (14.3% vs 29.0%, respectively) among patients in the erlotinib cohort compared with those in the placebo cohort. No significant difference in OS was reported (OS median not reached in either treatment arm; HR, 1.09; P = .8153).

In the EGFR mutation–positive cohort, grade 3/4 rash (19% vs 0%, respectively) and diarrhea (5% vs 0%, respectively) were higher in the erlotinib arm compared with the placebo arm. Overall, the rate of treatment discontinuations due to AEs was higher with erlotinib therapy (25%) than with placebo (0%).

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FACULTY PERSPECTIVES Perspectives This trial suggests the benefit of erlotinib in EGFR mutation–positive tumors.

However, the small percentage of patients with this mutation and the imbalances of the arms make the data somewhat difficult to interpret.

-Roy S. Herbst, MD, PhD The subgroup analysis of the RADIANT trial revealed prolonged DFS in the arm treated with erlotinib. The patients in this group also experienced lower rates of relapse. These results may be partially explained by the fact that erlotinib-treated patients had lower-stage disease. Adjuvant therapy with erlotinib may be more beneficial for patients with high stage of disease at resection.

-Marianne Davies, RN, MSN, ACNP, AOCN Managing oncology drugs requires a combination of clinical expertise from oncology specialists and general knowledge of treatment options by the Pharmacy and Therapeutics (P&T) committees of the various health plans. The P&T Committee has to assess value from clinical data even when primary end points are not reached and determine where to place specific drugs on the formulary for coverage. The RADIANT trial demonstrates close to 2 years of DFS benefit compared with placebo as well as lower relapse rates in the erlotinib arm. Although the results did not reach statistical significance, these data may support a positive response from a health plan P&T Committee.

-James T. Kenney, Jr, RPh, MBA

Erlotinib plus Bevacizumab versus Erlotinib Although EGFR-TKIs improve PFS significantly compared with standard chemotherapy, the median PFS achieved is only approximately 9.2 to 13.1 months in patients with EGFR mutation–positive NSCLC.2-5 In order to further improve PFS rates, research efforts have focused on the addition of other active agents to EGFR-TKIs. Results from the phase 3 BeTa Lung study in a subgroup of patients with EGFR-positive mutations suggest that erlotinib-plus-bevacizumab combination therapy may prolong PFS.12 At ASCO 2014, Kato and colleagues presented the results of an openlabel, randomized trial evaluating erlotinib plus bevacizumab in chemotherapy-naïve patients with stage IIIb/IV or recurrent nonsquamous EGFR mutation–positive NSCLC.13 Activating EGFR mutations included exon 19 deletion and exon 21 L858R; patients with T790 mutations were excluded from the study. Stratification factors included gender, smoking status, clinical stage, and EGFR mutation type. Eligible patients were randomized to receive erlotinib 150 mg/day plus bevacizumab 15 mg/kg every 3 weeks or erlotinib 150 mg/day alone until disease progression or unacceptable toxicity.13 The primary end point was PFS by Response Evaluation Criteria in Solid Tumors (RECIST) and independent review committee; secondary end points included OS, objective response rate (ORR), safety, and quality of life.13 The addition of bevacizumab to erlotinib treatment was associated with a statistically significant 46% reduction in the risk for progression compared with the use of erlotinib alone (HR, 0.54; log-rank, P = .0015). Median PFS was 16.0 months with erlotinib plus bevacizumab versus 9.7 months with erlotinib alone.13 The subgroup of patients with EGFR exon 19 deletion benefited more from erlotinib-plus-bevacizumab therapy than did those with exon 21 L858R, with a median PFS of 18.0 months (vs 10.3 months with erlotinib alone; HR, 0.41) and 13.9 months (vs 7.1 months with erlotinib alone; HR, 0.67), respectively.13 ORR did not differ significantly between the 2 treatment groups (69.3% with erlotinib plus bevacizumab vs 63.6% with erlotinib alone; P = .4951).

A higher incidence of grade 3/4 AEs was reported in the combination group (91%) than in the erlotinib monotherapy group (53%), driven mostly by hypertension events related to bevacizumab therapy (60% with bevacizumab plus erlotinib vs 10% with erlotinib alone). The incidence of serious AEs was similar between the 2 treatment arms. Proteinuria (all grades) was also higher in the combination treatment group compared with the er-

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Table 1. Combined OS Analysis of LUX-Lung 3 and LUX-Lung 6 Trials: Afatinib versus Chemotherapy16 Afatinib versus chemotherapy Median OS, months

Hazard ratio; P value

All common mutations (N = 631)

27.3 vs 24.3

0.81; .0374

Exon 19 deletion (n = 355)

31.7 vs 20.7

0.59; < .001

Exon 21 L858R mutation (n = 276)

22.1 vs 26.9

1.25; .1600

Population

OS indicates overall survival.

lotinib monotherapy group (52% vs 4%, respectively) and was the reason for discontinuation of bevacizumab in 15% of the patients.13 Perspectives This Japanese study is quite exciting and confirms our work in EGFR mutation–positive patients in the BeTa trial. Clearly, this combination therapy seems to have an effect on preventing resistance and should be analyzed in future studies.

-Roy S. Herbst, MD, PhD Combination regimens challenge providers to screen for and manage a broader range of side effects. Collaboration with onco-cardiologists may help screen patients at risk for hypertension and may allow for early management of this condition. Patients need to be well educated about the increased toxicity profile of certain regimens and strategies for effective management.

-Marianne Davies, RN, MSN, ACNP, AOCN A 46% reduction in the risk of progression is a compelling result that would support coverage of this combination of erlotinib plus bevacizumab in the treatment of patients with NSCLC. Combining injectable and oral therapies may present management challenges for health plans due to the application of separate benefits for the coverage of each agent.

Coordination of the pharmacy and medical benefits is needed to effectively monitor and coordinate care. Differences in the out-of-pocket costs across the 2 benefits may present challenges for providers in ensuring that patients can afford, and will comply with, complex treatment regimens.

-James T. Kenney, Jr, RPh, MBA

Afatinib versus Chemotherapy: Pooled Analysis of LUX-Lung 3 and LUX-Lung 6 Trials Afatinib is an oral, irreversible pan-ErbB TKI that inhibits signaling via the ErbB family members, including EGFR, HER2, ErbB3, and ErbB4. In the United States, afatinib is indicated for previously untreated patients with advanced NSCLC harboring common EGFR mutations (exon 19 deletion/exon 21 L858R).1 Two large, randomized, phase 3 trials—LUX-Lung 3 (LL3)14 and LUXLung 6 (LL6)15—compared afatinib with cisplatin plus pemetrexed and cisplatin plus gemcitabine, respectively, in 345 patients recruited globally14 and 364 Asian patients,15 respectively. The primary analyses for both of these trials showed significant prolongation of PFS with afatinib versus standard first-line therapy in the overall EGFR mutation–positive population (LL3: 11.1 months vs 6.9 months, respectively; HR, 0.58; P = .00114; LL6: 11.0 months vs 5.6 months, respectively; HR, 0.28; P < .000115). However, this did not translate into improvement in OS in either of the studies (LL3: 28.2 months vs 28.2 months, respectively; HR, 0.88; P = .385014; LL6: 23.1 months vs 23.5 months, respectively; HR, 0.93; P = .613715).

At ASCO 2014, Yang and colleagues presented a pooled analysis of mature OS data from the LL3 and LL6 studies.16 Eligible patients enrolled in these trials were randomized in a 2:1 ratio to afatinib 40 mg or up to 6 cycles

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CONTINUING EDUCATION

Table 2. Results of the LUX-Lung 8 Trial: Afatinib versus Erlotinib17 Efficacy end point

Afatinib (n = 335)

Erlotinib (n = 334)

P value

Median PFS (IRR)

2.4 months

1.9 months

.043

Median PFS (IR)

2.7 months

1.9 months

.005

DCR

45.7%

36.8%

.020

ORR

4.8%

3.0%

.233

DCR indicates disease control rate; IR, investigator review; IRR, independent radiological review; ORR, objective response rate; PFS, progression-free survival.

of standard chemotherapy. The pooled analysis included 631 and 709 patients with the common exon 19 deletion/exon 21 L858R EGFR mutations who were randomized into the LL3 and LL6 trials, respectively. At a median follow-up of 36.5 months, OS was significantly improved with afatinib versus chemotherapy (median: 27.3 months vs 24.3 months; HR, 0.81; P = .0374) (Table 1).16 Patients with the exon 19 deletion derived a particular benefit from afatinib therapy, with a 41% reduction in the risk for death compared with chemotherapy and a median OS of 31.7 months versus 20.7 months, respectively (HR, 0.59; P < .001). In contrast, there was no significant difference in OS among patients with exon 21 L858R mutations (HR, 1.25; P = .1600).16

The EGFR T790M resistance mutation is detected in approximately 60% of TKI-resistant patients, with no approved treatments directed toward this common mutation currently available.

Perspectives These findings, which demonstrate a survival benefit in patients with the exon 19 deletion, are compelling, and make a case for the use of afatinib in this population. Certainly, one might expect similar results in these patients with the use of other EGFR inhibitors, although such data remain to be reported.

-Roy S. Herbst, MD, PhD Afatinib should perhaps be considered as frontline treatment for patients with select exon 19 deletions. In patients with exon 21 L858R, the treatment selection should consider toxicity profile, ability to adhere to a daily regimen, and quality of life.

-Marianne Davies, RN, MSN, ACNP, AOCN These trials highlight the challenges faced by health plans in trying to interpret and appreciate the clinical value of trials with mixed results. OS is the gold standard for P&T Committee evaluation of oncology treatments and PFS is used when OS data are not available. The results highlight the complexity of evaluating targeted therapies in patients with unique genetic profiles and determining the true value of the products.

-James T. Kenney, Jr, RPh, MBA

Afatinib versus Erlotinib: LUX-Lung 8 Trial At ESMO 2014, Goss and colleagues presented results of the global, randomized, phase 3 LUX-Lung 8 (LL8) study, which compared afatinib versus erlotinib in patients with stage III/IV relapsed/refractory squamous cell carcinoma of the lung following failure of first-line chemotherapy.17 The primary analysis of the trial (based on 414 PFS events by independent radiological review [IRR] in the first 669 patients randomized) showed that afatinib therapy was associated with significant improvements in PFS (IRR: 2.4 months vs 1.9 months; P = .043) and disease control rate (45.7% vs 36.8%; P = .020) compared with erlotinib treatment (Table 2).17 Although the ORRs were

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numerically higher with afatinib than with erlotinib (4.8% vs 3.0%, respectively; P = .233), they did not reach statistical significance. This safety analysis demonstrated that the AE profile was comparable between the 2 treatment arms and was typical of that seen with EGFR inhibitors. Afatinib-treated patients experienced a higher incidence of treatment-related grade 3/4 diarrhea (9.7% vs 2.4%) and stomatitis (3.3% vs 0.0%), whereas erlotinib-treated patients reported a higher incidence of grade 3 rash/acne (5.5% vs 9.0%).

Perspectives It is my belief that afatinib and erlotinib, for the most part, should be reserved for EGFR mutantâ&#x20AC;&#x201C;positive patients with NSCLC. -Roy S. Herbst, MD, PhD Diarrhea is an anticipated side effect associated with afatinib-based therapy. Most often, this is managed with an anti-diarrheal; however, dose reduction may be required in some individuals. Patients may choose to receive erlotinib or afatinib based on the toxicity profiles of these agents.

A shared decision-making approach regarding treatment selection may support improved adherence to therapy.

-Marianne Davies, RN, MSN, ACNP, AOCN This trial presents a common question for the health plan clinical team regarding statistical significance from clinical trials and whether or not the results are clinically meaningful. The challenge for reviewers will be to determine whether the PFS increase of 0.5 months is worth any decrease in quality of life due to adverse drug effects.

-James T. Kenney, Jr, RPh, MBA

Treatment of EGFR Inhibitorâ&#x20AC;&#x201C;Resistant NSCLC Although first-line EGFR-TKI therapy significantly improves clinical outcomes, including PFS, compared with standard chemotherapy, the effects are not long-lasting, with the majority of patients developing resistance, driven mostly by the acquisition of secondary mutations.6 The EGFR T790M resistance mutation is detected in approximately 60% of TKIresistant patients, with no approved treatments directed toward this common mutation currently available.6 Gefitinib Plus Chemotherapy versus Chemotherapy Alone At ESMO 2014, Mok and colleagues presented results of the phase 3, double-blind IRESSA Mutation Positive Multicentre Treatment Beyond ProgRESsion Study (IMPRESS), which evaluated the efficacy and safety of continuing gefitinib plus cisplatin/pemetrexed therapy versus placebo plus cisplatin/pemetrexed therapy in 265 patients with gefitinib-resistant NSCLC.18 Second-line gefitinib plus chemotherapy did not provide a statistically significant improvement in PFS (median PFS: 5.4 months in both arms; HR, 0.86; P = .273) or ORR compared with chemotherapy alone. OS was immature (33% of patients had died), with better OS for placebo plus cisplatin/pemetrexed versus gefitinib plus cisplatin/pemetrexed suggested (statistically significant difference: HR, 1.62; confidence interval [CI], 1.052.52; P = .029).18 The safety profiles of both arms were consistent with those already described, with gefitinib combination therapy associated with increased grade 1/2 gastrointestinal toxicities. These results suggest that continuation of gefitinib plus chemotherapy provided no additional clinical benefit compared with chemotherapy alone in patients with acquired resistance to first-line gefitinib.18 Perspectives Results from this study will affect my treatment approach, as I am now much less likely to continue using an EGFR inhibitor with chemotherapy upon the emergence of refractory disease, which had been my practice.

-Roy S. Herbst, MD, PhD

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FACULTY PERSPECTIVES It is difficult to discontinue therapy for a patient with a cancer diagnosis when there is no demonstrated clinical benefit to a particular treatment regimen. Health plans rely heavily on oncologists to make the decision to avoid additional treatment and subsequent AEs in an effort to reduce unnecessary clinical and financial costs to the healthcare system.

-James T. Kenney, Jr, RPh, MBA

Table 3. Objective Response Rates Associated with AZD9291 Therapy in EGFR-Resistant NSCLC20

Overall population (N = 157)

20 mg

40 mg

80 mg

160 mg

240 mg

53%

55%

44%

54%

58%

67%

T790M-positive (n = 107)

64%

50%

62%

68%

64%

83%

T790M-negative (n = 50)

22%

67%

12%

24%

23%

0%

EGFR indicates epidermal growth factor receptor; NSCLC, non–small-cell lung cancer.

Phase 1/2 Study of AZD9291 AZD9291 is an oral, irreversible, selective third-generation EGFR TKI that has demonstrated clinical activity against both EGFR-TKI sensitizing and resistant T790M mutations, while showing less activity against WT-EGFR, in preclinical experimental models.19 At ASCO 2014, Janne and colleagues presented preliminary results of a phase 1/2 dose-escalation and dose-expansion cohort study of AZD9291 in Asian and Caucasian patients with EGFR mutation–positive advanced NSCLC who have documented radiologic progression on EGFR-TKI therapy.20 In the dose-escalation phase, a total of 31 patients in 5 cohorts received AZD9291 at a dose of 20 to 240 mg once daily.

In the 201 patients in the dose-expansion cohort, confirmation of tumor T790M mutation status from a new biopsy sample was required.

Among the 205 patients evaluable for efficacy analysis in the total cohort, the ORR was 53% (Table 3).20 The longest duration of response was >9 months ongoing at the time of data cutoff. Importantly, the ORR was 64% among 107 patients from the expansion cohort with centrally confirmed T790M-positive NSCLC, but was only 22% in patients with T790Mnegative NSCLC. Consistently, the PFS in patients with T790M-positive NSCLC was prolonged compared with those who had T790M-negative disease. No clear dose-response relationship was observed in any of the subgroups tested. The highest ORR (67%) in the total cohort was achieved in the 240-mg dose group, followed by 58% in the 160-mg dose group; the lowest ORR was reported in the 40-mg dose group. The phase 2 dose of 80 mg once daily was selected, based on both antitumor activity and incidence of toxicity reported in patients with T790M-positive NSCLC.20 No dose-limiting toxicities were observed, and the maximum tolerated dose (MTD) has not been defined. In the total patient population, common AEs of any grade were reported in 93% of patients, including diarrhea, rash, nausea, dry skin, pruritus, decreased appetite, and fatigue; however, AEs leading to treatment discontinuation were reported in only 4% of patients.

Grade 3/4 AEs occurred in 24% of patients.20 Perspectives These next-generation EGFR inhibitors are game changing. We now have effective therapy for the 50% of patients with NSCLC who develop T790M mutation–positive disease.

-Roy S. Herbst, MD, PhD AZD9291 offers next-line therapy for patients who develop resistance to first-line TKIs, and this agent appears to be well tolerated in most patients.

Re-biopsy of tumors to test for new mutations is a paradigm shift in the decision-making process. Patients, caregivers, and providers need to be educated about the importance and significance of this approach to treatment.

-Marianne Davies, RN, MSN, ACNP, AOCN Early trial data can be encouraging for select patient groups with specific genetic profiles. However, because there are ongoing clinical trials of more than 900 oncology therapies, health plans typically wait until approval and launch of a drug before expending significant effort and energy on potential new compounds, as the approved product list is formidable enough to challenge the scarce clinical resources available to manage and monitor the current FDA-approved oncology products.

-James T. Kenney, Jr, RPh, MBA

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All doses

Dose-Finding Study of CO-1686 CO-1686 is a selective, potent oral TKI that targets key activating EGFR mutations and the common T790M resistance mutation, while sparing WTEGFR signaling. At ASCO 2014, Sequist and colleagues presented the results of an ongoing dose-finding study in patients with EGFR who had mutated advanced or recurrent NSCLC. Eligible patients must have documented activating EGFR mutation and must have been previously treated with EGFR-TKI therapy.21 Of the 88 patients who were treated with CO-1686, 57 received CO-1686 free base (up to 900 mg twice daily) and 31 received CO-1686 hydrogen bromide (HBr) salt formulation (500-1000 mg twice daily); 10 patients transitioned from the free base to the HBr formulation.21 In this report, 72 patients treated at efficacious doses were included in the analysis. The ORR for 40 patients with EGFR T790M mutation–positive disease within the therapeutic dosing range was 58%; responses were observed across all dose levels.21 The current estimate of PFS exceeds 12 months; the median PFS has not yet been reached.21

In the pharmacokinetic analysis, CO-1686 demonstrated dose-linearity across the dose ranges tested; the half-life of the agent was suitable for a twice-daily dosing regimen.

Common AEs (all grades) occurring in >10% patients included nausea (34%), impaired glucose tolerance (IGT)/hyperglycemia (52%), diarrhea (23%), vomiting (17%), decreased appetite (21%), myalgia (11%), and QTc prolongation (15%). Grade 3 IGT/hyperglycemia occurred in 22% of patients but was manageable with oral hypoglycemics and/or dose reduction.

Dose-related WT-EGFR–driven diarrhea and rash have not been observed.

A recommended phase 2 dose of 750 mg twice daily was selected.21 In the pharmacokinetic analysis, CO-1686 demonstrated dose-linearity across the dose ranges tested; the half-life of the agent was suitable for a twice-daily dosing regimen. Moreover, the HBr formulation demonstrated 3 times greater exposure than did the equivalent free base dose.21 Perspectives CO-1686 is clearly active in EGFR T790M mutation–positive NSCLC. However, the toxicities of hyperglycemia and QTc prolongation could be an issue in a reasonable number of our patients.

-Roy S. Herbst, MD, PhD The overall response and PFS rates associated with the use of CO-1686 in this trial are encouraging. However, the toxicity profile of targeted agents is not benign. Providers must be diligent in closely monitoring patients for AEs and implementing effective intervention and management strategies to ensure adherence to therapy.

-Marianne Davies, RN, MSN, ACNP, AOCN A potent targeted therapy may offer promise for a select subset of patients with NSCLC. Agents with the potential for predictable responses based on a patient with specific EGFR mutations can offer greater value for the dollars spent on the therapy. A key goal of health plan pharmacy

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CONTINUING EDUCATION cisplatin 75 mg/m2 or carboplatin area under the curve 5-6 every 3 weeks for ≤6 cycles; n = 171). The primary end Chemotherapy point of the study was PFS; secondary end points included Efficacy end point Crizotinib (n = 172) (n = 171) Hazard ratio; P value ORR, OS, safety, and patient-reported outcomes.27 Median PFS 10.9 months 7.0 months 0.454; < .0001 At this interim analysis, crizotinib was associated with significantly prolonged PFS (median: 10.9 months vs 7.0 ORR 74% 45% < .0001 months with chemotherapy) and reduced the risk for proMedian DOR 49.0 weeks 22.9 weeks gression by 54% (HR, 0.454; 95% CI, 0.346-0.596; P < Onset of response 6.1 weeks 12.1 weeks .0001; Table 4).27 The ORR was significantly higher with DOR indicates duration of response; ORR, objective response rate; PFS, progression-free survival. crizotinib than with chemotherapy (74% vs 45%, respectively; P < .0001).27 Use of crizotinib was associated with a longer duration of response (median: 49.0 weeks vs 22.9 weeks) and a more management is to avoid use in patients in whom a response is not supported by the evidence presented in the trial data. rapid onset of response (median: 6.1 weeks vs 12.1 weeks) compared with the use of pemetrexed plus platinum-based chemotherapy. With 68% of patients still in follow-up, a median OS was not reached. At the time of data -James T. Kenney, Jr, RPh, MBA cutoff, 109 patients had crossed over to the crizotinib arm.27 AEs with crizotinib were consistent with those previously reported in patients with advanced ALK-positive NSCLC. Common AEs associated ALK-Positive Advanced NSCLC with crizotinib therapy versus chemotherapy, respectively, included vision ALK is a receptor tyrosine kinase that is constitutively activated in 2% to disorders (71% vs 14%), diarrhea (61% vs 17%), edema (49% vs 13%), 7% of all NSCLCs by chromosomal rearrangement due to generation of an vomiting (46% vs 40%), constipation (43% vs 31%), and elevated transamaberrant oncogenic EML4-ALK fusion gene.22 Crizotinib is an ALK inhibiinases (36% vs 13%). tor that has demonstrated efficacy in this disease subgroup, and was approved by the US Food and Drug Administration (FDA) for the treatment Phase1 Study of Ceritinib of patients with ALK-positive NSCLC in November 2013.23-25 In a phase 1 At ASCO 2014, Kim and colleagues presented updated results of the study, treatment with crizotinib monotherapy was associated with an ORR ongoing ASCEND-1 trial, which followed the enrollment of 246 patients of 60.8%, a median duration of response of 49.1 weeks, a median PFS of 9.7 across 11 countries who were treated with a ceritinib MTD of 750 mg/ months, and an estimated 1-year OS rate of 74.8%.23 In a phase 3, randomday.28 Of the enrolled patients, 163 had previously received crizotinib ized, open-label study of 347 patients with ALK-positive NSCLC who had received 1 prior platinum-based regimen, crizotinib demonstrated superior therapy and 83 were ALK inhibitor–naïve. Ceritinib 750 mg/day was assoefficacy compared with standard second-line chemotherapy (pemetrexed or ciated with high antitumor activity, regardless of prior treatment with docetaxel), reducing the risk for progression by 51% (HR, 0.49; P < .001).

ALK inhibitors. The ORR in the total cohort was 58.5%, with ORRs in The median PFS was 7.7 months in the crizotinib arm versus 3.0 months in the ALK inhibitor–treated patients and ALK inhibitor–naïve patients of the chemotherapy arm; the ORR was higher with crizotinib than with che54.6% and 66.3%, respectively (Table 5).28 The median duration of 24 motherapy (65% vs 20%, respectively; P < .001). Crizotinib-treated paresponse in patients with a confirmed complete response or a partial response was 9.69 months in the total cohort, 7.39 months in the ALK tients invariably relapse, however, typically within 1 year, because of the inhibitor–treated arm, and not estimable in the ALK inhibitor–naïve arm. development of drug resistance.25 The median PFS was 8.21 months in the total cohort, 6.90 months in the ALK inhibitor–treated group, and not estimable in the ALK inhibitor– A subset analysis of 124 patients with clinically and naïve group.28 In the 255 patients evaluable for the safety analysis, the most common neurologically stable brain metastases at baseline AEs and laboratory abnormalities (all grades) were diarrhea (86%), nausea showed a high rate of responses and prolonged PFS. (80%), vomiting (60%), abdominal pain (54%), fatigue (52%), alanine transaminase (ALT) increased (80%), and aspartate transaminase (AST) increased (75%). Of these, grade 3/4 AEs and laboratory abnormalities inCeritinib (LDK378) is a potent, selective ALK inhibitor that was evalucluded elevations in ALT (27%), elevations in AST (13%), elevations in ated in a dose-escalation phase 1 study (ASCEND-1), in which 59 patients glucose (13%), and diarrhea (6%).28 At the 750-mg/day dosage, at least 1 with advanced ALK-positive NSCLC received ceritinib at doses of 50 to 26 750 mg/day. The MTD of ceritinib was established at 750 mg/day, with dose reduction due to an AE was reported in 59% of patients and treatment discontinuation due to an AE was reported in 9.4% of patients.28 Overall, 10 dose-limiting toxicities, including diarrhea, vomiting, dehydration, elevated 26 aminotransferase levels, and hypophosphatemia. An expansion phase folpatients developed interstitial lung disease/pneumonitis, 3 of whom discontinued ceritinib treatment, including 1 fatal case; the remaining cases were lowed in which an additional 71 patients received treatment with ceritinib, managed by dose adjustments and/or interruptions.28 for a total of 130 patients overall. Of 114 patients with NSCLC who received ceritinib doses ≥400 mg, the ORR was 58%. Among 80 patients who A subset analysis of 124 patients with clinically and neurologically stable had progressed on crizotinib, the ORR was 56%.26 Based on the results of the brain metastases at baseline showed a high rate of responses and prolonged PFS. The ORR in the total subset of patients with brain metastases was ASCEND-1 trial, ceritinib received FDA approval in April 2014 for the 54.0%, with responses achieved in both ALK inhibitor–treated (n = 98; treatment of the ALK-positive nonsquamous subset of patients with NSCLC 50.0%) and ALK inhibitor–naïve (n = 26; 69.2%) groups. Median PFS was who had failed prior ALK inhibitor therapy.

6.90 months, 6.70 months, and 8.31 months, respectively, in the total subset, ALK inhibitor–treated arm, and ALK inhibitor–naïve arm. In the 14 First-Line Crizotinib Pemetrexed plus Cisplatin or Pemetrexed plus patients with measurable brain metastases at baseline, the overall intracraCarboplatin nial response rate was 50.0%.28 The efficacy and safety of crizotinib compared with chemotherapy as firstline treatment for patients with ALK-positive NSCLC is currently unknown. At ASCO 2014, Mok and colleagues presented results of the multicenter, open-label, randomized, crossover, phase 3 PROFILE 1014 trial, Perspectives which compared the efficacy and safety of crizotinib versus pemetrexed plus All TKIs will produce resistance. These new agents are potent in NSCLC platinum-based chemotherapy in the front-line setting.27 In this trial, a total and have demonstrated activity in patients with brain metastasis, which offers new hope against this disease. of 343 patients with previously untreated, advanced nonsquamous ALKpositive NSCLC were randomized in a 1:1 ratio to receive crizotinib 250 mg -Roy S. Herbst, MD, PhD twice daily (n = 172) or chemotherapy (pemetrexed 500 mg/m2 plus either Table 4. Efficacy Analysis of Crizotinib in the PROFILE 1014 Trial27

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FACULTY PERSPECTIVES Crizotinib and ceritinib offer options for the small subTable 5. Efficacy Analysis of Ceritinib Therapy in the ASCEND-1 Trial28 population of patients with ALK-positive NSCLC. The ALK inhibitor–treated ALK inhibitor–naïve All patients ASCEND-1 trial supports the use of ceritinib as first-line Efficacy end point (n = 163) (n = 83) (N = 246) treatment in patients with known brain metastases.

ORR 54.6% 66.3% 58.5% Current recommendations are for both agents to be taken on an empty stomach. This likely contributes to DOR 7.39 months Not estimable 9.69 months the gastrointestinal toxicities reported. Further studies on Median PFS 6.90 months Not estimable 8.21 months taking these agents with food may help decrease the 12-month PFS rate 28.4% 61.3% 39.1% incidence of toxicities. All patients who are treated with ALK indicates anaplastic lymphoma kinase; DOR, duration of response; ORR, objective response rate; crizotinib should have baseline and ongoing ophthalmolPFS, progression-free survival. ogy examinations. Providers also need to monitor glucose and transaminases levels closely, and should anticipate the need for dose reductions in order to successfully manage AEs. the efficacy of the agent for a particular cancer.

-Marianne Davies, RN, MSN, ACNP, AOCN

-James T. Kenney, Jr, RPh, MBA

The high relapse rates of patients on crizotinib after 1 year supports the need for additional treatment options in ALK-positive patients. This early data from the ASCEND-1 trial suggests the potential value of ceritinib in patients with brain metastases, notably an ORR of 54%. Concerns regarding resistance will need to be evaluated as newer agents progress through clinical trials. In particular, we will need to look at data that may support use in patients with resistance to first-generation ALK-positive treatments.

Neratinib in HER2-Positive NSCLC Somatic HER2 mutations are detected in approximately 2% of patients with NSCLC and appear to be mutually exclusive of such other genetic aberrations as KRAS, EGFR, and ALK in NSCLC.32,33 Preclinical and early clinical trial evidence suggests that combined HER2/mTOR inhibition has synergistic effects on HER2-driven lung tumors.34 Based on these results, a phase 2, multicenter, randomized, 2-stage study was conducted to compare the irreversible pan-HER TKI neratinib with or without temsirolimus in patients with stage IIIB/IV HER2 mutation–positive NSCLC. The results of the stage I component of the trial (n = 27) were presented by Besse and colleagues at ESMO 2014.35 In stage I of this study, neratinib plus temsirolimus therapy was associated with an ORR of 21%, compared with 0% with the use of neratinib alone; partial responses were observed in 3 patients and 0 patients, respectively. A median PFS of 4.0 months was reported in the neratinib-plus-temsirolimus arm versus 2.9 months in the neratinib-only arm. In terms of safety, grade 3 AEs in the neratinib-plus-temsirolimus group versus the neratinib-alone group, respectively, included dyspnea (14% vs 8%), diarrhea (14% vs 8%), vomiting (21% vs 0%), and nausea (14% vs 0%).35 One grade 4 event each of dyspnea, blood uric acid elevation, and cardiorespiratory arrest occurred; 3 deaths were reported due to pleural effusion, cerebrovascular accident, and respiratory failure. All grade 4 and 5 events reported were considered to be unrelated to neratinib. The use of neratinib plus temsirolimus combination therapy has now been expanded into the stage II part of the study following fulfillment of efficacy criteria in stage I.35

-James T. Kenney, Jr, RPh, MBA

NOVEL TARGETED APPROACHES IN NSCLC

Dabrafenib in BRAF V600E Mutation–Positive NSCLC Activating BRAF mutations are present in approximately 2% of lung carcinomas, and are associated with shorter disease-free survival and OS rates.29,30 Since approximately 80% of these are BRAF V600E mutations,30 a multicenter, open-label, phase 2 study evaluated the BRAF TKI dabrafenib in 78 patients with BRAF V600E mutation–positive NSCLC.31 Planchard and colleagues presented the results of this trial at ESMO 2014. After 12 weeks of dabrafenib treatment, an ORR of 32% was achieved in patients who had previously received ≥1 prior treatments, with a disease control rate of 56%.The median duration of response was 11.8 months.31 The most common AEs reported included pyrexia (36%), asthenia (30%), hyperkeratosis (30%), loss of appetite (29%), nausea (27%), cough (26%), fatigue (26%), and skin papilloma (26%). Cutaneous squamous cell carcinomas, including keratoacanthoma, were reported in 18% of patients.31

Perspectives

Perspectives As we seek more personalized care of our patients, dabrafenib offers a good option for those with BRAF V600E–positive disease. However, the side effects will need to be managed effectively.

-Roy S. Herbst, MD, PhD

Neratinib is yet another option in a small subgroup of patients with advanced NSCLC. -Roy S. Herbst, MD, PhD

Dabrafenib offers a treatment option for patients with BRAF V600E mutations. However, there are significant dermatologic and gastrointestinal toxicities associated with this therapy. Twice-daily dosing on an empty stomach and associated gastrointestinal AEs may influence adherence to the treatment regimen and hence impact outcomes. Consultation and collaboration with dermatologists who have expertise in targeted therapeutics should be recommended.

These early data are focused on combining HER2/mTOR inhibition as a potential target for a small subset of patients with NSCLC. A new mechanism of action (MOA) is always an exciting option for the pharmacy program, as patients without good clinical options may benefit from a new targeted treatment approach. The minimal efficacy improvement is not sufficient at this time to suggest that this could be a key treatment approach in the future. Additional studies will need to focus on the potential to target additional subsets of the overall population that may achieve clinical benefit from neratinib.

-Marianne Davies, RN, MSN, ACNP, AOCN

-James T. Kenney, Jr, RPh, MBA

Although select therapies may present compelling clinical trial results, AE rates may severely limit the value of them in treatment protocols. A balance of efficacy, safety, and tolerability are key pharmacologic criteria that must be evaluated to assess the true value of a new oncology agent.

The oncologist must assess the risk-benefit options in selecting an appropriate therapy for a patient based on genetics, prior treatment history, and

Pembrolizumab in NSCLC Immune checkpoint blockade with monoclonal antibodies directed at the inhibitory immune receptors cytotoxic T-lymphocyte–associated protein 4, (CTLA-4), programmed death-1 (PD-1), and programmed death-ligand 1 (PD-L1) has emerged as a successful treatment approach for patients with advanced melanoma.36 Pembrolizumab, a humanized antibody that exerts

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CONTINUING EDUCATION dual blockade of the immune checkpoint receptor PD-1 to overcome tumormediated immunosuppression, is in clinical development for various types of cancer. At ESMO 2014, Garon and colleagues reported efficacy and safety results from the phase 1b KEYNOTE-001 study of pembrolizumab 2 mg/kg every 3 weeks, 10 mg/kg every 3 weeks, or 10 mg/kg every 2 weeks in 282 patients with advanced NSCLC, who were either treatment-naïve or had failed prior EGFR and ALK TKI therapy.37 At a median follow-up of 5.4 months, ORRs per RECIST v1.1 by central review and per immune-related response criteria by investigator review in the overall population were 21% and 23%, respectively.37 Pooled data analysis yielded a median PFS of 13 weeks, 24-week PFS rate of 30%, median OS of 8.2 months, and 6-month OS rate of 64%. In the treatment-naïve cohort of patients, the ORR was 26%, median PFS was 27 weeks, 24-week PFS rate was 51%, median OS was not yet reached, and 6-month OS rate was 86%. In previously treated patients, however, these efficacy end points were lower, with median PFS of 10 weeks, 24-week PFS rate of 26%, median OS of 8.2 months, and 6-month OS rate of 59%. Grades 3 to 5 drug-related AEs were reported in 24 patients (9%), most commonly pneumonitis.37

These results indicate that immunotherapy with MAGE-A3 in the adjuvant setting is not yet a feasible strategy in NSCLC with current technology.

Perspectives

The immune checkpoint inhibitors have transformed our view of lung cancer treatment, based on their specific and durable responses and side effect profiles that are much more favorable than those associated with standard chemotherapy.

-Roy S. Herbst, MD, PhD Immune checkpoint inhibitors have demonstrated promising outcomes in terms of PFS, OS, and ORR for patients with advanced NSCLC. Assessing for PDL-1 expression in the tumor at baseline and at time of progression is of uncertain value in selecting patients who may benefit from targeting the PD-1 pathway. Combination blockade may be useful. Immune-related AEs may be observed with this class of drug; early identification and management of these events are necessary for successful continued treatment.

-Marianne Davies, RN, MSN, ACNP, AOCN

The PD-1 target is gaining a lot of attention in drug development and clinical trials and offers a new MOA that may yield valuable clinical results in treatment-naïve and previously treated patients. Data on OS, PFS, and ORR suggests the potential clinical value of this new monoclonal antibody in NSCLC and many other cancers.

-James T. Kenney, Jr, RPh, MBA

recMAGE-A3 + AS15 as Adjuvant Therapy in Resected MAGE-A3– Positive NSCLC At ESMO 2014, Vansteenkiste and colleagues discussed results of the randomized, double-blind, placebo-controlled, phase 3 MAGRIT trial, which evaluated recMAGE-A3 + AS15 immunotherapeutic (MAGE-A3 CI) as adjuvant treatment in 2272 patients with resected MAGE-A3–positive NSCLC regardless of the use of prior adjuvant chemotherapy.38 Patients were randomized in a 1:1 ratio to receive 13 intramuscular injections of MAGE-A3 CI or placebo over a 27-month treatment period. At a median follow-up of 38.8 months, administration of 13 injections of MAGE-A3 CI over a 27-month treatment period was not associated with any significant difference in median DFS compared with placebo treatment

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(60.5 vs 57.9 months, respectively; HR, 1.024; P = .7379).38 Consistently, no improvement in OS was reported between the 2 treatment arms. Subset analysis also did not reveal any survival benefit for any patient subgroups analyzed, including by age, disease stage, histopathology, chemotherapy, tumor region, and MAGE-A3 quantitative expression. Common AEs, which were mostly grade 1/2 in severity, included pyrexia, injection-site pain, injection-site reaction, fatigue, pain, influenza-like illness, and myalgia. These results indicate that immunotherapy with MAGE-A3 in the adjuvant setting is not yet a feasible strategy in NSCLC with current technology.38 References 1. Peters S, Adjei AA, Gridelli C, et al. Metastatic non-small-cell lung cancer (NSCLC): ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up. Ann Oncol.

2012;23(suppl 7):vii56-vii64.

2. Maemondo M, Inoue A, Kobayashi K, et al. Gefitinib or chemotherapy for non–small-cell lung cancer with mutated EGFR. N Engl J Med. 2010;362:2380-2388.

3. Mitsudomi T, Morita S, Yatabe Y, et al; West Japan Oncology Group. Gefitinib versus cisplatin plus docetaxel in patients with non-small-cell lung cancer harbouring mutations of the epidermal growth factor receptor (WJTOG3405): an open label, randomised phase 3 trial. Lancet Oncol. 2010;11:121-128.

4. Rosell R, Carcereny E, Gervais R, et al; on behalf of the Spanish Lung Cancer Group in collaboration with the Groupe Français de Pneumo-Cancérologie and the Associazione Italiana Oncologia Toracica. Erlotinib versus standard chemotherapy as first-line treatment for European patients with advanced EGFR mutation-positive non-small-cell lung cancer (EURTAC): a multicentre, open-label, randomised phase 3 trial. Lancet Oncol.

2012;13:239-246.

5. Zhou C, Wu YL, Chen G, et al. Erlotinib versus chemotherapy as first-line treatment for patients with advanced EGFR mutation-positive non-small-cell lung cancer (OPTIMAL, CTONG-0802): a multicentre, open-label, randomised, phase 3 study. Lancet Oncol.

2011;12:735-742.

6. Yu HA, Arcila ME, Rekhtman N, et al. Analysis of tumor specimens at the time of acquired resistance to EGFR-TKI therapy in 155 patients with EGFR-mutant lung cancers.

Clin Cancer Res. 2013;19:2240-2247.

7. Goss GD, O’Callaghan C, Lorimer I, et al. Gefitinib versus placebo in completely resected non–small-cell lung cancer: results of the NCIC CTG BR19 study. J Clin Oncol. 2013; 31:3320-3326.

8. Kelly K, Chansky K, Gaspar LE, et al. Phase III trial of maintenance gefitinib or placebo after concurrent chemoradiotherapy and docetaxel consolidation in inoperable stage III non–small-cell lung cancer: SWOG S0023. J Clin Oncol. 2008;26:2450-2456.

9. D’Angelo SP, Janjigian YY, Ahye N, et al. Distinct clinical course of EGFR-mutant resected lung cancers: results of testing of 1118 surgical specimens and effects of adjuvant gefitinib and erlotinib. J Thorac Oncol. 2012;7:1815-1822.

10. Pennell NA, Neal JW, Chaft JE, et al. SELECT: a multicenter phase II trial of adjuvant erlotinib in resected early-stage EGFR mutation-positive NSCLC. J Clin Oncol (ASCO Annual Meeting Abstracts). 2014;32(suppl):Abstract 7514.

11. Shepherd FA, Altorki NK, Eberhardt WEE, et al. Adjuvant erlotinib (E) versus placebo (P) in non-small cell lung cancer (NSCLC) patients (pts) with tumors carrying EGFRsensitizing mutations from the RADIANT trial. J Clin Oncol (ASCO Annual Meeting Abstracts). 2014;32(suppl):Abstract 7513.

12. Herbst RS, Ansari R, Bustin F, et al. Efficacy of bevacizumab plus erlotinib versus erlotinib alone in advanced non-small-cell lung cancer after failure of standard first-line chemotherapy (BeTa): a double-blind, placebo-controlled, phase 3 trial. Lancet. 2011;377:1846-1854.

13. Kato T, Seto T, Nishio M, et al. Erlotinib plus bevacizumab (EB) versus erlotinib alone (E) as first-line treatment for advanced EGFR mutation–positive nonsquamous non-small cell lung cancer (NSCLC): an open-label randomized trial. J Clin Oncol (ASCO Annual Meeting Abstracts). 2014;32(suppl):Abstract 8005.

14. Sequist LV, Yang JC-H, Yamamoto N, et al. Phase III study of afatinib or cisplatin plus pemetrexed in patients with metastatic lung adenocarcinoma with EGFR mutations. J Clin Oncol. 2013;31:3327-3334.

15. Wu YL, Zhou C, Hu CP, et al. Afatinib versus cisplatin plus gemcitabine for first-line treatment of Asian patients with advanced non-small-cell lung cancer harbouring EGFR mutations (LUX-Lung 6): an open-label, randomised phase 3 trial. Lancet Oncol. 2014; 15:213-222.

16. Yang JC-H, Sequist LV, Schuler MH, et al. Overall survival (OS) in patients (pts) with advanced non-small cell lung cancer (NSCLC) harboring common (Del19/L858R) epidermal growth factor receptor mutations (EGFR mut): pooled analysis of two large open-label phase III studies (LUX-Lung 3 [LL3] and LUX-Lung 6 [LL6]) comparing afatinib with chemotherapy (CT). J Clin Oncol (ASCO Annual Meeting Abstracts). 2014;32(suppl):Abstract 8004.

17. Goss G, Felip E, Cobo M, et al. A randomized, open-label, phase III trial of afatinib (A) vs erlotinib (E) as second-line treatment of patients (pts) with advanced squamous cell carcinoma (SCC) of the lung following first-line platinum-based chemotherapy: LUXLung 8 (LL8). Ann Oncol (ESMO Annual Meeting Abstracts). 2014;25(suppl 4):Abstract 1222O. 18. Mok TS, Wu Y-L, Nakagawa K, et al. LBA2_PR - Gefitinib/chemotherapy vs chemotherapy in epidermal growth factor receptor (EGFR) mutation-positive non-small-cell lung cancer

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FACULTY PERSPECTIVES (NSCLC) after progression on first-line gefitinib: the phase III, randomised IMPRESS study.

Ann Oncol (ESMO Annual Meeting Abstracts). 2014;25(suppl 4):Abstract LBA2_PR. 19. Cross DAE, Ashton SE, Ghiorghiu S, et al. AZD9291, an irreversible EGFR TKI, overcomes T790M-mediated resistance to EGFR inhibitors in lung cancer. Cancer Discov.

2014;4:1046-1061.

20. Janne PA, Ramalingam SS, Yang JC-H, et al. Clinical activity of the mutant-selective EGFR inhibitor AZD9291 in patients (pts) with EGFR inhibitor–resistant non-small cell lung cancer (NSCLC). J Clin Oncol (ASCO Annual Meeting Abstracts). 2014;32 (suppl):Abstract 8009.

21. Sequist LV, Soria J-C, Gadgeel SM, et al. First-in-human evaluation of CO-1686, an irreversible, highly selective tyrosine kinase inhibitor of mutations of EGFR (activating and T790M). J Clin Oncol (ASCO Annual Meeting Abstracts). 2014;32(suppl):Abstract 8010.

22. Kwak EL, Bang Y-J, Camidge DR, et al. Anaplastic lymphoma kinase inhibition in non– small-cell lung cancer. N Engl J Med. 2010;363:1693-1703.

23. Camidge DR, Bang Y-J, Kwak EL, et al. Activity and safety of crizotinib in patients with ALK-positive non-small-cell lung cancer: updated results from a phase 1 study. Lancet Oncol. 2012;13:1011-1019.

24. Shaw AT, Kim D-W, Nakagawa K, et al. Crizotinib versus chemotherapy in advanced ALK-positive lung cancer. N Engl J Med. 2013;368:2385-2394.

25. Katayama R, Shaw AT, Khan TM, et al. Mechanisms of acquired crizotinib resistance in ALK-rearranged lung cancers. Sci Transl Med. 2012;4:120ra17.

26. Shaw AT, Kim D-W, Mehra R, et al. Ceritinib in ALK-rearranged non–small-cell lung cancer. N Engl J Med. 2014;370:1189-1197.

27. Mok T, Kim D-W, Wu Y-L, et al. First-line crizotinib versus pemetrexed–cisplatin or pemetrexed–carboplatin in patients (pts) with advanced ALK-positive non-squamous non-small cell lung cancer (NSCLC): results of a phase III study (PROFILE 1014). J Clin Oncol (ASCO Annual Meeting Abstracts). 2014;32(suppl):Abstract 8002.

28. Kim D-W, Mehra R, Tan DS-W, et al. Ceritinib in advanced anaplastic lymphoma kinase (ALK)-rearranged (ALK+) non-small cell lung cancer (NSCLC): results of the ASCEND-1 trial. J Clin Oncol (ASCO Annual Meeting Abstracts). 2014;32(suppl): Abstract 8003.

29. Kris MG, Johnson BE, Berry LD, et al. Using multiplexed assays of oncogenic drivers in lung cancers to select targeted drugs. JAMA. 2014;311:1998-2006.

30. Marchetti A, Felicioni L, Malatesta S, et al. Clinical features and outcome of patients with non–small-cell lung cancer harboring BRAF mutations. J Clin Oncol. 2011;29:3574-3579.

31. Planchard D, Kim TM, Mazieres J, et al. Dabrafenib in patients with BRAF V600E-mutant advanced non-small cell lung cancer (NSCLC): a multicenter, open-label, phase 2 trial (BRF113928). Ann Oncol (ESMO Annual Meeting Abstracts). 2014;25(suppl 4):Abstract LBA38_PR. 32. Mazières J, Peters S, Lepage B, et al. Lung cancer that harbors an HER2 mutation: epidemiologic characteristics and therapeutic perspectives. J Clin Oncol. 2013;31:1997-2003.

33. The Cancer Genome Atlas Research Network. Comprehensive molecular profiling of lung adenocarcinoma. Nature. 2014;511:543-550.

34. Gandhi L, Bahleda R, Tolaney SM, et al. Phase I study of neratinib in combination with temsirolimus in patients with human epidermal growth factor receptor 2–dependent and other solid tumors. J Clin Oncol. 2014;32:68-75.

35. Besse B, Soria J-C, Yao B, et al. Neratinib (N) with or without temsirolimus in patients (pts) with non-small cell lung cancer carrying HER2 somatic mutations: an international randomized phase II study. Ann Oncol (ESMO Annual Meeting Abstracts). 2014;25(suppl 4):Abstract LBA39_PR. 36. Ott PA, Hodi FS, Robert C. CTLA-4 and PD-1/PD-L1 blockade: new immunotherapeutic modalities with durable clinical benefit in melanoma patients. Clin Cancer Res. 2013;19: 5300-5309.

37. Garon EB, Gandhi L, Rizvi N, et al. Antitumor activity of pembrolizumab (Pembro; MK3475) and correlation with programmed death ligand 1 (PD-L1) expression in a pooled analysis of patients (pts) with advanced non–small cell lung carcinoma (NSCLC). Ann Oncol (ESMO Annual Meeting Abstracts). 2014;25(suppl 4):Abstract LBA43.

38. Vansteenkiste JF, Cho B, Vanakesa T, et al. MAGRIT, a double-blind, randomized, placebo-controlled phase III study to assess the efficacy of the recMAGE-A3 + AS15 cancer immunotherapeutic as adjuvant therapy in patients with resected MAGE-A3-positive non-small-cell lung cancer (NSCLC). Ann Oncol (ESMO Annual Meeting Abstracts).

2014;25(suppl 4):Abstract 11730.

COE168-3

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CONTINUING EDUCATION

Faculty Perspectives

JANUARY 2015 • VOLUME 6 • NUMBER 2

™

Latest Treatment Advances for Individualized Care of CRC PUBLISHING STAFF Group Director, Sales & Marketing John W. Hennessy john@greenhillhc.com Editorial Director Susan A. Berry susan@coexm.com Senior Copyeditor BJ Hansen Copyeditors Dana Delibovi Rosemary Hansen The Lynx Group President/CEO Brian Tyburski

OVERVIEW This 4-part Faculty Perspectives™ series will provide readers with summaries of pivotal emerging data from 2 recent international oncology meetings—the 50th Annual Meeting of the American Society of Clinical Oncology (ASCO) and the 39th European Society for Medical Oncology (ESMO) Congress—as well as expert perspectives on the application of the data to daily patient care. The first 3 issues in this series discussed recent advances in the management of breast cancer, melanoma, and non–small-cell lung cancer. This fourth issue focuses on the latest advances in the treatment of colorectal cancer (CRC).

Chief Operating Officer Pam Rattananont Ferris Vice President of Finance Andrea Kelly Human Resources Jennine Leale Associate Director, Content Strategy & Development John Welz Director, Quality Control Barbara Marino Quality Control Assistant Theresa Salerno Director, Production & Manufacturing Alaina Pede Director, Creative & Design Robyn Jacobs Creative & Design Assistant Lora LaRocca

FACULTY Leonard Saltz, MD Chief, Gastrointestinal Oncology Service Head, Colorectal Oncology Section Memorial Sloan Kettering Cancer Center New York, NY

Director, Digital Media Anthony Romano Jr Digital Media Specialist Charles Easton IV Web Content Manager Anthony Trevean Digital Programmer Michael Amundsen Meeting & Events Planner Linda Sangenito

Ellen M. Hollywood, MSN, RN, OCN Clinical Research Nurse Gastrointestinal Medical Oncology Service Memorial Sloan Kettering Cancer Center New York, NY

James T. Kenney, Jr, RPh, MBA Manager, Specialty and Pharmacy Contracts Harvard Pilgrim Health Care Wellesley, MA

Senior Project Managers Alyson Bruni Jini Gopalaswamy Project Manager Deanna Martinez Project Coordinator Mike Kodada IT Manager Kashif Javaid

This activity is jointly provided by Global Education Group and Center of Excellence Media, LLC.

Administrative Services Team Leader Rachael Baranoski Office Coordinator Robert Sorensen Center of Excellence Media, LLC 1249 South River Road - Ste 202B Cranbury, NJ 08512

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Supported by an educational grant from Boehringer Ingelheim.

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FACULTY PERSPECTIVES Target Audience This activity is directed toward medical and surgical oncologists, advanced practice oncology nurses, research nurses, and clinical oncology pharmacists involved in the personalized management of patients with solid tumors, and interested in the use of molecular biomarkers to help optimize patient care.

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

Educational Objectives After completing this activity, the participant should be better able to: • Assess emerging data from ASCO 2014 and ESMO 2014 on the discovery of molecular biomarkers and their impact on the management of patients with solid tumors • Discuss the advances from ASCO 2014 and ESMO 2014 on the personalized therapy for patients with solid tumors • Outline the practical aspects of integrating molecular biomarkers and emerging targeted agents into everyday clinical practice in the personalized treatment of cancer patients Faculty Leonard Saltz, MD Chief, Gastrointestinal Oncology Service Head, Colorectal Oncology Section Memorial Sloan Kettering Cancer Center New York, NY Ellen M. Hollywood, MSN, RN, OCN Clinical Research Nurse Gastrointestinal Medical Oncology Service Memorial Sloan Kettering Cancer Center New York, NY James T. Kenney, Jr, RPh, MBA Manager, Specialty and Pharmacy Contracts Harvard Pilgrim Health Care, Wellesley, MA Term of Offering Estimated time to complete activity: 1.0 hour Date of initial release: January 20, 2015 Valid for CME/CPE/CE credit through: January 20, 2016 Physician Accreditation Statement This activity has been planned and implemented in accordance with the Essential Areas and Policies of the Accreditation Council for Continuing Medical Education (ACCME) through the joint providership of Global Education Group (Global) and Center of Excellence Media, LLC. Global is accredited by the ACCME to provide continuing medical education for physicians.

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MAC OS X 10.6 or higher Flash Player v10.0 or higher Latest version of Firefox, Google Chrome, or Safari Adobe Acrobat Reader v7.0 or higher*

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Fee Information & Refund/Cancellation Policy There is no fee for this educational activity.

Disclosure of Conflicts of Interest Global Education Group (Global) requires instructors, planners, managers, and other individuals and their spouse/life partner who are in a position to control the content of this activity to disclose any real or apparent conflict of interest they may have as related to the content of this activity. All identified conflicts of interest are thoroughly vetted by Global for fair balance, scientific objectivity of studies mentioned in the materials or used as the basis for content, and appropriateness of patient care recommendations.

The faculty reported the following financial relationships or relationships to products or devices they or their spouse/life partner have with commercial interests related to the content of this CME/ CPE/CE activity: Name of Faculty or Presenter Leonard Saltz, MD

Reported Financial Relationship Consultant for Eli Lilly and Roche

Ellen M. Hollywood, MSN, RN, OCN

Nothing to disclose

James T. Kenney, Jr, RPh, MBA Nothing to disclose

The planners and managers reported the following financial relationships or relationships to products or devices they or their spouse/life partner have with commercial interests related to the content of this CME/CPE/CE activity: Name of Planner or Manager Susan Berry Andrea Funk Sy Schlager Amanda Glazar, PhD Ashley Marostica, RN, MSN

Reported Financial Relationship Nothing to disclose Nothing to disclose Nothing to disclose Nothing to disclose Nothing to disclose

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Updates from ASCO 2014 and ESMO 2014 INTRODUCTION The 50th Annual Meeting of the American Society of Clinical Oncology (ASCO) was held in Chicago, Illinois, May 30-June 3, 2014, and the 39th European Society for Medical Oncology (ESMO) Congress was held in Madrid, Spain, September 26-30, 2014. Both meetings brought together thousands of oncology professionals from a wide range of specialties. This supplement will address important topics in colorectal cancer (CRC) treatment presented at these meetings. Leonard Saltz, MD, and Ellen M. Hollywood, MSN, RN, OCN, of Memorial Sloan Kettering Cancer Center, and James T. Kenney, Jr, RPh, MBA, of Harvard Pilgrim Health Care, after reviewing the presented data, provide their key take-home messages for community oncology practices.

Addition of Oxaliplatin to 5-FU–Based Neoadjuvant and Adjuvant Regimens In 2004, results of the CAO/ARO/AIO-94 trial showed that use of preoperative chemoradiotherapy (CRT) versus postoperative CRT, along with total mesorectal excision (TME) surgery and adjuvant 5-fluorouracil (5-FU) chemotherapy, was associated with persistent, significant improvements in local control of advanced rectal cancer, although no effect on overall survival (OS) was reported.1 The subsequent randomized, phase 3 CAO/ARO/ AIO-04 trial sought to integrate more effective systemic treatment, and initial results of early secondary end points have already been published.2 At ASCO 2014, Rödel and colleagues presented results of the primary end point—disease-free survival (DFS) at 3 years.3 A total of 1265 patients with cT3/4 or cN+ rectal cancer were randomized into 1 of 2 treatment arms: (1) preoperative CRT 50.4 Gy plus infusional 5-FU, followed by TME surgery and 4 cycles of bolus 5-FU (arm 1; n = 637); or (2) preoperative CRT 50.4 Gy plus infusional 5-FU and oxaliplatin, followed by TME surgery and

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8 cycles of adjuvant oxaliplatin, leucovorin, and infusional 5-FU (arm 2; n = 628).3 After a median follow-up of 50 months, 198 patients in arm 1 experienced a DFS-related event versus 159 patients in arm 2 (hazard ratio [HR], 0.79; 95% confidence interval [CI], 0.64-0.98; P = .03). At 3 years, the DFS rate was 71.2% in arm 1 and 75.9% in arm 2. Grade 3/4 late overall treatment-related toxicity was reported in 23% of patients in arm 1 and 26% in arm 2 (P = .14).

Grade 3/4 sensory neuropathy was reported in 7% of patients in the oxaliplatin-containing arm during treatment, decreasing to 3% at 1 year of follow-up.3 Perspectives Interpretation of this trial is problematic for several reasons. First, the regimens of 5-FU in the 2 arms are so different that this alone could account for the modest differences reported; it also makes it impossible to interpret the potential contribution of oxaliplatin. Second, the standard biweekly infusional 5-FU/leucovorin of the postoperative 5-FU/leucovorin/oxaliplatin

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Table 1. Results from the Phase 3 AIO KRK 0207 Trial6 Median TFS, months

Median OS from start of maintenance, months

Median PFS1, months

Arm A Maintenance (fluoropyrimidines plus bevacizumab)

6.8

23.8

6.2

Arm B (bevacizumab alone)

6.5

26.2

4.6

Arm C Observation

6.1

23.1

3.6

OS indicates overall survival; PFS1, first progression; TFS, time to failure of strategy.

(FOLFOX) in the experimental arm has been shown to be superior to bolus 5-FU used in the postoperative control arm. Thus, in both preoperative and postoperative treatment, the superiority of the 5-FU regimen, in my opinion, obscures interpretation of the role of oxaliplatin. Furthermore, the addition of oxaliplatin to the preoperative CRT and the postoperative chemotherapy makes it difficult to determine the degree to which the addition of oxaliplatin to the preoperative CRT regimen is beneficial, and the use of a more toxic 5-FU control arm makes it difficult to determine how much additional toxicity can be attributed to oxaliplatin. Given the findings of the R-04 trial and the STARR studies, which have shown no benefit (but increased toxicity) for the addition of oxaliplatin to neoadjuvant CRT, and the limitation of this trial, I do not feel it would be appropriate to incorporate oxaliplatin into preoperative combined therapy for rectal cancer.

-Leonard Saltz, MD It is difficult to draw a conclusion that the addition of oxaliplatin is beneficial because of the different regimens of 5-FU. It is important to remember that less can be more. Oxaliplatin is associated with adverse events including transient peripheral neuropathy and/or laryngopharyngeal dysesthesias, cumulative neuropathy, fatigue, and hypersensitivity reactions. All of these can impact patient quality of life (QOL).

-Ellen M. Hollywood, MSN, RN, OCN This study shows a modest efficacy benefit that must be balanced with the potential for increased toxicity. These results would not prompt a plan to aggressively manage patients with either regimen.

-James T. Kenney, Jr, RPh, MBA

Preoperative Fluoropyrimidine-Based Chemotherapy plus Oxaliplatin Interim results of the PETACC-6 (Pan-European Trials in Adjuvant Colon Cancer 6) were presented at ASCO 2014 by Schmoll and colleagues.4 This trial investigated whether the addition of oxaliplatin to a preoperative regimen that included oral fluoropyrimidine-based CRT followed by postoperative adjuvant fluoropyrimidine-based chemotherapy would improve DFS in patients with locally advanced rectal cancer.

Between November 2008 and September 2011, a total of 1094 patients with rectal adenocarcinomas (within 12 cm from the anal verge; T3/4 and/or node positive, with no metastatic disease who were either considered, or were expected to become, resectable) were randomized to 1 of 2 treatment arms.4 Each arm received 5 weeks of preoperative CRT with capecitabine, followed by 6 cycles of adjuvant chemotherapy with capecitabine. Arm 2 (n = 547) also received oxaliplatin before and after surgery, whereas arm 1 (n = 547) did not.4 After a median follow-up of 31 months, 124 and 121 DFS events were reported in arm 1 and arm 2, respectively. The 3-year DFS rate was 74.5% in arm 1 versus 73.9% in arm 2. Because 440 DFS events were required for the trial to have 80% power, careful follow-up has been recommended until these DFS events have been met.4 Perspectives Results from this trial are easier to interpret, as there is really only 1 variable: the addition of oxaliplatin to pre- and postoperative capecitabine

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chemotherapy. Although further follow-up will be necessary before results are definitive, currently, this study supports the majority of the literature, which finds increased toxicity, decreased compliance, and no benefit when oxaliplatin is added to preoperative CRT. -Leonard Saltz, MD The oxaliplatin did not prove at this time to add benefit preoperatively. In addition, the toxicities caused by oxaliplatin can decrease compliance.

Sensory neuropathy associated with this agent is cumulative over time and there are no proven treatments to alleviate this complication. It is very important for nurses to have a good understanding of the toxicities related to treatment and to recognize early signs and symptoms so that appropriate interventions can be initiated.

-Ellen M. Hollywood, MSN, RN, OCN The data from this trial are not sufficient to impact the formulary discussion on these treatment options. Hopefully, results after the 440 DFS events are met will yield some actionable results.

-James T. Kenney, Jr, RPh, MBA

Adjuvant FOLFOX versus FL Updated results of the randomized, phase 2 ADORE trial were reported by Sang Hong and colleagues at ASCO 2014.5 This trial investigated the use of FOLFOX or 5-FU/leucovorin alone (FL) in patients with curatively resected rectal cancer following preoperative fluoropyrimidine-based CRT. A total of 321 patients were randomized between November 2008 and June 2012 to adjuvant chemotherapy with either the FL regimen for 4 cycles (n = 161) or the FOLFOX regimen for 8 cycles (n = 160). The primary end point was 3-year DFS. After a median follow-up of 38.2 months, the 3-year DFS rate was 71.6% in the FOLFOX arm versus 62.9% in the FL arm (HR, 0.657; 95% CI, 0.434-0.994; P = .047). Grade 3/4 adverse events did not differ significantly between the 2 treatment arms.5 Perspectives This trial also has 2 variables to contend with, making interpretation difficult. In addition to the fact that some patients received oxaliplatin while others did not, the 5-FU regimens were markedly different. The 5-FUâ&#x20AC;&#x201C;only arm used a bolus daily x 5 regimen similar to the Mayo Clinic schedule, but with doses lower than those typically recommended. As such, I do not feel that much can be determined from this trial.

-Leonard Saltz, MD A relative risk reduction of 34% in the FOLFOX arm is positive for this regimen. The comparable adverse events avoid any concerns that increased efficacy may be offset by additional toxicity. However, more data are needed to effectively use the results of this study to impact treatment protocols.

-James T. Kenney, Jr, RPh, MBA

Maintenance with Fluoropyrimidines plus Bevacizumab versus Bevacizumab Alone versus No Treatment The phase 3 AIO KRK 0207 trial was conducted in patients with metastatic colorectal cancer (mCRC) to evaluate a maintenance strategy of fluoropyrimidines plus bevacizumab, bevacizumab alone, or no treatment, following a standard 24-week induction regimen of fluoropyrimidines, oxaliplatin, and bevacizumab. Arnold and colleagues presented results from this trial at ASCO 2014.6 The objective of the trial was to determine whether no treatment or treatment with bevacizumab alone was noninferior to treatment with fluoropyrimidines plus bevacizumab. The primary end point was time to failure of strategy (TFS). Secondary end points included time to first progression (PFS1) and OS.6 Patients repeated the initial treatment if disease progression occurred.

A total of 473 patients were randomized to 1 of 3 treatment regimens: (1) arm A: standard maintenance treatment with fluoropyrimidines plus bevacizumab; (2) arm B: bevacizumab alone; and (3) arm C: no treatment. After a median follow-up of 27 months, median PFS1 was 6.2 months in arm A,

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FACULTY PERSPECTIVES 4.6 months in arm B, and 3.6 months in arm C (P < .0001 for arm A vs arm C).6 TFS favored arm A over arm C (HR, 1.31; 95% CI, 1.01-1.69; P = .038), but no significant difference was reported between arm A and arm B (HR, 1.04; 95% CI, 0.81-1.36; P = .74; Table 1). After first progression, 24% of patients in arm A repeated their initial treatment, compared with 47% in arms B and C. The preliminary OS was 23.4 months from randomization, with no significant difference among treatment arms (P = .69).6

Table 2. Results from the Phase 3 CAIRO 3 Trial7 Maintenance (capecitabine plus bevacizumab) Observation

Median PFS2, months

Median OS, months

11.7 P < .0001

21.6

8.5

18.1

OS indicates overall survival; PFS2, second progression.

Perspectives This trial uses a statistical design that I do not find appropriate, with noninferiority design employed when a superiority design would appear to be called for. The authors conclude that the use of bevacizumab maintenance is not noninferior to not using anything (no treatment). This triple-negative interpretation is based on a difference of 12 days between arms. I do not see anything in this trial that supports the use of maintenance bevacizumab.

-Leonard Saltz, MD A median PFS1 difference of less than 3 months in arm A versus arm C is not a particularly compelling result in this study. The formulary committee would want to consult with the oncologists with regard to the clinical relevance of this difference. OS is the primary measure that the committee prefers to focus on and with no significant difference in this end point between the treatment arms, an inconclusive formulary decision would be likely.

-James T. Kenney, Jr, RPh, MBA

Maintenance with Capecitabine plus Bevacizumab versus Observation Results of the randomized, phase 3 CAIRO 3 trial were presented by Koopman and colleagues at ASCO 2014.7 This trial investigated the efficacy of maintenance treatment with capecitabine plus bevacizumab versus observation in patients with mCRC who did not progress during induction therapy with capecitabine, oxaliplatin, and bevacizumab (CAPOX-B). A total of 558 patients were randomized to either observation (arm A) or maintenance treatment with capecitabine plus bevacizumab (arm B).7 Patients in both arms were to be treated with CAPOX-B upon PFS1 and until second progression (PFS2; the primary end point). Secondary end points included OS, time to second progression (TTP2), and QOL. Results showed that CAPOX-B was reintroduced in 61% of patients in arm A and 47% in arm B. A significant benefit for maintenance treatment was reported for PFS1, TTP2, and PFS2, with a median of 11.7 months versus 8.5 months for observation (HR, 0.67; P < .0001; Table 2). Results of a multivariable analysis conducted in 180 patients with synchronous metastases who had a resected primary tumor showed a significant interaction for treatment with OS (median OS, 18 months in arm A vs 25 months in arm B). QOL remained the same during maintenance treatment and was clinically noninferior compared with QOL in the observation arm.7 Perspectives This trial does show an improvement in PFS with continued versus interrupted therapy. This is expected. What is interesting to note, however, is the fact that the data do not show a detriment in OS for patients who were given a chemotherapy-free holiday. The reported difference is not statistically significant, with a P value of 0.22. This was measured from the time of randomization, which is after 4 months on study. When the difference in OS is evaluated from the start of therapy (a more traditional approach), there is even less significance to the OS difference between arms. Furthermore, comparisons of patients with and without the primary tumor resected are of little value, because the decision to resect or not resect was not randomized, and many nonrandomized clinical factors may have contributed to any apparent perception of differences.

-Leonard Saltz, MD Treatment interruptions appear to be safe and desirable. With this knowledge, nurses can counsel their patients and provide emotional support during the decision-making process.

-Ellen M. Hollywood, MSN, RN, OCN

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In this trial, maintenance therapy produced a compelling improvement in OS of 7 months compared with observation. QOL was not sacrificed for an efficacy benefit in patients and would lead to a favorable formulary decision.

-James T. Kenney, Jr, RPh, MBA

Is There Value to Maintenance Therapy? The Price of Stability In a virtual meeting at ASCO 2014, Leonard Saltz, MD, discussed the impact of incorporating a treatment-free interval into a therapeutic strategy for patients with mCRC, focusing specifically on the CAIRO 3 and AIO KRK 0207 studies, both of which examined treatment-free periods.

According to Dr Saltz, results from CAIRO 3 do not show a clear disadvantage associated with taking a treatment break. Responding patients are likely to benefit from continued treatment, at least until maximal response is achieved. Although treatment breaks for all patients at 4 months may mean too many breaks too early, treatment break strategies should not be abandoned, but rather individualized. Furthermore, although QOL remained the same during maintenance therapy in this trial, Dr Saltz noted that more specific, sensitive tools are needed to measure QOL. Findings from AIO KRK 0207 demonstrated that combination therapy with fluoropyrimidines plus bevacizumab was a better treatment strategy than bevacizumab alone in terms of TFS. Within the context of no difference in OS, and a median difference in TFS of 12 days and in PFS of 36 days, however, Dr Saltz believed that may be an overstatement of the data.

Using a benefit-to-cost ratio (with cost being defined as the price and toxicity of treatment, as well as the patient’s time), Dr Saltz calculated the price of stability on the basis of treatment with bevacizumab alone in this study.

Based on an observation period of approximately 3.6 months, or 15.5 weeks, during which time about 3100 mg of bevacizumab would have been used, he established a cost savings per patient of approximately $19,189 (according to average sales price of the drug). According to Dr Saltz, of approximately 40,000 patients with mCRC in the United States, approximately 28,000 are likely taking bevacizumab; of these, about 15,400 are likely eligible for a treatment break, translating into a drug savings of $308,000,000 per year.8 “The good news is our patients are doing better and living longer with metastatic disease; the bad news is that it is a long time to be on chemotherapy,” he said.

“In the AIO KRK 0207 study, fully one-third of patients, even on a simplified maintenance schedule, chose to come off therapy for reasons other than progression. Many patients declined to restart.” Clearly, a substantial number of patients see value in treatment breaks, and with a median TFS of 12 days between bevacizumab and observation, Dr Saltz does not believe the results from the AIO KRK 0207 study support the use of bevacizumab as single-agent maintenance therapy.8 “CAIRO 3 and AIO KRK 0207 explored the value of a treatment break versus capecitabine and bevacizumab or 5-FU/leucovorin/bevacizumab maintenance in oxaliplatin/bevacizumab-based chemotherapy. Compared with a treatment break, maintenance does delay progression and prolongs time to failure of treatment. However, no significant difference in OS was seen. In the absence of compelling negative data, treatment interruptions appear to be safe and desirable.” Emphasizing that like all cancer care, use and timing must be individualized, Dr Saltz concluded, “Personalized medicine will require understanding not only the individual molecular characteristics of the tumor, but also the personal characteristics, goals, and preferences of the patient. Appropriately timed chemotherapy-free intervals remain a viable and important treatment strategy to be further explored and understood.”8

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Table 3. Response to Cetuximab plus FOLFOX4 According to RAS Mutation Status10 RAS wild-type (all loci)

New RAS mutation

RAS mutation (any locus)

FOLFOX4 + cetuximab (n = 38)

FOLFOX4 (n = 49)

FOLFOX4 + cetuximab (n = 15)

FOLFOX4 (n = 16)

FOLFOX4 + cetuximab (n = 92)

FOLFOX4 (n = 75)

Response rate, %

57.9

28.6

53.3

43.8

37.0

50.7

Median PFS, months

12.0

5.8

7.5

7.4

5.6

7.8

Median OS, months

19.8

17.8

18.4

17.8

13.5

17.8

OS indicates overall survival; PFS, progression-free survival.

Table 4. Response to Cetuximab plus FOLFIRI According to RAS Mutation Status12 RAS wild-type (all loci)

New RAS mutation

RAS mutation (any locus)

FOLFIRI + cetuximab (n = 178)

FOLFIRI (n = 189)

FOLFIRI + cetuximab (n = 32)

FOLFIRI (n = 31)

FOLFIRI + cetuximab (n = 246)

FOLFIRI (n = 214)

Response rate, %

66.3

38.6

34.4

35.5

31.7

36.0

Median PFS, months

11.4

8.4

7.2

6.9

7.4

7.5

Median OS, months

28.4

20.2

18.2

20.7

16.4

17.7

OS indicates overall survival; PFS, progression-free survival.

Addition of Cetuximab to FOLFOX4 in Patients with RAS Wild-Type Tumors The randomized, phase 2 OPUS (Oxaliplatin and Cetuximab in First-Line Treatment of Metastatic Colorectal Cancer) trial previously established the efficacy of cetuximab plus FOLFOX4 as first-line treatment for patients with KRAS wild-type mCRC and confirmed KRAS mutation status as an effective predictive biomarker.9 Bokemeyer and colleagues presented recent study results at ASCO 2014, in which the investigators screened OPUS study patients for 26 tumor mutations (new RAS) in 4 additional KRAS codons (exons 3 and 4) and 6 NRAS codons (exons 2, 3, and 4) with the use of BEAMing technology.10 The outcome was assessed according to RAS mutation status (KRAS exon 2 + new RAS). The authors found new RAS mutations in 31 of 118 evaluable patients (26%) with KRAS exon 2 wild-type tumors. Results showed that the addition of cetuximab to the FOLFOX4 regimen in patients with RAS wild-type tumors was associated with a significantly improved response (Table 3). Those with new RAS tumor mutations could not be definitively assessed, and in patients with any tumor RAS mutation (KRAS exon 2 + new RAS), no benefit from the addition of cetuximab to FOLFOX4 was observed.10 Perspectives When you reduce the number of patients in this trial to those with RAS wild-type tumors, the numbers are quite small indeed. The data support what has been demonstrated convincingly in larger trials such as PRIME and CRYSTAL, which is that all-RAS genotyping is necessary for proper use of anti-EGFR agents, and the presence of any KRAS or NRAS mutation in any exon (not just exon 2 KRAS) should be regarded as an absolute contraindication to the use of anti-EGFR agents.

-Leonard Saltz, MD These results demonstrate the importance of proper use of anti-EGFR therapies in the appropriate population. For patients with any KRAS or NRAS mutations, the addition of anti-EGFR therapy will provide no benefit and will expose them to adverse events, such as an acne-like rash, fatigue, and low magnesium levels, as well as place them at risk for anaphylactic reactions.

The acne-like rash can be severe, and because it is so visible, it can be very disturbing to patients and impact their interactions with others. Management of this rash includes moisturizing the area, limiting sun exposure with sunscreen, and the use of doxycycline 100 mg twice daily at the start of therapy.

-Ellen M. Hollywood, MSN, RN, OCN The ability to more accurately target patients for a specific drug based on genetic mutations is a very encouraging area of cancer therapy. The benefits include limiting waste due to nonresponse, avoiding adverse

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events related to ineffective treatment options, and achieving more predictable outcomes when establishing treatment protocols for patients.

-James T. Kenney, Jr, RPh, MBA

FOLFIRI with and without Cetuximab in Patients with RAS Wild-Type Tumors The CRYSTAL (Cetuximab Combined With Irinotecan in First-Line Therapy for Metastatic Colorectal Cancer) study previously showed that patients with KRAS codon 12/13 (exon 2) wild-type mCRC experienced improvement in PFS and OS when treated with cetuximab in addition to 5-FU/ leucovorin/irinotecan (FOLFIRI) as first-line therapy.11 Patients with KRAS exon 2 tumor mutations, however, did not experience a treatment benefit.

At ASCO 2014, Ciardiello and colleagues presented results from their study in which they screened patients from CRYSTAL for 26 mutations (new RAS) in 4 additional KRAS codons (exons 3 and 4) and 6 NRAS codons (exons 2, 3, and 4) with the use of BEAMing technology.12 The outcome was assessed according to RAS mutation status (KRAS exon 2 + new RAS). The investigators evaluated mutation status in 430 of 666 patients (65%) with KRAS exon 2 wild-type tumors and detected new RAS mutations in 15% (63 of 430) of the patients. In patients with RAS wild-type tumors, a significant benefit across all end points was associated with the addition of cetuximab to FOLFIRI (Table 4).12 In those with new RAS tumor mutations, on the other hand, no difference in efficacy outcomes was observed between the treatment groups. Patients with any tumor RAS mutation (KRAS exon 2 + new RAS) did not experience any benefit from the addition of cetuximab to FOLFIRI.12 Perspectives This larger phase 3 trial confirms that all-RAS wild-type patients are the only ones who should be considered for anti-EGFR therapy at any point in their treatment plan.

-Leonard Saltz, MD Data from this trial reinforce the fact that only RAS wild-type patients are to receive anti-EGFR therapies. Nurses should educate patients and their families on this research and its implications to their treatment plan.

-Ellen M. Hollywood, MSN, RN, OCN This study demonstrates one of the challenges faced by health plans in terms of covering select genetic tests when an outcome may not be improved with further testing. In this case, additional testing did not identify an opportunity for improved outcomes with combination treatment. However, it suggests that patients with new RAS mutations will not benefit from the

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FACULTY PERSPECTIVES

FOLFIRI or FOLFOX6 plus Bevacizumab or Cetuximab in Patients with KRAS Wild-Type Untreated mCRC At ASCO 2014, Venook and colleagues presented results of the phase 3 CALGB/SWOG (Cancer and Leukemia Group B/Southwest Oncology Group) 80405 trial, which examined FOLFIRI or FOLFOX6 plus bevacizumab or cetuximab as first-line treatment for patients with KRAS wild-type untreated mCRC.13 A total of 2334 patients with KRAS wild-type (codons 12 and 13) mCRC and a performance status (PS) of 0 to 1 received either FOLFIRI or FOLFOX6 (regimen of their choice; 26.6% selected FOLFIRI and 73.4% selected FOLFOX6), and were then randomized to either cetuximab or bevacizumab.13 Treatment continued until disease progression, death, unacceptable toxicity, or curative surgery occurred. Treatment breaks of 4 weeks were permitted. Study end points included OS and PFS, with OS analysis planned at 849 events. OS and PFS results after a median follow-up of 40 months are shown in the Figure.13 A total of 94 patients were free of disease following surgery.13 Additional analyses are under way (expanded RAS, FOLFOX vs FOLFIRI, subsequent therapies, long-term survivors, and correlates). The investigators concluded that although either regimen is appropriate as first-line treatment, patient preference for FOLFOX limited chemotherapy comparison.13 Perspectives This is the definitive trial addressing the question of using either bevacizumab or an anti-EGFR agent (in this case, cetuximab, although results can likely be extrapolated to panitumumab). The study was performed in patients with KRAS wild-type tumors, but a preliminary analysis of the all-RAS wild-type population supports the same conclusions. The authors concluded that the use of first-line cetuximab or bevacizumab is equally acceptable. However, I respectfully disagree. The dermatologic toxicity associated with cetuximab is a major deterrent to the use of this agent as front-line treatment. Maneuvers to mitigate this toxicity are marginally effective, and only those patients who develop a substantial skin rash derive benefit from cetuximab. In addition, the cost of cetuximab is approximately twice the cost of bevacizumab, an unwarranted surplus expense when there are no advantages in terms of tolerability or efficacy.

-Leonard Saltz, MD I have worked with patients who have received cetuximab as well as those who have received bevacizumab. The skin toxicity associated with cetuximab use can be severe; it often causes discomfort and may lead to lifestyle disturbances. The management tools we have for this condition are limited. Patients who are treated with bevacizumab may develop hypertension; however, this can be treated with medication. Overall, bevacizumab seems to be well tolerated. I feel that the skin toxicity related to cetuximab makes it an unacceptable option in the first-line setting.

-Ellen M. Hollywood, MSN, RN, OCN

FOLFIRI or mFOLFOX6 plus Cetuximab or Bevacizumab in Patients with Untreated mCRC: Expanded RAS Analysis An expanded analysis of the CALGB/SWOG 80405 study was presented at ESMO 2014 by Lenz and colleagues.14 Patients with RAS wild-type (codons 12 and 13) mCRC and a PS of 0 to 1 were treated with FOLFIRI or mFOLFOX6 at enrollment (patient or physician choice), then randomized to either cetuximab or bevacizumab. The original study was designed to randomize patients to cetuximab, bevacizumab, or both; the expanded analysis was amended to include only patients with KRAS wild-type tumors (codons 12 and 13). Expanded RAS was tested in all wild-type RAS exon 2 tumors with the use of BEAMing technology, including KRAS exons 3 and 4, and NRAS exons 2, 3, and 4. The primary end point was OS.14 Among a total of 3058 patients enrolled between November 2005 and March 2012, 2334 patients with KRAS wild-type tumors were randomized.

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Figure. OS and PFS for chemotherapy plus bevacizumab or cetuximab in patients with KRAS wild-type untreated metastatic colorectal cancer.13 45 40 35 Patients (%)

addition of cetuximab. This provides an opportunity to avoid additional costs and adverse events with a less intensive treatment regimen of FOLFIRI. -James T. Kenney, Jr, RPh, MBA

10.84

10.45

30 PFS (months) OS (months)

25 20 15

29.04

29.93

FOLFIRI or FOLFOX6 + bevacizumab (n=559)

FOLFIRI or FOLFOX6 + cetuximab (n=578)

10 5 0

OS indicates overall survival; PFS, progression-free survival.

The final analysis ultimately included 1137 patients, 559 of whom received bevacizumab plus chemotherapy and 578 of whom received cetuximab plus chemotherapy. Overall, 73.4% of patients were treated with the mFOLFOX6 regimen and 26.6% with the FOLFIRI regimen.14 Results showed that in the expanded RAS wild-type population, median OS exceeded 30 months; however, no significant difference was reported between the treatment groups (32.0 months for patients who received cetuximab plus chemotherapy vs 31.2 months for those who received bevacizumab plus chemotherapy). Median PFS also did not differ between the treatment groups. A higher response was observed, however, among patients in the cetuximab arm versus the bevacizumab arm in the expanded RAS population (68.6% vs 53.6%, respectively; P < .01).14 Perspectives As discussed earlier, expanded RAS testing has not demonstrated a survival benefit for one agent over another. Therefore, I feel that the use of first-line cetuximab would still be inappropriate. In the very unusual circumstance in which tumor shrinkage per se, in the absence of a survival benefit, is felt to justify the increased skin toxicity and cost increase, cetuximab could be used.

-Leonard Saltz, MD The lack of a significant difference in OS and PFS does not provide actionable data for the formulary committee. Whether or not a higher response in the cetuximab group has any value is unknown. Health plans could make the case that providers use the less expensive option in an effort to control costs in the treatment of mCRC. -James T. Kenney, Jr, RPh, MBA

CALGB/SWOG 80405: Patients with mCRC Undergoing Surgery Following Chemotherapy At ESMO 2014, Venook and colleagues reported on the results of a subset analysis of CALGB/SWOG 80405, the goal of which was to determine the characteristics and long-term outcomes of patients with mCRC who elected to undergo surgery following chemotherapy.15 Eligible patients with KRAS wild-type (codons 12 and 13) mCRC and a PS of 0 to 1 received FOLFIRI or mFOLFOX6 (physician or patient choice at study enrollment) and were then randomized to either cetuximab or bevacizumab. Treatment goals (palliative or neoadjuvant therapy as a component of a curative treatment plan) were determined by the physician.

Therapy continued until progression, death, unacceptable toxicity, or surgery with curative intent. Treatment holidays of 4 weeks were permitted. Patients who elected to have surgery were usually removed from the study. The primary end point was OS.15 A total of 3058 patients were enrolled between November 2005 and

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CONTINUING EDUCATION

Table 5. Association Between MMR Status and Treatment Outcomes17 TTR: 5-year recurrence-free rate, %

5-year OS, %

dMMR

pMMR

dMMR

pMMR

Surgery alone (n = 307)

89

74

90

78

5-FU monotherapy (n = 1155)

88

83

88

87

Surgery alone (n = 264)

60

47

59

54

5-FU monotherapy (n = 2723)

72

64

77

71

Stage II

Stage III

dMMR indicates deficient mismatch repair; 5-FU, 5-fluorouracil; MMR, mismatch repair; OS, overall survival; pMMR, MMR-proficient; TTR, time to recurrence.

March 2012, of whom 2334 patients with KRAS wild-type tumors were randomized. The final analysis included 1137 patients. Median follow-up was 32 months. After receiving chemotherapy, 179 patients (15.7%) underwent surgery: 24.6% had an intact primary tumor, 36.9% had curative intent, 80% had received FOLFOX, and 58% had received cetuximab.15 According to the results, 130 of the 179 patients had no evidence of disease (NED) immediately following surgery. The median time from study entry to surgery was 6.8 months, and the median OS from randomization was 60 months. DFS among NED patients was 16.1 months from the time of surgical resection and 26.0 months from the time of randomization. A total of 96 patients are still alive after surgery, 50 of whom remain NED, after a median of 37 months’ postsurgical follow-up.15 Perspectives It is difficult to draw many conclusions from this analysis. It confirms that some patients who undergo R0 resections of metastatic disease are either cured or have long-term DFS. The numbers are too small to say anything definitive about a preference for one agent over another in this setting.

Until pretreatment scans are independently reviewed, we cannot say whether these patients were truly converted from unresectable to resectable or whether they had disease that was potentially resectable prior to starting therapy.

-Leonard Saltz, MD These results demonstrate that some patients with mCRC have potentially resectable disease and can be cured, which has always been true.

However, it is unclear whether the use of different monoclonal antibodies had an impact in this setting.

-Ellen M. Hollywood, MSN, RN, OCN This study offers evidence of the potential benefit of surgery following chemotherapy as a valid treatment approach. A protocol that requires chemotherapy prior to surgery could be applied by health plans to take advantage of this potential strategy.

-James T. Kenney, Jr, RPh, MBA

Extended RAS Analysis from the FIRE-3 Trial The FIRE-3 trial compared first-line therapy with FOLFIRI plus either cetuximab or bevacizumab in patients with mCRC having 592 KRAS exon 2 wild-type tumors. Analysis from FIRE-3 was extended to KRAS and NRAS exons 2, 3, and 4 (codons 12, 13, 59, 61, 117, and 146) using pyrosequencing. Radiologic data were evaluated independently to determine tumor response, and to define early tumor shrinkage (ETS) and depth of response (DOR). Results of the study were presented at ESMO 2014 by Stintzing and colleagues.16 ETS was defined as a reduction in tumor diameter of >20% at the first tumor assessment after baseline (at week 6); DOR was defined as the maximal tumor shrinkage observed in a particular patient. Results were calculated for both the intent-to-treat (ITT) and the extended RAS wild-type populations.16

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Study results showed that within the ITT population, 475 patients (80.2%) were successfully tested for all RAS locations, 459 of whom were evaluable according to Response Evaluation Criteria in Solid Tumors criteria. The FOLFIRI-plus-cetuximab arm was also associated with postprogression survival (Bravais Pearson test; P < .0001).16 Objective response rate significantly favored the FOLFIRI-plus-cetuximab arm over the FOLFIRI-plus-bevacizumab arm (71.4% vs 56.4%, respectively; P = .015). The proportion of patients who achieved ETS was significantly greater in the FOLFIRI-plus-cetuximab–treated population versus the FOLFIRI-plus-bevacizumab–treated population (67.5% vs 47.9%, respectively; P = .0013). DOR was significantly greater in the FOLFIRI-plus-cetuximab group than in the FOLFIRI-plus-bevacizumab group (48.2 months vs 33.0 months, respectively; P = .0005). PFS was 10.3 months with FOLFIRI plus cetuximab and 10.2 months with FOLFIRI plus cetuximab; OS was 33.1 months in the FOLFIRI-plus-cetuximab arm vs 25.0 months in the FOLFIRIplus-bevacizumab arm.16 Perspective I think that one needs to be careful not to overinterpret the survival differences reported in this trial. First, the prespecified primary end point was objective response rate in the ITT population, and the trial was negative in terms of a statistically significant difference in this respect. As such, this is a negative trial, and any other comparisons should be regarded as hypothesis-generating at best. Second, we need to look at the survival curves. The first-line PFS was 10 months in each arm (chemotherapy was stopped after only 5 months in each arm) and yet the curves do not separate until 24 months. More information is necessary regarding what did or did not occur in the intervening months. Furthermore, the use of second-line anti-EGFR agents was only 28% in the ITT analysis of patients who received first-line cetuximab. It is concerning that 72% of RAS wild-type patients never received an anti-EGFR agent as second- or third-line therapy. We know from the Canadian C-017 trial that the use of third-line single-agent cetuximab in KRAS wild-type patients resulted in a 4.5-month OS benefit over placebo, and we could expect an even larger benefit in an all-RAS wild-type population. As such, it is quite likely that if patients had received an anti-EGFR agent second or third line, the survival differences in this study would not be significant, and results would be more in line with the substantially larger 80405 trial.

-Leonard Saltz, MD

Deficient Mismatch Repair in Patients with Stage II or III Disease Mismatch repair (MMR) status is known to be an important prognostic factor in patients with CRC. Using the Adjuvant Colon Cancer End Points database, Sargent and colleagues determined the association of deficient MMR (dMMR) status with clinical/pathologic features and prognosis in 7803 patients with stage II or III CRC, and presented their results at ASCO 2014.17 They examined microsatellite instability (MSI) from 14 studies and immunohistochemical analysis from 1 study for MLH1/MSH2/MLH6 proteins.17 Of the 7803 patients enrolled, 571 underwent surgery alone, 3878 received 5-FU monotherapy, 2299 were treated with 5-FU plus oxaliplatin, and 1055 received 5-FU plus irinotecan. Tumors with MSI-high or an absent protein were classified as dMMR; the remaining tumors were considered MMR-proficient (pMMR). End points of the study included OS and time to recurrence (TTR).17 After a median follow-up of 7 years, 524 of 2270 patients (23.1%) with stage II CRC and 823 of 5533 patients (14.9%) with stage III CRC exhibited dMMR. Compared with pMMR, dMMR was strongly associated with improved OS (HR, 0.27; P = .01) and TTR (HR, 0.27; P = .01) in patients with stage II disease who were treated with surgery alone (Table 5).17 MMR association was prognostic, but of attenuated impact in 5-FU–treated patients with stage II or III CRC. Significance was confined to patients with stage III disease treated with 5-FU monotherapy (HR, 0.80; P = .02 for TTR; HR, 0.79; P = .02 for OS).17 The investigators confirmed the prognostic utility of MMR status in patients with stage II CRC. Although they believe that MMR impacts outcomes in patients with stage III disease as well, MMR status currently does not alter the authors’ management of individuals with CRC.17

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FACULTY PERSPECTIVES Perspectives These findings reinforce the current practice of not treating stage II disease with adjuvant therapy, and treating stage III patients, albeit with somewhat less enthusiasm.

-Leonard Saltz, MD

This study demonstrates the value of adjuvant FOLFOX over 5-FU in terms of RFS. However, the addition of oxaliplatin to 5-FU also provides benefits. The health plan would rely on the oncology providers to determine the best option for patients when comparing these regimens based on efficacy and tolerability, as well as the option to avoid the leucovorin in the FOLFOX regimen.

-James T. Kenney, Jr, RPh, MBA

These data provide further justification for not treating stage II disease with adjuvant therapy and indicate that MMR does not influence treatment for stage III disease at this time. MMR is a prognostic indicator in CRC, and nurses should be prepared to explain this mechanism to their patients.

-Ellen M. Hollywood, MSN, RN, OCN

REFERENCES

Diagnostic screening that more effectively matches patients to a specific regimen is preferred by health plan managers when deciding on therapeutic and surgical options. MMR status could be added to the development of treatment pathways in CRC. -James T. Kenney, Jr, RPh, MBA

Adjuvant Chemotherapy with 5-FU or FOLFOX in Patients with MSI CRC MSI is detected in 12% of all CRCs and is associated with a low recurrence rate following curative surgery.18 Although adjuvant chemotherapy with 5-FU has appeared to be ineffective, small studies have recently suggested that adjuvant chemotherapy with FOLFOX may be effective.19 At ASCO 2014, Tougeron and colleagues reported the results of their multicenter, retrospective study designed to determine the efficacy of adjuvant chemotherapy with 5-FU or FOLFOX on relapse-free survival (RFS) in 433 patients with stage II or III MSI CRC.18 All participants underwent curative surgery between 2000 and 2012. Of the 433 patients analyzed, 57% had stage II disease and 43% had stage III disease. Overall, 263 patients (61%) received surgery alone, 119 (27%) were treated with adjuvant FOLFOX, and 51 (12%) received adjuvant 5-FU. Most of the patients (70%) who received adjuvant chemotherapy had stage III disease. After a median follow-up of 35 months, recurrence rates were 6% in those with stage II MSI CRC and 21% in patients with stage III MSI CRC. According to the investigators, adjuvant chemotherapy was associated with better RFS in univariate analysis in FOLFOX-treated patients (HR, 0.46; 95% CI, 0.23-0.79) but not in 5-FU–treated patients (HR, 1.02; 95% CI, 0.60-1.73). The 3-year RFS rates were 75% with surgery alone, 66% with 5-FU, and 84% with FOLFOX (P = .02).18 A multivariate analysis in which other prognostic factors were considered showed that adjuvant chemotherapy with oxaliplatin remains significantly associated with better RFS (HR, 0.29; 95% CI, 0.13-0.65; P = .003), leading the investigators to conclude that the addition of oxaliplatin to 5-FU can restore the chemosensitivity of MSI CRCs.18 Perspectives This trial further supports the use of standard fluoropyrimidine/oxaliplatin adjuvant therapy in patients with stage III dMMR tumors. It does not give enough direct information to inform the decisions regarding stage II due to small numbers and excellent outcomes; however, as noted above, use of adjuvant therapy in stage II dMMR tumors is not routinely indicated.

-Leonard Saltz, MD

1. Sauer R, Liersch T, Merkel S, et al. Preoperative versus postoperative chemoradiotherapy for locally advanced rectal cancer: results of the German CAO/ARO/AIO-94 randomized phase III trial after a median follow-up of 11 years. J Clin Oncol. 2012;30:1926-1933.

2. Rödel C, Liersch T, Becker H, et al; for German Rectal Cancer Study Group. Preoperative chemoradiotherapy and postoperative chemotherapy with fluorouracil and oxaliplatin versus fluorouracil alone in locally advanced rectal cancer: initial results of the German CAO/ARO/AIO-04 randomised phase 3 trial.

Lancet Oncol. 2012;13:679-687.

3. Rödel C, Liersch T, Fietkau R, et al. Preoperative chemoradiotherapy and postoperative chemotherapy with 5-fluorouracil and oxaliplatin versus 5-fluorouracil alone in locally advanced rectal cancer: results of the German CAO/ARO/AIO-04 randomized phase III trial. J Clin Oncol (ASCO Annual Meeting Abstracts). 2014;32(suppl):Abstract 3500.

4. Schmoll H-J, Haustermans K, Price TJ, et al. Preoperative chemoradiotherapy and postoperative chemotherapy with capecitabine and oxaliplatin versus capecitabine alone in locally advanced rectal cancer: disease-free survival results at interim analysis. J Clin Oncol (ASCO Annual Meeting Abstracts). 2014;32(suppl):Abstract 3501.

5. Sang Hong Y, Nam B-H, Kim K-P, et al. Adjuvant chemotherapy with oxaliplatin/5-fluorouracil/leucovorin (FOLFOX) versus 5-fluorouracil/leucovorin (FL) for rectal cancer patients whose postoperative yp stage 2 or 3 after preoperative chemoradiotherapy: updated results of 3-year disease-free survival from a randomized phase II study (The ADORE). J Clin Oncol (ASCO Annual Meeting Abstracts). 2014;32(suppl):Abstract 3502.

6. Arnold D, Graeven U, Lerchenmuller CA, et al. Maintenance strategy with fluoropyrimidines (FP) plus bevacizumab (Bev), Bev alone, or no treatment, following a standard combination of FP, oxaliplatin (Ox), and Bev as first-line treatment for patients with metastatic colorectal cancer (mCRC): a phase III non-inferiority trial (AIO KRK 0207). J Clin Oncol (ASCO Annual Meeting Abstracts). 2014;32(suppl):Abstract 3503.

7. Koopman M, Simkens L, May AM, et al. Final results and subgroup analyses of the phase 3 CAIRO3 study: maintenance treatment with capecitabine + bevacizumab versus observation after induction treatment with chemotherapy + bevacizumab in metastatic colorectal cancer (mCRC). J Clin Oncol (ASCO Annual Meeting Abstracts). 2014;32(suppl):Abstract 3504.

8. Saltz L. At what price stability? Value of maintenance therapy. Presented at: 2014 ASCO Annual Meeting; May 30-June 3, 2014; Chicago, IL. http://meetinglibrary.asco.org/presentationBySession/6674/ 1344. Accessed November 23, 2014.

9. Bokemeyer C, Bondarenko I, Hartmann JT, et al. Efficacy according to biomarker status of cetuximab plus FOLFOX-4 as first-line treatment for metastatic colorectal cancer: the OPUS study. Ann Oncol.

2011;22:1535-1546.

10. Bokemeyer C, Kohne C-H, Ciardiello F, et al. Treatment outcome according to tumor RAS mutation status in OPUS study patients with metastatic colorectal cancer (mCRC) randomized to FOLFOX4 with/ without cetuximab. J Clin Oncol (ASCO Annual Meeting Abstracts). 2014;32(suppl):Abstract 3505.

11. Van Cutsem E, Köhne C-H, Hitre E, et al. Cetuximab and chemotherapy as initial treatment for metastatic colorectal cancer. N Engl J Med. 2009;360:1408-1417.

12. Ciardiello F, Lenz H-J, Kohne C-H, et al. Treatment outcome according to tumor RAS mutation status in CRYSTAL study patients with metastatic colorectal cancer (mCRC) randomized to FOLFIRI with/ without cetuximab. J Clin Oncol (ASCO Annual Meeting Abstracts). 2014;32(suppl):Abstract 3506.

13. Venook AP, Niedzwiecki D, Lenz H-J, et al. CALGB/SWOG 80405: phase III trial of irinotecan/5-FU/ leucovorin (FOLFIRI) or oxaliplatin/5-FU/leucovorin (mFOLFOX6) with bevacizumab (BV) or cetuximab (CET) for patients (pts) with KRAS wild-type (wt) untreated metastatic adenocarcinoma of the colon or rectum (MCRC). J Clin Oncol (ASCO Annual Meeting Abstracts). 2014;32(suppl):Abstract LBA3.

14. Lenz H, Niedzwiecki D, Innocenti F, et al. CALGB/SWOG 80405: phase III trial of irinotecan/5-FU/ leucovorin (FOLFIRI) or oxaliplatin/5-FU/leucovorin (mFOLFOX6) with bevacizumab (BV) or cetuximab (CET) for patients with expanded RAS analyses untreated metastatic adenocarcinoma of the colon or rectum (mCRC). Ann Oncol (ESMO Annual Meeting Abstracts). 2014;25(suppl 4):Abstract 5010.

15. Venook AP, Niedzwiecki D, Lenz H, et al. CALGB/SWOG 80405: analysis of patients undergoing surgery as part of treatment strategy. Ann Oncol (ESMO Annual Meeting Abstracts). 2014;25(suppl 4):Abstract LBA10.

16. Stintzing S, Modest DP, von Weikersthal LF, et al. Independent radiological evaluation of objective response, early tumor shrinkage, and depth of response in FIRE-3 (AIO KRK-0306) in the final RAS evaluable population. Ann Oncol (ESMO Annual Meeting Abstracts). 2014;25(suppl 4):Abstract LBA11.

17. Sargent DJ, Shi Q, Yothers G, et al. Prognostic impact of deficient mismatch repair (dMMR) in 7,803 stage II/III colon cancer (CC) patients (pts): a pooled individual pt data analysis of 17 adjuvant trials in the ACCENT database. J Clin Oncol (ASCO Annual Meeting Abstracts). 2014;32(suppl):Abstract 3507.

18. Tougeron D, Sickersen G, Lecomte T, et al. Impact of adjuvant chemotherapy with 5-FU or FOLFOX in colon cancers with microsatellite instability: an AGEO multicenter study. J Clin Oncol (ASCO Annual Meeting Abstracts). 2014;32(suppl):Abstract 3508.

19. Zaanan A, Fléjou J-F, Emile J-F, et al. Defective mismatch repair status as a prognostic biomarker of disease-free survival in stage III colon cancer patients treated with adjuvant FOLFOX chemotherapy. Clin Cancer Res. 2011;17:7470-7478.

COE168-4

www.TheOncologyNurse.com

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cancer care

Routine Imaging Costly in B-Cell Lymphoma, Rarely Picks Up Relapse After Remission Wayne Kuznar

Chicago, IL—Routine surveillance imaging of asymptomatic patients in first remission after treatment for diffuse large B-cell lymphoma offers little clinical benefit at substantial cost, according to Scott F. Huntington, MD, of Abramson Cancer Center, University of Pennsylvania, Philadelphia, and colleagues. Strategies utilizing 2 years of routine computed tomography (CT) or positron emission tomography (PET)/ CT scans were associated with minimal survival benefit compared with follow-up without routine imaging.

“Surveillance imaging limited to 4 scans over 2 years is associated with significant aggregate costs,” noted Dr Huntington at the 2014 American Society of Clinical Oncology meeting.

The goal of routine surveillance imaging is the detection of early relapse, but “there’s increasing data showing that the majority of patients who have diffuse large B-cell lymphoma who relapse will be symptomatic. So, the utility of imaging is questioned,” he said.

Dr Huntington and colleagues created a decision analytic Markov model and compared 3 surveillance strategies in cohorts of 55-year-old patients. The baseline model was biased to favor imaging strategies by associating asymptomatic imaging-detected relapses with improved clinical outcome, said Dr Huntington. Quality-adjusted utility, lifetime costs, and incremental cost-­ effectiveness ratios were calculated for each follow-up strategy.

“One trial found that patients with image-detected disease were more likely to have lower IPI [International Prognostic Index] scores, so they were basically having more favorable outcomes posttransplant,” he pointed out.

“The data from that trial was used to bias toward imaging.”

The benefit of imaging-based follow-up remained small after quality-of-life adjustments. The costs associated with imaging-based surveillance strategies are considerable, and incremental cost-effectiveness ratios were $202,300 per quality-adjusted life-year (QALY) for CT strategies and $312,600 per QALY for PET/CT strategies. Incremental cost-effectiveness ratios for imaging strategies remained at >$100,000 per QALY or were dominated by routine follow-up in multiway sensitivity analyses over clinically relevant ranges.

“The question is if routine surveillance imaging or serial surveillance imaging should be used, and there are providers who suggest against surveil-

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lance imaging,” Dr Huntington noted.

“Certainly you want to see patients routinely, every 3 to 6 months, and perform a close history and physical exam, because that is actually the ma-

jority of relapse—the patient is symptomatic. The patient may have changing symptoms or recurrent night sweats, and we may see new physical exam findings and new laboratory findings.”

™

Brief Summary of Prescribing Information for Chronic Lymphocytic Leukemia 1 INDICATIONS AND USAGE 1.1 Chronic Lymphocytic Leukemia (CLL) TREANDA® is indicated for the treatment of patients with chronic lymphocytic leukemia. Efficacy relative to first line therapies other than chlorambucil has not been established.

2 DOSAGE AND ADMINISTRATION 2.1 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: 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 (5.1)] 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.

2.3 Preparation for Intravenous Administration Each vial of TREANDA Injection is intended for single use only. Aseptically withdraw the volume needed for the required dose from the 90 mg/mL solution.

Immediately transfer the solution 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 - 0.7 mg/mL. The admixture should be a clear colorless to yellow solution.

Use 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 to be compatible.

Parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration whenever solution and container permit. Any unused solution should be discarded according to institutional procedures for antineoplastics.

2.4 Admixture Stability TREANDA Injection 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 under refrigerated conditions at 2°-8°C (36°-46°F) or for 2 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.

3 DOSAGE FORMS AND STRENGTHS TREANDA Injection is supplied in single-use vials containing either 45 mg/0.5mL or 180 mg/2mL of bendamustine HCl. 4 CONTRAINDICATIONS TREANDA is contraindicated in patients with a known hypersensitivity (e.g., anaphylactic and anaphylactoid reactions) to bendamustine. [See Warnings and Precautions (5.3)] 5 WARNINGS AND PRECAUTIONS 5.1 Myelosuppression TREANDA caused severe myelosuppression (Grade 3-4) in 98% of patients in the two NHL studies. Three patients (2%) died from myelosuppressionrelated 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 frequently. In the clinical trials, blood counts were monitored every week initially. Hematologic nadirs were observed predominantly in the third week of therapy. Myelosuppression may require dose delays and/or subsequent dose reductions if recovery to the recommended values has 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 (2.1)]

He added that, “Usually, routine surveillance imaging is not picking up those relapses. Even in the best-case scenario for the utility of imaging, it’s still not likely to be cost-effective.” n

5.2 Infections Infection, including pneumonia, sepsis, septic shock, and death have occurred in adult and pediatric patients in clinical trials and in postmarketing reports. Patients with myelosuppression following treatment with TREANDA are more susceptible to infections. Advise patients with myelosuppression following TREANDA treatment to contact a physician if they have symptoms or signs of infection.

5.3 Anaphylaxis and Infusion Reactions 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. Ask patients about symptoms suggestive of infusion reactions after their first cycle of therapy. Patients who experience Grade 3 or worse allergic-type reactions should not be rechallenged. Consider measures to prevent severe reactions, including antihistamines, antipyretics and corticosteroids in subsequent cycles in patients who have experienced Grade 1 or 2 infusion reactions. Discontinue TREANDA for patients with Grade 4 infusion reactions. Consider discontinuation for Grade 3 infusions reactions as clinically appropriate considering individual benefits, risks, and supportive care.

5.4 Tumor Lysis Syndrome Tumor lysis syndrome associated with TREANDA treatment has occurred in patients in clinical trials and in postmarketing 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 vigorous hydration 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 [see Warnings and Precautions (5.5)].

5.5 Skin Reactions Skin reactions have been reported with TREANDA treatment in clinical trials and postmarketing safety reports, including rash, toxic skin reactions and bullous exanthema. Some events occurred when TREANDA was given in combination with other anticancer agents.

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. Monitor patients with skin reactions closely. If skin reactions are severe or progressive, withhold or discontinue TREANDA. 5.6 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.

5.7 Extravasation Injury TREANDA extravasations have been reported in post marketing resulting in hospitalizations from erythema, marked swelling, and pain. Assure good venous access prior to starting TREANDA infusion and monitor the intravenous infusion site for redness, swelling, pain, infection, and necrosis during and after administration of TREANDA. 5.8 Embryo-fetal Toxicity 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.

6 ADVERSE REACTIONS 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 (5.1); Infections (5.2); Anaphylaxis and Infusion Reactions (5.3); Tumor Lysis Syndrome (5.4); Skin Reactions (5.5); Other Malignancies (5.6); Extravasation injury (5.7). The data described below reflect exposure to TREANDA in 153 patients who participated in an actively-controlled trial for the treatment of CLL. 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.

6.1 Clinical Trials Experience in CLL The data described below reflect exposure to TREANDA in 153 patients with CLL studied in an active-controlled, randomized trial.The population was 45-77 years of age, 63% male, 100% white, and were treatment naïve.

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. Nonhematologic adverse reactions (any grade) in the TREANDA group that

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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 CLL trial and in 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 (N=153) System organ class Preferred term Total number of patients with at least 1 adverse reaction Gastrointestinal disorders Nausea Vomiting Diarrhea General disorders and administration site conditions Pyrexia Fatigue Asthenia Chills Immune system disorders Hypersensitivity Infections and infestations Nasopharyngitis Infection Herpes simplex Investigations Weight decreased Metabolism and nutrition disorders Hyperuricemia Respiratory, thoracic and mediastinal disorders Cough Skin and subcutaneous tissue disorders Rash Pruritus

Chlorambucil (N=143)

All Grades

Grade 3/4

All Grades

Grade 3/4

121 (79)

52 (34)

96 (67)

25 (17)

31 (20) 24 (16) 14 (9)

1 (<1) 1 (<1) 2 (1)

21 (15) 9 (6) 5 (3)

1 (<1) 0 0

36 (24) 14 (9) 13 (8) 9 (6)

6 (4) 2 (1) 0 0

8 (6) 8 (6) 6 (4) 1 (<1)

2 (1) 0 0 0

7 (5)

2 (1)

3 (2)

0

10 (7) 9 (6) 5 (3)

0 3 (2) 0

12 (8) 1 (<1) 7 (5)

0 1 (<1) 0

11 (7)

0

5 (3)

0

11 (7)

3 (2)

2 (1)

0

6 (4)

1 (<1)

7 (5)

1 (<1)

12 (8) 8 (5)

4 (3) 0

7 (5) 2 (1)

3 (2) 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 TREANDA N=150

Chlorambucil N=141

Laboratory Abnormality

All Grades n (%)

Grade 3/4 n (%)

All Grades n (%)

Grade 3/4 n (%)

Hemoglobin Decreased

134 (89)

20 (13)

115 (82)

12 (9)

Platelets Decreased

116 (77)

16 (11)

110 (78)

14 (10)

Leukocytes Decreased

92 (61)

42 (28)

26 (18)

4 (3)

Lymphocytes Decreased

102 (68)

70 (47)

27 (19)

6 (4)

Neutrophils Decreased

113 (75)

65 (43)

86 (61)

30 (21)

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In the CLL trial, 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 further deterioration does not occur.

6.3 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 phlebitis, pruritus, irritation, pain, and swelling; pneumocystis jiroveci pneumonia and pneumonitis.

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 (5.5)] 10 OVERDOSAGE The intravenous LD50 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. 15 REFERENCES 1. OSHA Hazardous Drugs. OSHA. [Accessed on June 19, 2013, from http://www.osha.gov/SLTC/hazardousdrugs/index.html] 16 HOW SUPPLIED/STORAGE AND HANDLING 16.1 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 Injection. 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.

TREANDA is a cytotoxic drug. Follow special handling and disposal procedures1.

16.2 How Supplied TREANDA (bendamustine hydrochloride) Injection is supplied as a 90 mg/mL clear colorless to yellow solution as follows: NDC 63459-395-02: 45 mg/0.5 mL of solution in an amber single-use vial NDC 63459-396-02: 180 mg/2 mL of solution in an amber single-use vial Vials are supplied in individual cartons.

16.3 Storage TREANDA Injection must be stored refrigerated between 2°-8°C (36°-46°F).

Retain in original package until time of use to protect from light.

Distributed By: Teva Pharmaceuticals USA, Inc. North Wales, PA 19454 TREANDA is a trademark of Cephalon, Inc. or its affiliates. ©2008-2014 Cephalon, Inc., a wholly owned subsidiary of Teva Pharmaceutical Industries Ltd. or its affiliates.

All rights reserved.

(Label Code: 00016287.06) 9/2013 TRE-40360 This brief summary is based on TRE-009 TREANDA full Prescribing Information.

january 2015 I VOL 8, NO 1

39

NEW—LIQUID FORMULATION

Start with TREANDA® (bendamustine HCI) Injection for established front-line CLL therapy

Preparing for IV administration is:

Fast

Precise

Convenient

Less preparation time

No reconstitution necessary

Fewer steps prior to admixing

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.

Important Safety Information Contraindication: TREANDA is contraindicated in patients with a known hypersensitivity (e.g., anaphylactic and anaphylactoid reactions) to bendamustine.

Myelosuppression: TREANDA caused severe myelosuppression (Grade 3-4) in 98% of patients in the two NHL studies. Three patients (2%) died from myelosuppression-related adverse reactions. If myelosuppression occurs, monitor leukocytes, platelets, hemoglobin (Hgb), and neutrophils frequently. Myelosuppression may require dose delays and/or subsequent dose reductions if recovery to the recommended values has not occurred by the first day of the next scheduled cycle.

Infections: Infection, including pneumonia, sepsis, septic shock, and death have occurred. Patients with myelosuppression following treatment with TREANDA are more susceptible to infections.

Anaphylaxis and Infusion Reactions: 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 (Grade 3-4) reactions.

Ask patients about symptoms suggestive of infusion reactions after their first cycle of therapy. Consider measures to prevent severe reactions, including antihistamines, antipyretics, and corticosteroids in subsequent cycles in patients who have experienced Grade 1 or 2 infusion reactions.

Tumor Lysis Syndrome: Tumor lysis syndrome associated with TREANDA treatment has occurred. 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 vigorous hydration and close monitoring of blood chemistry, particularly potassium and uric acid levels.

There may be an increased risk of severe skin toxicity when TREANDA and allopurinol are administered concomitantly.

Skin Reactions: Skin reactions have been reported with TREANDA treatment and include rash, toxic skin reactions, and bullous exanthema. 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. 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. Where skin reactions occur, they may be progressive and increase in severity with further treatment. Monitor patients with skin reactions closely. If skin reactions are severe or progressive, withhold or discontinue TREANDA. 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 Injury: TREANDA extravasations have been reported in postmarketing resulting in hospitalizations from erythema, marked swelling, and pain. Ensure good venous access prior to starting TREANDA infusion and monitor the intravenous infusion site for redness, swelling, pain, infection, and necrosis during and after administration of TREANDA. Embryo-fetal Toxicity: TREANDA can cause fetal harm when administered to a pregnant woman. Women should be advised to avoid becoming pregnant while using TREANDA. Most Common Adverse Reactions: The most common non-hematologic adverse reactions for CLL (frequency ≥15%) are pyrexia, nausea, and vomiting. The most common hematologic abnormalities (frequency ≥15%) are anemia, thrombocytopenia, neutropenia, lymphopenia, and leukopenia.

Please see accompanying brief summary of Full Prescribing Information on the following pages.

Learn more at TREANDAHCP.com

©2014 Cephalon, Inc., a wholly-owned subsidiary of Teva Pharmaceutical Industries Ltd. All rights reserved. TRE-40090 November 2014