TOP Oct 2014 | Vol 7 | No 4 by The Oncology Pharmacist

october 2014

www.TheOncologyPharmacist.com

Vol 7, No 4

COMPLIMENTARY CE Faculty Perspectives™: Latest Treatment Advances for Individualized Care of Breast Cancer

see page 18

Breast Cancer

Cancer Center Profile

Cancer Hospital of New Jersey at Robert Wood Johnson University Hospital

Relation Between Stomatitis and Clinical Outcomes of Everolimus Treatment Examined by Trial Investigators Caroline Helwick

Some of the oncology pharmacy team members at the Cancer Hospital of New Jersey (left to right): Jigisha Patel, PharmD; Jon Lalli, PharmD, BCOP; and Isabel Caratenuto, PharmD.

he Cancer Hospital of New Jersey at Robert Wood Johnson University Hospital (RWJUH) is the flagship hospital of the Rutgers Cancer Institute of New Jersey. It is the only Comprehensive Cancer Center in New Jersey designated by the National Cancer Institute. The partnership between RWJUH and Rutgers Cancer Institute of New Jersey allows patients to receive care from research physicians in a state-of-the-art environment. Continued on page 6

Conference News

Highlights From the American Society for Radiation Oncology 2014 Annual Meeting Alice Goodman

he annual meeting of the American Society for Radiation Oncology (ASTRO) took place in San Francisco, California, on September 14-17, 2014. The meeting draws more than 11,000 attendees, bringing together clinicians, scientists, and researchers from all oncology disciplines. ASTRO highlights how technology and biology advance the field of radiation oncology and improve out-

comes and quality of life for patients. As ASTRO’s needs statement for the annual meeting points out, nearly twothirds of the estimated 1.6 million people who will be diagnosed with cancer this year will receive radiation therapy—this makes it imperative that all members of the multidisciplinary team be aware of best practices. Below are summaries of some highlights from the meeting. Continued on page 9

n patients receiving everolimus in clinical trials, stomatitis frequently occurred in the initial weeks of treatment, but this did not compromise clinical outcomes, according to Hope S. Rugo, MD, Professor of Medicine and Director of Breast Oncology and Clinical Trials at the University of California San Francisco Helen Diller Family Comprehensive Cancer Center. In fact, there was some indication that the occurrence of stomatitis was actually predictive of greater treatment benefit, she noted at the American Society of Clinical Oncology’s 2014 Breast Cancer Symposium.

“In this retrospective analysis, stomatitis appeared to be associated with longer progression-free survival [PFS]” in most of the trials, Rugo indicated, though she cautioned that this was an unplanned analysis. “In many patients with stomatitis, we reduced or held doses. We can’t say the outcome is better in patients who got stomatitis, but it’s certainly not worse. It tells us that patients who get stomatitis, even though we hold or reduce doses, have at least the same PFS, and in some patients, stomatitis may be a marker [of prognosis],” Rugo said. Continued on page 5

Education

The Path to Oncology Pharmacy Eric Urnoski, 2015 PharmD candidate

y philosophy has always been to cherish each educational opportunity or experience not only for professional development but also for personal growth. Adhering to this principle, I took advantage of every available chance to learn and grow as a pharmacy student. While in high school, I had the opportunity to transition from a grocery

store cashier to a pharmacy technician after waiting for a position within the company to become available. In addition, I was briefly employed at a specialty mail order pharmacy to help diversify my work experiences and explore the many work settings pharmacy has to offer. Over the next several years, I was able to use these experiences to develop my Continued on page 8

i n s i d e The Whole Patient . . . . . . . . . 12 Renal Cancer. . . . . . . . . . . . . . . 28 The Psychosocial Effects of Chemotherapy-Induced Alopecia

Side Effects Management. . . . . . . . . . . . . . . . . . 15 Generic Docetaxel Increases Neutropenia Risk and Healthcare Costs Vaginal DHEA May Improve Sexual Function in Women With Breast/ Gynecologic Cancer

Highest Response Rate to Date in mRCC With Pazopanib as Third-Line VEGF Inhibitor

Melanoma . . . . . . . . . . . . . . . . . . . . Potential New Approach to Treat Melanoma Combination of BRAF and MEK Inhibitors Improves Survival in Advanced Melanoma

Now enrolling

Investigating ABT-199 (GDC-0199) in Chronic Lymphocytic Leukemia Phase II Open-Label Study of the Efficacy and Safety of ABT-199 in Patients With Relapsed or Refractory Chronic Lymphocytic Leukemia Harboring the 17p Deletion N=100

ABT-199 is an investigational agent that has not been approved by regulatory agencies for the use under investigation in this trial. Primary Endpoint

Secondary Endpoints

• Overall response rate

• • • • • • • •

Complete remission rate Partial remission rate Duration of response Progression-free survival Time to progression Overall survival Percentage of patients who move on to stem-cell transplant Safety and tolerability of ABT-199

Key Inclusion Criteria • Adult patients ≥18 years of age • Diagnosis of CLL that meets 2008 IWCLL NCI-WG criteria (relapsed/refractory after receiving ≥1 prior line of therapy and 17p deletion) • ECOG performance score of ≤2 • Adequate bone marrow function • Adequate coagulation, renal, and hepatic function, per laboratory reference range

NCT#01889186 Reference: ClinicalTrials.gov.

To learn more about this study, please visit www.ClinicalTrials.gov.

Editorial Board EDITOR-IN-CHIEF

Patrick Medina, PharmD, BCOP Oklahoma University College of Pharmacy Tulsa, OK

Anjana Elefante, PharmD, BSc, BSc Pharm, RPh

Dwight Kloth, PharmD, FCCP, BCOP

Timothy G. Tyler, PharmD, FCSHP

Beth Faiman, PhD(c), MSN, APRN-BC, AOCN

Jim Koeller, MS

John M. Valgus, PharmD, BCOP

Christopher Fausel, PharmD

Christopher J. Lowe, PharmD

Roswell Park Cancer Institute Buffalo, NY

Fox Chase Cancer Center Philadelphia, PA

Desert Regional Medical Center Palm Springs, CA

ASSOCIATE EDITOR-IN-CHIEF

Steve Stricker, PharmD, MS, BCOP Samford University McWhorter School of Pharmacy Birmingham, AL

John F. Aforismo, BSc Pharm, RPh, FASCP

University of Texas at Austin San Antonio, TX

Cleveland Clinic Taussig Cancer Institute Cleveland, OH

Indiana University Simon Cancer Center Indianapolis, IN

Indiana University Hospital Indianapolis, IN

David Baribeault, BS, BCOP

Rebecca S. Finley, PharmD, MS

Emily Mackler, PharmD, BCOP

Betty M. Chan, PharmD, BCOP

David C. Gammon, BSPh

Laura Boehnke Michaud, PharmD, BCOP, FASHP

RJ Health Systems International, LLC Wethersfield, CT

Boston, MA

USC/Norris Cancer Hospital Los Angeles, CA

Jefferson School of Pharmacy Philadelphia, PA

OncologyPharmacist.net Warwick, RI

University of Michigan Health System & College of Pharmacy Ann Arbor, MI

The University of Texas MD Anderson Cancer Center Houston, TX

University of North Carolina Hospitals and Clinics Chapel Hill, NC

Gary C. Yee, PharmD, FCCP, BCOP University of Nebraska College of Pharmacy Omaha, NE

Burt Zweigenhaft, BS

Onco360/OncoMed New York, NY

Marlo Blazer, PharmD, BCOP James Cancer Hospital & Solove Research Institute Columbus, OH

Heidi D. Gunderson, PharmD, BCOP Mayo Clinic Cancer Center Rochester, MN

Steven L. Dâ&#x20AC;&#x2122;Amato, RPh, BCOP Maine Center for Cancer Medicine Scarborough, ME

www.TheOncologyPharmacist.com

Lew Iacovelli, BS, PharmD, BCOP, CPP

Moses H. Cone Health System Greensboro, NC

LeAnn Best Norris, PharmD, BCPS, BCOP South Carolina College of Pharmacy Columbia, SC

Kamakshi V. Rao, PharmD, BCOP University of North Carolina Hospitals and Clinics Chapel Hill, NC

october 2014 I VOL 7, NO 4

From The EditorS PUBLISHING STAFF Senior Vice President, Sales & Marketing Nicholas Englezos nenglezos@the-lynx-group.com Senior Vice President, Sales & Marketing Philip Pawelko ppawelko@the-lynx-group.com Vice President/Director of Sales & Marketing Joe Chanley jchanley@the-lynx-group.com Group Director, Sales & Marketing John W. Hennessy jhennessy2@the-lynx-group.com Publishers Russell Hennessy rhennessy@the-lynx-group.com Cristopher Pires cpires@the-lynx-group.com Editorial Director Kristin Siyahian ksiyahian@the-lynx-group.com Managing Editor Kristen Olafson kolafson@the-lynx-group.com Copy Editors Hina Khaliq Mollie Friedman Peggy Roeske Production Manager Lynn Hamilton

Editor-in-Chief Patrick Medina, PharmD, BCOP

This issue of The Oncology Pharmacist (TOP) presents highlights from a variety of recent conferences—including the American Society of Clinical Oncology’s 2014 Breast Cancer Symposium, the American Society for Radiation Oncology 2014 Annual Meeting, and the 2014 Congress of the European Society for Medical Oncology. Also, we talk to Jon Lalli, PharmD, BCOP, from the Cancer Hospital of New Jersey at the Robert Wood Johnson University Hospital. Jon tells us about his responsibilities at the cancer hospital and how he “found his way into” becoming an oncology pharmacist. Please participate in our reader poll (see below), which asks if you have provided information about the profession of oncology pharmacy. The poll ties into the article, The

Associate Editor-in-Chief Steve Stricker, PharmD, MS, BCOP

Path to Oncology Pharmacy, by Eric Urnoski. Eric tells us about how he is wending his way through pharmacy school, a career he has been interested in since high school. Specialization as an oncology pharmacist requires training and board certification—a lot of work, to say the least. We want to know if you have been asked about how to become an oncology pharmacist. Please visit our website, www.TheOncologyPharmacist.com, to answer the question and add your comments. When you visit the TOP website to participate in the poll, please take the time to give us your feedback about what you see in print and online. Send your comments to editorial@greenhillhc.com. We look forward to hearing from you. l

The Lynx Group President/CEO Brian Tyburski 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 Director, Digital Media Anthony Romano Web Content Managers David Maldonado Anthony Trevean Digital Programmer Michael Amundsen Meeting & Events Planner Linda Sangenito Senior Project Managers Alyson Bruni Jini Gopalaswamy Project Manager Deanna Martinez Project Coordinator Mike Kodada IT Specialist Carlton Hurdle Executive Administrator Rachael Baranoski Office Coordinator Robert Sorensen

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October 2014 I VOL 7, NO 4

Reader Poll Have you ever given guidance to someone asking about becoming an oncology pharmacist? o Yes o No In his article, The Path to Oncology Pharmacy, Eric Urnoski talks about his education as a pharmacy student—telling us how he tries to take advantage of each educational opportunity or experience for professional and personal growth. Becoming a

pharmacist, especially an oncology pharmacist, takes a lot of work and training. Have you ever been asked about your profession? What do you say to people who are considering pursuing an education to become an oncology pharmacist?

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

The Oncology Pharmacist®, ISSN 1944-9607 (print); ISSN 1944-9593 (online) is published 4 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 ©2014 by Green Hill Healthcare Communications, LLC. All rights reserved. The Oncology Pharmacist® 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 Pharmacist®, 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 Pharmacist® 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 Pharmacist® 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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Breast Cancer

Relation Between Stomatitis and Clinical Outcomes... Continued from cover

Dose reductions and interruptions of everolimus were necessary for approximately onequarter of patients, usually those with grade 3 or 4 stomatitis.

trials. Most stomatitis was grade 1/2, with grade 3/4 observed in only 8.6%. Only 25 patients (1.7%) discontinued treatment as the result of stomatitis.

Photo by © ASCO/Todd Buchanan 2014.

Meta-Analysis of Key Trials The relationship between stomatitis and clinical outcomes in patients treated with mTOR inhibitors had not been evaluated prior to this meta-analysis. The study also aimed to assess the incidence, time to occurrence, and severity of stomatitis in patients treated with everolimus. The researchers examined data from 7 randomized, double-blind, phase 3 clinical trials of everolimus in patients with advanced breast cancer (BOLERO-2 and -3), neuroendocrine tumors (RADIANT-2 and -3), renal cell carcinoma (RECORD-1), and tuberous sclerosis complex (EXIST-1 and -2).

Hope S. Rugo, MD

“Stomatitis occurred rapidly,” Rugo noted. More than 60% of the 973 patients reporting this toxicity developed it by 2 months; median time to the first episode was 0.82 months and 89% of all first episodes were observed within 8 weeks. “Sixty percent of patients who experienced stomatitis experienced only 1 episode. Regardless of whether a patient experienced 1 or 2 episodes, most were of grade 1 or 2 severity,” Rugo indicated. Dose reductions and interruptions were necessary for approximately one-quarter of patients, usually those with grade 3 or 4 stomatitis.

Altogether, of the 1455 cancer patients treated with everolimus, 67% experienced stomatitis of any grade. A second episode was reported in 40% of these patients, with the episodes tending to be less severe. The incidence was highest (71%) in the breast cancer

Adjustments were most likely during the breast cancer trials.

patients 2 weeks after the start of treatment, and managing grade 2 or higher toxicity with dose delays or reduc-

Progression-Free Survival Improved? Development of stomatitis within 8 “A big issue with weeks of everolimus treatment initieverolimus is toxicity. ation, compared with everolimus- treated patients without this toxiciGrade 2 stomatitis is ty, was associated with longer PFS in the BOLERO-2 (hazard ratio [HR] = actually very unpleasant. 0.78) and RADIANT-3 (HR = 0.70) Altogether, about 30% trials. A similar trend was observed of our breast cancer for the RECORD-1 (HR = 0.90) and RADIANT-2 (HR = 0.87), but not for patients are bothered by BOLERO-3, the analysis showed. this, the majority within In BOLERO-2, median PFS was 8.48 months in everolimus-treated patients the first 6 weeks, but it who developed stomatitis, 6.90 months for patients without stomatitis, and doesn’t impact efficacy.” 3.17 months for the control arms. In Hope S. Rugo, MD RADIANT-3, median PFS was 13.86 months, 8.31 months, and 4.60 months, respectively. tions. She treats stomatitis with steroid mouthwash and is studying the mouthRecommendations wash as prophylaxis as well. “A big issue with everolimus is toxic“My personal experience is that you ity. Grade 2 stomatitis is actually very have to stop the drug for grade 2 stomaunpleasant. Altogether, about 30% of titis, use the steroids, then restart everour breast cancer patients are bothered olimus with the patient on the mouthby this, the majority within the first 6 wash. Many patients can escalate back weeks, but it doesn’t impact efficacy,” up to the same dose. Patient education Rugo said. is also critical,” Rugo said. l “These findings support continuing everolimus with dose adjustments and Reference Rugo HS, Yao JC, Pavel M, et al. Stomatitis incidence management according to the approved and its relationship with efficacy: a meta-analysis of prescribing information in patients who everolimus clinical studies. J Clin Oncol. 2014;32(suppl 26):abstract 151. Poster presented at: American Society experience stomatitis,” she said. of Clinical Oncology 2014 Breast Cancer Symposium; Rugo recommended checking on September 4-6, 2014; San Francisco, CA.

Less May Be “More” With Zoledronic Acid Caroline Helwick

www.TheOncologyPharmacist.com

bone metastases who had received at least 9 doses of an intravenous bisphosphonate

Photo by © ASCO/Scott Morgan 2014.

n breast cancer patients with bone metastasis, less frequent infusion of zoledronic acid was as effective as the standard monthly dose, the randomized OPTIMIZE-2 study showed. “We found that less frequent treatment may reduce the risk of serious side effects, with the additional benefits of reduced inconvenience to the patient and less cost,” said Gabriel N. Hortobagyi, MD, Professor of Medicine at the University of Texas MD Anderson Cancer Center, Houston, at the American Society of Clinical Oncology (ASCO) 2014 annual meeting. Zoledronic acid 4 mg given every 3 months was as effective as infusions given every 3 to 4 weeks, which is the schedule approved by the US Food and Drug Administration. OPTIMIZE-2 compared the schedules in 403 women with breast cancer and

Gabriel N. Hortobagyi, MD

(either zoledronic acid or pamidronate) before enrolling in the study. The rate of skeletal-related events

was 22% in the monthly group and 23.2% in the every-12-week group, indicating that less frequent dosing is not inferior. Other efficacy measures, such as time to first skeletal-related event and change from baseline in bone turnover markers, were also similar between the arms, and safety profiles were similar as well. ASCO press briefing moderator Patricia Ganz, MD, a supportive care specialist from the University of California Los Angeles, commented, “It’s not necessary for women to come in every 4 weeks.” The data are important because there are no evidence-based guidelines for the optimal treatment schedule after 1 year of treatment. Importantly, less frequent dosing seemed to ameliorate some of the safety concerns for bisphosphonates as a class. Like all agents in the class, “zoledronic

acid has some safety concerns,” said Hortobagyi, indicating osteonecrosis of the jaw (ONJ), long-bone fractures (ie, atypical femoral fractures), and chronic kidney function impairment. The less frequent dosing in this study was associated with fewer cases of ONJ (0 vs 2) and lower rates of renal impairment (7.9% vs 9.6%) compared with monthly dosing. No patients experienced long-bone fractures. Since the study size was, in Hortobagyi’s terms, “relatively modest” and there were some “design limitations,” he said the findings should be “interpreted with caution.” l Reference

Hortobagyi GN, Lipton A, Chew HK, et al. Efficacy and safety of continued zoledronic acid every 4 weeks versus every 12 weeks in women with bone metastases from breast cancer: results of the OPTIMIZE-2 trial. Presented at: 50th Annual Meeting of the American Society of Clinical Oncology; May 30-June 3, 2014; Chicago, IL. Abstract LBA9500.

october 2014 I VOL 7, NO 4

Cancer Center Profile

Cancer Hospital of New Jersey at Robert Wood Johnson… Continued from cover that the right medications are given to the right patients at the right doses. In other words, I am ensuring quality control and safety with regard to dispensing drugs as prescribed. Also, if I think that a medication is being prescribed for a patient who has contraindications or who would do better on an alternative drug, I will discuss this with the oncologist.

Jon Lalli, PharmD, BCOP

The cancer hospital has 103 beds. In addition to such oncology-focused services as diagnostic, laboratory, and pain-management services, the cancer hospital offers patients education and psychological and spiritual support. Supportive services include the care of an oncology social worker, an oncology nutritionist, and a chaplain, as well as support groups, inpatient hospice, and complementary therapies. The Oncology Pharmacist spoke with Jon Lalli, PharmD, BCOP, about his role in the management of cancer patients at RWJUH. Can you describe your role at the Cancer Hospital? Jon Lalli (JL): My job is to make sure

What are the biggest challenges in your job? JL: The biggest challenge is juggling my responsibilities in an ever-dynamic environment. I have no control of work flow so there are many times I am trying to prioritize targets that are constantly moving, all while simultaneously making sure that I am thoroughly checking high-risk work. What are your biggest rewards? JL: I would say that hearing that a patient was helped through my actions—indirectly or directly—is extremely gratifying. What are you excited about in the field of oncology? JL: I think everyone in the field is excited about the potential of targeted therapy for specific cancer types. The first 2 targeted therapies to have a big payoff—imatinib for chronic myelogenous leukemia and trastuzumab for HER2positive breast cancer—showed us all

the promise of therapy targeted to a specific abnormality. Since then there have been other breakthroughs with targeted therapies, like crizotinib for ALK-positive non–small cell lung cancer. How has the role of the oncology pharmacist changed over the past 5 years? JL: The role of the oncology pharmacist is constantly evolving. There have been many advances in treatment as well as advances in the understand-

8 years old, and growing up I would avoid conversations about cancer. But now that I am taking part in the fight against cancer I actually keep her in my thoughts while working, and that keeps her closer to me. What is your advice for someone entering the field? JL: There is a growing need for oncology pharmacists, and pharmacists have the ability to make a significant contribution to the care of cancer patients.

“The biggest challenge is juggling my responsibilities in an ever-dynamic environment. I have no control of work flow so there are many times I am trying to prioritize targets that are constantly moving, all while simultaneously making sure that I am thoroughly checking high-risk work.” ing of cancer on the molecular level. Keeping up with the new material is very challenging. What inspired you to become an oncology pharmacist? JL: I really found my way into it. I never thought that I would feel a level of comfort in this field. My mother fell victim to breast cancer when I was

So, my advice is to learn as much as possible to maximize that contribution. If you weren’t an oncology pharmacist and could do anything you wanted to, what would you be doing? JL: I would have stayed in the sciences and probably would have found my way into cancer research. l

Take action: get YOUR cancer center profiled! We are looking to interview oncology pharmacists 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. 6

October 2014 I VOL 7, NO 4

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Education

The Path to Oncology Pharmacy Continued from cover direct patient communication skills as I learned how to have a genuine rapport with patients. Also, being exposed to patients on many different therapeutic regimens helped prepare me for the challenges of pharmacy school. I attended undergraduate school with a future career in pharmacy as my goal. During this time, I became involved with research—new drug development in a medical chemistry lab. Under the direction of a pharmaceutical sciences professor, I worked in a basic sciences laboratory on synthesizing a microtubule-stabilizing analog similar to paclitaxel. I began to realize how research and drug development of new chemotherapeutic agents were on the rise and how innovation was propelling the pharmacy profession into becoming an integral part of the cancer care team—that these new agents require the vigilant monitoring that a pharmacist can provide. When I started pharmacy school at the Jefferson School of Pharmacy, I was eager to get involved in clinical research. Remarkably, one of my professors, Dr Ginah Nightingale, was seeking students to assist with an ambitious longitudinal research opportunity. Dr Nightingale was collecting data about the role of a pharmacist in a multidisciplinary care team for patients of the recently established Senior Adult Oncology Team at Thomas Jefferson University Hospital. Specifically, pharmacists performed a medication review (prescription, over-the-counter, and herbal medications) at the patient’s first visit. The focus was to evaluate polypharmacy and potentially inappropriate medication use before complex chemotherapy regimens were started for this at-risk senior adult population. Despite having had limited interaction with Dr Nightingale previously, I inquired about assisting in the data collection. Afterward, I was able to assist with her senior adult oncology research study for nearly 2 years. Initially, I performed literature searches for background information about inappropriate medication use in senior adult oncology patients. I obtained Institutional Review Board (IRB) certification through the Collaborative Institutional Training Initiative (CITI), and collected pertinent information from patient charts about cancer diagnosis and staging, comorbidities, Eastern Cooperative Oncology Group (ECOG) functional status, and medication use. In addition to my coursework and pharmacy school experiences, I applied for an internship in the Department of Pharmacy at Thomas Jefferson University Hospital and was accept-

October 2014 I VOL 7, NO 4

ed. Although I was not working in the oncology pharmacy, I compounded and delivered medications to patients’ rooms and was able to see firsthand the complexity of the medications prescribed for hospitalized cancer patients. Most striking to me were the patients who were being cared for in the bone marrow transplant unit who were sometimes receiving dozens

It is no secret that oncology is one of the most heavily researched and progressive specialties of pharmacy. of supportive medications, including anti-infection prophylaxis, immunosuppressants, and colony-stimulating factors. In addition, these patients were receiving total parenteral nutrition and palliative care. This complexity truly underscored the importance of having an oncology pharmacist assisting in the care of patients with cancer. I view pharmacists as integral to the multidisciplinary team. Oncology pharmacists are particularly valuable members of this interdisciplinary care team, with the responsibility of managing complex therapies, medication-related toxicities, and comorbidities experienced by many cancer patients. Oncology pharmacists also must ensure that chemotherapy and supportive medications are delivered at the appropriate intervals. It is no secret that oncology is one of the most heavily researched and progressive specialties of pharmacy. As such, the role of oncology pharmacists will become more important. Another area I am interested in is infectious diseases, and the fact that oncology pharmacists constantly need to manage immunocompromised patients makes the field even more appealing to me. As immunocompromised patients have limited ability to fight bacterial, viral, or fungal pathogens, a pharmacist must carefully monitor these patients and ensure they receive sufficient anti-infective prophylaxis and treatment while simultaneously minimizing the toxicities of each agent. Dr Nightingale is a pharmacist I have developed a profound respect for over these past several years. Since I have been able to observe her ability to balance didactic teaching, precepting students, working collaboratively with other health disciplines, and conduct-

ing practice-based research, I have become inspired to pursue a similar path in my professional career. I am looking forward to this fall when I will be one of her advanced pharmacy practice experience (APPE) students within a medical oncology team at Thomas Jefferson University Hospital. The advanced training and certification oncology pharmacists pursue reinforces the dedication of many pharmacists to stay current on breakthroughs in oncology research. I foresee pharmacists—especially oncology-trained pharmacists—providing even more services in the upcoming years. Oncology pharmacists will increase their involvement in the management of both inpatients and outpatients. Not only will oncology pharmacists continue to help improve patient outcomes and overall care by providing insight to new targeted biologic therapies, but they will also have the opportunity to work in a variety of settings. Oncology pharmacists can practice in more diverse settings, such as ambulatory care/outpatient centers, specialty pharmacies, or even in-home infusion. Because of the widespread improvements in cancer therapy, patients are living longer. Pharmacists can fill a necessary role in the healthcare system by providing optimal medication-re-

lated education to patients as well as their families before, during, and after chemotherapy. Pharmacists will present information about any potential adverse events that patients may experience as well as discuss any drug-food and/or drug-drug interactions that may be possible with oral chemotherapy. I find this aspect of direct patient interaction to be particularly appealing and rewarding. A pharmacist’s ability to quell the anxiety of a newly diagnosed cancer patient and to coach the patient and family throughout the entire treatment process is something that is truly rewarding. Naturally, there is no telling where these next few years will take me. I would venture to guess that many readers of The Oncology Pharmacist never envisioned a career as an oncology or hematology pharmacy specialist when they were in high school or even when they were starting their pharmacy education. I am confident that oncology pharmacists will continue to advance the profession by establishing a major role as part of the multidisciplinary team. Oncology pharmacists will expand their role by providing medication education to the team, ultimately leading to improvements in cancer care and patient outcomes and in the healthcare system overall. l

have you ever wanted to write an article for TOP ?

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

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

Conference News: ASTRO Continued from cover

ASTRO’s Choosing Wisely List Continuing its participation in the American Board of Internal Medicine’s Choosing Wisely campaign, ASTRO released its second list of 5 radiation treatments that should be questioned and not used routinely in clinical practice. The 2014 list follows: • Don’t recommend radiation following hysterectomy for endometrial cancer patients with low-risk disease. • Don’t routinely offer radiation therapy for patients who have resected non–small cell lung cancer (NSCLC), negative margins, N0-1 disease. • Don’t initiate noncurative radiation therapy without defining the goals of treatment with the patient and con-

sidering palliative care. • Don’t routinely recommend follow-up mammograms more often than annually for women who have had radiotherapy following breast conserving surgery. • Don’t routinely add adjuvant whole brain radiation to stereotactic radiosurgery for limited brain metastases. Along with ASTRO’s 2013 list, this totals 10 radiation treatments that should not be used routinely without thorough discussion between patients and physicians. ASTRO’s 2013 Choosing Wisely list included these recommendations: • Don’t initiate whole breast radio-

therapy as a part of breast conservation therapy in women age ≥50 with early stage invasive breast cancer without considering shorter treatment schedules. • Don’t initiate management of lowrisk prostate cancer without discussing active surveillance. • Don’t routinely use extended fractionation schemes (>10 fractions) for palliation of bone metastases. • Don’t routinely recommend proton beam therapy for prostate cancer outside of a prospective clinical trial or registry. • Don’t routinely use intensity-modulated radiotherapy (IMRT) to deliver

whole breast radiotherapy as part of breast conservation therapy. 2014 ASTRO President Bruce Haffty, MD, was quick to note that there are specific circumstances where these treatments are warranted but said that they should not be prescribed routinely. He also noted that there is some evidence that clinical practice has shifted as a result of the campaign. Choosing Wisely is aimed at reducing unnecessary healthcare expenditures while at the same time providing appropriate high-quality care. To see all the recommendations from medical societies in the United States, go to www.choosingwisely.org. l

Preserving Sexual Function in Patients With Prostate Cancer It may be possible to preserve sexual function in men with prostate cancer undergoing curative radiation therapy (RT) by using a vessel-sparing radiation technique, according to a 5-year follow-up of a group of men who underwent vessel-sparing radiation therapy in this setting.1 The study included 90 men diagnosed with prostate cancer; about 50% underwent external beam RT alone and 50% had the external beam RT plus brachytherapy. No patient received androgen deprivation therapy. “Using MRI to define the patient’s anatomy, the vessels involved in maintaining an erection can be spared in some patients,” explained author Patrick McLaughlin, MD, of the University of Michigan Providence Cancer Institute in Novi. “This is not possible in all patients, for example, those with prostate cancer at the apex of the prostate,” he said. All forms of cancer therapy affect sexual function, McLaughlin continued. A 2009 study found that among patients with good baseline erectile

capacity, after 36 months erectile capacity was present in only one-third of those treated with prostatectomy, 50% of those who got external beam RT, and 80% of those who received brachytherapy.2 In 2005, McLaughlin and his colleagues defined the vessel-sparing technique. At the 2014 ASTRO annual meeting, he presented a 5-year follow-up on patients treated with it. Two patient-reported metrics were used to assess sexual function: Metric A, which measured erections sufficient for sexual intercourse; and Metric B, which was more general about any form of sexual activity. Using Metric A, which looked only at erectile function sufficient for sexual intercourse, at 2 years, erectile capacity was achieved in 16.5% of those in the RT-alone group and 20.8% of the group receiving RT plus brachytherapy. At 5 years, 15.4% and 16.9%, respectively, were able to maintain an erection. Using Metric B, erectile function sufficient for sexual activity with or without aids was preserved in 78.6% of RT-alone patients and 91.8% of those

who received RT plus brachytherapy at 5 years. McLaughlin said that as people age, sexuality changes and many couples engage in types of sexual activity other than sexual intercourse, which can be painful to women after menopause. That’s why he thinks Metric B is more reflective of sexuality in older people. Cure rates were excellent. At 5 years, cure rates were 98% among low-risk men (55% of the 90 patients), 96% among intermediate-risk men (30% of the patients), and 87% in the high-risk patients (5% of the sample). l References

1. Liss AL, Evans C, Narayana V, et al. Comparison of external beam and combination therapy for prostate cancer: patient reported outcomes of sexual function with 5-year follow-up. Int J Radiat Oncol Biol Phys. 2014;90(1)(suppl):S54. Presented at: 56th Annual Meeting of the American Society for Radiation Oncology; September 14-17, 2014; San Francisco, CA. Abstract 111. 2. Chen RC, Clark JA, Talcott JA. Individualizing quality-of-life outcomes reporting: how localized prostate cancer treatments affect patients with different levels of baseline urinary, bowel, and sexual function. J Clin Oncol. 2009;27(24):3916-3922.

Radiation Does Not Increase Lymphedema Risk Radiation therapy (RT) does not increase the risk of lymphedema in patients with node-negative breast cancer beyond that of surgery, according to a secondary analysis of the NSABP (National Surgical Adjuvant Breast and Bowel Project) B-32 trial. “These results should reassure breast cancer patients that radiation therapy to the level 1 axilla when radiating the whole breast does not contribute to lymphedema risk beyond surgery,” stated lead author Susan McCloskey, MD, of the David Geffen School of Medicine at the University of California Los Angeles. McCloskey added, “This analysis suggests that lymphedema should not be an impediment to women choosing breast conservation surgery and radiation therapy.” The original study compared sen-

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tinel node biopsy (SNB) plus axillary node dissection (ALND) with SNB alone in 5611 women with no involved nodes.

The original study compared sentinel node biopsy (SNB) plus axillary node dissection with SNB alone in 5611 women with no involved nodes. Data from that trial were used to evaluate the impact of RT on the risk

of lymphedema in those who underwent SNB or ALND. Ninety-three percent of the women underwent breast-conserving surgery and 97% received breast or chest wall–only radiation (nonregional node radiation). Objective measurements (relative arm volume difference [RAVD]) were available for 3894 women (80% received RT), and subjective metrics were available for 730 women (80% had RT). No impact of radiation was observed on physician-reported lymphedema based on RAVD or on patient-reported lymphedema in either SNB+ALND patients or SNB patients. At 36 months, lymphedema (RAVD >10%) was detected in 13% of the SNB+ALND group and 8% of the SNB group, with no difference between those treated with

RT and those who did not have RT. Interestingly, a lack of agreement was observed between patient-reported bothersome lymphedema and physician-measured lymphedema according to RAVD. At 36 months, 12.4% of the SNB+ALND and 7.4% of the SNB patients had measurable lymphedema on RAVD. Among these women, 7.4% and 3.2%, respectively, said their lymphedema was bothersome. “We still have a lot to learn,” McCloskey stated. l Reference

McCloskey SA, Bandos H, Julian T, et al. The impact of radiation therapy on lymphedema risk and the agreement between subjective and objective lymphedema measures: NSABP B-32 secondary data analysis. Int J Radiat Oncol Biol Phys. 2014;90(1)(suppl):S4-S5. Presented at: 56th Annual Meeting of the American Society for Radiation Oncology; September 14-17, 2014; San Francisco, CA. Abstract CT-06.

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Conference News: AStr0 Continued from page 9

Risk of Second Primary Lung Cancers Remains High in Smokers Patients who are diagnosed with lung cancer but continue to smoke are at much higher risk of developing a secondary primary lung cancer (SPLC) compared with never smokers as well as those who have quit smoking, according to the largest analysis of its kind. “This study, which looked at the relationship between smoking history and developing a second lung cancer, adds to the evidence of the harmfulness of cigarette smoking. We presumed that never smokers would have a lower risk than current smokers, but we were encouraged to find that quitting smoking lowered the risk of SPLC and quitters had similar overall surviv-

al rates as never smokers,” said John Michael Boyle, MD, lead author, a radiation oncology resident at Duke Cancer Institute in Durham, North Carolina. “These findings confirm that smoking cessation is crucial and should be an integral part of patient care for all patients as well as cancer survivors.” The study included 1484 patients who underwent surgery for stage I-IIIA non–small cell lung cancer between 1995 and 2008; this included 372 current smokers, 1014 former smokers, and 98 never smokers. The 5-year incidence of SPLC was 13%, 7%, and 0%, respectively, which was statistically significant when both current and former smokers

were compared with never smokers (P = .03). During follow-up, only 1 never smoker developed a second lung cancer 7 years later. The risk of SPLC increased with the number of years of tobacco exposure, equaling an 8% increased risk with every 10 pack-years. The risk of developing SPLC was driven by cumulative smoking history, never smokers having zero risk at 5 years, and those who quit (whether <5 years ago or >5 years ago) having a similar 5-year risk of 7%; current smokers had a 12.8% risk. Results for overall survival (OS) were quite different, Boyle explained.

“OS was the worst for current smokers. Quitting smoking mitigated increased risk of mortality,” he noted. The rate of 5-year OS was 54.1% in never smokers, 46.1% in those who quit >5 years ago, 47.1% in those who quit <5 years ago, and 39% in current smokers. No difference in rates of local control or distant metastasis was evident based on smoking status. l Reference

Boyle JM, Chino JP, Tandberg D, et al. Tobacco use and secondary lung malignancies after surgery for non-small cell lung cancer. Int J Radiat Oncol Biol Phys. 2014;90(1)(suppl):S79-S80. Presented at: 56th Annual Meeting of the American Society for Radiation Oncology; September 14-17, 2014; San Francisco, CA. Abstract 170.

Simple Blood Test to Predict Outcome Researchers reported that results of a simple blood test measuring VEGF-A and TGF-β1 can be used as predictive markers for response to treatment in patients with squamous cell esophageal cancer undergoing concurrent chemotherapy and radiation therapy (CCRT) followed by esophagectomy, or removal of part of the esophagus. “The blood levels of these two proteins can be used as biomarkers to predict tumor response to therapy. This simple test can help tailor treatment decisions in patients with esophageal cancer,” stated lead author Yun Chiang, MD, National Taiwan University Hospital, Taipei. From 2004 to 2013, blood samples were collected from 103 patients with esophageal squamous cell carcinoma before and after CCRT. Serum samples were measured for 15 potential markers to correlate the levels of these markers with pathologic response and survival. The assay used to screen tiny blood samples was developed at Stanford University and is called proximity ligation assay (PLA), said Chiang.

The biomarkers significantly associated with pathologic response and survival rates were further analyzed by enzyme-linked immunoabsorbent assay (ELISA) to confirm findings using PLA.

“This simple test can help tailor treatment decisions in patients with esophageal cancer.” Yun Chiang, MD

Only 2 of the markers were significantly associated with disease-free survival (DFS; P = .009) and these were of borderline significance for overall survival (OS; P = .07). Patients with low levels of VEGF-A pre-CCRT were more likely to achieve a pathologic

complete response to CCRT than those with higher levels: 57.1% versus 26.5%, respectively (P = .002). Patients with high pre-CCRT serum VEGF-A/ TGF-β1 levels had significantly worse median DFS versus those with lower levels, and worse median OS (19.2 months vs 46.2 months, respectively; P = .07). “Low serum levels of VEGF-A increased the chance of pathological complete tumor regression, and high serum levels of VEGF-A and TGF-β1 were associated with significantly worse disease control and borderline worse survival,” Chiang told listeners. The clinical implication of high serum levels of both proteins suggests that more intensive therapy is needed, he said. l Reference

Chiang Y, Cheng J, Graber M, et al. Serum vascular endothelial growth factor-A and transforming growth factor-β1 can predict pathological response and disease-free survival of esophageal cancer patients treated with neoadjuvant chemoradiotherapy followed by esophagectomy. Int J Radiat Oncol Biol Phys. 2014;90(1)(suppl):S9-S10. Presented at: 56th Annual Meeting of the American Society for Radiation Oncology; September 14-17, 2014; San Francisco, CA. Abstract 10.

Single Fraction Radiation for Bone Metastases A study based on patient-reported outcomes in a broad sample of cancer patients with bone metastases showed that single fraction radiation therapy (SFRT) was as effective as multiple fraction radiation therapy (MFRT) for alleviating pain and improving function and quality of life (QOL). This study has cost implications as well as implications for patient convenience, noted senior author Robert Olson, MD, a radiation oncologist at the British Columbia (BC) Cancer Agency Centre for the North, Canada. “We see variations in patterns of use of MFRT. No doubt some of the use of MFRT [in the United States] is driven by cost considerations,” he noted. “Previous studies have shown that

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SFRT is equally effective as the more costly and inconvenient MFRT for patients with painful bone metastases. Many patients typically seen in clinical practice—those with fractures, neurologic damage—are excluded from these trials, though. There is a low utilization of SFRT worldwide, partly because oncologists are often reluctant to treat patients who do not mirror those in clinical trials,” he said. The study is ongoing. Results presented at ASTRO were based on self-reports from 648 patients treated with RT for bone metastasis. Patients were asked about pain levels, physical function, and symptom frustration. No major differences were seen between SFRT and MFRT for these

parameters. Partial pain response was achieved in 73% of those treated with SFRT or MFRT; complete pain

This study has cost implications as well as implications for patient convenience.

observed in 71% and 77%, respectively; and at least a 1-point improvement in symptom frustration was reported by 77% and 80%, respectively. “These findings indicate that SFRT should be the standard management policy for uncomplicated bone metastases. Although the study is limited by a small sample size thus far, there is no evidence of inferiority for SF versus MF in complicated bone metastases,” Olson stated. l Reference

response was achieved in 19% and 22%, respectively. Improvement by 1 point or more was similar in both groups: improvement in functional complaints by at least 1 point was

Olson RA, Olivotto L, Tiwana M, et al. Impact of program-wide dissemination of the inconsistent utilization of single fraction radiation therapy for bone metastases across a provincial program. Int J Radiat Oncol Biol Phys. 2014;90(1)(suppl):S691. Presented at: 56th Annual Meeting of the American Society for Radiation Oncology; September 14-17, 2014; San Francisco, CA. Abstract 3222.

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Take a bite out of G-CSF acquisition costs* GRANIX is another option in short-acting G-CSF therapy TM

GRANIX™ is an option for hospitals and payers to consider when determining health system budgets » FDA approved through the rigorous BLA† process » Teva’s short-acting G-CSF was first introduced in Europe in 2008 and is available in 42 countries‡1 » GRANIX J Code: J 1446-Injection, tbo-filgrastim, 5 micrograms, effective January 1, 2014 †Biologics License Application. ‡As of February 2014. *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

» GRANIX 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 colonystimulating 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. » 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 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. » 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. Data on file. Teva Pharmaceuticals: Filgrastim MA Approvals Worldwide. February 2014.

The Whole Patient

The Psychosocial Effects of Chemotherapy-Induced Alopecia Meg Barbor

ontroversies in treatment-induced alopecia and hair adverse events were brought to the attention of the medical community in a presentation by Mario Lacouture, MD, at the Multinational Association of Supportive Care in Cancer/

International Society of Oral Oncology 2014 annual meeting. The controversies lie in the prevention and treatment of alopecia. “Hair adverse events are frequent with anticancer therapies,” said Lacouture, a dermatologist at Memorial Sloan Kettering

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.

October 2014 I VOL 7, NO 4

Cancer Center in New York City, specializing in conditions that result from cancer treatments. “Patient counseling is critical so that doctors can make recommendations and assess the impact of these events on quality of life.” In alopecia due to cytotoxic che-

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.

motherapy, there is a reduction in the number of cells that make hair, resulting in hair loss; inhibited growth; weak, brittle, and constricted hair shafts subject to breakage; and a reduction in diameter of the hair shaft. Typically, people who lose a lot of hair lose it very fast; people who lose hair slowly have a longer recovery. “This may be important for counseling of patients as well as for understanding the mechanisms of toxicity,” Lacouture said. The Psychosocial Implications The psychosocial ramifications of chemotherapy-induced alopecia must not be underestimated. Alopecia is the most traumatic effect of chemotherapy, according to 47% of breast cancer patients surveyed, 8% of whom said they would reject chemotherapy because of alopecia alone. Some women report that losing a breast due to a mastectomy would be less traumatic than losing all of their hair, Lacouture noted. Additionally, there is a gender difference in terms of the psychosocial impact of hair loss. Women are much more concerned about scalp alopecia, whereas men tend to be more concerned about body alopecia. Children undergoing cytotoxic chemotherapy tend to suffer social isolation as a result of alopecia, while people older than 60 years tend to be more affected by its psychosocial impact. Additionally, there is the issue of stigma; everyone knows the patient is receiving chemotherapy, which results in a feeling of loss of privacy. The relative impact of alopecia depends on tumor type and stage. It is the second most important toxicity in breast and lung cancers, whereas it is not even in the top 10 in gastrointestinal cancers or stage 4 disease. Chemotherapy-induced alopecia is graded by the Common Terminology Criteria for Adverse Events, but other grading systems have been implemented in the past few years, primarily led by Elise Olsen, MD, at Duke University Medical Center in Durham, North Carolina, one of the world’s leading hair experts. She has devised a grading system in which a person has to lose more than 50% of his or her hair in order for other people to notice. “This is reassuring to patients,” said Lacouture. “It also helps us to understand the severity of hair loss.” There is a lesser severity of alopecia with the use of targeted therapies. It is important to keep in mind, though, that patients exposed to epidermal growth factor receptor (EGFR) inhibi-

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The Whole Patient

Reference

Lacouture ME. Controversies in chemotherapy and endocrine agent-induced alopecia [meet the expert]. Presented at: 2014 Annual Meeting of the Multinational Association of Supportive Care in Cancer/International Society of Oral Oncology; June 26-28, 2014; Miami, FL.

T O D A Y I

O C

www.TheOncologyPharmacist.com

R E G I S T E R

ask frequently, ‘Am I going to lose my eyebrows and my eyelashes?’ ” added Lacouture. “The best answer we have for them is ‘Maybe.’ We want to have numbers.” l

Monitoring, Treatment, and Counseling—What Can Be Done? Lacouture and his colleagues have found that for EGFR inhibitor–induced toxicities and the prevention and management of alopecia, over-the-counter minoxidil is effective for regrowth of eyebrows, as is prescription bimatoprost for eyelashes. Camouflaging hair

density, color, or structure of their hair after it has been lost and recovered. It is important to keep this in mind when counseling patients prior to the start of chemotherapy, Lacouture advised. Chemotherapy-induced alopecia reminds patients of their disease, negatively affects social interactions, and can lead to decreased self-esteem, sexuality, and sensuality. Therefore, patient counseling is critical. “Women

Persistent Alopecia and Its Consequences “I’ve never seen patients as upset as those on cytotoxic agents whose hair never fully grows back, because these people were never told that this could happen,” said Lacouture. The incidence of persistent alopecia is unknown, but one group significantly affected is children who receive chemotherapy. In an analysis of over 40,000 patients from the Childhood Cancer Survivor Study, about 40% of children experienced persistent hair loss, which led to a higher risk of depression and anxiety when they became adults. “This is important for us to know since childhood cancer survivors are living longer and longer,” stated Lacouture. “I favor the term ‘persistent’ because that connotes that there is something that can be done. If you see a patient and you tell them they have ‘permanent’ chemotherapy-induced alopecia, that means there is probably nothing that can be done. I don’t think we know yet that there is nothing that can be done, and the histology does not support the notion that there is nothing that can be done,” he said. It is important to evaluate chemotherapy-induced alopecia at baseline and again every 3 months with standardized photos, trichoscopies, and, in some cases when inflammation or infection is suspected, with scalp biopsies. This allows for careful quantification, as patients who rely on memory can be very disappointed by their hair regrowth.

powders, thickeners, and wigs are also recommended. In observational and autopsy studies, scalp cooling has been shown to be safe and cost-effective for alopecia prevention. According to some studies, in patients who develop complete alopecia, shaving the head is less traumatic than seeing clumps of hair falling out. Additionally, in anecdotal studies, about 65% of patients report changes in

tors develop a myriad of skin toxicities and infections. Therefore, alopecia is not only a mechanism-based effect; it can also be a consequence of infection. Patients can present with alopecia that is actually an infection on the scalp, Lacouture explained. “The problem with this and what makes patients very upset,” he said, “is that once these patients have an infection on the scalp, it leads to a scar. And when there is a scar on the scalp the hair is never going to grow back there again. This is a very undertreated problem.” Patients on EGFR inhibitors who develop crust on their scalp should have the areas cultured; these patients are likely to have an infection that will need oral antibiotics, Lacouture advised.

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LETTER

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EDITOR-IN-CHIEF

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

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

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

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

Sonali M. Smith, MD

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

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

2014 PROSPECTUS

Steve M. Horwitz, MD

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

Supported by an educational grant from Celgene Corporation

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Side Effects Management

Generic Docetaxel Increases Neutropenia Risk and Healthcare Costs Caroline Helwick

he use of generic docetaxel instead of branded docetaxel appears to be associated with a significantly higher event rate of neutropenia, as well as increased healthcare costs, during the 6 months following drug initiation, according to a US Oncology Research study that compared resource utilization and costs.1 The study authors found that breast cancer patients treated with generic docetaxel were about 40% more likely to have a medical claim for neutropenia, relative to branded docetaxel treatment. This cost the healthcare system an additional $9000 per patient, reported Stephen Jones, MD, and colleagues at the American Society of Clinical Oncology 2014 annual meeting. Before and after its approval in March 2011 in the United States, generic docetaxel has raised some concerns. It has been reported that 90% of the generic docetaxel formulations contain an insufficient amount of active drug, high levels of impurities, or both, which can affect both efficacy and safety.2 The authors compared the disease burden and resource utilization of 1955 breast cancer patients treated with the 2 taxanes between April 2011 and June 2012. The retrospective inception cohort study used the Clinformatics DataMart national healthcare claims database, which contains clinical diagnoses, therapeutic procedures, pharmacy dispensing records, and healthcare resource utilization and expenditures from a large US national health insurer. The study examined emerging differences between generic and branded formulations during the 6 months after docetaxel initiation by using a hierarchical mixed effects model for adjustment of patient characteristics during the 6 months prior to starting the drug. The final analysis included 360 patients whose baseline characteristics were similar, including use of anthracy-

clines, cyclophosphamide, and growth factors, as well as comorbidities and the occurrence of prior neutropenia. More Problems With Generics at 6-Month Follow-up During the 6-month follow-up period, the generic docetaxel cohort showed a higher rate of healthcare claims for neutropenia (67.3% vs 48.9%; P < .01) and malaise and fatigue (22.4% vs 13.7%; P < .05) compared with the branded docetaxel cohort. However, the branded cohort had higher rates of nausea and vomiting (43.5% vs 29.6%; P = .02) than the generic cohort. The following baseline variables were adjusted for the estimation of neutropenia: age, baseline neutropenia, inpatient admission, total healthcare costs, adjuvant therapy, comorbidities, use of

The study authors found that breast cancer patients treated with generic docetaxel were about 40% more likely to have a medical claim for neutropenia, relative to branded docetaxel treatment. granulocyte colony-stimulating factor (G-CSF) and fosaprepitant, and number of treatment cycles. Fosaprepitant, which is indicated for the prevention of delayed vomiting, can cause neutropenia (<1%). After these adjustments, the rate of neutropenia remained higher with generic than with branded docetaxel (73.9% vs 52.8%; P < .01), even after accounting for history of neutropenia and baseline use of G-CSF or fosaprepitant.

In addition, the generic group used more fosaprepitant at follow-up than the branded group (54.1% vs 30.2%; P < .01). Fosaprepitant use increased the odds of developing neutropenia almost 2.5-fold among generic docetaxel users versus those using the branded drug (P = .03); in the absence of fosaprepitant, neutropenia was 1.4 times higher in the generic group, but this was not statistically significant (P = .31). Further investigation showed that the difference in neutropenia between generic and branded docetaxel (58.4% vs 35.4%; P = .003) was observed only in patients without a history of neutropenia, whereas there was no betweengroup difference seen in patients with a prior diagnosis of neutropenia at baseline, in which case the risk was approximately 98% regardless of drug used. Generic Costs Were Actually Higher Excluding the cost of branded docetaxel, the mean outpatient cost after initiating treatment was significantly higher for generic docetaxel in both the unadjusted model and the model adjusted for age, comorbidities, inpatient admissions, total costs, and adjuvant therapy at baseline. In the unadjusted model, the mean cost was $59,177 for the generic cohort and $50,243 for the branded cohort (P = .009), and the cost remained significantly higher after adjustments for baseline healthcare costs, inpatient admissions, and other baseline patient characteristics ($54,282 vs $46,698; P = .03). The mean total healthcare costs after initiating treatment were $83,982 with generic docetaxel and $74,832 with branded docetaxel (P = .05) in the unadjusted model and $76,454 versus $70,736, respectively (P = .22) in the adjusted model. “The cost differential seems more than offsetting the potential differ-

ence in acquisition costs relative to the branded docetaxel,” the authors suggested in a poster.

It has been reported that 90% of the generic docetaxel formulations contain an insufficient amount of active drug, high levels of impurities, or both, which can affect both efficacy and safety. William Sikov, MD, of Brown University in Providence, Rhode Island, commented while viewing the poster that he found the results interesting and somewhat surprising. He said that he is not aware of whether the patients in his center receive branded or generic products but that he has had some concerns and has often questioned whether generic products may, indeed, be equivalent. “At times, I have tried to influence the pharmacy to buy a brand name, when the cost differential is minimal, but have been told that I am not allowed [to request that],” he said. “I wonder if the pharmacokinetics are really the same? We are given assurances by the FDA, but we don’t know how extensively they are really tested.” l References

1. Jones SE, Liao L, Xiao Z, et al. Resource utilization in patients with breast cancer treated with generic versus branded docetaxel. J Clin Oncol. 2014;32(15 suppl):1015. Presented at: 50th Annual Meeting of the American Society of Clinical Oncology; May 30-June 3, 2014; Chicago, IL. Abstract 1015. 2. Vial J, Cohen M, Sassiat P, et al. Pharmaceutical quality of docetaxel generics versus originator drug product: a comparative analysis. Curr Med Res Opin. 2008; 24(7):2019-2033.

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side effects management

Vaginal DHEA May Improve Sexual Function in Women With Breast/Gynecologic Cancer Meg Barbor

aginal dehydroepiandrosterone (DHEA) may improve sexual function, without negative systemic effects, in women with breast and gynecologic cancer with vaginal and sexual-related complaints. Breast and gynecologic cancer patients can experience a range of symptoms associated with sexual dysfunction, among them vaginal dryness and dyspareunia. According to findings presented by Debra Barton, RN, PhD, AOCN, at the Multinational Association of Supportive Care in Cancer/International Society of Oral Oncology 2014 annual meeting, effective treatment is needed for female sexual dysfunction associated with breast and gynecologic cancer, and vaginal DHEA has proven beneficial. Current Interventions The vagina is highly regulated by estrogen. “When estrogen is depleted it leads to changes in vaginal tissues, resulting in a vagina that is dry, uncomfortable, and susceptible to infections,” said Barton, professor and the Mary Lou Willard French Endowed Chair in Oncology at the University of Michigan School of Nursing in Ann Arbor.

Previous work with DHEA has supported the hypothesis that when used vaginally it does not produce systemic effects.

The focus of treatment for vaginal symptoms is local, noted Barton. Current evidence-based interventions include lubricants, which are used solely for the purpose of reducing friction during intercourse, and vaginal moisturizers, which are used several times a week and for the purpose of hydrating vaginal tissue. Vaginal estrogen is the gold standard for treatment, but it is a last resort in women with cancer due to safety concerns. “There is a need for effective treatment without systemic estrogenic effects,” Barton said. DHEA—A Possible Solution “One possible solution is DHEA,” said Barton. DHEA is a prohormone made by the adrenal gland. A prohormone

October 2014 I VOL 7, NO 4

has no known activity in and of itself but has to be converted, mostly in target tissue, to either estrogens or androgens. Previous work with DHEA has supported the hypothesis that when used vaginally it does not produce systemic effects. Barton and her colleagues conducted a study on postmenopausal women with a history of breast/gynecologic cancer who had completed chemotherapy and radiation and had no evidence of disease. Women were eligible if they reported at least moderately severe vaginal complaints present for no less than 2 months. This analysis of secondary physiological end points examined the impact of vaginal DHEA on vaginal health, hormone concentrations, bone turnover, and sexual function. A total of 464 women were accrued from 82 sites; 21 withdrew prior to randomization and 2 could not classify worst symptom. The remaining women were randomized to study arms of 3.25 versus 6.5 mg of DHEA versus plain moisturizer (PM). DHEA was compounded into a bioadhesive vaginal moisturizer gel, which was designed to adhere to the vaginal wall. Women inserted the DHEA using a prefilled syringe nightly for 12 weeks, just before sleep and subsequent to any sexual activity. Laboratory tests, maturation index, and vaginal pH were evaluated at baseline and again at 12 weeks. Safety and Physiological Effects Blood samples were taken from the 147 women on each of the 3 study arms; a total of 47 women provided pre- and postvaginal tissue samples. Women in all arms experienced a decrease in pH, which is the desired direction, with a greater decrease in the DHEA arms. While none in the control arm (who had levels >5 at baseline) achieved a pH 5, this lower level was achieved by 9% with DHEA 3.25 mg and 7% with DHEA 6.5 mg. Vaginal cell maturation (no intermediate superficial cells vs some/ any) was observed in 100% receiving DHEA 3.25 mg, 86% with DHEA 6.5 mg, and 64% with PM. Regarding systemic hormone concentrations, DHEA levels increased in each DHEA arm, significantly different from the PM group. However, while the increases were considered to be significant, these values at 12 weeks were not out of line with the normal range for women in that age group, Barton explained. Bone biomarkers were essentially

Table Results of FSFI Questionnairea No DHEA, mean

3.25-mg DHEA, mean

6.5-mg DHEA, mean

Desire

.5b

Arousal

.7b

1.0b

1.1

1.3

3.0b

Orgasm

1.0

Satisfaction

1.1b

Pain

1.0

1.4b

2.0b

Overall total

3.8

5.5

7.1b

FSFI Subscale

Lubrication

Abbreviations: DHEA, dehydroepiandrosterone; FSFI, Female Sexual Function Index. a Higher numbers equal better function. b Statistically significant difference compared with no DHEA.

unchanged. “Based on our data, there is no evidence that vaginal DHEA was having effects on the bones,” she added. A lack of effect on bone markers indicates the absence of estrogenic activity.

Self-reported adverse effects included vaginal discharge, which was experienced by women in all 3 arms.

accompanied by hormone changes, although these changes were small and concentrations for all hormones still stayed in the lower normal ranges. Based on the bone biomarker data, there was no indication of extravaginal effects of the DHEA. The adverse and physiological effects led to the hypothesis that vaginal DHEA is working through androgenic means at the site of the vagina, with only minor systemic androgenic effects. Based on these data, Barton and her colleagues concluded that DHEA improved physiological vaginal health and overall female sexual function more than did PM alone. l Reference

DHEA—Did It Work? In all arms, a significant reduction in the primary symptom was observed compared with baseline, with severity reduced by almost half, and there were no significant differences between the study arms. “However, the 2 doses of DHEA did significantly improve sexual function, with the 6.5-mg dose improving every single subscale of sexual function except for orgasm,” Barton noted (Table). Self-reported adverse effects included vaginal discharge, which was experienced by women in all 3 arms, as well as voice change experienced by women in the DHEA arms. “In concert possibly with the testosterone levels, we did see some evidence of androgenic side effects, with voice change being statistically different in the DHEA arms compared to moisturizer, although these differences are quite small,” added Barton. This study provided evidence of some systemic absorption of DHEA

Barton D, Sloan JA, Shuster LT, et al. Physiologic effects of vaginal dehydroepiandrosterone (DHEA): Alliance Trial N10C1. Presented at: 2014 Annual Meeting of the Multinational Association of Supportive Care in Cancer/International Society of Oral Oncology; June 26-28, 2014; Miami, FL.

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CONTINUING EDUCATION

Faculty Perspectives

OCTOBER 2014 • VOLUME 5 • NUMBER 1

™

Latest Treatment Advances for Individualized Care of Breast Cancer

PUBLISHING STAFF Group Director, Sales & Marketing John W. Hennessy john@greenhillhc.com Editorial Director Susan A. Berry susan@coexm.com Senior Copy Editor BJ Hansen Copy Editors Dana Delibovi Rosemary Hansen The Lynx Group President/CEO Brian Tyburski Chief Operating Officer Pam Rattananont Ferris Vice President of Finance Andrea Kelly 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 and ESMO 2014 as well as expert perspectives on the application of the data to daily patient care. The first issue will focus on the latest advances in the treatment of breast cancer, with subsequent issues covering the topics of non-small-cell lung cancer, metastatic melanoma, and colorectal cancer.

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FACULTY

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 Web Content Managers David Maldonado Anthony Trevean Digital Programmer Michael Amundsen Meeting & Events Planner Linda Sangenito Senior Project Managers Alyson Bruni Jini Gopalaswamy Project Manager Deanna Martinez

Lisa A. Carey, MD Physician-in-Chief, North Carolina Cancer Hospital Chief, Division of Hematology-Oncology UNC School of Medicine Preyer Distinguished Professor in Breast Cancer Research Medical Director, UNC Breast Center Lineberger Cancer Center University of North Carolina Chapel Hill, NC Lillie D. Shockney, RN, BS, MAS University Distinguished Service Associate Professor of Breast Cancer Johns Hopkins University School of Medicine Baltimore, MD

Atheer A. Kaddis, PharmD Senior Vice President Sales and Business Development Diplomat Specialty Pharmacy Flint, MI

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October 2014 I VOL 7, NO 4

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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 Lisa A. Carey, MD Physician-in-Chief, North Carolina Cancer Hospital Chief, Division of Hematology-Oncology, UNC School of Medicine Preyer Distinguished Professor in Breast Cancer Research Medical Director, UNC Breast Center Lineberger Cancer Center, University of North Carolina Chapel Hill, NC Lillie D. Shockney, RN, BS, MAS University Distinguished Service Associate Professor of Breast Cancer Johns Hopkins University School of Medicine, Baltimore, MD Atheer A. Kaddis, PharmD Senior Vice President, Managed Markets/Clinical Services Diplomat Specialty Pharmacy, Flint, MI Term of Offering Estimated time to complete activity: 1.0 hour Date of initial release: October 15, 2014 Valid for CME/CPE/CE credit through: October 15, 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. Physician Credit Designation Global Education Group designates this enduring material for a maximum of 1.0 AMA PRA Category 1 Credit™. Physicians should claim only the credit commensurate with the extent of their participation in the activity.

Global Education Group is accredited by the Accreditation Council for Pharmacy Education as a provider of continuing pharmacy education. Nursing Continuing Education Global Education Group is accredited as a provider of continuing nursing education by the American Nurses Credentialing Center’s COA. This educational activity for 1 contact hour is provided by Global Education Group. Nurses should claim only the credit commensurate with the extent of their participation in the activity. Pharmacist Accreditation Statement Global Education Group is accredited by the Accreditation Council for Pharmacy Education as a provider of continuing pharmacy education. Credit Designation Global Education Group designates this continuing education activity for 1 contact hour(s) (0.1 CEU) of the Accreditation Council for Pharmacy Education. (Universal Activity Number 0530-9999-14-186-H01-P) This is a knowledge-based activity. For information about the accreditation of this program, please contact Global at 303-395-1782 or inquire@globaleducationgroup.com System Requirements PC

Windows 7 or above Flash Player v10.0 or higher Internet Explorer v9.0 or higher Latest version of Firefox, Google Chrome, or Safari Adobe Acrobat Reader v7.0 or higher*

MAC

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/CE activity: Name of Faculty or Presenter Lisa A. Carey, MD Lillie D. Shockney, RN, BS, MAS Atheer A. Kaddis, PharmD

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

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life partner have with commercial interests related to the content of this CME/CPE/CE activity: Name of Planner or Manager Reported Financial Relationship Susan Berry Nothing to disclose Andrea Funk Nothing to disclose Sy Schlager Nothing to disclose Amanda Glazar, PhD Nothing to disclose Ashley Marostica, RN, MSN Nothing to disclose Disclosure of Unlabeled Use This educational activity may contain discussion of published and/or investigational uses of agents that are not indicated by the FDA. Global Education Group (Global) and Center of Excellence Media, LLC, do not recommend the use of any agent outside of the labeled indications. The opinions expressed in the educational activity are those of the faculty and do not necessarily represent the views of any organization associated with this activity. Please refer to the official prescribing information for each product for discussion of approved indications, contraindications, and warnings. Disclaimer Participants have an implied responsibility to use the newly acquired information to enhance patient outcomes and their own professional development. The information presented in this activity is not meant to serve as a guideline for patient management. Any procedures, medications, or other courses of diagnosis or treatment discussed in this activity should not be used by clinicians without evaluation of patient conditions and possible contraindications on dangers in use, review of any applicable manufacturer’s product information, and comparison with recommendations of other authorities. To obtain a digital version, download a free QR code app on your SmartPhone and then scan this code.

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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 breast cancer (BC) treatment presented at these meetings. Lisa A. Carey, MD, of the University of North Carolina School of Medicine and UNC Breast Center; Lillie D. Shockney, RN, BS, MAS, of Johns Hopkins University School of Medicine; and Atheer A. Kaddis, PharmD, of Diplomat Specialty Pharmacy, after reviewing the presented data, provide their key take-home messages for community oncology practices.

Weekly Paclitaxel and Trastuzumab With or Without Lapatinib: Gene Expression Signatures At ASCO 2014, Carey and colleagues presented results from Cancer and Leukemia Group B (CALGB) 40601, a neoadjuvant phase 3 trial that evaluated weekly paclitaxel and trastuzumab with or without lapatinib in 305 patients with stage II–III human epidermal growth factor receptor 2 (HER2)positive BC.1 Patients were randomly assigned to receive 16 weeks of preoperative paclitaxel and trastuzumab; paclitaxel, trastuzumab, and lapatinib; or paclitaxel and lapatinib, and were observed for pathologic complete response (pCR). Previous results showed that the addition of lapatinib did not statistically significantly impact pCR,2 but did show that response to chemotherapy and HER2 targeting varied by molecular subtype. In the present study, the investigators used mRNA sequencing to determine gene expression in 271 pretherapy samples and in 136 matched posttherapy samples. The investigators found that HER2-positive disease is molecularly heterogeneous: 30%

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were the Luminal A intrinsic subtype, 31% Luminal B, 31% HER2-Enriched, 5% Basal-Like, 2% Normal-Like, and 1% Claudin-Low. The pCR rates varied significantly according to subtype: pCR was 34% for Luminal A; 36% for Luminal B; 36% for Basal-Like; and 70% for HER2-Enriched (P<.0001). Gene expression studies also showed that several other variables in addition to treatment significantly and independently affected pCR, including immune cells, proliferation, and having a p53 mutation. The investigators concluded that with pCR rates in excess of 70% in the HER2-Enriched samples with paclitaxel and trastuzumab alone, dual HER2-targeting or more aggressive chemotherapy may be unnecessary in that biologic subtype.1 Perspectives I am obviously biased about this abstract, but I think it is a seminal study for several reasons. First, it was designed to answer clinical and correlative

october 2014 I VOL 7, NO 4

CONTINUING EDUCATION questions simultaneously, and second, simultaneous examination showed that while treatment mattered in HER2-positive BC, it only mattered a little, and that equally important were biologic considerations such as intrinsic subtype (the HER2-Enriched subtype had double the pCR rates regardless of treatment arm) and microenvironment (expression of immune cells significantly and independently influenced pCR). These findings should be replicated in other datasets, but if confirmed, they suggest that we may be able to identify tumors with an excellent outcome with minimal chemotherapy and single HER2 targeting. -Lisa A. Carey, MD This is valuable research using epigenetics to help guide decisions about which genes need to be targeted and with what systemic agent in order to increase the likelihood of the best pathologic response to treatment. Recognizing that patients with these stages of BC and prognostic factors are at increased risk of recurrence, such results provide optimism for the longevity of these patients. Incorporating the risk of recurrence into the drug selection provides added information about what combination of drugs may produce the best results. -Lillie D. Shockney, RN, BS, MAS As we have observed in clinical trials, including those in BC, genetic subtypes can play a major role in treatment efficacy. However, results from this clinical trial demonstrated that the addition of the oral oncolytic lapatinib does not improve pCR rates, compared with trastuzumab and paclitaxel alone, for the most common biologic subtypes. Not only is this consistent with past results, it also provides value in that it may spare some patients unnecessary added therapies that may not improve outcomes. -Atheer A. Kaddis, PharmD

Neoadjuvant Lapatinib Plus Trastuzumab for Early Breast Cancer in Patients With PIK3CA Mutations At ESMO 2014, Guarneri and colleagues presented results from CherLOB, a study that included 121 patients with HER2-positive early-stage BC who were randomly assigned to neoadjuvant anthracycline-/taxane-based chemotherapy plus trastuzumab, lapatinib, or both.3 PIK3CA mutations were evaluated in 106 of the 121 patients, in an effort to evaluate the correlation of PIK3CA mutational status with pCR. Exon 9 and exon 20 PIK3CA mutations were evaluated on formalin-fixed paraffin-embedded core biopsies using pyrosequencing. The researchers also conducted an event-based pooled analysis of several trials (NeoALTTO and GeparSixto) that reported pCR events according to PIK3CA mutation status. Results showed that 22 (20.8%) of the 106 evaluable patients in CherLOB had a PIK3CA mutation. Rates of pCR in both CherLOB and the pooled analysis were similar between patients who had wild-type PIK3CA (33.3%) and those who had a PIK3CA mutation (22.7%). However, patients with wild-type PIK3CA who had received trastuzumab plus lapatinib were more likely to achieve pCR compared with those who had a PIK3CA mutation (48.5% vs 12.5%; P=.06). The researchers concluded that the increased activity of the dual anti-HER2 blockade of trastuzumab plus lapatinib appears to be limited to tumors that do not have PIK3CA mutations.3 Perspectives This is another interesting study that suggests that fundamental features of the tumor are as important as the drugs we give in determining responsiveness. In this case, the presence of activating mutations in PIK3CA, which has long been known to interact with HER2 signaling, conferred resistance to HER2 targeting. Given the high cost of dual HER2 targeting, identifying those tumors likely to truly benefit is crucial. -Lisa A. Carey, MD In the past, we had limited prognostic information when assessing patients with early-stage BC, such as grade and estrogen receptor (ER), progesterone receptor (PR), and HER2 receptor status. However, we have now entered an age of personalized medicine, and our prognostic tools continue to evolve. I think this is evidenced by results of the CherLOB study,

October 2014 I VOL 7, NO 4

which reinforce the value of using genetic information from BC cells to tailor treatment more effectively. -Lillie D. Shockney, RN, BS, MAS

Genomic Analysis of Immune Function Genes and Clinical Outcomes Results from the North Central Cancer Treatment Group N9831 adjuvant trastuzumab trial were presented by Perez and colleagues at ASCO 2014.4 Because 20% to 25% of patients with HER2-positive BC relapse after adjuvant trastuzumab, the investigators used a genomic approach (whole-genome DASL® technology) to identify genes associated with relapse-free survival (RFS) among 1282 patients enrolled in the trial. They used Cox proportional hazard ratios (HRs) to determine the association between genes and RFS for 433 patients who received chemotherapy alone and 849 patients who received chemotherapy plus trastuzumab. Ten of 13 significantly enriched biological processes associated with increased RFS (P<.01) were linked to immune functions, and these 10 processes defined a cohort of 87 immune function genes. Patients with immune-enriched tumors based on the 87 genes had a more favorable outcome when given trastuzumab (HR, 0.36; P<.0001). Patients whose tumors were not immune enriched had similar outcomes regardless of whether or not they were treated with trastuzumab (HR, 0.99; P=.91). Among patients who received chemotherapy alone, enriched immune function was not associated with increased RFS (HR, 1.01; P =.96). The investigators concluded that improved RFS after treatment with adjuvant trastuzumab may be associated with a heightened state of immunological function, and may indicate a significant biological process linked to the efficacy of HER2-targeted therapy, provide a method of predicting relapse probability after treatment with adjuvant trastuzumab, and lead to a discovery of possible routes of therapeutic enhancement.4 Perspectives In N9831, which is one of the seminal adjuvant trastuzumab trials, the benefit of trastuzumab was driven by those tumors with high immune function expression. This is now the third cooperative group trial to find that the immune microenvironment is a key contributor to response to HER2 targeting; the others are the CALGB 40601 trial,1 which examined immune signatures, and the FinHER trial,5 which examined tumor-infiltrating lymphocytes. -Lisa A. Carey, MD Science has finally reached a critical juncture in which immunological function can be identified and targeted. As shown in N9831, this may indicate a significant biological process linked to the efficacy of HER2targeted therapy and provide a method of predicting relapse probability after treatment with adjuvant trastuzumab. This is an excellent example of personalized medicine, targeting the genomic behavior of the tumors. -Lillie D. Shockney, RN, BS, MAS This clinical trial evaluated the impact of specific gene targeting in patients with immune function enrichment. Adding an immune targeting agent such as trastuzumab to chemotherapy for such patients provided higher RFS than chemotherapy alone. This demonstrates the importance of genetic testing and suggests that appropriate targeting with current therapies may lead to better outcomes for patients with BC. -Atheer A. Kaddis, PharmD

Women Who Choose Mastectomy for Early-Stage Breast Cancer Overestimate Their Risk Covelli and colleagues reported at ASCO 2014 on results of their study that sought to understand why mastectomy rates have been increasing.6 They conducted a grounded-theory qualitative study to examine the surgeon’s practice and the patient’s decision-making that led to a choice for unilateral mastectomy (UM) and/or contralateral prophylactic mastectomy (CPM). The study population consisted of 45 surgeons across Ontario, Canada, and 29 female patients in Toronto who were eligible for breast-conserving thera-

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FACULTY PERSPECTIVES py but opted for UM with or without CPM. The investigators collected data through semistructured interviews and used constant comparative analysis to identify key ideas. Results showed a desire for control to be the motivation behind the patients’ decision; the women believed they could improve their outcomes by undergoing more extensive surgery. Surgeons described breast-conserving therapy and UM as equivalent treatment options for early-stage BC but frequently recommended the breast-conserving option and discouraged CPM as there is no evidence of survival advantage. Despite surgeon recommendations, women often initiated a request for UM plus CPM, and their requests for CPM appeared to be most influenced by their personal experiences with family and friends and not their surgical consultation. Previous negative experience with BC led the women to overestimate their risk of recurrence, contralateral cancer, and subsequent mortality; thus, women chose UM plus CPM to ensure they would “never go through this again.” Although they remained confident in their choice, many women interviewed continued to experience pain and issues with cosmesis and body image after UM with or without CPM. The investigators recommend more education, including exposure to other patients’ postoperative concerns, to assist in decision-making.6 Perspectives This study reinforces the emerging finding that fear, rather than information, drives some women’s decision for mastectomy over breast conservation. Although mastectomy may be a reasonable choice for some, it is a morbid procedure, and it is important that patients are fully informed about the risk of local recurrence as well as complications of therapy for both mastectomy and breast conservation. -Lisa A. Carey, MD This research confirms that although there may not be a clinical reason (eg, increased survival rates) for having CPM, patients with early BC still seek it out for peace of mind, as well as for desired cosmetic results. Body image is an important quality-of-life factor that should not be ignored. Providing more education about the facts associated with doing prophylactic surgery of this kind and what outcomes the patient might expect, and comparing these to the desired outcomes, are important in the decision-making process. When a patient inquires about CPM, surgeons should engage in a more specific discussion as to what exactly is the driving force for this being requested. This will help ensure that a patient is not requesting it for a reason that such surgery will not provide—improved survival. -Lillie D. Shockney, RN, BS, MAS

Impact of Physicians on Cancer Screening Despite the success of cancer screening in reducing morbidity and mortality, participation remains suboptimal. At ASCO 2014, Chen and Cheung reported on results of a study designed to characterize the frequency of breast, colorectal, cervical, and prostate cancer screening in a US population–based setting of 7327 patients of average risk; describe the clinical factors associated with screening uptake; and examine the effect of patient contact with their physicians and the quality of these interactions in modifying screening behavior.7 The investigators developed a scoring system, based on patientreported patterns of care, to characterize the quality of patients’ interactions with physicians. Results showed screening rates to be suboptimal in each of the cancer cohorts (Table 1). Patients of advanced age, those with a family history of any cancer, high-income earners, those who visited their physicians frequently, and those who rated their interactions with their physicians highly were generally more likely to undergo screening. Although quality of the physician was a stronger predictor of screening than frequency of physician contact, the odds of screening were greatest for patients who indicated both frequent and high-quality interactions with their physicians. The investigators concluded that interventions to improve both of these provider-related factors may improve cancer screening rates.7 Perspectives These results mirror those from studies in non-cancer populations that

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Table 1. Cancer Screening Rates and Odds Ratios for Patients More Likely to Undergo Screening7

Cancer screening rate (%)

Breast Cancer (n=1696)

Colorectal Cancer (n=2377)

Cervical Cancer (n=2240)

Prostate Cancer (n=1014)

Characteristics associated with cancer screening (odds ratio) Advanced age

0.99

1.05a

0.96

1.06

Family history

1.26

1.17

1.10

1.82a

High income

1.08

1.22a

1.18a

1.22a

Frequent visits with physician

1.41a

1.36a

1.06

1.39a

Good interactions with physician

1.87a

1.27a

1.67a

1.19

P<.05.

suggest that healthy behaviors are augmented in patients who are being cared for regularly in the healthcare system. While one explanation may be that these patients were more aware of screening needs because of their interactions with physicians, another equally plausible explanation may be that their screening behavior and their interaction with physicians are both separately reflective of healthy behavior. Not surprisingly, those with exposure to cancer risk directly through a family member were also more likely to undergo screening themselves. -Lisa A. Carey, MD The quality of the physician, as rated by the patient, plays a significant role in whether cancer screening is pursued after a visit. Although the frequency of the visits also carried weight, combining both quality and frequency seems to be the most likely way to encourage patients to follow through with the screenings they need. Often, when a patient is visiting his or her doctor, it is for an acute illness. The majority of the time spent with the doctor during that visit is dedicated to determining the cause of that illness and providing appropriate treatment. Providers need to remember that every encounter with their patient is an opportunity to provide personalized care and to discuss overall healthcare needs, including cancer screening and monitoring tests. -Lillie D. Shockney, RN, BS, MAS

Confidence in Efficacy of Cancer Screening in Vulnerable Versus Nonvulnerable Populations Since 2005, EDIFICE surveys have been conducted every 3 years to characterize behavior related to recommended, organized breast and colorectal cancer screening services. In the present study, Eisinger and colleagues focused on levels of confidence in screening efficacy for cancer locations for which only opportunistic screening is available, and presented their results at ASCO 2014 comparing vulnerable and nonvulnerable populations.8 They conducted phone interviews with 1600 individuals between the ages of 40 and 75 years, using the method of quotas, and assessed opinions on efficacy of cancer screening for 8 anatomic locations. The investigators analyzed data according to a validated vulnerability score. Results showed that for cancer locations with no organized screening services, the level of confidence in screening efficacy was high, and significantly higher in vulnerable than in nonvulnerable populations (Figure 1a). Organized screening programs resulted in similarly high levels of confidence in the 2 populations (Figure 1b). The investigators concluded that their results showed an excess of confidence in the efficacy of cancer screening, especially by vulnerable populations. They believe that individuals may allow themselves greater exposure to known risk factors because they feel protected by screening (a phenomenon termed “moral hazard”).8 Perspectives Both vulnerable (in this case defined as patients with unhealthy habits or behaviors) and nonvulnerable populations have equally high confidence

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CONTINUING EDUCATION

Figure 1a. Level of confidence in screening efficacy for cancer locations with no organized screening programs8 180

Nonvulnerable population Vulnerable population

160

Patients (%)

140 120

78% P<.05

100

60%

56%

48%

52%

63%

59%

60 40

27%

85%

69%

67%

20 0

34% Lung Cancer

Leukemia

Gastric Cancer Liver Cancer

Esophageal Central Nervous Cancer System Cancers

Figure 1b. Level of confidence in screening efficacy for cancer locations with organized screening programs8 250

Patients (%)

200 150

Nonvulnerable population Vulnerable population

96%

94%

95%

92%

100 50 0

Breast Cancer

Colorectal Cancer

in known screening for breast and colon cancer, but a high proportion of the vulnerable population also believes that screening for diseases for which we do not have validated tools is effective. This may reflect irrational exuberance, or a lack of health literacy resulting in both incorrect beliefs regarding screening tools and unhealthy habits. Either way, it is a problem. -Lisa A. Carey, MD This research study points out the need for more consumer education regarding the purpose of specific types of cancer screenings. Breast cancer screening using mammography can be misinterpreted by a patient as being in some way a form of protection from the disease when the goal is early detection. On the flip side, colonoscopies can prevent colorectal cancer by identification and removal of colon polyps. In recognition of the higher risk of developing cancer among vulnerable populations, there is a need for more education regarding risk factors for various types of cancer and promotion of healthier lifestyle behaviors to help reduce risk. Clinicians as well as community outreach workers need to take advantage of every patient and consumer encounter to correct the myths and reinforce the facts. -Lillie D. Shockney, RN, BS, MAS

Adjuvant Exemestane Plus Ovarian Function Suppression Compared With Tamoxifen Plus Ovarian Function Suppression in Premenopausal Women With Hormone Receptor–Positive Breast Cancer Adjuvant endocrine therapy with aromatase inhibitors (AIs) compared with tamoxifen has previously been shown to improve outcomes in postmenopausal women with hormone receptor–positive BC. At ASCO 2014,

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Pagani and colleagues presented the results of the Tamoxifen and Exemestane Trial (TEXT) and the Suppression of Ovarian Function Trial (SOFT).9 These phase 3 trials were designed to examine whether adjuvant AI therapy improved outcomes in premenopausal women with hormone receptor–positive BC treated with ovarian function suppression (OFS) and to determine the value of OFS in women who remain premenopausal and are eligible for adjuvant tamoxifen therapy. Between the years 2003 and 2011, the 2 trials collectively enrolled 5738 premenopausal women with hormone receptor– positive early-stage BC (TEXT, n=2672; SOFT, n=3066). In TEXT, patients were randomly assigned within 12 weeks of surgery to 5 years of exemestane plus OFS or tamoxifen plus OFS. Chemotherapy was optional and concurrent with OFS. In SOFT, patients were randomly assigned to 5 years of exemestane plus OFS, tamoxifen plus OFS, or tamoxifen alone, either within 12 weeks of surgery if no chemotherapy was planned, or within 8 months of completing neoadjuvant or adjuvant chemotherapy. OFS was accomplished by a choice of 5 years of triptorelin, oophorectomy, or ovarian irradiation. The primary end point of the joint analysis was disease-free survival (DFS). After a median follow-up of 5.7 years, 514 (11%) DFS events were found in the intention-to-treat population comparing exemestane plus OFS (n=2346) versus tamoxifen plus OFS (n=2344). Patients who were given exemestane plus OFS had a significantly reduced risk of recurrence (HR, 0.72; 95% confidence interval [CI], 0.60–0.86; P=.0002) compared with those given tamoxifen plus OFS, with results showing a 5-year DFS rate of 91.1% versus 87.3%. The investigators found similar reductions for secondary end points of BC-free interval (HR, 0.66; 95% CI, 0.55–0.80), rate of freedom from BC at 5 years (92.8% vs 88.8%), and distant recurrence-free interval (HR, 0.78; 95% CI, 0.62–0.97). However, no reduction in overall survival (OS) with exemestane plus OFS was seen at this early follow-up (HR=1.14; 95% CI, 0.86–1.51). Grade 3/4 adverse events (AEs) were reported in 31% of patients given exemestane plus OFS and in 29% of patients given tamoxifen plus OFS.9 Perspectives The combined analysis from SOFT and TEXT found that in premenopausal women, it was better to give ovarian suppression plus an AI than ovarian suppression plus tamoxifen. This differed from the results of the ABCSG-12 study,10 in which there was a survival disadvantage to the AI arm. There are potential methodologic reasons for the discrepancy; regardless, the question that has not yet been answered is the extent to which either of these approaches improves outcome over tamoxifen alone. Clearly, there are quality-of-life and comorbidity complications related to premature loss of ovarian function. We hope that this question will be answered at the San Antonio Breast Cancer Symposium in December 2014. -Lisa A. Carey, MD New information regarding the management of hormone receptor–positive BC is being generated with considerable speed now that clinical trials that required 5 years of treatment have concluded. This study showed that those patients given exemestane plus OFS had a significantly reduced risk of recurrence. It is, however, important to remember that AEs from OFS as well as from hormonal drugs impact the quality of life for this patient population, making it more difficult for some to adhere to these treatment guidelines. Minimizing side effects needs to be part of the treatment planning process. -Lillie D. Shockney, RN, BS, MAS These results demonstrate again the advantages of AIs plus OFS over the use of tamoxifen plus OFS. Aromatase inhibition has become the standard of care as adjuvant endocrine therapy for premenopausal patients with BC. The risk of AEs is similar to those we have seen with tamoxifen. -Atheer A. Kaddis, PharmD

First-Line Pertuzumab, Trastuzumab, and Docetaxel in Patients With HER2-Positive Metastatic Breast Cancer At ESMO 2014, Swain and colleagues discussed final results from the

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FACULTY PERSPECTIVES CLEOPATRA trial, in which 808 patients with HER2-positive metastatic BC (MBC) were randomly assigned to either first-line placebo/trastuzumab/ docetaxel or pertuzumab/trastuzumab/docetaxel.11 The primary end point of the study was progression-free survival (PFS) (independently assessed). Secondary end points included PFS (investigator-assessed), objective response rate, safety, and OS. An interim analysis previously reported in May 2011 showed that pertuzumab increased PFS significantly; by the second interim analysis in May 2012, OS had also improved to a statistically significant, clinically meaningful degree. In July 2012, patients in the placebo arm were offered the chance to cross over to pertuzumab. After a median follow-up of 50 months, OS was shown to be 56.5 months for patients in the pertuzumab arm, compared with 40.8 months in the placebo arm (HR, 0.68; P=.0002). PFS was 18.7 months in the pertuzumab arm compared with 12.4 months in the placebo arm (HR, 0.68; P<.0001). The median time spent on study treatment was 17.4 months for patients in the pertuzumab arm compared with 11.4 months for those in the placebo arm. Side effects experienced by patients in the pertuzumab arm included diarrhea, rash, mucosal inflammation, pruritus, dry skin, and muscle spasm. Longer follow-up did not lead to new safety concerns and no evidence of cumulative or late toxicity was observed. The cardiac safety profile was also maintained in the long term. The researchers asserted that the median OS of 56.5 months is unprecedented in first-line treatment of MBC and confirms that a pertuzumabcontaining regimen is now the standard of care in this setting.11 Perspective This study established the role of pertuzumab added to trastuzumab and a taxane in the first-line setting for metastatic HER2-positive disease, and this update on survival lends even more support to this approach. The 6-month improvement in PFS is impressive alone, but a nearly 1.5-year improvement in OS is unprecedented. In part, this spectacular finding may reflect the study population, in whom access to HER2-targeted drugs outside of the trial was limited, but it remains a highly positive trial in favor of dual HER2 targeting. -Lisa A. Carey, MD

Trastuzumab Alone, Trastuzumab Plus Lapatinib, and Trastuzumab Followed by Lapatinib At ASCO 2014, Piccart-Gebhart and colleagues presented results from the Adjuvant Lapatinib and/or Trastuzumab Treatment Optimisation (ALTTO) trial, a multicenter, randomized, phase 3 trial that compared 3 oral lapatinib-containing regimens with trastuzumab in the adjuvant treatment of women with HER2-positive early-stage BC.12 Each regimen was given for 1 year. A total of 8381 patients were randomly assigned between June 2007 and July 2011 to treatment with lapatinib plus trastuzumab, trastuzumab followed by lapatinib, or trastuzumab alone. The trial originally consisted of a fourth arm of lapatinib alone, but that arm was discontinued in August 2011 due to futility. HER2-targeted therapy was given after chemotherapy was completed in 4613 patients; concurrently with a taxane following anthracycline in 3337 patients; or concurrently with a nonanthracycline, platinum-containing regimen in 431 patients. The primary end point was invasive DFS. The investigators tested lapatinib plus trastuzumab versus trastuzumab alone for superiority and trastuzumab followed by lapatinib versus trastuzumab alone for noninferiority. Among the total number of patients, 40% were node-negative and 57% were hormone receptor–positive. After a median follow-up of 4.5 years and 555 DFS events, results showed no significant difference between lapatinib plus trastuzumab versus trastuzumab alone (HR for DFS, 0.84; 97.5% CI, 0.70–1.02; P=.048; 4-year DFS rate, 88% vs 86%). The HR was 0.93 (97.5% CI, 0.76–1.13; noninferiority P=.04; 4-year DFS rate, 87% vs 86%) for patients given trastuzumab followed by lapatinib versus trastuzumab alone. Diarrhea (75% vs 20%), rash (55% vs 20%), and hepatobiliary AEs (23% vs 16%) occurred more frequently in patients given lapatinib plus trastuzumab versus those given trastuzumab alone. The investigators pointed out that the results were unexpected given the success of the NeoALTTO trial, which

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showed that the combined use of lapatinib and trastuzumab doubled the pCR rate compared with trastuzumab alone.13 Perspectives Some, but not all, neoadjuvant studies have suggested that dual HER-2 targeting improves pCR compared with single HER-2 targeting. The ALTTO study tested the adjuvant use of lapatinib added to trastuzumab-based therapy, and results suggest that dual targeting with lapatinib is unlikely to markedly improve outcomes, at least in this overall good-risk population. Identifying patients for whom less is needed (versus more) is a key question in HER-2 positive BC; the role of pertuzumab added to trastuzumab will be addressed by the ongoing APHINITY trial.14 For now, chemotherapy plus trastuzumab remains the adjuvant best option. -Lisa A. Carey, MD In this study, there were some surprising (and perhaps disappointing) results associated with the AEs that patients experienced in the trastuzumab followed by lapatinib arm. Therefore, risks and benefits need to be weighed carefully given that the benefits can be great (doubled complete response rate); but the side effects can be severe (eg, 75% diarrhea, 55% rash, 23% hepatobiliary AEs). -Lillie D. Shockney, RN, BS, MAS These results point to a need for additional clinical trials to determine the true benefit of lapatinib plus trastuzumab. Interestingly, the outcomes in this trial were different than those reported in a previous study using the same regimen.15 Given that the incidence of AEs was much higher with the addition of lapatinib, this will be an important question to answer. -Atheer A. Kaddis, PharmD

Neoadjuvant Treatment in HER2-Positive Breast Cancer: Docetaxel Plus Lapatinib, Trastuzumab, or Both, Followed by an AnthracyclineBased Regimen Results from the randomized, phase 2 European Organisation for Research and Treatment of Cancer (EORTC) 10054 study were presented at ESMO 2014 by Bonnefoi and colleagues.16 Previous neoadjuvant trials using a double HER2 blockade of lapatinib and trastuzumab along with paclitaxel-containing chemotherapy regimens have shown high toxicity, which the researchers hypothesized may have been due to a specific interaction between paclitaxel and lapatinib. Therefore, the objective of EORTC 10054 was to assess the toxicity and activity of the combination of docetaxel with lapatinib and trastuzumab. The trial enrolled 128 patients with stage IIA–IIIC HER2positive BC from October 2010 to January 2013. Patients received 6 cycles of chemotherapy every 3 weeks (3 cycles of docetaxel followed by 3 cycles of fluorouracil, epirubicin, and cyclophosphamide). During the first 3 cycles, patients were randomly assigned to receive lapatinib (arm A, n=22), trastuzumab (arm B, n=52), or trastuzumab and lapatinib (arm C, n=48). The primary end point was pCR. Secondary end points included safety and toxicity. Arm A closed because of futility in June 2012. Results showed that when pCR was defined as absence of invasive cancer in the breast, it was achieved in 45.5% of patients in arm A, 51.9% in arm B, and 60.4% in arm C. When pCR was defined more strictly as absence of invasive cancer in the breast and lymph nodes, it was achieved in 38.1%, 51.9%, and 56.3%, respectively. Grade 3/4 toxicities experienced included febrile neutropenia in 23%, 15%, and 10% in arms A, B, and C, respectively; diarrhea in 9%, 2%, and 18%, respectively; other infection in 9%, 4%, and 8%, respectively; and liver enzyme alteration in 0%, 4%, and 10%, respectively. Dose reductions were required in 36%, 13%, and 48% of patients in arms A, B, and C, respectively.16 Perspectives This study joins the legions of neoadjuvant trials demonstrating that the addition of lapatinib to trastuzumab-based therapy modestly augments pathologic response, but at a cost of side effects regardless of which taxane you use. Like others, they found that the impact on response of

october 2014 I VOL 7, NO 4

CONTINUING EDUCATION adding lapatinib was far greater in the hormone receptor–negative subset. Efforts to define the group within HER2-positive BC who will derive real benefit from more aggressive approaches is key. -Lisa A. Carey, MD AEs that disrupt activities of daily living must be factored into the discussion of treatment options for BC. Some patients cannot tolerate certain toxicities, especially if they interfere with the ability to continue working, which may be necessary to pay medical bills and maintain insurance benefits. Financial concerns can be a barrier to optimal treatment, and out-of-pocket expenses must be discussed between patients and the healthcare team. There may be resources that can help to offset some of this burden; however, these must be investigated up front. Nurse navigators can play an important role by meeting with a financial counselor to calculate treatment-related expenses and help patients explore their options. -Lillie D. Shockney, RN, BS, MAS

Docetaxel Weekly Versus Cyclophosphamide, Methotrexate, and Fluorouracil as Adjuvant Chemotherapy for Elderly Patients With Early-Stage Breast Cancer Perrone and colleagues presented final results at ESMO 2014 from the randomized, phase 3 study ELDA (Elderly Breast Cancer—Docetaxel in Adjuvant Treatment), which evaluated whether weekly docetaxel in elderly patients with early-stage BC was more effective than cyclophosphamide, methotrexate, and fluorouracil (CMF).17 Patients were eligible for study inclusion if they were between the ages of 65 and 79 years and had metastatic nodes or an average to high risk of recurrence. A total of 302 patients were randomly assigned between July 2003 and April 2011 to either weekly docetaxel or CMF, both administered every 4 weeks and given for 4 cycles to ER-positive patients and for 6 cycles to patients who were ER-negative. After chemotherapy, patients who were ER-positive received endocrine treatment and those who were HER2-positive received trastuzumab. The most frequent comorbidities were hypertension, arthropathy, osteoporosis, and controlled diabetes. Median follow-up was 5.5 years. The HR for DFS for those who received weekly docetaxel versus CMF was 1.20 (95% CI, 0.82–1.75; P=.35); the HR for death was 1.23 (95% CI, 0.73–2.07; P=.42). Multivariable analysis showed similar results. Patients who received weekly docetaxel experienced worse quality of life in terms of emesis, appetite loss, diarrhea, impaired body image, diminished future perspective, hair loss, allergy, fatigue, dysgeusia, abdominal pain, neuropathy, and cardiac and skin toxicity. Patients who received CMF experienced worse hematologic toxicity, mucositis, and nausea. The researchers concluded that weekly docetaxel was not more effective than CMF and resulted in worse quality of life and greater toxicity. They stated that CMF remains the standard of care for elderly patients with early-stage BC.17 Perspectives Older patients with high-risk tumors need polychemotherapy. This is the second trial to demonstrate that standard approaches to adjuvant therapy should be used, regardless of age (CALGB 49907, which compared capecitabine alone vs standard first-generation regimens, was the first). The fact is, physiologic age is probably more important to consider in determining treatment than chronologic age, but our tools for assessing this are still undeveloped. -Lisa A. Carey, MD An important issue to consider is whether any of these patients were candidates for Oncotype DX™. If they were, I think it would be important to utilize this tool to determine whether chemotherapy would truly be beneficial. In this elderly cohort of patients, it is not unusual to see a high incidence of comorbidities, which can be exacerbated by certain therapies. It makes us reflect back on the Hippocratic Oath—Do no harm. -Lillie D. Shockney, RN, BS, MAS

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Maintenance Bevacizumab With or Without Capecitabine After Initial First-Line Bevacizumab Plus Docetaxel for HER2-Negative Breast Cancer At ESMO 2014, Gligorov and colleagues presented results from the open-label, randomized phase 3 IMELDA trial, which examined whether the addition of capecitabine to maintenance bevacizumab after initial treatment with bevacizumab and docetaxel would improve PFS.18 Patients with HER2-negative MBC, an Eastern Cooperative Oncology Group score less than 2, and no prior chemotherapy for mBC were eligible for study inclusion. A total of 284 patients were enrolled between June 2009 and March 2011 (at which point enrollment was prematurely terminated). Patients who had had 3 to 6 cycles of bevacizumab and docetaxel and who had not experienced disease progression (n=185, 65%) were then randomly assigned to bevacizumab alone (n=94) or bevacizumab plus capecitabine (n=91), until disease progression. The primary end point was PFS from randomization; secondary end points included response rate, OS, safety, and quality of life. Median follow-up ranged from 30.4 months for the bevacizumab group to 31.6 months for the bevacizumab plus capecitabine group. Results showed median PFS to be 4.3 months for the patients who received bevacizumab alone compared with 11.9 months (HR, 0.38; 95% CI, 0.27– 0.55; P<.001) for patients who received bevacizumab plus capecitabine. Median OS was 23.7 months for the bevacizumab-alone group compared with 39 months (HR, 0.43; 95% CI, 0.26–0.69; P<.001) for the bevacizumab plus capecitabine group. AEs of grade 3 or higher, including hand-foot syndrome, hypertension, proteinuria, and gastroenteritis, were experienced by 30% of the patients who received bevacizumab and 52% of those who received the bevacizumab-capecitabine combination.18 Perspectives The results of this trial could be interpreted to show that the combination of bevacizumab plus capecitabine is a good—and relatively well-tolerated—regimen in the metastatic setting, which has been demonstrated in the past. However, skeptics may point out that the contribution of bevacizumab is unclear; this could just reflect the activity of capecitabine, which is an effective second-line drug. From a practical standpoint, I also would not advocate for taking the approach used in this trial of stopping 1 cytotoxic regimen that is working in order to start a completely different cytotoxic regimen. -Lisa A. Carey, MD In this trial, not only was there an improvement in PFS of 7.6 months, but OS was increased by greater than 15 months. That is a long time for a patient with BC to survive and enjoy additional time with her family. What may be a barrier to treatment in the future, however, relates to the increased cost of drugs, which will be shared by the patient and her insurance company. Deductibles and copayments will continue to climb, and patients with metastatic disease do not want to leave financial debt for their family to pay after they are gone, especially if it is related to their cancer treatment. This means thoughtful discussions are needed among the family members as well as between the patient and the oncology team. -Lillie D. Shockney, RN, BS, MAS

Luteinizing Hormone–Releasing Hormone Analog During Chemotherapy in Early-Stage, Hormone Receptor–Negative Breast Cancer At ASCO 2014, Moore and colleagues presented results from the Prevention of Early Menopause Study (POEMS), a phase 3 trial coordinated by the Southwest Oncology Group that evaluated whether luteinizing hormone–releasing hormone (LHRH) analog administration with chemotherapy for early-stage BC would reduce premature ovarian failure (POF).19 The study population consisted of 257 premenopausal patients younger than 50 years with stage I–IIIA ER/PR-negative BC. Patients were randomly assigned to receive standard cyclophosphamide-containing chemotherapy with or without monthly goserelin, beginning 1 week before the first dose of chemotherapy. The primary end point was 2-year POF (defined as amenorrhea for the prior 6 months and postmenopausal level of follicle-stimulating hormone

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FACULTY PERSPECTIVES [FSH]). Other end points included pregnancies and survival. Results showed POF rates were 22% among patients who received standard treatment and 8% among those who received goserelin (odds ratio [OR], 0.36; 95% CI, 0.11–1.14; P=.08 on adjusted analysis). A sensitivity analysis that defined 2-year POF more liberally (as either amenorrhea or elevated FSH) showed POF rates to be 45% among those receiving standard treatment and 20% in those who received goserelin (OR, 0.29; 95% CI, 0.12–0.70; P=.006). There were 13 pregnancies among the patients who received standard treatment and 22 among those who received goserelin (OR, 2.22; 95% CI, 1.00–4.92; P=.05). Patients who received goserelin experienced better rates of DFS and OS compared with those who received standard treatment (HR, 0.49; 95% CI, 0.24–0.97; P=.04 and HR, 0.43; 95% CI, 0.18–1.00; P=.05, respectively).19 Perspectives Premature ovarian failure and infertility are major issues for young patients with BC. This study examined an LHRH agonist given concurrently with chemotherapy in hormone receptor–negative BC and found that patients treated with this regimen were more likely to maintain ovarian function and to successfully become pregnant. This is a reasonable option for this cohort of women; however, it should not be generalized to the hormone receptor–positive group given the possibility of an interaction between the endocrine therapy and the chemotherapy. -Lisa A. Carey, MD Preservation of fertility is a priority to many premenopausal women diagnosed with BC. Consideration regarding this life goal needs to be acknowledged and incorporated in the treatment planning process whenever feasible. This study provides a new treatment option to enable this to happen, which is associated with DFS and OS benefits. -Lillie D. Shockney, RN, BS, MAS This clinical trial demonstrated a novel use for the LHRH agonist goserelin. Given in hormone receptor–negative, early-stage BC, this agent can help to preserve ovarian function in patients receiving chemotherapy, with some patients even achieving successful pregnancies. Disease-free survival and OS were also better in patients who received goserelin. -Atheer A. Kaddis, PharmD

Zoledronic Acid Every 4 Weeks Versus Every 12 Weeks in Women With Bone Metastases From Breast Cancer OPTIMIZE-2 was a phase 3, prospective, randomized, double-blind, multicenter study that examined the efficacy and safety of continued zoledronic acid every 4 weeks compared with every 12 weeks in women with bone metastases from BC. The objective was to determine whether zoledronic acid given every 12 weeks was noninferior to zoledronic acid given every 4 weeks in patients who previously received monthly intravenous bisphosphonate therapy for at least 1 year (approximately 9 or more doses of zoledronic acid or pamidronate during the first 10–15 months of therapy). Hortobagyi and colleagues discussed the results at ASCO 2014.20 A total of 403 patients were randomly assigned to a schedule of zoledronic acid every 4 weeks (n=200) or every 12 weeks with placebo given between doses (n=203), for 1 year. The primary end point was the proportion of patients with at least 1 skeletal-related event (SRE). Secondary end points included time to first SRE, skeletal morbidity rate (SMR), bone pain score, change in bone turnover markers, and safety. The investigators found an SRE rate of 22% for patients in the 4-week group and 23.2% in the 12-week group, demonstrating noninferiority of zoledronic acid administered every 12 weeks compared with every 4 weeks. The 2 groups experienced similar time to first on-study SRE (HR, 1.06; 95% CI, 0.70–1.60; P=.79); mean SMRs were also similar (0.46 vs 0.50, respectively; P=.85). Changes in bone turnover markers and incidence of treatment-emergent AEs were also similar in the 2 groups. The 4-week group experienced more renal treatment-emergent AEs than the 12-week group (9.6% vs 7.9%), and 2 cases of osteonecrosis of the jaw were found in the 4-week group.20

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Perspectives The optimal schedule and duration of bisphosphonate treatment in MBC is uncertain. This study, which examined women after 1 year of monthly administration, found that it appears safe to change at that point to every-third-month administration. This is a very appealing finding from a practical and toxicity standpoint. Denosumab has some benefits in outcome and toxicity over zoledronic acid, but now zoledronic acid has the benefit of a far more tolerable schedule to consider. -Lisa A. Carey, MD This is a good example of how research is able to validate that more treatment does not necessarily mean better treatment, enabling patients to receive zoledronic acid every 12 weeks instead of every 4 weeks with approximately the same clinical outcomes for those with stage IV BC that has metastasized to the bone. -Lillie D. Shockney, RN, BS, MAS The results of this trial are important not only for patients and providers, but for payers as well, since less frequent administration of zoledronic acid may result in less cost while still achieving similar clinical results compared with administration every 4 weeks. -Atheer A. Kaddis, PharmD

50 YEARS OF ADVANCES IN BREAST CANCER TREATMENT: WHAT WE HAVE LEARNED AND THE CHALLENGES AHEAD

At ASCO 2014, Harold Burstein, MD, PhD, discussed the evolution of BC treatment over the past 50 years as well as where treatment is headed.21 Therapies for the disease have progressed from an era in which the focus was on local treatment only to one in which local and systemic therapy is the standard. Almost all patients today, he said, will receive adjuvant therapy. In years past, treatment was stage-centered, whereas now it has become tumor-centered; the biological features of the tumor determine therapy. Evolution of Treatment The advantages of effective (neo)adjuvant systemic therapy are many. When given preoperatively, this includes locally advanced BCs becoming “operable”; downstaging a tumor to permit breast-conserving surgery; diminishing the need for axillary dissection and enabling sentinel node biopsy; reducing local recurrence after breast-conserving surgery; facilitating radiotherapy survival benefit; and improving survival after local–regional recurrence. Whether given pre- or postoperatively, systemic therapy used in stage I–III BC improves both distant and local RFS and OS. Similar, although less impressive, advances are seen with prolonged survival in the metastatic setting, particularly for hormone receptor–positive and HER2-positive BC. The 3 Strands of Therapy Three strands of therapy have developed, the first consisting of adjuvant chemotherapy. The confounding factors that have existed for the past 40 years, Dr Burstein said, including age, menopausal status, differences in the biologic behavior of the tumor, modest treatment effects, short- and longterm follow-up, and concern over possible late side effects, have since been sorted out through robust trials with many patients, collaborative research, long-term follow-up, and careful correlative/translational science. In the end, dozens of trials and tens of thousands of patients have demonstrated the efficacy of anthracycline-based chemotherapy over CMF-based chemotherapy and taxane-based regimens over nontaxane-based regimens. Endocrine therapy comprises the second strand of therapy. The benefit of tamoxifen was eventually found to correlate with ER status, with research confirming that it was not beneficial for women who were ER-negative but clearly valuable for women who were ER-positive. Although tamoxifen treatment longer than 5 years was not believed to be of benefit about 15 years ago, trials since have shown up to 10 years of tamoxifen to be beneficial in some patients. Trials that compared 5 years of tamoxifen with new approaches showed that incorporating an AI lowered the risk of recurrence in postmenopausal women who were ER-positive, and this is now part of the standard regimen for postmenopausal women with early-stage BC. The final strand of therapy involves the protein known as HER2, which is

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CONTINUING EDUCATION

Table 2. Adjuvant Treatment for Breast Cancer21 ER-Negative

ER-Positive

Chemotherapy

Endocrine therapy (eg, tamoxifen, AI) ± chemotherapy

Chemotherapy + trastuzumab

Endocrine therapy + chemotherapy + trastuzumab

HER2-Negative

HER2-Positive

AI indicates aromatase inhibitor; ER, estrogen receptor; HER2, human epidermal growth factor receptor 2.

Table 3. Simplified Guideline-Based Care21 Breast Cancer Subtype

Preferred Adjuvant Chemotherapy Regimen

Preferred Non-anthracycline Regimen

• HER2-negative • ER-positive • Triple-negative

Anthracycline (doxorubicin/ cyclophosphamide) followed by taxane (paclitaxel)

Docetaxel/ cyclophosphamide

HER2-positive

Anthracycline (doxorubicin/ cyclophosphamide) followed by taxane (paclitaxel) and trastuzumab

Docetaxel/carboplatin/ trastuzumab

ER indicates estrogen receptor; HER2, human epidermal growth factor receptor 2.

associated with about 15% to 20% of BCs and is now recognized as an adverse prognostic factor. The discovery of HER2 led to a revolution in cancer diagnostics and therapeutics, paving the way for high-quality testing for HER2 and leading to the discovery of trastuzumab, which has altered the natural history of HER2-positive BC and has been one of the great successes of medical oncology in the past 25 years. Adjuvant Chemotherapy: Yes or No? The decision to administer adjuvant chemotherapy to a patient has typically been a difficult one. Because there has been a shift from a stage- and risk-informed process to a tumor biology–driven process, however, treatment today can be guided by the general classification of patients as ER-negative or ER-positive, and HER2-negative or HER2-positive (Table 2).21 Pre- and perimenopausal women may choose tamoxifen for initial endocrine therapy, then for extended therapy remain on tamoxifen or switch to an AI (if they are postmenopausal). Postmenopausal women may choose an AI or tamoxifen for initial and extended therapy. For women with early-stage BC, CMF-based regimens have been replaced by anthracycline-based regimens, which in turn have given way to taxaneand anthracycline-based regimens (regardless of age, stage, grade, or ER status). Best evidence supports the idea that women should receive both anthracyclines and taxanes for treating higher-risk BC. Simplified guideline-based care, as summarized by Dr Burstein, can be seen in Table 3.21 Challenges That Lie Ahead: The Genomic Era, Improving on Good Prognoses, Evolving Healthcare, and Metastatic Disease The many challenges that remain ahead include mainstreaming genomic medicine, identifying hereditary and acquired mutations, and reconciling discordant stage and biology findings. Significant inroads have been made in sequencing vast numbers of BCs, and many mutations have been identified, but incidence is rare, and the more common mutations have been difficult to target with a drug, according to Dr Burstein. Among critical mutations that should be targeted include BRCA3, “although,” he said, “at this point it does not appear to exist,” and triple-negative BC, for which a biologically based redefinition of the syndrome is badly needed. The most vexing challenge, however, is the persistent problem of discordance between anatomic stage and biologic risk. For example, should chemotherapy be given for a 3-mm triple-negative cancer? Or for a 4-cm lobular

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cancer affecting 3 or more lymph nodes and having a recurrence score of 8? “At these extremes,” Dr Burstein said, “most of our clinical data break down, although that doesn’t stop these types of patients from being treated.” Results of a recent multicenter, open-label study of paclitaxel and trastuzumab for small, HER2-positive BCs showed a very low risk of recurrence (2% per 4 years of follow-up). Improving on a good prognosis, caring for patients in the new healthcare marketplace, and metastatic disease are more of the challenges that remain on the horizon. The National Surgical Adjuvant Breast and Bowel Project (NSABP) B-18 study was conducted in the 1990s, and from that trial, 3 things were learned: 1. The outcomes were the same with pre- or postoperative treatment. 2. Among patients who required a mastectomy at baseline, 27% converted to breast-conserving surgery. 3. Those women with a pCR had a more favorable long-term prognosis. “Alas, I am not sure that the field has radically transformed itself in the 20 years since this study,” Dr Burstein said. “Can we successfully develop and use NSABP B-18 as a model for drug discovery, for acceleration of treatment for early-stage BC, or to tailor or adapt treatment based on response?” Additionally, the evolving changes in healthcare delivery in the United States present opportunities and challenges for BC care, namely value-based care; integrated, streamlined care across the spectrum of health, disease/treatment, and survivorship; guideline-driven care; and concerns about access to specialists and costs that need to be addressed. Finally, Dr Burstein concluded, although great strides have been made in the past 50 years with regard to metastatic disease and undoubtedly will continue to be made, “fundamentally we do not have the tools we need.” Patients with MBC are typically given 4 or 5 lines of chemotherapy, and improvements have been seen in quality and longevity. But, he said, “we need the next big thing.”21 Perspectives Dr Burstein beautifully highlights the evolution of BC systemic therapy and the pivot from a single-minded focus on anatomic extent of disease to a perspective that incorporates both anatomy and biology. The explosion of our understanding of cancer pathophysiology has had real clinical benefits. Endocrine therapy now includes multiple active agents and drugs designed to circumvent resistance to anti-estrogen approaches. Similarly, we have 4 approved HER2-targeted agents and effective dual- and single-targeted approaches. However, triple-negative BC remains a thorny clinical problem. Although we have improved cure rates in early-stage triple-negative disease, systemic therapy remains limited to cytotoxics; we have not yet identified a targeted therapy for this entity. -Lisa A. Carey, MD Great strides have been made in the field of diagnosing and treating BC. We have transitioned over time from the poison, slash, and burn methods to more innovative ways that include the timing of phases of treatment, with more neoadjuvant chemotherapy being performed, to also launching into an epigenetic field of treatment, which is likely where the future lies. There are now more surgical options, better reconstruction methods, improved chemotherapy regimens, and less harsh radiation treatments today. We have seen a decline in the death rate as a result of earlier diagnosis and better treatments; however, for those battling stage IV BC, more needs to be done. Quality of life is now on the radar screen, whereas 50 years ago, the only measure of success was survival. Personalized medicine is a blossoming field, with epigenetic treatments becoming the new wave of systemic therapies for the future. -Lillie D. Shockney, RN, BS, MAS

References 1. Carey LA, Barry WT, Pitcher B, et al. Gene expression signatures in pre- and post-therapy specimens from CALGB 40601 (Alliance), a neoadjuvant phase III trial of weekly paclitaxel and trastuzumab with or without lapitinib for HER2-positive breast cancer. J Clin Oncol (ASCO Annual Meeting Abstracts). 2014;32(suppl):Abstract 506. 2. Carey LA, Berry DA, Ollila D, et al. Clinical and translational results of CALGB 40601: a neoadjuvant phase III trial of weekly paclitaxel and trastuzumab with or without lapatinib

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FACULTY PERSPECTIVES for HER2-positive breast cancer. J Clin Oncol (ASCO Annual Meeting Abstracts). 2013;31 (suppl):Abstract 500. 3. Guarneri V, Dieci M, Carbognin L, et al. Activity of neoadjuvant lapatinib plus trastuzumab for early breast cancer according to PIK3CA mutations: pathological complete response rate in the CherLOB study and pooled analysis of randomized trials. Ann Oncol (ESMO Annual Meeting Abstracts). 2014;25(suppl 4):Abstract 2540. 4. Perez EA, Thompson EA, Anderson SK, et al. Association of genomic analysis of immune function genes and clinical outcome in the NCCTG (Alliance) N9831 adjuvant trastuzumab trial. J Clin Oncol (ASCO Annual Meeting Abstracts). 2014;32(suppl): Abstract 509. 5. Loi S, Michiels S, Lambrechts D, et al. Tumor PIK3CA mutations, lymphocyte infiltration, and recurrence-free survival (RFS) in early breast cancer (BC): Results from the FinHER trial. J Clin Oncol (ASCO Annual Meeting Abstracts). 2012;30(suppl):Abstract 507. 6. Covelli AM, Baxter NN, Fitch M, et al. Why women are choosing mastectomy: influences beyond the surgeon. J Clin Oncol (ASCO Annual Meeting Abstracts). 2014;32(suppl): Abstract 1094. 7. Chen L, Cheung WY. A population-based analysis of the impact of physicians on cancer screening. J Clin Oncol (ASCO Annual Meeting Abstracts). 2014;32(suppl):Abstract 1572. 8. Eisinger F, Morère J-F, Touboul C, et al. Vulnerable populations and overconfidence in cancer screening. J Clin Oncol (ASCO Annual Meeting Abstracts). 2014;32(suppl):Abstract 1574. 9. Pagani O, Regan MM, Walley B, et al. Randomized comparison of adjuvant aromatase inhibitor exemestane plus ovarian function suppression (OFS) vs tamoxifen plus OFS in premenopausal women with hormone receptor-positive early breast cancer: joint analysis of IBCSG TEXT and SOFT trials. J Clin Oncol (ASCO Annual Meeting Abstracts). 2014;32 (suppl):Abstract LBA1. 10. Pfeiler G, Königsberg R, Fesl C, et al. Impact of body mass index on the efficacy of endocrine therapy in premenopausal patients with breast cancer: an analysis of the prospective ABCSG-12 trial. J Clin Oncol. 2011;29:2653-2659. 11. Swain S, Kim S, Cortes J, et al. Final overall survival analysis from the CLEOPATRA study of first-line pertuzumab, trastuzumab, and docetaxel in patients with HER2-positive metastatic breast cancer. Ann Oncol (ESMO Annual Meeting Abstracts). 2014;25(suppl 4): Abstract 3500_PR. 12. Piccart-Gebhart M, Holmes AP, Baselga J, et al. First results from the phase III ALTTO trial (BIG 2-06; NCCTG [Alliance] N063D) comparing one year of anti-HER2 therapy with lapatinib alone, trastuzumab alone, their sequence, or their combination in the adju-

vant treatment of HER2-positive early breast cancer. J Clin Oncol (ASCO Annual Meeting Abstracts). 2014;32(suppl):Abstract LBA4. 13. de Azambuja E, Holmes AP, Piccart-Gebhart M, et al. Lapatinib with trastuzumab for HER2-positive early breast cancer (NeoALTTO): survival outcomes of a randomized, open-label, multicentre, phase 3 trial and their association with pathological complete response. Lancet Oncol. 2014;15:1137-1146. 14. ClinicalTrials.gov. A study of pertuzumab in addition to chemotherapy and Herceptin (trastuzumab) as adjuvant therapy in patients with HER2-positive primary breast cancer. http://clinicaltrials.gov/show/NCT01358877. Accessed October 6, 2014. 15. Baselga J, Bradbury I, Eidtmann H, et al. Lapatinib with trastuzumab for HER2-positive early breast cancer (NeoALTTO): a randomised, open-label, multicentre, phase 3 trial. Lancet. 2012;379:633-640. 16. Bonnefoi H, Jacot W, Saghatchian M, et al. Neoadjuvant treatment with docetaxel plus lapatinib, trastuzumab, or both followed by an anthracycline based chemotherapy in HER2positive breast cancer: results of the randomized phase II EORTC 10054 study. Ann Oncol (ESMO Annual Meeting Abstracts). 2014;25(suppl 4):Abstract 2530. 17. Perrone F, Nuzzo F, Di Rella F, et al. Weekly docetaxel vs CMF as adjuvant chemotherapy for elderly early breast cancer patients: final results from the randomised phase 3 ELDA trial. Ann Oncol (ESMO Annual Meeting Abstracts). 2014;25(suppl 4):Abstract 2560. 18. Gligorov J, Doval D, Bines J, et al. Efficacy and safety of maintenance bevacizumab with or without capecitabine after initial first-line bevacizumab plus docetaxel for HER2-negative metastatic breast cancer: IMELDA randomised phase III trial. Ann Oncol (ESMO Annual Meeting Abstracts). 2014;25(suppl 4):Abstract 3520. 19. Moore HCF, Unger JM, Phillips K-A, et al. Phase III trial (Prevention of Early Menopause Study [POEMS]-SWOG S0230) of LHRH analog during chemotherapy to reduce ovarian failure in early-stage, hormone receptor–negative breast cancer: an international Intergroup trial of SWOG, IBCSG, ECOG, and CALGB (Alliance). J Clin Oncol (ASCO Annual Meeting Abstracts). 2014;32(suppl):Abstract LBA505. 20. Hortobagyi GN, Lipton A, Chew HK, et al. Efficacy and safety of continued zoledronic acid every 4 weeks versus every 12 weeks in women with bone metastases from breast cancer: results of the OPTIMIZE-2 trial. J Clin Oncol (ASCO Annual Meeting Abstracts). 2014; 32(suppl):Abstract LBA9500. 21. Burstein H. 50 years of advances in breast cancer treatment: what have we learned? Where are we going? Presented at: 2014 ASCO Annual Meeting; May 30–June 3, 2014; Chicago, IL. http://meetinglibrary.asco.org/presentationBySession/6472/1280?media=vm. Accessed October 3, 2014.

COE168-1 www.TheOncologyPharmacist.com

october 2014 I VOL 7, NO 4

Renal Cancer

Highest Response Rate to Date in mRCC With Pazopanib as Third-Line VEGF Inhibitor Charles Bankhead

lmost 50% of patients with metastatic renal cell carcinoma (mRCC) had objective responses to third-line treatment with the angiogenesis inhibitor pazopanib, according to the results from a small clinical trial reported at the 2014 American Association for Cancer Research annual meeting. Overall, 12 of 28 patients achieved objective responses (including 1 complete response), and another patient had an unconfirmed partial response. In the subgroup of responding patients, the duration of response to pazopa nib exceeded the duration of previous responses in a majority of cases. The cohort had a median progression-free survival of 16.5 months, a “remarkable” clinical outcome for such a heavily pretreated group of patients, said principal investigator Sumanta K. Pal, MD, assistant professor of medical oncology and therapeutics research at City of Hope, Duarte, California. “This is the highest objective response rate observed to date in a trial of thirdline therapy for metastatic renal cell carcinoma,” said Pal. “Equally unprecedented is the median progression-free survival, which is remarkable for this group of patients.” Pazopanib, a multitargeted tyrosine kinase inhibitor, is approved for the treatment of advanced RCC. Previous studies of the agent included a phase

3 trial of patients who were refractory to cytokine therapy or were treatment naive. No previous trial had determined pazopanib’s activity in the third-line setting or examined temporal changes in molecular profile during therapy.

“This is the highest objective response rate observed to date in a trial of third-line therapy for metastatic renal cell carcinoma. Equally unprecedented is the median progressionfree survival, which is remarkable for this group of patients.” Sumanta K. Pal, MD

Study Details Pal and colleagues evaluated pazopa nib’s third-line potential for mRCC in a well-defined group of previously treated patients. They performed a phase 3, single-arm trial involving patients whose disease had progressed after 2 previous systemic regimens, 1 of which had to

be an inhibitor of vascular endothelial growth factor (VEGF). Other eligibility criteria included Eastern Cooperative Oncology Group (ECOG) performance status of 0 to 2, and clear cell histology. The primary outcome was response rate, and the trial was statistically powered to detect a 23% overall response rate, defined as “clinically encouraging.” Investigators also examined immunologic markers associated with treatment failure or success. Patients received pazopanib 800 mg daily on 28-day cycles. Treatment continued until disease progression, unacceptable toxicity, or death. None of the patients enrolled in the study had good-risk characteristics. Approximately 60% had intermediate-risk features, and approximately 40% had poor-risk features. Overall, 23 of the 28 patients received anti-VEGF therapy as first-line treatment, and the most frequently used second-line therapy was the mammalian target of rapamycin (mTOR) inhibitor class. Some of the patients received antiVEGF therapy as first- and second-line therapy. The median duration of previous anti-VEGF therapy was 4 months. In addition to the 13 patients who had responses (including the 1 unconfirmed response), 9 had stable disease, resulting in a clinical benefit rate of 78%. After a median follow-up of 17.1 months, the median overall survival

had yet to be reached. Biomarker analysis showed that response was associated with lower levels of hepatocyte growth factor, VEGF, interleukin (IL)-8, IL-6, and soluble IL-2 receptor (P <.05 for each analysis).

Pazopanib, a multitargeted tyrosine kinase inhibitor, is approved for the treatment of advanced RCC. The most frequently reported adverse event was hypertension (93%, all grades), which was grade 3/4 in 50% of the cases. Blood pressure was manageable with antihypertensive medications, and no patient stopped treatment because of uncontrolled blood pressure. In addition, 14% of patients had grade 3 proteinuria. The most frequently reported laboratory abnormalities were hyponatremia and elevated creatinine. l Reference

Pal SK, Hossain DMS, Zhang Q, et al. Pazopanib as third-line therapy for metastatic renal cell carcinoma: clinical efficacy and temporal analysis of cytokine profile. Presented at: 2014 Annual Meeting of the American Association for Cancer Research; April 5-9, 2014; San Diego, California. Abstract CT334.

Melanoma

Potential New Approach to Treat Melanoma Phoebe Starr

reliminary results suggest that an investigational antibody-drug conjugate called DEDN6526A has activity against melanoma, including cutaneous, mucosal, and ocular melanoma, which is considered difficult to treat. The new drug comes on the heels of trastuzumab emtansine, the first antibody-drug conjugate approved by the US Food and Drug Administration for the treatment of breast cancer. The conjugate links an antibody to a toxic chemotherapy that remains inactive until the antibody recognizes a protein on the surface of cancer cells and releases its toxic “payload” into the cancer cells. This is one of the first clinical trials to test an antibody-drug conjugate for the treatment of melanoma, explained

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Jeffrey R. Infante, MD, director of the Drug Development Program at the Sarah Cannon Research Institute, Nashville, Tennessee. “We are encouraged by the

This is one of the first clinical trials to test an antibody-drug conjugate for the treatment of melanoma. initial responses. DEDN6526A is well tolerated and, more important, benefits a substantial proportion of patients. It is particularly promising to see clinical

activity in patients with mucosal, as well as ocular, melanoma, and we hope that patients who enroll in the ongoing expansion phase of the trial gain similar benefit,” Infante told attendees at the recent American Association for Cancer Research annual meeting. Infante presented the results of the dose-escalation phase of the first-in-human phase 1 trial of this new therapy. The antibody recognizes the endothelin B receptor (ETBR), which Infante estimates is elevated in approximately 50% of melanomas; the toxic chemotherapy is monomethyl auristatin E (MMAE). When DEDN6526A is administered to a patient, the antibody attaches to ETBR on the cancer cell surface, and MMAE is released to kill the melano-

ma cells. Infante said that he and his coinvestigators are still working on a reliable assay to measure ETBR levels to get a more precise handle on how this drug works. “We need a companion diagnostic to go along with this drug to identify patients who express ETBR. We are working on it,” Infante noted. The dose-escalation phase included 28 patients with metastatic or unresectable melanoma (17 with cutaneous melanoma, 8 with ocular melanoma, and 3 with mucosal melanoma). Patients were given DEDN6526A every 3 weeks; the maximum tolerated dose was determined as 2.4 mg/kg every 3 weeks, and this is the dose being tested in the expansion phase of the trial.

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Melanoma Adverse events thought to be drug- related included fatigue, chills, alopecia, sensory neuropathy, decreased appetite, headache, nausea, and vomiting. Neutropenia was the most frequent grade 3 adverse event. Infusion-related reactions were also observed, but these were reduced with steroid premedication. Among 19 patients in the dose-escalation phase who received ≥1.8 mg/ kg of DEDN6526A, clinical benefit was observed in 12 patients; 2 patients with cutaneous melanoma and 2 with mucosal melanoma had confirmed partial responses. Of the remaining 8 patients, 5 with cutaneous melanoma, 2 with ocular melanoma, and 1 with mucosal melanoma had stable disease for 6 months or longer. In some cases, dis-

ease was stable for a prolonged period. Infante said that 1 patient has been stable and in the study for 2 years. Infante emphasized that this was an

with elevated expression of ETBR. An expansion cohort of an additional 24 patients with melanoma is now being studied.

“It is particularly promising to see clinical activity in patients with mucosal, as well as ocular, melanoma, and we hope that patients who enroll in the ongoing expansion phase of the trial gain similar benefit.”

Jeffrey R. Infante, MD

unselected population. It may be that responses will be even better once a companion diagnostic can identify patients

Thomas J. Lynch, Jr, MD, director of the Yale Cancer Center, New Haven, Connecticut, commented on this study.

“These are exciting results, because there are not that many examples of antibody-drug conjugates that work. The demonstration of clinical response is important. This was not an enriched population, and we still don’t know the biomarker, but if a test is developed to identify responders, then this may turn out to be a new approach to treatment of patients with melanoma,” Lynch stated. l Reference

Infante JR, Sandhu SK, McNeil CM, et al. A first-inhuman phase I study of the safety and pharmacokinetic (PK) activity of DEDN6526A, an anti-endothelin B receptor (ETBR) antibody-drug conjugate (ADC), in patients with metastatic or unresectable melanoma. Presented at: 2014 Annual Meeting of the American Association for Cancer Research; April 5-9, 2014; San Diego, California. Abstract CT233.

Combination of BRAF and MEK Inhibitors Improves Survival in Advanced Melanoma Phoebe Starr

ombination therapy with a BRAF inhibitor and an MEK inhibitor improves outcomes in advanced BRAF-positive melanoma, according to two phase 3 studies presented at the 2014 Congress of the European Society for Medical Oncology (ESMO). These studies support the hypothesis that inhibition of both BRAF and MEK will improve survival in melanoma by overcoming the mechanism of acquired resistance to vemurafenib, which is thought to be reactivation of cell growth through MEK. In the CoBRIM study, first-line treatment of advanced melanoma with the combination of vemurafenib + cobimetinib (not approved by the US Food and Drug Administration [FDA]) improved progression-free survival (PFS) and overall response rate (ORR) versus vemurafenib alone.1 In the COMBI-v study, the FDA-approved combination of dabrafenib + trametinib improved overall survival (OS) compared with vemurafenib alone.2 CoBRIM Study CoBRIM was a phase 3, double-blind, placebo-controlled study of vemurafenib/cobimetinib versus vemurafenib plus placebo in previously untreated BRAFV600 mutation–positive metastatic melanoma. The study randomized 495 patients to either arm in a 1:1 ratio, with PFS as the primary end point. “This study is very important, as it shows that using 2 drugs together to turn off 2 individual proteins [BRAF and MEK] that interact and bind to each other in the cell gives improved results for patients. This is a fundamental concept that could have

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far-reaching consequences for how we treat many cancers,” said lead author Grant McArthur, PhD, head of the Cancer Therapeutics Program at the Peter MacCallum Cancer Centre in Melbourne, Australia. Median investigator-assessed PFS was 6.2 months for the vemurafenib arm versus 9.9 months for the combination arm, a highly statistically significant difference (P < .0001) representing a 49% reduction in risk of progression or death for the combination therapy arm. The ORR was significantly better with the combination therapy: 68% versus 45%; complete response (CR) rates were 10% versus 4%, respectively. An interim analysis of OS suggested that the risk of death would be reduced by 35% in patients who received both drugs versus those who got vemurafenib plus placebo (P < .05). The combination was tolerable, McArthur said, with a manageable adverse event profile consistent with previous reports. Gastrointestinal (GI) events were more common with the combination, and these were mostly grade 1 and manageable with medication and dose reduction. Photosensitivity was also more common on the combination therapy. Hyperkeratosis was significantly lower with the combination, because MEK inhibition reduces this side effect of vemurafenib, McArthur explained. Creatine phosphokinase level was increased with the combination, but other adverse events were similar in the two arms. “This study provides clear definitive evidence that cobimetinib combined with vemurafenib results in improved progression-free survival and increased

overall response rates. The preliminary overall survival is promising, and the combination was tolerable, consistent with previous trials of this combination,” McArthur stated. “We anticipate that the combination of a BRAF and MEK inhibitor will become a new standard treatment for advanced BRAFmutant melanoma.” COMBI-v Study COMBI-v is an ongoing open-label phase 3 study of BRAFV600-mutated advanced melanoma in treatment-naive patients randomized to receive the combination of dabrafenib + vemurafenib (MEK inhibitor and BRAF inhibitor). The study enrolled 704 patients with advanced or metastatic melanoma and good performance status. In COMBI-v, brain metastases were allowed but only if treated and stable for at least 12 weeks. The combination therapy reduced the risk of death by 31%, according to a preplanned interim analysis of OS presented at ESMO. Median overall survival is not yet reached in the combination arm and was 17.2 months in the vemurafenib-alone arm (P = .005). “These results further corroborate the early preclinical data that more complete blockade of the MAP kinase pathway delays the emergence of resistance, translating into longer survival for our patients,” said lead author Caroline Robert, MD, head of dermatology at the Institut Gustave Roussy in Paris, France. Because of the excellent results at the interim analysis, the study was stopped early and patients originally randomized to the vemurafenib arm were allowed to cross over to combination treatment.

Robert presented the results of the interim analysis, which is now considered the final analysis, she said. Additionally, the combination reduced the risk of disease progression by 44% versus vemurafenib monotherapy. Median PFS was 11.4 months for the combination versus 7.3 months for vemurafenib (P < .001). ORR was 64% versus 51%, respectively, a significant difference of 13% (P < .001). CR was 13% versus 8%, respectively, and partial response was 51% versus 44%, respectively. Duration of response was almost twice as long for the combination arm: 13.8 months versus 7.5 months. The rate of adverse events was similar in the 2 arms. The combination was associated with increased incidence of pyrexia and decrease in left ventricular ejection fraction compared with vemurafenib alone, while the incidence of cutaneous malignancies, hyperproliferative cutaneous events, and photosensitivity was much lower in the combination arm. “Both of these trials of combination therapy go in the same direction,” Robert commented. l References

1. McArthur G, Ascierto PA, Larkin J, et al. Phase 3, double-blind, placebo-controlled study of vemurafenib versus vemurafenib + cobimetinib in untreated BRAFV600 mutation-positive patients with unresectable locally advanced or metastatic melanoma. Presented at: 2014 Congress of the European Society for Medical Oncology; September 26-30, 2014; Madrid, Spain. Abstract LBA5. 2. Robert C, Karaszewska B, Schachter J, et al. COMBI-v: a randomized, open-label, phase III study comparing the combination of dabrafenib (D) and trametinib (T) with vemurafenib (V) as first-line therapy in patients (pts) with unresectable or metastatic BRAF V600E/K mutation-positive cutaneous melanoma. Presented at: 2014 Congress of the European Society for Medical Oncology; September 26-30, 2014; Madrid, Spain. Abstract LBA4.

october 2014 I VOL 7, NO 4

Ovarian Cancer

PARP Inhibitor Veliparib Active in Recurrent BRCA-Positive Ovarian Cancer Charles Bankhead

he PARP inhibitor veliparib demonstrated activity in relapsed/ refractory BRCA-mutated ovarian cancer, according to results from a phase 2 trial conducted by the Gynecologic Oncology Group. Almost one-fourth of 50 evaluable patients had objective responses, including 2 patients with complete responses. Additionally, about half of the patients had stable disease of 16 weeks or longer. Median progression-free survival was 8.1 months among patients who had received as many as 3 prior systemic regimens, according to Robert L. Coleman, MD, at the Society of Gynecologic Oncology annual meeting in Tampa, Florida. “Veliparib demonstrated activity in both platinum-sensitive and platinum- resistant disease,” said Coleman, professor of gynecologic oncology and reproductive medicine at MD Anderson Cancer Center in Houston, Texas. “A criticism of PARP inhibitors is that they are not active in patients who have developed resistance to other therapies. These results indicate that veliparib has activity in some of the patients, who generally have few remaining treatment options.” Laboratory studies suggested targeting of the DNA-repair defect in BRCA-

mutant tumors had potential as a therapeutic strategy. In contrast to some other PARP inhibitors in development, veliparib blocks both isomers of the enzyme. The small-molecule inhibitor demonstrated efficacy across several preclinical models of tumors, including ovarian cancer.

“Veliparib demonstrated activity in both platinumsensitive and platinumresistant disease.” Robert L. Coleman, MD Coleman reported data from a nonrandomized, open-label trial involving patients with germline BRCA mutations. Investigators enrolled patients who had BRCA1/2-deficient epithelial ovarian, fallopian tube, or primary peritoneal cancers. The patients had received from 1 to 3 prior regimens. All patients received veliparib at a dose of 400 mg twice a day, and treatment continued until disease progression, development of unacceptable tox-

icity, or voluntary withdrawal from the study. The statistical design of the trial specified a response rate ≥25% for continuing clinical investigation. Of the 50 patients included in the analysis of safety and efficacy, 8 remain in the study. A majority of the patients (58%) were 40 to 59 years of age, and an additional 30% were 60 to 69 years of age. Twothirds of the patients had performance status 0 and the rest had performance status 1. More than 80% of the patients had high-grade serous tumors. Treatment history consisted of 1 prior regimen in 14 patients (28%), 2 in 18 patients (36%), and 3 in 18 patients (36%). All but 4 patients had received radiotherapy, all but 3 had exposure to immunotherapy, and only 1 patient had not undergone debulking surgery. A majority of the patients (30 [60%]) had platinum-resistant disease, which investigators defined as a platinum-free interval <6 months. Three-fourths of the patients had BRCA1-mutant tumors, and 12 had founder mutations, which were BRCA1 in 8 patients and BRCA2 in 4 patients. Hematologic adverse events were generally mild, as 1 patient had grade 3

neutropenia and 1 patient had grade 4 thrombocytopenia. The most common nonhematologic adverse events were nausea (42 of 50 patients) and other gastrointestinal adverse events (32 patients). No patient had grade 4 nonhematologic events, and grade 3 events consisted of 2 cases of nausea and 1 case related to metabolism/ nutrition. Coleman reported that 11 patients had confirmed partial responses and 2 had confirmed complete responses, resulting in an overall response rate of 26%, which met the predefined criteria for continuing clinical evaluation of veliparib. Response assessment was ongoing in 6 patients, some of whom had unconfirmed responses. A similar proportion of patients with platinum-sensitive or platinum-resistant disease derived benefit from treatment with veliparib. l

Reference

Coleman RL, Sill M, Aghajanian C, et al. A phase II evaluation of the potent, highly selective PARP inhibitor veliparib in the treatment of persistent or recurrent epithelial ovarian, fallopian tube, or primary peritoneal cancer in patients who carry a germline BRCA1 or BRCA2 mutation—a Gynecologic Oncology Group study. Presented at: 2014 Annual Meeting of the Society of Gynecologic Oncology; March 22-25, 2014; Tampa, FL. Abstract 136.

Noteworthy Numbers

Breast Cancer Awareness National Breast Cancer Awareness Month (NBCAM) originated in October 1985 when the American Cancer Society (ACS) partnered with the pharmaceutical division of Imperial Chemical Industries, now part of AstraZeneca, to sponsor a weeklong event. Today, the ACS is only one of many public and private organizations that help sponsor NBCAM programs in the United States, and Breast Cancer Awareness Month is now observed worldwide. The first Susan G. Komen Race for the Cure was held in Dallas, Texas, in 1983 with 800 participants. By 2002, races were being held in more than 100 US cities and 2 foreign countries, with more than 1.3 million participants. In 2014, plans include over 150 races worldwide. Events are planned for the Bahamas, Belgium, Georgia, Germany, Greece, Italy, and Tanzania. Recognizing that breast cancer is a global disease that requires local solutions based on differences in cultures, healthcare systems, and economic conditions, International Komen Race for the Cure events are unique in each country.1 Some aspects of the US approach to breast cancer have had global influence. The first support program for breast cancer patients, Reach to Recovery, was founded in 1952 by Terese Lasser, became an official program of the ACS in 1969, and was adopted in Europe in 1974.2 Traditionally, physicians in

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Poland opposed patient involvement, but Zbigniew Wronkowski, MD, and Krystyna Mika, PhD, at the Centre of Oncology in Warsaw started a small (only 3 women!) support group focused on rehabilitation. Not until the mid 1990s, however, did Polish physicians begin to accept the patient-to-patient support model.2 Breast cancer survivors became known as “Amazons,” and in 1993, the Polish Federation of Breast Cancer Support Groups—Amazons was organized. By 2010 there were more than 200 Amazon groups with over 15,000 members.3 In Australia, the Pink Lady icon is a symbol for breast cancer awareness. Last October, Breast Cancer Network Australia organized the presentation of a Tribute Field of Women, for which 15,000 Pink Lady silhouettes, representing the estimated 15,000 Australian women who would be diagnosed with breast cancer in 2013, were placed in Bennelong Lawn in the Royal Botanic

Gardens, near the Sydney Opera House.4 In 1992, Evelyn H. Lauder, then Senior Corporate Vice President, launched the Estée Lauder Companies Breast Cancer Awareness (BCA) Campaign. In 2000, the “Global Landmarks Illumination Initiative” was created. Since then, historic landmarks around the world have been illuminated with pink lights annually in October. In 2010, the BCA Campaign illuminated 38 global sites, including the Taj Mahal, the Tokyo Tower, the Hotel Majestic in France, and the Empire State Building in New York City.5 Sources 1. http://ww5.komen.org/AboutUs/GlobalReach.html. 2. http://pinkribbonblues.org/resources/beyond-awareness-workbook/ background/support-groups/. 3. http://www.reachtorecoveryinternational.org/bloom/. 4. http://www.bcna.org.au/news/2013-09/october-breast-cancerawareness-month. 5. http://www.elcompanies.com/Pages/The-Lauder-Family.aspx.

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In melanoma…

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References: 1. Kaufman HL, Disis ML. J Clin Invest. 2004;113:664-667. 2. Klebanoff CA, Gattinoni L, Restifo NP. Immunol Rev. 2006;211:214-224. 3. den Boer AT, van Mierlo GJD, Fransen MF, Melief CJM, Offringa R, Toes REM. J Immunol. 2004;172:6074-6079. ©2014 Amgen Inc. All rights reserved. 8/14 USA-678-100568