TOP February Digital

February 2014

www.TheOncologyPharmacist.com

Vol 7, No 1

Visit the TOP booth at the HOPA 10th Annual Conference!

Oncology Pharmacy Safety

Cancer Center Profile

Kimmel Cancer Center: Safety Procedures for Pharmacists and Patients Safe Handling of Chemotherapy Agents

This is the third in a series of articles that will discuss issues related to hazardous materials in the workplace.

Chemotherapy: Biomarkers of Exposure, Effect, Reproductive Hazards, and Cancer Christine Roussel, PharmD, BCOP Clinical Pharmacy Manager, Doylestown Hospital Pharmacy Thomas H. Connor, PhD Research Biologist, National Institute for Occupational Safety and Health

I

n the May 2013 issue of The Oncology Pharmacist, Roussel and Connor described some of the hazards associated with handling chemotherapeutic drugs in the pharmacy and defined what constitutes a hazardous drug.1 Next, in the October 2013 issue, the authors focused on sources of hazardous drug

contamination and the evaluation of surface contamination as an indicator of environmental contamination.2 The present article describes the use of biomarkers for the evaluation of occupational exposure to chemotherapeutic drugs, in an effort to better evaluate Continued on page 10

Leukemia

Raising the Bar: 4 Drugs for CLL Donna deRemus, CPhT, decontaminates vials in the pharmacy at the Kimmel Cancer Center at Thomas Jefferson University Hospital.

B

oth oral and intravenous chemotherapy agents, and other drugs used to treat patients with cancer, can be hazardous to medical personnel who prepare, dispense, and administer these drugs, as well as to patients and their families.

The Oncology Pharmacist spoke about safe-handling procedures and guidelines with Anne Marie Oberle, PharmD, BCOP, Advance Practice Clinical Oncology Pharmacist at the Kimmel Cancer Center at Thomas Jefferson University Hospital in Philadelphia, Pennsylvania.

Continued on page 22

Conference News

Highlights From ASH and SABCS Alice Goodman

T

he American Society of Hematology (ASH) and the San Antonio Breast Cancer Symposium (SABCS) held back-to-back meetings in December 2013. The ASH annual meeting hosted approximately 20,000 attendees in New Orleans,

Louisiana, where more than 5300 abstracts were presented, orally or as posters.

About 7500 participants from more than 90 countries attended the breast cancer symposium. Below are selected brief highlights from these meetings.

Alice Goodman

S

everal new drugs for the treatment of chronic lymphocytic leukemia (CLL) are considered major advances: 2 have been approved and 2 are under review by the US Food and Drug Administration (FDA). At the recent Chemotherapy Foundation Symposium,

experts discussed ibrutinib, idelalisib, ofatumumab, and obinutuzumab.1,2 “Ibrutinib and idelalisib are 2 potent BCR [B-cell receptor] pathway inhibitors that are highly effective in both untreated and treated CLL,” stated Morton Continued on page 22

inside Multiple Myeloma . . . . . . . . . . . . . .

Benefit Shown for Pomalidomide 4 mg Daily on Intermittent Schedule Breast Cancer Eribulin Mesylate Plus Trastuzumab Yields High Response Rates as First-Line Metastatic Breast Cancer Treatment. . . . . . . . . . . . . . . . . . .

Ovarian Cancer Bevacizumab Appears to Benefit High-Risk Patients. . . . . . . . . . . . . . . . . . .

Trebananib in Platinum-Sensitive Ovarian Cancer. . . . . . . . . . . . . . . . . . . . . .

Continued on page 14 ©2014 Green Hill Healthcare Communications, LLC

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17 19 19

Antiangiogenesis Pursued in High-Risk Ovarian Cancer . . . . . . . . . . .

Side Effects Management NEPA Superior to Palonosetron in CINV Prevention . . . . . . . . . . . . . . . . . .

Osteonecrosis of the Jaw Associated With Cumulative Dose in Myeloma. . . . . . . . . . . . . . . . . . . .

Understanding FOLFOX Toxicity: Some Subsets Have Higher Risks . . . . . . . . . . . . . . . . . . . . . . . .

23 20 20 21

Amgen is researching ways to help T cells target cancer.

Find it T cell

Reference: 1. Melcher A, Parato K, Rooney CM, Bell JC. Thunder and lightning: immunotherapy and oncolytic viruses collide. Mol Ther.

2011;19:1008-1016. Š2013 Amgen Inc. All rights reserved. 11/13 74385-R2-V7

Fight it ONCOLYTIC IMMUNOTHERAPY

Cancer cell

is an innovative area of research that uses a modified virus designed to help T cells find and fight cancer cells as part of a hypothesized systemic, tumor-specific immune response.1

Learn more at: www.oncolyticimmunotherapy.com

Amgen. Leading the way in the study of Oncolytic Immunotherapy.

Editorial Board EDITOR-IN-CHIEF

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

Anjana Elefante, PharmD, BSc, BSc Pharm, RPh Roswell Park Cancer Institute Buffalo, NY

Dwight Kloth, PharmD, FCCP, BCOP

Timothy G. Tyler, PharmD, FCSHP

Fox Chase Cancer Center Philadelphia, PA

Desert Regional Medical Center Palm Springs, CA

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

Jim Koeller, MS

John M. Valgus, PharmD, BCOP

Christopher Fausel, PharmD

Christopher J. Lowe, PharmD

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, RPh, 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 Medical Center 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

OncoMed Onco360 Great Neck, 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. D’Amato, RPh, BCOP Maine Center for Cancer Medicine Scarborough, ME

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February 2014 I VOL 7, NO 1

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

www.TheOncologyPharmacist.com

Cancer Multiple Center Myeloma Profile

Benefit Shown for Pomalidomide 4 mg Daily on Intermittent Schedule Caroline Helwick

T

he optimal dosing of pomalidomide in the treatment of multiple myeloma has not been established. Yale University investigators compared continuous and intermittent dosing regimens, and while the intermittent schedule was associated with more toxicity, they concluded that it is preferable, said Kartik Sehgal, MD, a postdoctoral fellow at Yale University School of Medicine, who reported the study at the 2013 American Society of Hematology Annual Meeting.

“Both continuous and intermittent dosing regimens of pomalidomide with dexamethasone have remarkable clinical activity in heavily pretreated, relapsed/ refractory multiple myeloma patients,” Sehgal said. “Our objective was to determine the optimal dosing strategy for patients who relapse after treatment with standard regimens. These 2 dosing regimens have been evaluated in clinical trials but not compared head to head.”

The investigators found that while the intermittent regimen was associated with more grade 3/4 adverse events (AEs)—probably due to a higher dose of pomalidomide—it led to greater maximal reduction in tumorassociated immunoglobulin. The intermittent schedule, therefore, is being used in his clinic, Sehgal said.

Details of the Comparison The single-center randomized phase 2 trial involved 39 patients with myeloma, all of whom were resistant to lenalidomide; approximately 80% were also resistant to bortezomib, and 80% were resistant to both agents. About two-thirds of the group had abnormal molecular cytogenetic profiles.

The continuous dosing group received pomalidomide 2 mg/d on days 1 to 28 of

Table

Clinical Efficacy of 2 Pomalidomide Dosing Regimens Continuous Dosing (2 mg/d, 28/28 d) (n = 19)

Intermittent High-Dose (4 mg/d, 21/28 d) (n = 20)

Response rate, n (%) ORR VGPR PR

4 (21) 2 (11) 2 (11)

9 (45) 2 (10) 7 (35)

Stable disease

10 (53)

9 (45)

19 (49)

Progressive disease

5 (26)

2 (10)

7 (18)

28

54

Outcome

Maximum reduction in disease, mean %

Difference Between Arms

Total (N = 39)

P = .18

13 (33) 4 (10) 9 (23)

P = .02

41

Abbreviations: ORR, objective response rate; PR, partial response; VGPR, very good partial response.

a 28-day cycle, while the intermittent group received pomalidomide 4 mg/d on days 1 to 21 of a 28-day cycle. All patients received dexamethasone 40 mg/wk on days 1, 8, 15, and 22, beginning with cycle 2, until disease progression.

“The question is whether we should give a higher or lower dose of pomalidomide, but at the same time we want to decrease adverse events, so we give a higher dose but with 1 week off, which lessens side effects,” he said.

Outcomes With the 2 Regimens The intermittent/higher-dose arm had numerically higher response rates, but the difference was not statistically significant.

What was significant, however, was the difference in maximum reduction in dis-

ease, Sehgal reported (Table).

Median progression-free survival was similar, 4.4 months with continuous dosing and 5.1 months with intermittent dosing (P = .56). Median overall survival was the same, 17.7 months, in each arm.

“Despite a greater decrease in maximum reduction of disease with the intermittent dose, we did not see a difference in progression-free or overall survival,” he noted.

He said pomalidomide was “pretty well tolerated” but there was a significant increase in pomalidomide-related grade 3/4 AEs with the higher, intermittent dose. Serious drug-related AEs were observed in 8 patients (40%) in the intermittent arm versus 5 patients (26%) in the continuous arm (P = .5), and drug-re-

lated grade 3/4 AEs were observed in 18 patients (90%) in the intermittent arm versus 10 patients (53%) with continuous dosing (P = .013).

“We recommend going with the higher, intermittent dosing,” Sehgal told The Oncology Pharmacist. “This leads to a greater reduction in disease, and this probably gives the patient a better chance for a good outcome. Although there is the possibility of more grade 3 and 4 toxicity, in our experience the side effects are manageable.”

Reference

Sehgal K, Kocoglu MH, Deng Y, et al. Comparison of intermittent and continuous dosing regimens of pomalidomide in relapsed/refractory myeloma: results of a phase II randomized trial. Poster presented at: 2013 American Society of Hematology Annual Meeting; December 8, 2013; New Orleans, LA. Abstract 3205.

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February 2014 I VOL 7, NO 1

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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 Mollie Friedman Peggy Roeske Editorial Assistant Jennifer Brandt Production Manager Cara Nicolini

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 Associate Editorial Director, Projects Division Terri Moore 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 Andrea Boylston Jini Gopalaswamy Project Coordinators Jackie Luma Deanna Martinez IT Specialist Carlton Hurdle Executive Administrator Rachael Baranoski Office Coordinator Robert Sorensen

Green Hill Healthcare Communications, LLC 1249 South River Road - Ste 202A Cranbury, NJ 08512 phone: 732-656-7935 • fax: 732-656-7938

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February 2014 I VOL 7, NO 1

Patrick Medina, PharmD, BCOP Editor-in-Chief

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

elcome to the first issue of The Oncology Pharmacist (TOP) for 2014. We’ll be publishing 4 issues this year, keeping you up-to-date about what is happening in the world of oncology research and bringing you information that helps you in your day-today practice.

In this issue, we continue our series on oncology pharmacy safety. Christine Roussel, PharmD, BCOP, and Thomas H. Connor, PhD, discuss the use of biomarkers for the evaluation of occupational exposure to chemotherapeutic drugs, noting that “As a group, chemotherapeutic drugs have been shown in animal studies to be some of the most potent teratogenic agents known, at doses typically used in cancer treatment.”

Anne Marie Oberle, PharmD, BCOP, an advance practice clinical oncology pharmacist, tells us about the guidelines for safe-handling practices at the Kimmel Cancer Center at Thomas Jefferson University Hospital.

She also discusses how safety concerns are addressed with patients.

This issue provides you with information about some of the news coming out of the American Society of Hematology annual meeting and the San Antonio Breast Cancer Symposium. Our coverage includes research about optimal dosing of pomalidomide in the treatment of patients with multiple myeloma and results of a review of patients with non-Hodgkin lymphoma at the Cleveland Clinic showing that primary prophylaxis against febrile neutropenia can safely be administered on the same treatment day, if necessary.

As always, we encourage you to visit our website, www.TheOncologyPharmacist.com. Be sure to tell us what topics you want to see covered in TOP. We want to hear from you, and we appreciate your feedback—positive and negative—about what you see in print and on the website. l

W

Reader Poll Are you involved in developing policies or training staff about safe-handling practices for chemotherapeutic drugs? o Yes o No ©iStockphoto.com/Slobodan Vasic

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 mention 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.

www.TheOncologyPharmacist.com

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.

©2014 Cephalon, Inc., a wholly-owned subsidiary of Teva Pharmaceutical Industries Ltd. GRANIX is a trademark of Teva Pharmaceutical Industries Ltd. All rights reserved. GRX-40178 February 2014.

Noteworthy Numbers

Clinical Trials Clinical trials are a vital component of the continued search for safe and effective treatments. Along with the researchers, the patients and healthy volunteers who participate in testing devices, diagnostic procedures, new drugs, and new uses for established therapies contribute to the advancement of knowledge and patient care. The following data provide a glimpse into this important aspect of research.

The national website ClinicalTrials.gov, a service of the US National Institutes of Health (NIH) that provides information

for patients and families, researchers, and study record managers, currently lists 158,491 clinical studies, including locations in all 50

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.

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February 2014 I VOL 7, NO 1

states and in 185 countries.1 As of January 5, 2014, there were 31,642 studies recruiting participants; 44% of these are recruiting only in

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.

the United States.2 ClinicalTrials.gov was made available to the public on February 29, 2000. As of January 5, 2014, there were 84,392 interventional studies of drugs or biologics registered; 8645 studies had posted results.2 Established in 1953 and expanded in 2005, the NIH Clinical Center in Bethesda, Maryland, is the largest hospital in the United States dedicated entirely to clinical research.

Currently, approximately 1500 clinical research projects are under way, about 50% of which are devoted to the study of diseases, especially rare diseases.

Clinical trials of new drugs, predominantly phase 1 and phase 2, account for most of the remaining research.

The NIH Clinical Center staff includes approximately 1200 physicians, dentists, and PhD researchers; 620 nurses; and 450 allied healthcare personnel.3 According to the American Cancer Society (ACS), only 5% of cancer patients currently participate in clinical trials.4 And although 61% of new cancer diagnoses are made in the elderly, they make up only 25% of the participants in cancer clinical trials.5 To help address this issue, the ACS website provides a video for clinicians titled Raising Awareness about Cancer Clinical Trials.4 Sources 1. www.ClinicalTrials.gov.

2. http://www.clinicaltrials.gov/ct2/resources/trends.

3. http://clinicalcenter.nih.gov/ccc/crc/index.html.

4. www.cancer.org/treatment/treatmentsandsideeffects/ clinicaltrials/rasing-awareness-about-cancer-clinicaltrials-video.

5. Lewis JH, et al. J Clin Oncol. 2003;21(7):1383-1389.

www.TheOncologyPharmacist.com

4TH ANNUAL CONFERENCE Cancer Center Profile

MAY 6-9, 2014 LOEWS HOLLYWOOD HOTEL • LOS ANGELES, CA Government and Employers Co-Chairs Jayson Slotnik, JD, MPH

F. Randy Vogenberg, PhD, RPh

Vice President of Reimbursement Strategy & Innovation United BioSource Corporation

Principal Institute for Integrated Healthcare

Personalized Medicine and Payers Co-Chairs Michael A. Kolodziej, MD National Medical Director Oncology Solutions Aetna

Grant Lawless, RPh, MD, FACP Program Director Associate Professor University of Southern California

Oncology Practice Management, Advocacy, and Navigation Co-Chairs Linda Bosserman, MD, FACP

President Wilshire Oncology Medical Group

Vicki Kennedy, LCSW

Vice President, Program Development and Delivery Cancer Support Community

AVBCC Leadership Burt Zweigenhaft, BS President and CEO OncoMed

Gary M. Owens, MD

President Gary Owens Associates

www.AVBCConline.org

Craig K. Deligdish, MD Hematologist/ Oncologist Oncology Resource Networks

HELD IN PARTNERSHIP WITH

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Oncology Pharmacy Safety

Chemotherapy: Biomarkers of Exposure… Continued from cover and mitigate healthcare workers’ risk of exposure during the care and treatment of patients. Current knowledge about adverse reproductive effects and cancer associated with occupational exposure to these highly toxic drugs is summarized.

This article discusses approaches that have been used to examine potentially adverse outcomes in healthcare professionals who work with or are exposed to chemotherapy drugs: (1) the use of biomarkers to evaluate genotoxic damage; (2) adverse reproductive outcomes; and (3) the association of cancer with exposure to chemotherapy drugs.

Biomarkers of exposure and effect have been used extensively to monitor both healthcare professionals who work with antineoplastic3-5 and other hazardous drugs, and workers in other occupational settings who may be exposed to genotoxic chemicals. In general, biomarkers are based on mutagenic or other end points of genotoxicity of the drugs. As most of the first generation of antineoplastic drugs were genotoxic in one test system or another, they were ideal candidates for use in exposed worker populations. However, these end points are typically nonspecific in nature and can result from exposure to any genotoxic compound, certain types of radiation, and possibly viral infections. Therefore, studies of worker populations must be carefully designed to rule out extraneous factors such as smoking history, diet, age, and other variables that may compromise test results. Nevertheless, more than half of the 100-plus published studies in the literature have reported a statistically significant association between exposure to antineoplastic drugs and the end point being investigated. Most of these studies have originated outside the United States, and they often have been conducted in countries where safety precautions may not be as rigorous as in the United States.

It has been hypothesized that many antineoplastic drugs actually target developing fetuses in the same way they target the rapidly proliferating cells and active DNA metabolism of cancer cells.6 Reproductive health is one of the most vulnerable end points because many hazardous drugs used for cancer treatment target rapidly dividing cells in the same way teratogens target rapidly dividing embryonic cells.

Some of the same genotoxic properties that make chemotherapy drugs good candidates for biomarker testing confer adverse reproductive properties to them. Laboratory studies have demonstrated that many chemotherapeutic drugs are teratogenic, often in more

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than one animal species. Some classes of drugs are more hazardous than others and, as a group, chemotherapeutic drugs have been shown in animal studies to be some of the most potent teratogenic agents known, at doses typically used in cancer treatment.

Chemotherapeutic agents have demonstrated the ability to induce multiple types of genetic damage in mammalian cells in both in vitro and in vivo models. DNA-damaging effects on healthy nontarget tissues have been documented in patients with cancer treated with chemotherapy drugs, and the risk of secondary malignancies from these treatments is factored into the treatment decisions made for each potentially curable patient. It was through identification of the risk of secondary malignancies in patients that concern shifted to occupational exposure from antineoplastics and the potential genotoxic effects in healthcare workers. While their systemic exposure does not approach the peak concentrations achieved through therapeutic administration, chronic low-level occupational exposure to chemotherapy drugs is a realistic concern, as workplace contamination is well documented in almost 100 studies worldwide, and worker absorption of chemotherapy has been detected in more than 50 studies.2,7-9 Although worker exposure has been well documented, relatively few studies of their risk of developing cancer have been published.

and positive associations exist between the types of agents, cumulative doses, and dose intensity.12 In patients with cancer, alkylating agent–induced leukemia and myelodysplastic syndromes generally have a latency period of 4 to 10 years and are associated with partial loss or deletions of chromosomes 5 and 7.10,13 A clear example of dose-response relationships was shown in pediatric patients with cancer, in whom a 5-fold increase in risk of secondary leukemia rose to greater than a 23-fold increase with high-dose alkylator therapy.14 Topoisomerase II inhibitors (etoposide and doxorubicin) are associated with translocations on chromosome 11 (11q23), loss or deletion of chromosome 7, and many other balanced translocations, and have a latency period of 1 to 3 years.13 One cohort and case control analysis reported that 3% of pediatric patients with germ cell tumors developed treatment-related AML (t-AML) after receiving etoposide <2 g/m2, compared with more than 11% of patients developing t-AML after receiving >2 g/m2.15 Cumulative dosing and treatment regimens in both children and adults have evolved based on this information.

Though the risk of secondary malignancies in patients treated with chemotherapy is its own topic, the dose-response relationship with chemotherapy highlights the need for genotoxic risk assessment of chronic subtherapeutic chemotherapy exposure in healthcare workers. Biomarkers of

As a group, chemotherapeutic drugs have been shown in animal studies to be some of the most potent teratogenic agents known, at doses typically used in cancer treatment.

Understanding genotoxicity and therapy-related secondary cancers in chemotherapy-treated patients can provide insight into the increased risks of cancer in occupationally exposed healthcare workers. Leukemias are the most common secondary malignancy following chemotherapy, with acute myelogenous leukemia (AML) being the predominant pathology. About 10% to 20% of myeloid neoplasms are therapy related, prompting the World Health Organization to classify “hematopoietic stem cell disorders related to previous exposure to chemotherapy and or radiation” separately in 2008.10,11 Only a small percentage of exposed patients develop therapy-related disorders (2%-20% of long-term survivors),

exposure and effect are tools employed by occupational toxicologists to help define risk. The same mechanisms that induce genetic damage in patients also affect healthcare workers—hematopoietic progenitor cells can incur DNA damage, resulting in acquired mutations that go unrepaired, which can lead to malignant transformation.

Evaluation of damage in healthcare workers has evolved but is limited to clinical research, which is currently beyond the reach of employees and employers.

Biomarkers of Exposure A biomarker of exposure is defined as an exogenous substance or its metabolite or the product of an interaction

between an exogenous agent and a target molecule or cell that is measured in a compartment within an organism. For most antineoplastic drugs, the intact drug and/or a metabolite of the drug is usually measured in urine samples.

Urinary Mutagenicity Urinary mutagenicity was first used as a marker of exposure to antineoplastic drugs in 1979 by Falck and colleagues using bacterial mutagenicity assays.16 The test is nonspecific and may be influenced by several extraneous factors, including dietary intake and smoking. For these reasons, this test is used sparingly. Nevertheless, the urinary mutagenicity test was instrumental in changing the use of horizontal flow cabinets for the preparation of antineoplastic drugs, which exposed the workers to high levels of drugs, to vertical flow biological safety cabinets (BSCs). This change greatly affected how these drugs were handled and helped reduce worker exposure to them.17 Urinary Excretion of Drugs/Metabolites Biomarkers of exposure to chemotherapy drugs most commonly include urinary cyclophosphamide and ifosfamide, urinary platinum (for all platinum-containing drugs), methotrexate, and the urinary metabolite of 5-fluorouracil, α-fluoro-β-alanine.7,18,19 A small number of other drugs have been measured in the urine, but less commonly.

Measurement of these drugs directly in the urine is an indication that exposure levels may be high and uptake of the drugs is taking place either dermally or by inhalation.9 When assessing the validity of urinary excretion studies, it is important to consider the pharmacokinetics of the drug being evaluated. For example, searching for mitomycin exposure through urinary excretion may provide a false-negative, as mitomycin is primarily hepatically metabolized, and only 10% of the dose is excreted unchanged in the urine.20 Identification of exposure is the first step, but quantifying the damage is considerably more difficult. The application of such testing to the general population and the commercial availability of assays for surface sampling but not for biologic monitoring remain an issue.

Biomarkers of Effect A biomarker of effect is defined as a measurable biochemical, physiological, behavioral, or other alteration within an organism that can be associated with a specific exposure.

Biomarkers of effect have been utilized

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Oncology Cancer Pharmacy Center Profile Safety as biomarkers of exposure when comparing potentially exposed to nonexposed (control) populations.

Chromosomal Aberrations A chromosomal aberration is a missing, extra, or irregular portion of chromosomal DNA. Numeric and structural abnormalities are evaluated in cultured peripheral blood lymphocytes or other cell types that are arrested at metaphase and stained in order to visualize individual chromosomes.

Chromosomal aberrations can result from exposure to many genotoxic agents, including chemicals and radiation, and are further divided by type of damage. Chromosome-type aberrations involve the same locus on both sister chromatids on one or multiple chromosomes, such as double-strand breaks like those caused by ionizing radiation. Chromatid-type aberrations affect only one of the sister chromatids on one or more chromosomes.

Examples include several insults: DNA cross-linking, base substitutions, and single-strand breaks such as the damage mediated by a variety of cytotoxic agents. Significant differences in various types of chromosomal damage have been reported in a large number of studies in potentially exposed healthcare workers, most with an increase 1.5 to 3.5 times that of appropriately matched controls. Selected references include Nikula and colleagues (1984), Burgaz and colleagues (2002), Tompa and colleagues (2006), MusĂĄk and colleagues (2006), Testa and colleagues (2007), Kopjar and colleagues (2009), McDiarmid and colleagues (2010), and El-Ebiary and colleagues (2013).21-28 Evaluation of chromosomal aberrations is a validated method to assess exposure to genotoxic agents, and their association with cancer risk has been demonstrated in prospective studies in which cohorts were followed for up to 25 years. Several studies have shown a significant association between increased frequency of chromosomal aberrations in peripheral blood lymphocytes and increased incidence of multiple cancer types in the healthy individuals tested. The cancer types documented were similar to the distribution of cancer in the general population, a finding that supports the assumption that genetic damage in the cells examined is reflective of similar genetic damage occurring in the tissues where carcinogenesis is occurring.29-32 Smerhovsky and colleagues were able to validate this relationship through cytogenetic assessment of mine workers exposed to radon beginning in 1975 in the Czech Republic.33 Their data showed a strong and significant relationship, such that a â&#x20AC;&#x153;1% increase in chromosomal aberrations was fol-

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lowed by a 64% increase in risk of cancer (P <.000).â&#x20AC;? While decadeslong follow-up in antineoplastic-exposed healthcare workers would be ideal, 5 studies published since 2002 have shown a statistically significant increase in chromosomal aberrations in exposed healthcare workers, with an average of 1.5 to 3.5 times the controls, supporting the sensitivity of this biomarker for detecting low-level DNA damage.22-26 More recently, McDiarmid and colleagues targeted chromosomes 5, 7, and 1127 because specific nonrandom chromosome damage to these genetic targets is known to be mediated by alkylating agents and topoisomerase II inhibitors, resulting in associated treatment-induced malignancies.

Compared with looking at aberrations in all chromosomes, this study allowed for increased sensitivity such that it detected a 7-fold increase in abnor-

exposure to genotoxic chemicals and radiation, and significant differences in increases in micronuclei frequencies in either peripheral blood lymphocytes or buccal epithelial cells have been reported in a large number of studies comparing potentially exposed healthcare workers with appropriately matched controls. Selected references include Thiringer and colleagues (1991), Maluf and Erdtmann (2000), Pilger and colleagues (2000), Hessel and colleagues (2001), Cavallo and colleagues (2007), Rekhadevi and colleagues (2007), Cornetta and colleagues (2008), and Cavallo and colleagues (2009).34-41 Preliminary evidence supports increased frequency of micronuclei formation in peripheral blood lymphocytes as being predictive of cancer risk.42-44 While most of the positive micronucleus studies show doubling in the frequency of micronuclei in exposed

Christine Roussel, PharmD, BCOP

Thomas H. Connor, PhD

malities on chromosome 5 in exposed healthcare workers versus nonexposed healthcare workers. Evaluation of chromosomal abnormalities is a validated biomarker for cancer risk, sensitive to low-level DNA damage induced by chemotherapeutic drugs; however, the large biological sample required, coupled with a labor-intensive analysis, does not lend itself to mass-scale biologic monitoring for occupational exposure.

healthcare workers compared with controls, the study by Rekhadevi and colleagues showed a 4.7-fold increase.39 This study, evaluating oncology nurses in southern India, also showed an increase in micronuclei associated with years of exposure, age, duration of exposure within the average workday, and detection of urinary cyclophosphamide, which was also recorded.

At the time of the study, there were fewer safety precautions for these test subjects than were commonly found in pharmacies in the United States that compounded hazardous drugs. Though not related to micronuclei, it is worth mentioning that the data did show an association between increased cyclophosphamide in the urine of the staff and increased age, years of exposure, and exposure per day.

Micronuclei Micronuclei are small collections of enveloped nuclear material present in the cytoplasm that separate from the main nucleus during cellular division. The formation of micronuclei in dividing cells results either from chromosome breakage (clastogenesis) or from chromosome mis-segregation due to mitotic malfunction.

Micronuclei content may correspond to whole chromosomes with a centromere or to acentric chromosomal fragments. Similar to chromosomal aberrations, micronuclei result from

Sister Chromatid Exchanges Sister chromatid exchanges (SCEs) result from symmetric exchange of DNA replication products between 2 identical sister chromatids at a given locus and do not result in any alter-

ation in chromosomal number or structure. The biological purpose of SCEs is not known, but they are hypothesized to be related to DNA repair and believed to be involved very early in the process of neogenesis. Their frequency is increased as a result of chromosomal fragility due to genetic or environmental factors such as ultraviolet or ionizing radiation and other mutagenic agents. To further increase the sensitivity of detection, some studies limit quantification to only high-frequency cells (HFCs), often defined as an increase in SCEs above the 95th percentile. SCE analysis has been applied in many earlier studies of occupational exposure to antineoplastic drugs, and 6 studies have reported increases in SCEs compared with control populations. Selected references include Norppa and colleagues (1980), Thiringer and colleagues (1991), Pilger and colleagues (2000), Jakab and colleagues (2001), Tompa and colleagues (2006), and Kopjar and colleagues (2009).23,26,34,36,45,46 However, the large population-based cohorts that validated chromosomal aberration analysis and risk for cancer did not validate the association between increased SCEs or HFCs and cancer.47 That, coupled with the unknown biological mechanism of SCE, has led to the decline in use of this biomarker despite the positive associations with exposure to genotoxic agents.

DNA Damage and Mutations Hypoxanthine-guanine phosphoribosyltransferase (HPRT) The HPRT gene controls the enzyme hypoxanthine-guanine phosphoribosyltransferase that plays a role in purine salvage. In addition to its normal substrates, HPRT catalyzes the transformation of purine analogues such as 6-thioguanine (6-TG), rendering them cytotoxic to normal cells. Cells with mutations in the HPRT gene cannot phosphoribosylate the analogue and survive treatment with 6-TG. HPRTdeficient T lymphocytes determined by the cloning assay are mutant cells resulting from in vivo mutations at the HPRT locus.48,49 A limited number of occupational studies of healthcare workers exposed to chemotherapy drugs have utilized this assay. Selected studies include Dubeau and colleagues (1994) and Thulin and colleagues (1995).50,51 Comet Assay The single cell gel electrophoresis assay (also known as the comet assay) is a sensitive technique for the detection of DNA damage at the level of the individual eukaryotic cell. Recently, it has increased in popularity as a stanContinued on page 12

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Oncology Pharmacy Safety

Chemotherapy: Biomarkers of Exposure… Continued from page 11 dard technique for evaluation of DNA damage/repair, biomonitoring, and genotoxicity testing. It involves the encapsulation of cells in a low-meltingpoint agarose suspension, lysis of the cells in neutral or alkaline (pH >13) conditions, and electrophoresis of the suspended lysed cells. The term comet refers to the pattern of DNA migration through the electrophoresis gel, which often resembles a comet. Undamaged cells have an intact nucleus without a tail, whereas damaged cells have a comet appearance in which the greater tail length is proportional to increased DNA damage.

A growing number of studies have employed the comet assay in comparing potentially exposed populations with controls, and most have shown significant differences between the 2 groups. Selected studies include Ündeger and colleagues (1999), Maluf and Erdtmann (2000), Kopjar and Garaj-Vrhovac (2001), Yoshida and colleagues (2006), Sasaki and colleagues (2008), Rekhadevi and colleagues (2007), and Connor and colleagues (2010).35,39,52-56 One comet assay study found equivalent results when comparing patients with therapeutic high-dose limitedduration exposure to healthcare workers with low-dose chronic exposure.8 Although the significance of this method as a biomarker remains unclear because of the lack of prospective data correlating it with an increased risk of cancer, the comet assay may be better suited as a biomarker of exposure.57 Cancer in Healthcare Workers Relatively few reports have addressed the relationship of cancer occurrence to healthcare workers’ exposures to antineoplastic drugs. A significantly increased risk of leukemia has been reported among oncology nurses identified in the Danish cancer registry for the period 1943−1987.58 The same investigators found an increased, but not significant, risk of leukemia in physicians employed for at least 6 months in a department where patients were treated with antineoplastic drugs.59 Hansen and Olsen reported elevated risks for nonmelanoma skin cancer (standardized incidence ratio [SIR] 1.5; 95% confidence interval [CI], 1.1-2.1) and non-Hodgkin lymphoma (SIR 3.7; 95% CI, 1.2-8.9) in 8500 Danish female pharmacy technicians.60 In addition, a Canadian study reported an increased risk for breast cancer (relative risk [RR] 1.83; 95% CI, 1.033.23) and cancer of the rectum (RR 1.87; 95% CI, 1.07-3.29) among nurses potentially exposed to antineoplastic drugs.61

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Biomarkers of Susceptibility A biomarker of susceptibility is an indicator of an organism’s inherent or acquired ability to respond to the challenge of exposure to a specific substance. Genetic polymorphisms have the ability to alter the body’s response to an assault from chemotherapeutic drugs and account for an individual’s increased susceptibility to damage. Genetic polymorphisms that alter drug metabolism and detoxification are increasingly being identified, and their use in clinical practice is emerging.

Furthermore, genetic polymorphisms that relate to DNA repair mechanisms are also emerging, with one study identifying at least a 10% incidence in decreased DNA repair capacity in lymphocytes exposed to genotoxic chemicals.62 Considering that only a small percentage of chemotherapy-treated patients develop a therapy-related malignancy, it is hypothesized that genetic predispositions may be involved related to either or both the ability to detoxify the toxicant and/or the ability to repair the damage caused by the toxicant. Differences in chromosomal aberrations and micronuclei tests in patients with cancer before and after receiving the same type of chemotherapy showed wide interpatient variability, even in those of the same sex and with the same type of cancer.63 The effects of genetic polymorphisms related to DNA repair are not fully understood, but there is enough evidence to warrant further evaluation of individual susceptibility to damage from chemotherapeutic drugs and potentially evaluate this association with occupational risk.

Adverse Reproductive Effects Studies of healthcare workers occupationally exposed to antineoplastic drugs have examined the occurrence of adverse reproductive outcomes, including infertility, spontaneous abortions, stillbirths, pregnancy outcomes, and congenital malformations. Seven studies and 1 meta-analysis of congenital malformations and occupational exposure to antineoplastic drugs were identified. Many studies of congenital malformations had small sample sizes (fewer than 20 exposed cases, resulting in several limitations, such as limited ability to adjust for confounding factors; grouping of anomalies that may have different etiologies; and wide confidence intervals, indicating poor power). However, of the studies that had more than 5 exposed cases, 3 studies showed significantly increased risks associated with exposure,64-66 and 2 showed increased risks that were not statistically significant.58,61 The

odds ratios (ORs) of adjusted models ranged from 1.36 (95% CI, 0.593.14)58 to 5.1 (95% CI, 1.1-23.6)66.

A meta-analysis of 4 studies67 with exposure periods ranging from 1966 to 200458,64,66,68 reported a crude OR of 1.64 (95% CI, 0.91-2.94) for all congenital anomalies combined. Although in general these studies suggest an increased risk for congenital anomalies with maternal occupational exposure, the limitations and wide confidence intervals make interpretation of the results inconclusive.

Previous studies of spontaneous abortion and maternal occupational exposure to antineoplastic drugs had mixed results, and several of these studies were limited by small sample sizes. The 4 largest studies69-72 showed increased occurrence of spontaneous abortions with self-reported exposure during the first trimester through handling or compounding of antineoplastic drugs. Most exposures were among oncology nurses and pharmacists (ORs ranged from 1.5 to 2.3 in samples that included 18 to 223 exposed cases).

Other studies that did not find statistically significant associations had ORs ranging from 0.7 to 2.8 and limited sample sizes (3 to 34 exposed cases). A meta-analysis that pooled the results of 5 studies58,66,69-71 found an overall adjusted increased risk of 46% among exposed workers (95% CI, 11%-92%).67

A number of biomarkers for genotoxicity have proved useful when evaluating occupational exposures of healthcare workers to antineoplastic drugs.

More research is needed to examine the effects of occupational exposure to antineoplastic drugs on stillbirth. One study showed a statistically significant 3-fold increased risk of menstrual cycle irregularities from occupational exposure to antineoplastic drugs.73 Another study showed an increased risk of learning disabilities among offspring of workers exposed to antineoplastic drugs.74 Summary Chemotherapy contamination in the workplace has been extensively documented, as has worker uptake of these hazardous drugs through their daily

workflow. The magnitude of the contamination has changed little over the past decade and, even with maximum compliance in optimally designed facilities (which may not always be the case), exposure has not been eliminated. It should be stressed that most of the biomarker studies reported herein were undertaken in countries outside of the United States. Therefore, the potential for exposure may have been greater in countries where exposure controls may not be as widely used as they are here. Quantification of genotoxic damage incurred in the workplace has the potential to offer invaluable information about the effectiveness or lack of it in current procedures and safety controls. Ultimately, this problem will not go away, as growing numbers of patients are receiving chemotherapy and other hazardous drugs prepared and/or administered by dedicated pharmacists, pharmacy technicians, and nurses.

A number of biomarkers for genotoxicity have proved useful when evaluating occupational exposures of healthcare workers to antineoplastic drugs. Early studies utilized urinary mutagenicity testing, but this assay is rarely used today. Many studies have used chromosomal aberrations, SCEs, and, more recently, the micronucleus assay to monitor workers who handle these drugs. Lately, the comet assay has proven to be a helpful tool for assessing damage to DNA. Because more than half of the published studies have demonstrated a significant association between occupational exposure to antineoplastic drugs and one of these biomarkers, it must be assumed that workers are being exposed to a degree sufficient enough to elicit a response in the biomarkers being studied.

Although the majority of the adverse reproductive effects observed in healthcare workers are related to exposures in the past decade or more, and most study results suffer from small sample size, there is evidence to support the theory that these exposures can have an adverse effect on a developing fetus. Increased rates of spontaneous abortion, malformations, and other outcomes have been documented in these studies, indicating that these outcomes are possible if sufficient exposures occur.

Certainly, studies of cancer outcomes in healthcare workers are lacking. Because it has not been possible to link cancer registry data to occupation in the United States, we will have to look to other countries for these types of data. The association between certain biomarkers (eg, chromosomal aberrations and micronuclei) and can-

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Oncology Cancer Pharmacy Center Profile Safety cer outcome in unexposed populations raises the question of whether exposed workers with increased levels of genotoxic damage are also at an elevated risk for cancer later in life. Currently, these types of studies are only employed on a population basis and do not translate to use in individual subjects. Many risk factors are involved in the complexity of the cancer process, and chromosomal damage may be one more potential risk factor.

Disclaimers The findings and conclusions of this report have not been formally disseminated by NIOSH and should not be construed to represent any agency determination or policy.

Mention of company names or products does not constitute endorsement by the National Institute for Occupational Safety and Health.

References

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2. Roussel C, Connor TH. Chemotherapy: every step you take, every move you make…. The Oncology Pharmacist. 2013;6(4):1, 12-16.

3. Baker ES, Connor TH. Monitoring occupational exposure to cancer chemotherapy drugs. Am J Health Syst Pharm. 1996;53(22):2713-2723.

4. Sorsa M, Anderson D. Monitoring of occupational exposure to cytostatic anticancer agents. Mutat Res. 1996;355(1-2):253-261.

5. Sessink PJ, Bos RP. Drugs hazardous to healthcare workers: evaluation of methods for monitoring occupational exposure to cytotoxic drugs. Drug Saf. 1999;20(4):347-359.

6. Selig BP, Furr JR, Huey RW, et al. Cancer chemotherapeutic agents as human teratogens. Birth Defects

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VBMAsize_Mitchell_21114

Res A Clin Mol Teratol. 2012;94(8):626-650.

7. Turci R, Sottani C, Spagnoli G, et al. Biological and environmental monitoring of hospital personnel exposed to antineoplastic agents: a review of analytical methods. J Chromatogr B Anaylt Technol Biomed Life Sci. 2003;789(2):169-209.

8. Suspiro A, Prista J. Biomarkers of occupational exposure to anticancer agents: a mini review. Toxicol Lett.

2011;207(1):42-52.

9. National Institute of Occupational Safety and Health.

Occupational exposure to antineoplastic agents. http://www.cdc.gov/niosh/topics/antineoplastic/.

Updated October 29, 2013. Accessed December 20, 2013.

10. Casorelli I, Bossa C, Bignami M. DNA damage and repair in human cancer: molecular mechanisms and contribution to therapy-related leukemias. Int J Environ Res Public Health. 2012;9(8):2636-2657.

11. National Cancer Institute. Classification of adult acute myeloid leukemia. http://www.cancer.gov/ cancertopics/pdq/treatment/adultAML/healthprofes sional/page2. Accessed December 12, 2013.

12. Leone G, Voso MT, Sica S, et al. Therapy related leukemias: susceptibility, prevention and treatment.

Leuk Lymphoma. 2001;41(3-4):255-276.

13. Guillem V, Tormo M. Influence of DNA damage and repair upon the risk of treatment related leukemia.

Leuk Lymphoma. 2008;49(2):204-217.

14. Tucker MA, Meadows AT, Boice JD Jr, et al.

Leukemia after therapy with alkylating agents for childhood cancer. J Natl Cancer Inst. 1987;78(3):459-464.

15. Hawkins MM, Wilson LM, Stovall MA, et al.

Epipodophyllotoxins, alkylating agents, and radiation and risk of secondary leukaemia after childhood cancer.

BMJ. 1992;304(6832):951-958.

16. Falck K, Gröhn P, Sorsa M, et al. Mutagenicity in urine of nurses handling cytostatic drugs. Lancet.

1979;1(8128):1250-1251.

17. Anderson RW, Puckett WH Jr, Dana WJ, et al. Risk of handling injectable antineoplastic agents. Am J Hosp Pharm. 1982;39(11):1881-1887.

18. Sessink PJ, Boer KA, Scheefhals APH, et al.

Occupational exposure to antineoplastic agents at several departments in a hospital: environmental contamination and excretion of cyclophosphamide and ifosfamide in urine of exposed workers. Int Arch Occup Environ Health. 1992;64(2):105-112.

19. Sessink PJ, Cerná M, Rössner P, et al. Urinary cyclophosphamide excretion and chromosomal aberrations in peripheral blood lymphocytes after occupational exposure to antineoplastic agents. Mutat Res. 1994;309(2):193-199.

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21. Nikula E, Kiviniitty K, Leisti J, et al. Chromosome aberrations in lymphocytes of nurses handling cytostatic agents. Scand J Work Environ Health. 1984;10(2):71-74.

22. Burgaz S, Karahalil B, Canhi Z, et al. Assessment of genotoxic damage in nurses occupationally exposed to antineoplastics by the analysis of chromosomal aberrations. Hum Exp Toxicol. 2002;21(3):129-135.

23. Tompa A, Jakab M, Biró A, et al. Chemical safety and health conditions among Hungarian hospital nurses. Ann N Y Acad Sci. 2006;1076:635-648.

24. Musák L, Vodicka P, Klimentová G, et al.

Chromosomal damage and polymorphisms of DNA repair genes XRCC1 and XRCC3 in workers exposed to cytostatics. Neuro Endocrinol Lett. 2006;27(suppl 2):57-60.

25. Testa A, Giachelia M, Palma S, et al. Occupational exposure to antineoplastic agents induces a high level of chromosome damage. Lack of an effect of GST polymorphisms. Toxicol Appl Pharmacol. 2007;223(1):46-55.

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Assessment of genotoxic risks in Croatian health care workers occupationally exposed to cytotoxic drugs: a multi-biomarker approach. Int J Hyg Environ Health.

2009;212(4):414-431.

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Chromosome 5 and 7 abnormalities in oncology personnel handling anticancer drugs. J Occup Environ Med. 2010;52(1):1028-1034.

28. El-Ebiary AA, Abuelfadl AA, Sarhan NI. Evaluation of genotoxicity induced by exposure to antineoplastic drugs in lymphocytes of oncology nurses and pharmacists. J Appl Toxicol. 2013;33(3):196-201.

29. Bonassi S, Hagmar L, Strömberg U, et al.

Chromosomal aberrations in lymphocytes predict human cancer independently of exposure to carcinogens. European Study Group on Cytogenetic Biomarkers and Health. Cancer Res. 2000;60(6):1619-1625.

30. Hagmar L, Brøgger A, Hansteen IL, et al. Cancer risks in humans predicted by increased levels of chromosomal aberrations in lymphocytes: Nordic study group on the health risk of chromosome damage. Cancer Res. 1994;54(11):2919-2922.

31. Hagmar L, Strömberg U, Bonassi S, et al. Impact of types of lymphocyte chromosomal aberrations on human cancer risk: results from Nordic and Italian cohorts.

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Conference News Continued from cover

In postmenopausal women with early breast cancer, bisphosphonates in the adjuvant setting reduced the risk of recurrence in bone by 34% and breast cancer death by 17% according to a large meta-analysis conducted by the Early Breast Cancer Trialists’ Collaborative Group.

The risk reductions in bone recurrence and death with adjuvant bisphosphonates were observed in postmenopausal women regardless of estrogen receptor status, nodal status, and chemotherapy. Bisphosphonates had no effect on outcomes in premenopausal women.

“In addition to the 17% reduction in breast cancer–related mortality, adjuvant bisphosphonates led to an absolute reduction of 3.4% in allcause mortality,” stated lead author Robert Coleman, MD, University of Sheffield, United Kingdom.

“These results are likely to be practice changing, leading to a new option for standard of care,” said Peter Ravdin, MD, who moderated a press conference at the San Antonio Breast Cancer Symposium at which these data were presented.

Ravdin, who was not involved in the

Photo © San Antonio Breast Cancer Symposium.

Bisphosphonates Lower Risk of Recurrence and Death in Postmenopausal Early Breast Cancer

“In addition to the 17% reduction in breast cancer– related mortality, adjuvant bisphosphonates led to an absolute reduction of 3.4% in all-cause mortality.”

Robert Coleman, MD

study, is the director of the Breast Health Clinic at the Cancer Therapy & Research Center of the University of Texas Health Science Center at San Antonio.

The large, individual patient metaanalysis was based on 36 randomized controlled trials with a total of 22,982 women that compared adjuvant use of bisphosphonate versus no bisphosphonate or placebo. Seven of the trials compared the bisphosphonate clodronate versus no bisphos-

phonate or placebo and 29 evaluated aminobisphosphonates versus no bisphosphonate or placebo (65% of the women taking aminobisphosphonates received zoledronic acid, 24% ibandronate, and 11% “other”).

In the overall trial, no significant difference was observed in the 10-year rate of all breast cancer recurrences or distant recurrences, including bone recurrences.

The effect of bisphosphonates was

confined to 11,306 postmenopausal women (including women aged >55 years if menopausal status was unknown); bisphosphonates achieved a highly significant difference compared with no bisphosphonates in distant recurrence (18.4% vs 21.9%, respectively; P = .0003) and in bone recurrence (5.9% and 8.8; P <.00001). Bisphosphonates did not significantly reduce distant recurrences other than in bone in postmenopausal women.

The rate of breast cancer mortality was 15.2% for postmenopausal women treated with bisphosphonates compared with 18.3% not receiving bisphosphonates (P = .004), and the rate of all-cause mortality was 21.5% versus 23.8%, respectively (P = .007). l

Reference

Coleman R, Gnant M, Paterson A, et al; Early Breast Cancer Clinical Trials Collaborative Group (EBCTCG)’s Bisphosphonate Working Group. Effects of bisphosphonate treatment on recurrence and cause-specific mortality in women with early breast cancer: a meta-analysis of individual patient data from randomized trials. Presented at: San Antonio Breast Cancer Symposium; December 12, 2013; San Antonio, TX. Abstract S4-07.

New Standard of Care for Transplant-Ineligible Patients With Myeloma Continuous treatment with lenalidomide and low-dose dexamethasone (Rd) was superior to standard treatment with melphalan, prednisone, and thalidomide (MPT) for 72 weeks in newly diagnosed patients with multiple myeloma (MM) who were transplant ineligible. Experts said that these results represented a new standard of care for these patients.

Patients treated with Rd were 28% less likely to progress or die compared with those patients who received standard MPT (the primary end point of the

more research on the efficacy and safety of continuous treatment for newly diagnosed patients to help maximize their changes for overall long-term survival,” stated lead author Thierry Facon, MD, Service des Maladies du Sang, Hôpital Claude Huriez, and CHRU Lille, France, at the American Society of Hematology annual meeting.

“For some patients with low-risk MM, this continuous regimen could make this disease a manageable, chronic condition,” he stated.

“For some patients with low-risk MM, this continuous regimen could make this disease a manageable, chronic condition.”

Thierry Facon, MD

trial). Rd was superior to MPT for all secondary end points, including overall survival, response rates, and duration of response. Patients treated with Rd had fewer secondary hematologic malignancies than those patients in the MPT arm.

“Traditionally, newly diagnosed MM patients have received short bursts of treatment, while continuous treatment was reserved for relapsed patients. However, we believe that these new results will help encourage

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The multicenter, phase 3 FIRST (Frontline Investigation of Lenalidomide + Dexamethasone Versus Standard Thalidomide) trial enrolled 1623 newly diagnosed patients with MM who were ineligible for stem cell transplant because of older age (>65 years) or other factors such as comorbidities.

Participants were randomized to 1 of 3 arms: 1.

Continuous Rd in 28-day cycles until disease progression,

2. Rd for 18 cycles (72 weeks), or 3. 12 cycles of MPT (72 weeks).

Antithrombotic prophylaxis was included in the protocol. Doses of antimyeloma drugs were adjusted for adverse events.

At a median follow-up of 37 months, the primary end point of progression-free survival (PFS) was reached, with a highly significant 28% reduction in risk of disease progression or death for those treated with Rd versus MPT (P = .00006). Median PFS was 25.5 months for continuous Rd compared with 21.2 months for MPT. Median survival was also significantly better for continuous Rd than for Rd for 18 cycles: 25.5 months versus 20.7 months (P = .00001).

Four-year overall survival was 59% with Rd compared with 51.4% for MPT; 4-year survival in patients receiving Rd for 18 cycles was 55.7%.

Adverse events were similar in both arms, with the exception of less myelosuppression and fewer secondary hematologic malignancies in the Rd arm. l

Reference

Facon T, Dimopoulos MA, Dispenzieri A, et al. Initial phase 3 results of the First (Frontline Investigation of Lenalidomide + Dexamethasone Versus Standard Thalidomide) trial (MM-020/IFM 07 01) in newly diagnosed multiple myeloma (NDMM) patients (Pts) ineligible for stem cell transplantation (SCT). Presented at: 2013 American Society of Hematology Annual Meeting; December 8, 2013; New Orleans, LA. Abstract 2.

www.TheOncologyPharmacist.com

Cancer Conference Center Profile News

Treatment with 5 years of anastrozole reduced the risk of developing a first breast cancer by 53% and reduced the risk of developing estrogen-receptor positive (ER+) invasive cancer by 58% in women at high risk for developing the disease. These results from the IBIS-II trial were reported at the San Antonio Breast Cancer Symposium.1 “We believe these results provide strong support for chemoprevention of breast cancer in high-risk women.

Longer-term follow-up is needed to determine if the preventive effect is sustained after treatment,” said lead author Jack Cuzick, PhD, Queen Mary University, Wolfson Institute of Preventive Medicine, London, United Kingdom.

IBIS-II randomized 3864 postmenopausal women at high risk of breast cancer, either because of family history and other risk factors (including atypia, lobular carcinoma in situ, or breast density), to treatment with anastrozole or use of placebo for 5 years.

At 7 years of follow-up, primary breast cancers (including ductal carcinoma in situ) developed in 5.6%

Photo © San Antonio Breast Cancer Symposium.

Anastrozole Halves Risk of First Breast Cancer

“We believe these results provide strong support for chemoprevention of breast cancer in high-risk women.”

Jack Cuzick, PhD

of women in the placebo group compared with 2.8% of the anastrozole group, representing a 53% decrease (P <.0001). ER+ invasive breast cancers developed in 3.3% of the placebo group versus 1.4% of the anastrozole group, representing a 58% decrease in risk (P = .001). Anastrozole had no protective effect against developing ER-negative tumors.

The full 5 years of the study was completed by 72% of placebo patients and 68% of those taking anastrozole.

Cuzick said this 4% difference in treatment continuation suggests that drop-

outs due to anastrozole-specific adverse effects were quite low.

Anastrozole was associated with bone fractures in 7.7% of placebo patients and 8.5% of those taking anastrozole.

Participants had a dual-energy X-ray absorptiometry (DEXA) scan at study initiation, and women with low bone mass were prescribed bisphosphonate treatment, which could account for the smaller-than-expected incidence of musculoskeletal/fracture adverse effects seen in this trial, Cuzick said.

Musculoskeletal aches and pains were 10% higher with anastrozole than

in placebo patients. Cuzick said that at baseline, many women in both groups reported joint pain. Other joint symptoms observed more frequently in the anastrozole group were joint stiffness and carpal tunnel syndrome.

Surprisingly, the incidence of other primary cancers was reduced in the group taking anastrozole: 40 patients in the anastrozole group developed other cancers while 70 patients in the placebo group developed other cancers, mainly skin and colorectal cancers.

“This merits further study, and the reasons for this effect are unclear,” Cuzick noted.

Study results were published online in the Lancet to coincide with Cuzick’s presentation at the 2013 San Antonio Breast Cancer Symposium.2 l References

1. Cuzick J, Sestak I, Forbes JF, et al. Breast cancer prevention using anastrozole in postmenopausal women at high risk. Presented at: San Antonio Breast Cancer Symposium; December 12, 2013; San Antonio, TX. Abstract S3-01.

2. Cuzick J, Sestak I, Forbes JF, et al; IBIS-II Investigators.

Anastrozole for prevention of breast cancer in high-risk postmenopausal women (IBIS-II): an international, double-blind, randomised placebo-controlled trial. Lancet.

December 12, 2013. Epublished ahead of print.

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Obinutuzumab Plus Chlorambucil in CLL: New Standard of Care Results of the German CLL11 randomized, controlled clinical trial promise to change the standard of care for first-line treatment of older, sicker patients with chronic lymphocytic leukemia (CLL).

The study showed that obinutuzumab (an anti-CD20 monocolonal antibody) plus chlorambucil (OC) was superior to rituximab plus chlorambucil (RC) with an acceptable safety profile, according to final results of the CLL11 trial, which were presented at the American Society of Hematology (ASH) annual meeting.

OC prolonged overall survival and progression-free survival, and also improved complete response rate, and minimal residual disease (MRD)-negative status versus RC. “These results suggest that obinutuzumab can replace rituximab in combination with chlorambucil as first-line therapy in the specific population studied, ie, older patients with comorbidities,” said Valentin Goede, MD, University Hospital Cologne, Germany.

The study showed that obinutuzumab (an anti-CD20 monocolonal antibody) plus chlorambucil was superior to rituximab plus chlorambucil.

“These findings are significant and potentially practice changing for this large patient population of older CLL patients with comorbidities.”

Goede noted that OC has less toxicity than RC, which is especially important in this compromised patient population that resembles compromised patients with CLL seen in the real world.

CLL11 randomized 781 patients in a 2:1:2 ratio to 3 arms: OC for 6 cycles; chlorambucil for 6 cycles (control); and RC for 6 cycles. At ASH, Goede

presented the first results of the direct comparison between OC and RC (but not vs chlorambucil alone).

More grade >3 infusion reactions were initially seen with OC, mainly occurring with the first infusion: 20% with OC compared with 4% with RC. Once this reaction became evident, prophylaxis is now used and fewer infusion reactions are seen. OC did not increase the risk of infection versus RC, he said.

OC was significantly better than RC

in achieving response rates and eradication of disease in blood and bone marrow; overall response rates were 78% versus 65%, respectively. The rate of MRD negativity in bone marrow was 19.5% for OC compared with 2.6% for RC (P <.0001); MRD-negative status in blood was achieved in 37.3% versus 3.3%, respectively (P <.0001).

OC led to a 61% improvement in the likelihood of achieving progression-free survival (the primary end point): median progression-free survival was 26.7 months versus 15.2 months for RC (P <.0001).

Overall survival data are not yet mature but, at present, survival is trending toward OC, Goede said. l Reference

Goede V, Fischer K, Busch R, et al. Head-tohead comparison of obinutuzumab (GA101) plus chlorambucil (Clb) versus rituximab plus Clb in patients with chronic lymphocytic leukemia (CLL) and co-existing medical conditions (comorbidities): final stage 2 results of the CLL11 trial. Presented at: 2013 American Society of Hematology Annual Meeting; December 8, 2013; New Orleans, LA. Abstract 6.

ASH List for Choosing Wisely Reduces Unnecessary Waste, Prevents Harm, and Saves Money Hematologists should not use 5 tests and procedures routinely, according to Choosing Wisely recommendations presented at the 2013 American Society of Hematology (ASH) annual meeting.

In 2009, the Institute of Medicine estimated that $210 billion was wasted on unnecessary healthcare services in the United States across all specialties.

“If we could redirect even a fraction of this to real people with real unmet healthcare needs, think of the good that we can do,” said ASH’s Choosing Wisely Task Force Chair Lisa Hicks, MD, of St. Michael’s Hospital and the University of Toronto, Canada.

Following are the 5 tests and procedures that were selected by the Task Force: 1.

Computed tomography scans.

Limit their use in asymptomatic patients following curative-intent treatment for aggressive lymphoma. They do not change outcomes.

2. Inferior vena cava filters should not be routinely used in patients with acute venous thromboembolism (VTE).

3.

Do not transfuse more than the minimum number of red blood cell units necessary to relieve symptoms of anemia or to return a patient to safe hemoglobin range (7 to 8 g/dL in stable noncardiac inpatients).

4. Do not test for thrombophilia in adults with VTE occurring in the setting of major transient risk factors such as surgery, trauma, or prolonged immobility.

5. Do not administer plasma or pro-

thrombin complex concentrates for nonemergent reversal of vitamin K antagonists (ie, outside the setting of major bleeding, intracranial hemorrhage, or anticipated emergent surgery).

The evidence for these recommendations was analyzed and reviewed over a year-long process by the ASH Task Force with input from the ASH membership.

The list includes only recommendations with strong evidence, and the main guiding principle of the process of making recommendations was to “do no harm.” Other guiding principles were level of evidence, cost, frequency, and scope of practice.

Hicks acknowledged that these 5 recommendations are probably only the tip

of the iceberg, but said they represent an important first step in providing top quality care and optimizing outcomes for patients and the healthcare system.

Choosing Wisely is a quality care initiative developed by the American Board of Internal Medicine in collaboration with leading medical societies.

It is expected to include more than 250 unnecessary tests and procedures from 30 medical specialty societies.

An article was published online in Blood to coincide with the presentation of the Choosing Wisely list at the ASH meeting. The list can be viewed at www. hematology.org/choosingwisely. l Reference

Hicks LK. ASH Choosing Wisely® list. Presented at: 2013 American Society of Hematology Annual Meeting; December 9, 2013; New Orleans, LA.

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Cancer Center Breast Cancer Profile

Eribulin Mesylate Plus Trastuzumab Yields High Response Rates as First-Line Metastatic Breast Cancer Treatment Caroline Helwick

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or the first-line treatment of HER2positive metastatic breast cancer, the combination of eribulin mesylate and trastuzumab yields higher response rates, with manageable toxicity.

In the phase 3 EMBRACE trial, eribulin mesylate demonstrated a survival benefit relative to commonly used agents in women with metastatic breast cancer who had received at least 2 prior regimens, which led to the drug’s approval in 2010 for later lines of treatment.

At the 2013 San Antonio Breast Cancer Symposium, Sharon Wilks, MD, of US Oncology–Cancer Care Centers of South Texas, presented the final results for the primary and secondary end points of a multicenter phase 2 trial that explored the efficacy and safety of eribulin mesylate plus trastuzumab as first-line treatment for patients with locally recurrent or metastatic HER2-positive breast cancer.

“This is the first study to look at this combination,” Wilks said in an interview. She noted that numerous studies have shown that trastuzumab is “still active” in combination with later lines of chemotherapy. “This is another piece of evidence that supports that,” she said.

Study Details Among the 52 patients in the study (mean age 59), 45 completed treatment; 8 patients remained in the extension phase of the treatment at the time of data cut-off.

Patients received 6 cycles of eribulin mesylate 1.4 mg/m2 on days 1 and 8 of each 21-day cycle and standard-dose trastuzumab on day 1 of each cycle.

Dose reductions for eribulin, but not for trastuzumab, were permitted, and eribulin could be considered as monotherapy if trastuzumab was discontinued. The primary end point was antitumor activity (objective response rate) of eribulin plus trastuzumab.

High Response Rates Observed Investigators determined the objective response rate to be 71.2%, the disease-control rate to be 96.2% (complete and partial responses plus stable disease), and the clinical benefit rate (complete and partial responses plus stable disease >6 months) to be 84.6%.

By investigator assessment, complete responses were observed in 5.8% of patients and partial responses in 65.4%.

The waterfall plot, showing the change in the total sum of target lesion diameters from baseline to postbaseline nadir, revealed that all

but 2 patients had some degree of tumor shrinkage. The median percent change from baseline was –62.4%, Wilks reported.

Encouraging Progression-Free Survival, Manageable Toxicity Median progression-free survival (PFS) was 11.6 months, and the estimated PFS rates were 96% at 3 months, 82% at 6 months, 67% at 9 months, and 49% at 12 months. For all patients, median time to response was 1.3 months and median duration of response was 11.1 months.

“This is a great PFS,” Wilks said, “and it’s an easy regimen to give and well tolerated.”

Patients received a median of 10 cycles of eribulin and 11 of trastuzumab, indicating that most patients given this regimen are able to complete treatment. Treatment-emergent adverse events were reported by all patients, but they were manageable, according to Wilks.

“Most patients don’t have much nausea and vomiting, and their overall condition remains good, but they do lose their hair,” she acknowledged.

Alopecia was observed in 88.5% of patients, fatigue in 69.2% (7.7% grade 3-4), peripheral neuropathy in 69.2% (26.9% grade 3-4), and neutropenia in

59.6% (38.5% grade 3-4).

“What is novel about this drug, however, is that even when patients continue therapy their hair grows back after 3 to 4 cycles, and you don’t usually see that with other drugs that cause alopecia,” she added.

She acknowledged that neuropathy can be difficult for patients, “but keep in mind that these patients have had other drugs that affect the nerve beds, and that may be a reason why we see neuropathy,” she said. “When we adjust the dosing or hold the drug for neuropathy, patients usually return to baseline.”

In the study, 40% needed dose reductions, 42.3% had dose interruptions or delays, and 21.2% discontinued the study medication(s).

“The take-away message from this study is this: when you are looking for later-line options, after you have used the [FDA-approved] up-front treatments—pertuzumab (Perjeta) and ado-trastuzumab emtansine (Kadcyla)—this is an active and tolerable third- or fourth-line regimen,” Wilks suggested. l Reference

Wilks S, Puhalla S, O’Shaughnessy J, et al. Phase 2, multicenter, single-arm study of eribulin mesylate + trastuzumab as first-line therapy for locally recurrent or metastatic HER2-positive breast cancer. Presented at: San Antonio Breast Cancer Symposium; December 13, 2013; San Antonio, TX. Poster P4-12-12.

Lymphoma

Same-Day G-CSF Shown Acceptable for Patients With NHL

F

or patients with non-Hodgkin lymphoma (NHL) receiving chemotherapy, primary prophylaxis against febrile neutropenia (FN) can safely be administered on the same treatment day, if necessary, according to a review of patients from the Cleveland Clinic, presented at the 2013 American Society of Hematology annual meeting.

Rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone (R-CHOP) chemotherapy for patients with NHL carries a significant risk for FN, a potentially life-threatening complication that typically requires hospital admission and can mandate delays and dose reduction of drugs. To ameliorate this potential complication, granulocyte colonystimulating factor (G-CSF) is indicated for primary prophylaxis in high-risk patients.

“Prescribing guidelines recommend that G-CSF not be given until 24 hours after the receipt of chemotherapy, but due to logistical issues of outpatient insurance coverage, travel, and patient convenience, it is not always practical to delay G-CSF administration until the day after chemo,” said James Karol, MD, PA-C, of the Hematologic Oncology and Blood Disorders section of the Cleveland Clinic. “Based upon existing

www.TheOncologyPharmacist.com

but limited safety data, some patients at our institution received G-CSF on the same day as chemotherapy, beginning in 2006.”

Karol and his colleagues evaluated the safety and efficacy of giving G-CSF early. They identified 113 patients with NHL treated with R-CHOP who received G-CSF primary prophylaxis at the Cleveland Clinic between June 2004 and July 2012. They retrospectively analyzed the incidence of FN and associated outcomes for patients who received prophylaxis on the same day (D1) as chemotherapy (n = 31), compared with those receiving it at least 24 hours afterward (D2+) (n = 82).

FN Incidence, Clinical Outcomes Similar The FN incidence was almost identical between the groups, occurring in 8 of 31 of the D1 patients (25.8%) and in 21 of the 82 patients in the D2+ group (25.6%) (P = .91). This contradicts previous prospective studies in small cohorts showing a higher rate of FN with D1 treatment, and more severe and prolonged neutropenia.

No significant differences in relapse-free or overall

survival were observed. Risk factors associated with mortality in the multivariate analysis included the development of FN (hazard ratio [HR] 4.33; P <.001) and receipt of R-CHOP while hospitalized as an inpatient (HR 7.16; P <.001).

After a median follow-up of 26.8 months, of the 113 patients, 3 developed therapy-related myelodysplastic syndrome (MDS). One of 31 patients developed therapy-related MDS in the D1 group, while 2 of 82 developed it in the D2+ group.

No cases of acute leukemia were observed, Karol reported.

“For patients who require G-CSF support, nextday administration remains the recommended schedule; however, same-day administration can be considered if you are concerned about access to care or patient compliance,” Karol told The Oncology Pharmacist. l —CH Reference

Karol J, Rybicki L, Sweetenham J, et al. Similar incidence of febrile neutropenia with same-day versus subsequent day G-CSF administration in non-Hodgkin lymphoma patients receiving R-CHOP chemotherapy.

Poster presented at: 2013 American Society of Hematology Annual Meeting; December 9, 2013; New Orleans, LA. Abstract 4357.

February 2014 I VOL 7, NO 1

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CONFERENCE Oncology Pharmacy NEWS: ESMO Safety Continued from page 13 33. Smerhovsky Z, Landa K, Rössner P, et al. Risk of cancer in an occupationally exposed cohort with increased level of chromosomal aberrations. Environ Health Perspect. 2001;109(1):41-45.

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CancerOvarian Center cancer Profile

Bevacizumab Appears to Benefit High-Risk Patients Alice Goodman

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wo phase 3 trials presented at the 2013 European Cancer Congress suggest that the optimal role of bevacizumab will be in high-risk patients.

AURELIA is the first phase 3 study to evaluate the addition of bevacizumab to chemotherapy in platinum-resistant ovarian cancer (defined as progression within 6 months of last platinum-containing therapy).1 The addition of bevacizumab to chemotherapy significantly improved progression-free survival (PFS) from 3.4 months to 6.7 months (P <.001), and median overall survival (OS) was improved from 13.3 months with chemotherapy alone to 16.6 months, but this did not reach statistical significance. Chemotherapy agents included paclitaxel, topotecan, and liposomal doxorubicin.

“No single agent has shown superiority to weekly paclitaxel, topotecan, or liposomal doxorubicin. Median survival in platinum-resistant ovarian cancer is typi-

cally around 12 months,” said lead author Petronella Witteveen, MD, DCOG, of University Medical Centre Utrecht, in the Netherlands.

The difference in survival for high-risk patients given bevacizumab was clinically meaningful.

AURELIA randomized 361 patients to receive bevacizumab plus investigator’s choice of chemotherapy versus chemotherapy alone. Treatment was continued until disease progression, unacceptable toxicity, or consent withdrawal.

At progression, patients in the chemotherapy arm were allowed to cross over to bevacizumab monotherapy; bevacizumab was discontinued after progression in the bevacizumab plus chemotherapy arm.

An exploratory subgroup analysis of OS suggested that weekly paclitaxel was the best partner for bevacizumab. In the weekly paclitaxel cohort, median OS was 22.4 months for bevacizumab versus 13.2 months in controls, representing a 35% relative improvement favoring bevacizumab. By contrast, in the cohort treated with liposomal doxorubicin, median OS was 13.7 months in those randomized to receive bevacizumab plus chemotherapy versus 14.1 months with chemotherapy only. For the topotecan-treated cohort, median PFS was 13.8 months for those treated with bevacizumab plus chemotherapy versus 13.3 months for chemotherapy only.

“The effect of weekly paclitaxel should be considered exploratory and requires prospective validation,” Witteveen said.

No new safety concerns were identified in an updated safety analysis. The main grade ≥3 toxicities in the bevacizumab arm were hypertension (7.8%)

Trebananib in Platinum-Sensitive Ovarian Cancer

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new antiangiogenesis inhibitor with a different mechanism of action than bevacizumab shows promise in platinum-sensitive ovarian cancer, according to results of the phase 3 TRINOVA-1 trial presented at the 2013 meeting of the European Cancer Congress. Trebananib added to paclitaxel prolonged the time to disease progression or death by 52% compared with paclitaxel plus placebo (P <.001), said Bradley Monk, MD, Creighton University School of Medicine and University of Arizona Cancer Center, Phoenix.

Although angiogenesis is a proven target in ovarian cancer, anti–vascular endothelial growth factor (VEGF) therapy (with bevacizumab) causes adverse effects.

Trebananib is a different approach, targeting a non-VEGF angiogenesis factor—angiopoietin 1 and angiopoietin 2. The hope is that this approach will be effective and have fewer adverse effects than a VEGF-targeted strategy, Monk said.

TRINOVA-1 enrolled 919 women with recurrent epithelial ovarian cancer and randomized them to receive treatment with weekly intravenous (IV) trebananib 15 mg/kg plus weekly IV paclitaxel (3 weeks on, 1 week off) or with placebo plus weekly paclitaxel (3 weeks on, 1 week off). Patients were treated until disease progression, toxicity, or withdrawal of consent.

Patients were stratified according to progression-free interval, measurable disease, and geographic region. At baseline, patients had received up to 3 prior cytotoxic regimens and had a progression-free interval of <12 months.

One prior regimen failed in 40% of patients, 2 prior therapies in 40%, and 3 prior therapies in 20%.

Monk presented primary progression-free survival (PFS) and interim overall survival (OS) results of this international trial. At a median follow-up of 10 months, median PFS was 7.2 months in the trebananib group and 5.4 months for placebo (hazard ratio, 0.66; 95% confidence interval, 0.56-0.76; P <.001).

A prespecified subgroup analysis found that trebananib improved PFS in all subgroups. Overall response rate was

www.TheOncologyPharmacist.com

38% with trebananib versus 30% with placebo (most were partial responses).

Trebananib did not appear to increase toxicity when added to paclitaxel, according to the safety analysis. The rate of adverse events of any grade was similar between the 2 treatment arms: 96% for trebananib and 97% for placebo.

The major toxicity of trebananib was edema: 57% versus 26% (any grade) for those in the placebo arm. Very few grade ≥3 adverse events were reported with trebananib. No increase in VEGF-associated adverse effects was seen with trebananib (ie, hypertension, proteinuria, wound healing complications, arterial thrombotic events).

Neutropenia and anemia were more common in the placebo arm, and neurotoxicity was more common in the trebananib arm, which may be attributable to increased exposure to paclitaxel in that arm.

An interim OS analysis showed a difference of approximately 2 months favoring trebananib (19 months vs 17.3 months for the placebo arm), but this is only a preliminary analysis, Monk reminded listeners.

TRINOVA-1 incorporated patient-reported outcomes using 3 different quality-of-life questionnaires: Functional Assessment of Cancer Therapy-Ovarian (FACT-O), Ovarian Cancer Screening (OCS), and EuroQol 5-dimension (EQ5D). On these measures, no quality-of-life differences were reported between the 2 treatment arms.

Trebananib is continuing to be developed for ovarian cancer.

The formal discussant of this trial, Antonio Casado, MD, Hospital Universitario San Carlos, Madrid, Spain, said, “Weekly paclitaxel and trebananib could be an option in patients who progress within 12 months after 1 to 3 previous lines of therapy.” l —AG Reference

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

Abstract LBA41.

and proteinuria (2.2%).

The ICON7 trial evaluated bevacizumab in women with newly diagnosed ovarian cancer. The primary analysis (previously reported) showed a median PFS of 17.3 months for chemotherapy alone versus 19 months for bevacizumab added to chemotherapy (P = .004).2 In the final survival analysis presented at the European Cancer Congress, median OS was 58 months in the study for both arms; however, poor-prognosis patients experienced a 4.8month prolongation of survival (from 34.5 months to 39.3 months) if they received bevacizumab.3 “The survival benefit in the overall trial of 0.9 months is not clinically meaningful.

However in the high-risk subgroup, bevacizumab did show a clinically meaningful benefit of 4.8 months,” said Amit Oza, MD, Princess Margaret Cancer Centre, University of Toronto, Canada.

The international study randomized 1528 women to 6 cycles of every-3-week carboplatin/paclitaxel versus carboplatin/ paclitaxel plus bevacizumab for 5 or 6 cycles followed by bevacizumab for 12 additional every-3-week cycles until disease progression. Patients were prestratified according to stage, extent of debulking, and time of therapy. A third of the women were considered high risk (stage III with >1 cm residual disease, stage IV, and nondebulked).

At a median follow-up of 49 months, PFS was not significantly different between the 2 arms, similar to the first interim analysis presented previously.

Over 4 years, the difference between the 2 curves was gradually eroded, Oza said. Because the curves are nonproportional, the final OS analysis was conducted using a restricted means analysis, and the difference between the 2 arms was 0.9 months, which was not statistically or clinically meaningful.

In a predefined high-risk subgroup of patients, the curves for the 2 arms separated and the bevacizumab arm was superior throughout the study, with a 4.8-month improvement over the control arm.

Oza said the difference in survival for high-risk patients given bevacizumab was clinically meaningful. l References

1. Witteveen P, Lortholary A, Fehm T, et al. Final overall survival (OS) results from AURELIA, an open-label randomized phase III trial of chemotherapy (CT) with or without bevacizumab (BEV) for platinum-resistant ovarian cancer. Presented at: 2013 European Cancer Congress; September 27-October 1, 2013; Amsterdam, the Netherlands. Abstract LBA5.

2. Perren TJ, Swart AM, Pfisterer J, et al; the ICON7 investigators. A phase 3 trial of bevacizumab in ovarian cancer. N Engl J Med. 2011;365:2484-2496.

3. Oza AM, Perren TJ, Swart AM, et al. ICON7: final overall survival results in the GCIG phase III randomized trial bevacizumab in women with newly diagnosed ovarian cancer. Presented at: 2013 European Cancer Congress; September 27-October 1, 2013; Amsterdam, the Netherlands. Abstract LBA6.

February 2014 I VOL 7, NO 1

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Side Effects Management

NEPA Superior to Palonosetron in CINV Prevention Caroline Helwick

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EPA, a fixed-dose combination of netupitant and palonosetron, proved more effective than palonosetron alone in preventing chemotherapy-induced nausea and vomiting (CINV) in a large multinational study of 1455 patients, according to data presented at the 2013 San Antonio Breast Cancer Symposium.

Hope S. Rugo, MD, Director of Breast Oncology and Clinical Trials at the Helen Diller Family Comprehensive Cancer Center of the University of California San Francisco, presented the results of a phase 3, randomized, dou-

“NEPA has been developed to allow patients to receive guideline-based targeted antiemetic prophylaxis in a single, convenient oral dose.”

Hope S. Rugo, MD

ble-blind trial of chemotherapy-naive patients undergoing doxorubicin/cyclophosphamide (AC) chemotherapy.

“Breast cancer patients receiving AC are at significant risk for developing CINV due not only to the emetoge-

Osteonecrosis of the Jaw Associated With Cumulative Dose in Myeloma

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ata from a large population of patients with multiple myeloma receiving zoledronic acid infusions indicate that osteonecrosis of the jaw (ONJ) remains a significant complication, especially for patients who receive it for prolonged periods, investigators from Greece reported at the 2013 American Society of Hematology annual meeting.

“The risk increases with the number of zoledronic acid infusions,” according to Efstathios Kastritis, MD, of the Department of Clinical Therapeutics at the National and Kapodistrian University of Athens School of Medicine.

“The risk is associated mainly with the cumulative dose.”

Zoledronic acid can reduce skeletal-related events in patients with symptomatic myeloma, and possibly improve survival, but its use increases the risk of ONJ. “Longer exposures and more infusions of zoledronic acid have been associated with a higher incidence of ONJ, and it has been suggested that longer intervals between infusions may reduce the risk; however, this has not been proven,” Kastritis said.

The investigators determined the incidence of ONJ in a prospective study of patients receiving zoledronic acid, specifically looking at dosing and scheduling as potential risk factors. The study included patients who received zoledronic acid and survived at least 6 months after their first infusion.

The relative dose frequency (RDF) was calculated as the average number of weeks between infusions. Time of exposure was calculated from the date of the first infusion until the date of the last infusion. All patients underwent dental evaluations before initiating treatment and were instructed to avoid procedures that predispose to ONJ. The 266 patients were followed for a median of 36 months; their median survival was 64 months, median number of zoledronic acid infusions was 16, median duration of exposure was 29 months, and median RDF was 7.9 weeks. Half the patients had an RDF of less than 8 weeks.

ONJ developed in 26 (10%) patients. The median time of exposure to zoledronic acid was not significantly associated with risk: 28 months for patients who developed ONJ versus 24 months for those who did not (P = .2). The

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median number of infusions, however, proved important: 23 infusions for those who developed ONJ compared with 14 for those who did not (P = .004), Kastritis reported.

“Increasing number of zoledronic acid infusions was associated with higher risk of ONJ,” he said. ONJ developed in 2.3% of patients who received less than 10 infusions versus 12% of patients who received 10 to 19 infusions and 15% who received 20 or more (P = .012), he indicated.

The time period in which patients received the drug was not associated with risk. The incidence rate of ONJ for patients who started zoledronic acid before 2008 was 0.31 per 100 person-months compared with 0.26 per 100 person-months for those patients who started it after 2008 (P = .4).

Number of Infusions Most Important The incidence of ONJ at 3 years was 13.6% for patients with an RDF less than 8 weeks versus 2.6% when the RDF was 8 weeks or longer (P = .018).

“After adjusting for RDF, only the number of infusions remained significant (P = .03) for the development of ONJ,” he said.

The multivariate analysis showed that both the number and frequency of zoledronic acid infusions were associated with a shorter time to ONJ development. More explicitly, the average frequency of infusions in less than 8 weeks was associated with a 15-fold increase in the risk of ONJ, and for every infusion the risk of ONJ increased by 9% (both, P <.001). Cumulative dose, therefore, was the chief risk factor, he concluded.

Prospective studies should determine whether less frequent administration of the drug can reduce the risk of ONJ without compromising its antiresorptive effect, the investigators suggested. l —CH Reference

Kastritis E, Terpos E, Melakopoulos I, et al. The cumulative dose but not the frequency of infusions is a risk factor for the development of osteonecrosis of the jaw (ONJ) in myeloma patients who receive zoledronic acid (ZA). Poster presented at: 2013 American Society of Hematology Annual Meeting; December 8, 2013; New Orleans, LA. Abstract 3196.

nicity of the chemotherapy but also to their young age and gender,” Rugo noted. “As recommended by international antiemetic guidelines, targeting multiple molecular pathways involved in emesis is important for maximizing control of CINV and improving the functional status of breast cancer patients during chemotherapy.”

She pointed out that in patients receiving AC, the guidelines now consistently recommend the prophylactic combination of an NK1 receptor antagonist, a 5-HT3 receptor antagonist, and dexamethasone, but adherence to these guidelines is suboptimal. “Many patients still suffer from CINV, particularly during the delayed phase following chemotherapy,” she indicated.

NEPA is a fixed-dose combination of netupitant (300 mg), a highly selective NK1 receptor antagonist, and the 5-HT3 receptor antagonist palonosetron (0.50 mg), which allows this 1 drug to target dual antiemetic pathways.

“NEPA has been developed to allow patients to receive guideline-based targeted antiemetic prophylaxis in a single, convenient oral dose,” Rugo said.

NEPA was consistently more effective than palonosetron during the delayed and overall phases for the secondary efficacy end points.

Randomized Study Details The study involved 1455 chemotherapy-naive patients (97% with breast cancer) scheduled to receive their first course of AC chemotherapy. They were randomly assigned to receive oral NEPA or oral palonosetron, each with oral dexamethasone 12 mg. The primary end point was complete response (no emesis, no rescue medication) during the delayed (25-120 hours) phase postchemotherapy.

Each patient completed a diary from the start of chemotherapy on day 1 through day 6, capturing the frequency and duration of each emetic episode, severity of nausea, and rescue medications taken.

The treatment’s impact on daily living

www.TheOncologyPharmacist.com

Side Cancer Effects Center Management Profile Table

Key End Points for NEPA Versus Palonosetron

End Point

NEPA (%)

Palonosetron (%)

P Value

Complete Response Acute phase Delayed phase Overall

88.4 76.9 74.3

85.0 69.5 66.6

.047 .001 .001

No Impact on Daily Living (FLIE) Nausea domain Vomiting domain Overall

71.5 90.1 78.5

65.8 84.4 72.1

.015 .001 .005

Abbreviation: FLIE, Functional Living Index-Emesis.

was assessed with the Functional Living Index-Emesis (FLIE) questionnaire.

“NEPA showed superior complete response rates during the acute, delayed,

and overall phases following chemotherapy compared with palonosetron. This superior prevention of CINV correlated with a significantly greater proportion of NEPA-treated patients experiencing no impact on daily living as a result of CINV, based on all domains of the FLIE,” Rugo reported. See the Table.

Similarly, NEPA was consistently more effective than palonosetron during the delayed and overall phases for the secondary efficacy end points of no emesis, no significant nausea, and complete protection, as well as during the acute phase for no emesis, she reported.

Adverse Events Similar “NEPA was well tolerated, with a similar safety profile to palonosetron,” Rugo reported.

Overall, the incidence, type, and intensity of treatment-emergent adverse events were comparable between the treatment

groups. Among patients reporting these, the majority (85%) indicated these events were mild-to-moderate in intensity. There were no treatment-related adverse events leading to discontinuation and very few (0.7%) severe treatmentrelated adverse events for NEPA-treated patients, and none were serious. There was also no evidence of any cardiac safety concerns for either drug, Rugo reported.

She concluded that as a fixed single-dose, guideline-recommended, convenient antiemetic drug combination, “NEPA offers improved efficacy and reduced interference with daily functioning” over palonosetron alone. l Reference

Rugo HS, Rossi G, Rizzi G, et al. NEPA, a fixed-dose combination of netupitant and palonosetron, prevents chemotherapy-induced nausea and vomiting (CINV) more effectively and reduces the impact on daily living for breast cancer patients compared with palonosetron.

Presented at: San Antonio Breast Cancer Symposium; December 12, 2013; San Antonio, TX. Poster P3-09-01.

Understanding FOLFOX Toxicity: Some Subsets Have Higher Risks Caroline Helwick

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ubsets of patients with colon cancer may benefit from increased surveillance for toxicities associated with adjuvant FOLFOX (leucovorin, fluorouracil, oxaliplatin) treatment, Canadian researchers suggest, based on their detailed analysis of the toxicity profile of this common regimen and their identification of factors that predict toxicity. They presented their findings at the 2014 Gastrointestinal Cancers Symposium, held January 16-18, 2014, in San Francisco, California.

The identification of patients with colon cancer at increased risk for side effects of adjuvant treatment allows clinicians to be more vigilant in preventing and managing these issues.

The identification of patients with colon cancer at increased risk for side effects of adjuvant treatment allows clinicians to be more vigilant in preventing and managing these issues. “This enables the optimal delivery of chemotherapy,” said lead author Gillian Gresham, formerly of the University of Ottawa and now a doctoral candidate at Johns Hopkins University School of Public Health, Baltimore, Maryland.

The study sought to identify the key side effects associated with adjuvant FOLFOX in early colon

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cancer, and to look for their associations with clinical and patient-related factors.

The study included patients with stage III colon cancer treated at the 5 regional cancer centers of the British Columbia Cancer Agency. The researchers retrospectively reviewed the charts of 475 patients who received adjuvant FOLFOX. Their median age was 62 years, and 55% were male.

Renal, Cardiovascular, and Sensory Toxicities Were Common The most common toxicities were abnormal kidney function (61.7%), neuropathy (54.9%), and cardiovascular-related side effects (hypertension, hypotension, thromboembolism, cardiac arrest; 51.4%).

Gastrointestinal (GI) toxicities, including nausea, vomiting, and diarrhea, were recorded in 44% of patients.

Other common toxicities included anemia (76%), abnormal liver enzymes (61.7%), neutropenia (27.8%), and thrombocytopenia (28%).

In a multivariate analysis, renal dysfunction (glomerular filtration rate [GFR] <50) carried a 69% increased risk of any GI toxicity.

The risk of significant neutropenia was increased 2- to 3-fold among patients whose time between diagnosis and receipt of adjuvant chemotherapy exceeded 8 weeks; those with poor performance status; those older than 70 years; and patients with low white blood cell count (<6.4 x 109).

Interestingly, multiple toxicities were more prevalent among patients who waited more than 8 weeks to initiate adjuvant FOLFOX, Gresham added.

“It’s possible that patients who wait longer to initiate adjuvant therapy may already be sicker at baseline,” she said. “Neuropathy was interesting,

because abnormal creatinine seemed to be predictive in both the univariate and multivariate models.”

Focus on GI Toxicities The researchers also developed a 5-point scoring system to stratify patients into low- and high-risk groups for GI toxicity, based on baseline clinical factors. Lowrisk patients (score 0-2) had a 45% risk for toxicity, whereas high-risk patients (score 3-5) had a 59% risk.

In the multivariate model for risk of any GI toxicity, age <70 years carried an odds ratio (OR) of 2.6 (P = .049); GFR <50 had an OR of 1.69 (P = .0038); and delayed time to adjuvant chemotherapy had an OR of 1.79 (P = .0059).

Patients received 2 points each for delayed time to adjuvant treatment and poor GFR, and 1 point for advanced age. Gresham said that the scoring system could be useful, but it needs to be validated first.

Gresham suggested that considering important baseline characteristics—such as time to adjuvant treatment, advanced age, renal function, and certain laboratory parameters—when recommending adjuvant FOLFOX can be useful in identifying patients who are likely to experience serious side effects.

“We think this group of patients may benefit from increased monitoring in order to enable optimal doses of curative chemotherapy to be delivered,” she said. “Our recommendation would be to look for and recognize these characteristics at baseline. Monitor these patients more closely, and treat more proactively.” l Reference

Gresham G, Sidhu J, Malhi N, et al. Predicting toxicities from adjuvant treatment in a population-based cohort of early colon cancer (CC) patients (pts): a strategy to improve use of curative chemotherapy. J Clin Oncol. 2014;32(suppl 3):Abstract 412.

February 2014 I VOL 7, NO 1

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Leukemia

Raising the Bar: 4 Drugs for CLL Continued from cover Coleman, MD, Weill Cornell Medical Center, New York City.

Idelalisib is a phosphatidylinositol 3kinase (PI3K) inhibitor that achieves dramatic nodal responses in patients with CLL; but along with nodal shrinkage, white blood cell counts rise when treatment is first initiated.

In one study, the nodal response rate was 81%, while the overall response rate (ORR) was 72% due to lymphocytosis. Median progression-free survival (PFS) was 17 months, and overall survival is not yet reached in heavily treated poor-prognosis patients with CLL. Idelalisib has been studied in combination with rituximab as well as with bendamustine. Both combinations achieved about a 90% response in the lymph nodes, with a concomitant rise in lymphocyte count, although less so than when idelalisib is used as a single agent.

A study of idelalisib plus rituximab as frontline therapy in 64 patients with CLL achieved an ORR of 97%. Partial response rate was 67% in patients with p53 abnormalities. The major adverse effect was grade 3 diarrhea in 15 patients (23%).3 A pivotal study of idelalisib is now ongoing in the United States and the drug is under review by the FDA. The same response pattern—a robust lymph node response with increased

lymphocytosis—is seen with the Bruton’s tyrosine kinase inhibitor ibrutinib. This drug is also under review by the FDA. A phase 1b/2 study included 116 patients with CLL/small lymphocytic leukemia treated with ibrutinib monotherapy; some were relapsed/refractory and some were treatment naive. The best ORR was 84% in treatment-naive patients and 88% in relapsed/refractory patients. At 26 months, 96% of treatment-naive patients are still part of the study and PFS was 75% for the relapsed/refractory patients. These outcomes were observed in patients with poor-prognosis cytogenetics, including deletions in 17p and 11q.1,4 “These are amazing results,” Coleman said.

Grade 3 and 4 adverse events included pneumonia and diarrhea, but the diarrhea is less intense than with idelalisib, Coleman noted.

Ibrutinib and ofatumumab were combined in a phase 2 trial, in which the ORR was 100%. Sustained improvement was observed among patients with pretreatment cytopenias.4 A pivotal study of ibrutinib is planned.

Ofatumumab and Obinutuzumab “Both ofatumumab and obinutuzumab [anti-CD20 monoclonal antibodies]

have a great future and an important place in the treatment of CLL,” said Kanti Rai, MD, Hofstra North ShoreLIJ School of Medicine, Hempstead, New York.

Rituximab was the first anti-CD20 antibody to be approved a number of years ago for the treatment of hematologic malignancies. Ofatumumab was approved in the past few years, and approval was granted to obinutuzumab in November 2013.

Ofatumumab has good activity in CLL as a single agent and in combination with other drugs. Recent studies show that ofatumumab can replace rituximab in the fludarabine/cyclophosphamide/rituximab regimen for patients with CLL. A phase 2 trial confirmed comparable high activity and safety of the O-FC (ofatumumab/fludarabine/cyclophosphamide) regimen as frontline treatment of previously untreated CLL. Investigators are moving forward with this regimen using the 1000-mg dose of ofatumumab.

Idelalisib in combination with ofatumumab versus idelalisib alone is in phase 1/2 testing. The combination of ofatuzumab and lenalidomide has been extremely effective as frontline therapy for CLL, Rai said.

The pivotal trial of obinutuzumab plus chlorambucil showed superiority

of this combination versus rituximab plus chlorambucil. The ORR was 75% with obinutuzumab/chlorambucil versus 65.9% with rituximab/chlorambucil. Complete response was achieved in 22% versus 8%, respectively; and median PFS was 23 months versus 16 months (P <.0001). Neutropenia was reported in 34% versus 25%, respectively, and grade 3 to 5 adverse events in 67% versus 48%.

“Ofatumumab and obinutuzumab have each demonstrated good activity in CLL as single agents. Now ongoing trials are showing that combinations with each of these drugs are extremely promising,” Rai said. l

References

1. Coleman M. Ibrutinib and idelalisib in CLL. Presented at: 2013 Chemotherapy Foundation Symposium; November 6, 2013; New York, NY. http://chemotherapyfoundationsymposium.org/ CMS/2013archives/110613_008_coleman.

2. Rai K. Anti-CD20 monoclonal antibodies in therapy of CLL: obinutuzumab and ofatumumab.

Presented at: 2013 Chemotherapy Foundation Symposium; November 6, 2013; New York, NY. http://chemotherapyfoundationsymposium.org/ CMS/2013archives/110613_009_rai.

3. O’Brien SM, Lamanna N, Kipps T, et al. A phase II study of the selective phosphatidylinositol 3-kinase delta (PI3Kδ) inhibitor idelalisib (GS-1101) in combination with rituximab (R) in treatment-naive patients (pts) 65 years with chronic lymphocytic leukemia (CLL) or small lymphocytic lymphoma (SLL). J Clin Oncol. 2013;31(15 suppl):Abstract 7005.

4. Byrd JC, Furman RR, Coutre SE, et al. Targeting BTK with ibrutinib in relapsed chronic lymphocytic leukemia. N Engl J Med. 2013;369(1):32-42.

Cancer Center Profile

Kimmel Cancer Center… Continued from cover

Which drugs used to treat cancer patients pose hazards to pharmacists and other staff who handle these drugs?

AMO: Many medications for cancer patients can cause acute and even long-term harm. This includes both oral and intravenous (IV) drugs. Most people don’t realize that oral drugs can be hazardous, and that crushing and dissolving them can also expose people and the environment. Employees must handle oral and IV drugs appro-

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priately with the same precautions.

Our Pharmacy Department has policies in place regarding handling, for both oral and IV formulations, to protect all staff, including nurses.

Can you give specific examples of hazardous drugs?

AMO: Older chemotherapy agents such as doxorubicin and ifosfamide; oral and IV formulations of methotrexate, cyclophosphamide, and tyrosine kinase inhibitors; and drugs used to treat other conditions outside of cancer, such as ganciclovir, ribavirin, and porfimer.

What are examples of some of the safe-handling policies?

AMO: Appropriate handling involves containing the substance with overwrap and clear labeling. When we dispense chemotherapy, we decontaminate the product with bleach prior to labeling, and prime the IV tubing with primary solution first and then adding chemotherapy to the bag. This is done to limit the risk to the nursing staff. Staff must

wear personal protective equipment when unpacking medications from the manufacturer.

The vials themselves can be contaminated on the surface when they come from the manufacturer.

According to an older article from ASHP, just putting medications on

Photos from the Kimmel Cancer Center.

Are there guidelines in place for safe handling of hazardous substances in the workplace?

Anne Marie Oberle (AMO): NIOSH [National Institute for Occupational Safety and Health], OSHA [Occupational Safety and Health Administration], and ASHP [American Society of HealthSystem Pharmacists] have developed guidelines for safe handling in the workplace. The ASHP guidelines were developed in 2007 and are mainly consistent with NIOSH regarding employee protection. I usually follow NIOSH guidelines, since they are the most recent.

Anne Marie Oberle, PharmD, BCOP

the shelf can expose you. The staff protect themselves the same way when compounding chemotherapy.

What about training oncology pharmacists for safe handling?

AMO: All our staff—technicians and pharmacists—go through rigorous training and education about gowning, double-gloving, wearing masks, and how to protect themselves from exposure.

How do you keep the staff up to date on safe-handling procedures?

AMO: We perform an annual review (and more often if necessary) and give the staff updated competency exams that they are required to complete.

After the initial training, we observe them and question them daily to make sure they are following our procedures. If they are not, we let them know that they are creating risks for the entire staff and that they need to follow our policies and guidelines.

There hasn’t been much change in safe-handling practice guidelines over the past 5 years or so. NIOSH

www.TheOncologyPharmacist.com

Cancer Center Profile publishes a list of hazardous medications and we update our policies based on that.

What do you tell patients about safety issues?

AMO: It is my impression that there is a deficit in patients’ understanding that oral medications may be contaminated and can pose risks to their family, including children and grandchildren. Patients can excrete toxins through their tears, sneezing, urine, and other body fluids. It is preferable that they use their own bathroom at home when on treatment, but if they

share a bathroom, they should flush the toilet twice, and need to wear gloves when cleaning, as well as using bleach to wipe down the bathroom.

Also they are told not to flush oral medications down the toilet.

If medications need to be crushed, they are taught the safest way to do this. Medications should never be smashed on the countertop, for example.

The main principle is containment.

Never use the same eating and drinking utensils that the patient has used until it has been sterilized in the dishwasher. In the hospital, when a

patient can’t swallow and we need to prepare a suspension, the tablet is crushed in a closed environment and handed back to the nurses in the safest way.

The American Cancer Society has good education materials for patients and families about how to handle chemotherapy safely.

How do you promote a culture of safety?

AMO: I have deep concerns about this. Education is key. The person in charge must be vigilant. A body of literature shows how to establish a

culture of safety. NIOSH publishes a list of components of evaluation for those handling hazardous drugs.

How do you think safe-handling procedures can be improved in cancer centers?

AMO: We need more strict and definitive guidelines to drive change. The ASHP 2007 guidelines made my job easier because they provided more specifics.

We need to be on top of our game.

Even though safe-handling procedures incur higher costs, this is a very important area of concern. l

Ovarian Cancer

Antiangiogenesis Pursued in High-Risk Ovarian Cancer Alice Goodman

A

ngiogenesis is an active area of clinical research in ovarian cancer, but proving that this approach extends overall survival (OS) has been somewhat challenging thus far. Michael Bookman, MD, reviewed studies of antiangiogenesis in high-grade serous ovarian cancer at the 2013 Chemotherapy Foundation Symposium, held in New York City.

Bookman is the director of medical oncology at the University of Arizona Cancer Center in Tucson.

“High-grade serous ovarian cancer is the most common subtype of epithelial ovarian cancer and it remains highly lethal. New approaches are needed beyond angiogenesis,” he told listeners.

“The key questions to consider in antiangiogenic trials are the best targets, the preferred strategy, and the optimal setting for these studies,” Bookman said.

“We need predictive biomarkers and we need to think about how we measure success in clinical trials.”

Trials of Primary Therapy Studies of frontline therapy have shown that primary therapy with weekly paclitaxel appears to be more effective than other schedules. The value of incorporating antiangiogenesis into up-front regimens is based on exploratory analysis of phase 3 trials, he said.

To date, the addition of an angiogenesis inhibitor, typically bevacizumab, to chemotherapy improves progression-free survival (PFS) but does not extend OS. Two trials of up-front treatment for high-grade serous ovarian cancer, ICON7 and GOG-0218, showed a modest difference in PFS and no difference in OS with the addition of the anti–vascular endothelial growth factor (VEGF) therapy bevacizumab

www.TheOncologyPharmacist.com

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

Michael Bookman, MD

compared with platinum-based chemotherapy. However, exploratory analysis suggests that patients with moderateto high-risk bulky disease have better outcomes with bevacizumab.

A contrary finding in the AGOOVAR12 trial that compared chemotherapy plus or minus nintedanib showed a slight PFS benefit, but in an exploratory analysis, the low-risk group did better with nintedanib. In addition, nintedanib inhibits VEGF receptor, fibroblast growth factor receptor, and platelet-derived growth factor receptor, and targets tumor cells directly; thus it may have a different effect than bevacizumab, Bookman said.

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

Weekly paclitaxel was identified as the preferred schedule for this drug, improving both PFS and OS. The next trial looked at weekly paclitaxel plus or minus bevacizumab.

GOG-0262/ACRIN 6695 showed no difference in PFS with the addition of bevacizumab to chemotherapy. In an exploratory analysis, median PFS was 10.6 months in patients treated with weekly paclitaxel minus bevacizumab and 14.2 months with the addition of bevacizumab.

Thus, weekly paclitaxel and bevaciz-

umab had the best results.

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

Trials in Advanced Recurrent Disease The OCEANS trial in platinum-sensitive disease showed that the addition of bevacizumab to chemotherapy improved PFS. The AURELIA study in platinum-resistant disease found that bevacizumab improved PFS. Both trials found no difference in OS favoring the addition of bevacizumab.

“These studies suggest that bevacizumab is effective in improving PFS in both platinum-sensitive and platinumresistant disease,” Bookman said.

In a subset analysis of AURELIA, in which chemotherapy was selected by physician’s choice, the most striking benefits were observed when bevacizumab was added to weekly paclitaxel.

No additional benefit was seen when bevacizumab was used with pegylated doxorubicin or topotecan, he noted.

The ICON6 trial in recurrent disease found that when added to chemotherapy, cediranib—a potent inhibitor of VEGF tyrosine kinase—improved OS: median OS was 20.3 months without cediranib versus 26 months

when this agent was added.

The TRINOVA-1 trial evaluated the addition of trebananib to chemotherapy. Trebananib is an investigational antiangiogenesis recombinant peptide that inhibits the binding of angiopoietin 1 and 2 to the Tie2 receptor—a different target than that of bevacizumab. In that study, PFS was extended with trebananib. Survival results are not yet available.

Trebananib has a different toxicity profile that includes edema, pleural effusion, ascites, and weight increase. Bookman suggested that these treatment-emergent adverse events may predict clinical response to this novel agent.

The GOG-3001 trial is evaluating carboplatin/paclitaxel plus or minus trebananib, and the trial is beginning accrual.

Remaining issues include the best target for antiangiogenesis—VEGF receptors, angiopoietin 1 and 2?

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

Reference

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

February 2014 I VOL 7, NO 1

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Now enrolling

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

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

Primary Endpoint

Secondary Endpoints

• Overall response rate

• • • • • • • •

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

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

NCT#01889186 Reference: ClinicalTrials.gov.

@ 2013 Genentech USA, Inc. All rights reserved. BIO0001961500 Printed in USA.

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