JHOP September Vol 4 No 3

SEPTEMBER 2014 VOL 4 I NO 3

JOURNAL OF

HEMATOLOGY ONCOLOGY ™ PHARMACY THE PEER-REVIEWED FORUM FOR ONCOLOGY PHARMACY PRACTICE

TM

EDITORIAL

ancer Therapy: Adverse Event Prevention and Management Education C for All Pharmacists Val R. Adams, PharmD, FCCP, BCOP ORIGINAL RESEARCH

Increased Incidence of Recurrent Venous Thromboembolism in Patients with Cancer Receiving Bevacizumab Tanis L. Welch, PharmD; Sarah M. Gressett Ussery, PharmD, BCOP; Kevin C. Kelly, PharmD, BCPS; Jonathan E. Dowell, MD; Sachin R. Shah, PharmD, BCOP, FCCP

Improving Patient Care and Medication Safety: Standardizing Antiemetic Agents in Chemotherapy Order Sets in a Large Healthcare System Maria Zarambo, PharmD, BCOP; Elizabeth A. Brenner, PharmD; Ann E. Sather, RPh, BCOP SYMPTOM MANAGEMENT OVERVIEW

Chemotherapy-Induced Peripheral Neuropathy

By Joseph Bubalo, PharmD, BCPS, BCOP FROM THE LITERATURE

Concise Reviews of Studies Relevant to Hematology Oncology Pharmacy With commentaries by Robert J. Ignoffo, PharmD, FASHP, FCSHP FDA UPDATE

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VOLUME 4, NUMBER 3

JOURNAL OF

HEMATOLOGY ONCOLOGY PHARMACY™ THE PEER-REVIEWED FORUM FOR ONCOLOGY PHARMACY PRACTICE

TM

TABLE OF CONTENTS EDITORIAL 73 Cancer Therapy: Adverse Event Prevention and Management Education

for All Pharmacists Val R. Adams, PharmD, FCCP, BCOP

ORIGINAL RESEARCH 75 Increased Incidence of Recurrent Venous Thromboembolism in Patients

with Cancer Receiving Bevacizumab

Tanis L. Welch, PharmD; Sarah M. Gressett Ussery, PharmD, BCOP; Kevin C. Kelly, PharmD, BCPS; Jonathan E. Dowell, MD; Sachin R. Shah, PharmD, BCOP, FCCP 88 Improving Patient Care and Medication Safety: Standardizing Antiemetic Agents in Chemotherapy Order Sets in a Large Healthcare System Maria Zarambo, PharmD, BCOP; Elizabeth A. Brenner, PharmD; Ann E. Sather, RPh, BCOP DEPARTMENTS

Symptom Management Overview NEW 85 Chemotherapy-Induced Peripheral Neuropathy

By Joseph Bubalo, PharmD, BCPS, BCOP From the Literature 93 Concise Reviews of Studies Relevant to Hematology Oncology Pharmacy With commentaries by Robert J. Ignoffo, PharmD, FASHP, FCSHP FDA Update 96 Recent Cancer Drugs Approved by the FDA MISSION STATEMENT The Journal of Hematology Oncology Pharm­acy is an independent, peer-reviewed journal founded in 2011 to provide hematology and oncology pharmacy practitioners and other healthcare professionals with high-quality peer-reviewed information relevant to hematologic and oncologic conditions to help them optimize drug therapy for patients.

Journal of Hematology Oncology Pharmacy™, ISSN 2164-1153 (print); ISSN 2164-1161 (online), is published 4 times a year by Green Hill Healthcare Communications, LLC, 1249 South River Rd, Suite 202A, Cranbury, NJ 08512. Telephone: 732.656.7935. Fax: 732.656.7938. Copyright © 2014

by Green Hill Healthcare Communications, LLC. All rights reserved. Journal of Hematology Oncology Pharmacy™ logo is a 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, Journal of Hematology Oncology Pharmacy™, 1249 South River Rd, Suite 202A, Cranbury, NJ 08512. E-mail: JHOP@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 Rd, Suite 202A, Cranbury, NJ 08512. The ideas and opinions expressed in Journal of Hematology Oncology Pharmacy™ do not necessarily reflect those of the Editorial Board, the Editorial Director, or the Publisher. Publication of an advertisement or other product mentioned in Journal of Hematology Oncology Pharmacy™ should not be construed as an endorsement of the product or the manufacturer’s claims. Readers are encouraged to contact the manufacturer with questions about the features or limitations of the products mentioned. Neither the Editorial Board nor the Publisher assumes any responsibility for any injury and/or damage to persons or property arising out of or related to any use of the material contained in this periodical. The reader is advised to check the appropriate medical literature and the product information currently provided by the manufacturer of each drug to be administered to verify the dosage, the method and duration of administration, or contraindications. It is the responsibility of the treating physician or other healthcare professional, relying on independent experience and knowledge of the patient, to determine drug dosages and the best treatment for the patient. Every effort has been made to check generic and trade names, and to verify dosages.

The ultimate responsibility, however, lies with the prescribing physician. Please convey any errors to the Editorial Director.

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Vol 4, No 3

BD PhaSeal™ Closed System Drug Transfer Device Work safe. Enjoy life.

Protecting Jacob the pharmacist, and Jacob the cyclist.

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BD, BD Logo and BD PhaSeal are trademarks of Becton, Dickinson and Company. © 2014 BD MSS0523f (04/14)

BD Medical 1 Becton Drive Franklin Lakes, NJ 07417 www.bd.com

EDITORIAL BOARD

CO-EDITORS-IN-CHIEF Patrick J. Medina, PharmD, BCOP Associate Professor Department of Pharmacy University of Oklahoma College of Pharmacy Oklahoma City, OK

Val R. Adams, PharmD, FCCP, BCOP Associate Professor, Pharmacy Program Director, PGY2 Specialty Residency Hematology/Oncology University of Kentucky College of Pharmacy Lexington, KY

SECTION EDITORS CLINICAL CONTROVERSIES

ORIGINAL RESEARCH

PRACTICAL ISSUES IN PHARMACY MANAGEMENT

REVIEW ARTICLES

Christopher Fausel, PharmD, BCPS, BCOP Clinical Director Oncology Pharmacy Services Indiana University Simon Cancer Center Indianapolis, IN

R. Donald Harvey, PharmD, FCCP, BCPS, BCOP Associate Professor, Hematology/Medical Oncology Department of Hematology/Medical Oncology Director, Phase 1 Unit Winship Cancer Institute Emory University Atlanta, GA Scott Soefje, PharmD, MBA, BCOP Director of Pharmacy University Medical Center Brackenridge Austin, TX

Timothy G. Tyler, PharmD, FCSHP Director of Pharmacy Comprehensive Cancer Center Desert Regional Medical Center Palm Springs, CA

FROM THE LITERATURE

Robert J. Ignoffo, PharmD, FASHP, FCSHP Professor of Pharmacy, College of Pharmacy Touro University–California Mare Island, Vallejo, CA

SYMPTOM MANAGEMENT OVERVIEW

Joseph Bubalo, PharmD, BCPS, BCOP Assistant Professor of Medicine Division of Hematology and Medical Oncology Oncology Clinical Pharmacy Specialist OHSU Hospital and Clinics Portland, OR

EDITORS-AT-LARGE

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Sandra Cuellar, PharmD, BCOP Director Oncology Specialty Residency University of Illinois at Chicago Medical Center Chicago, IL

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

Robert Mancini, PharmD, BCOP Oncology Pharmacist PGY2 Oncology Residency Director St. Luke’s Mountain States Tumor Institute Boise, ID

John M. Valgus, PharmD, BCOP, CPP Hematology/Oncology Senior Clinical Pharmacy Specialist University of North Carolina Hospitals and Clinics Chapel Hill, NC

Sachin Shah, PharmD, BCOP Associate Professor Texas Tech University Health Sciences Center Dallas, TX

Daisy Yang, PharmD, BCOP Clinical Pharmacy Specialist The University of Texas M. D. Anderson Cancer Center Houston, TX

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Vol 4, No 3

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-40134 February 2014.

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.

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.

EDITORIAL

Cancer Therapy: Adverse Event Prevention and Management Education for All Pharmacists Val R. Adams, PharmD, FCCP, BCOP Co-Editor-in-Chief, Journal of Hematology Oncology Pharmacy Associate Professor, Pharmacy; Program Director, PGY2 Specialty Residency Hematology/Oncology, University of Kentucky College of Pharmacy Lexington, KY

T

he number of new cancer diagnoses in the United States is estimated to be 1,665,540 (excluding basal-cell and squamous-cell skin cancers) in 2014.1 The study of tumor biology in drug development and as a guide for selecting therapy for the individual patient has translated into improved outcomes for many patients with cancer. Nearly all targeted therapies in oncology work by inhibiting cell signaling, which can make some cancers more of a chronic disease that can be managed for years, or, in some cases, for decades. However, targeted therapies are generally not curative, and optimal patient outcomes are typically achieved with long-term dosing that maintains therapeutic serum concentrations until disease progression.

One of the most notable targeted therapies is imatinib, which became the treatment of choice for chronic-phase (CP) chronic myeloid leukemia (CML) in 2001, when it gained US Food and Drug Administration approval. A recent analysis showed that 8-year survival for patients with newly diagnosed CP-CML was less than 20% before 1990, 45% between 1991 and 2001, and 75% since 2001.2 Despite an annual incidence of only 4800 cases of CML, the current prevalence is in excess of 70,000 patients.3 Other hematologic malignancies have also started to resemble chronic diseases, including multiple myeloma, which has a reported prevalence of 83,367 patients.4 There are notable improvements in the subsets of patients with 1 of the 4 leading cancers (ie, breast, prostate, lung, and colorectal cancer), which constitute more than 50% of new diagnoses and deaths in the United States.1 Collectively, improved treatments have led to an estimated cancer prevalence of 13,397,159 in the United States in 2011, where a significant number of patients are receiving long-term treatment.5 The number of oncology clinical specialists is growing, as reflected by the more than 1600 board-certified oncology pharmacists.6 However, most of these providers work at cancer centers and are focused on antineoplastic agents that are delivered in an inpatient setting or at a clinic. However, many new cancer drugs are oral targeted therapies that have caused a change in the drug delivery

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system. Targeted agents often have a limited patient population that will receive the treatment, similar to an orphan disease.

The business models that make this focus on new drugs for small populations feasible require charging large amounts of money for these drugs. In response to such high drug costs, payers have put in processes to ensure the drugs’ proper use (eg, prior authorization).7 Because of the high cost and relatively low use of the oral targeted agents, traditional outpatient pharmacies do not stock the agents, and generally do not have technicians or pharmacists who are proficient in solving issues related to prior authorization and copays.

Consequently, specialty pharmacies have become essentially the only place to obtain the expensive targeted therapies. They generally do a very good job helping patients solve their financial issues, which can take days.

Because the time from receiving the prescription to a payment approval and obtaining the medication takes days, distribution is often accomplished by mailing the medications to patients.8 A byproduct of this model is a forced polypharmacy, in which traditional supportive care drugs come from the local pharmacy. At this interchange, the pharmacist has the opportunity to provide face-to-face counseling and toxicity assessment, as well as obtain a medication history.

Although the potential for such services exists, I believe they are uncommon with regard to most prescriptions.

Having said that, pharmacists, particularly community pharmacists, are still the most readily accessible healthcare providers who are often sought out by patients for recommendations on drugs and/or disease-related symptoms.9 Many community pharmacists, however, do not have adequate training or knowledge to manage well the toxicities of cancer therapy. Without the anticancer drug prescription or the drug on the shelf, the pharmacist frequently does not even have access to the package insert.

Community pharmacists are well-positioned to impact the quality of life, and perhaps even the length of life (via compliance), of patients with cancer, by minimizing drug adverse events, yet these pharmacists

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arguably have the least amount of education on and resources for cancer treatments.

The scope of the problem is large and growing.7 For example, patients with lung cancer receiving oral afatinib daily will receive therapy for a median of approximately 11 months.10 Afatinib causes diarrhea in approximately 88% of patients, with the majority of cases being mild to moderate in severity (grade 1 or 2).10 Mild-to-moderate toxicity is historically a “sweet spot” for community pharmacists—problematic enough for an intervention, but not severe enough for patients to see a doctor.

This is a classic case where the patient would go to a community pharmacy and ask the pharmacist for advice about diarrhea. As a general rule, I would assume the pharmacist knows little about the patient’s disease; has an incomplete drug record; and has little baseline knowledge about the risks and side effects of afatinib, how to manage the toxicity, and whether a dose interruption or delay is recommended. Educating this group of pharmacists about cancer drug toxicities and how to manage them provides the opportunity to affect the quality of life of patients with cancer.

The optimal prevention and treatment of antineoplastic adverse events require knowledge of the adverse events, pathophysiology, risk factors, symptom presentation, as well as the methods to prevent and treat the toxicity. A traditional approach is to learn about toxicity on a drug-by-drug basis; however, many drugs can cause the same toxicities, and often the toxicities are managed in a similar fashion. Common toxicities include anemia, neutropenia, infection, neuropathy, diarrhea, mucositis, nausea, and vomiting. In fact, the American Society of Clinical Oncology and the National Comprehensive Cancer Network have established guidelines to help prevent and treat these adverse events. Because these guidelines are not focused on educating pharmacists, they often

contain what could be viewed as superfluous information.

Beginning with this issue of the Journal of Hematology Oncology Pharmacy, readers will find a new section on adverse events that is written by pharmacists for pharmacists. The goal is to educate pharmacists on how to prevent and manage common toxicities associated with cancer therapy. The format is intended to be practical, focusing on risk factors, symptoms, as well as prevention and management approaches. Dr Bubalo’s inaugural article in this issue on chemotherapy-induced peripheral neuropathy achieves the intended goals of this section. The journal’s Editorial Board is excited about this new section and its potential impact on patients’ quality of life. n

References

1. Siegel R, Ma J, Zou Z, Jemal A. Cancer statistics, 2014. CA Cancer J Clin. 2014;64:9-29.

2. Kantarjian H, O’Brien S, Jabbour E, et al. Improved survival in chronic myeloid leukemia since the introduction of imatinib therapy: a single-institution historical experience.

Blood. 2012;119:1981-1987.

3. Huang X, Cortes J, Kantarjian H. Estimations of the increasing prevalence and plateau prevalence of chronic myeloid leukemia in the era of tyrosine kinase inhibitor therapy.

Cancer. 2012;118:3123-3127.

4. National Cancer Institute. SEER stat fact sheets: myeloma. http://seer.cancer.gov/ statfacts/html/mulmy.html. Accessed August 10, 2014.

5. National Cancer Institute. SEER stat fact sheets: all cancer sites. http://seer.cancer.gov/ statfacts/html/all.html. Accessed August 10, 2014.

6. Board of Pharmacy Specialties. BPS 2013 annual report. 2013. http://viewer.epaper flip.com/Viewer.aspx?docid=db4e75c1-cdb3-4a14-9ece-a2eb00f9e596#?page=0.

Accessed August 10, 2014.

7. Robinson R. Specialty drugs: an evolving commercial model: a changing marketplace creates new challenges and new business models for specialty medications.

PharmaVOICE. 2014;14:12-19.

8. Schwartz RN, Eng KJ, Frieze DA, et al. NCCN Task Force report: specialty pharmacy.

J Natl Compr Canc Netw. 2010;8(suppl 4):S1-S12.

9. Giberson S, Yoder S, Lee MP. Improving patient and health system outcomes through advanced pharmacy practice: a report to the U.S. Surgeon General 2011. Office of the Chief Pharmacist. US Public Health Service. Revised December 2011. www.accp. com/docs/positions/misc/improving_patient_and_health_system_outcomes.pdf. Accessed August 10, 2014.

10. Wu Y-L, Zhou C, Hu C-P, et al. Afatinib versus cisplatin plus gemcitabine for firstline treatment of Asian patients with advanced non-small-cell lung cancer harbouring EGFR mutations (LUX-Lung 6): an open-label, randomised phase 3 trial. Lancet Oncol.

2014;15:213-222.

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ORIGINAL RESEARCH

Increased Incidence of Recurrent Venous Thromboembolism in Patients with Cancer Receiving Bevacizumab Tanis L. Welch, PharmD; Sarah M. Gressett Ussery, PharmD, BCOP; Kevin C. Kelly, PharmD, BCPS; Jonathan E. Dowell, MD; Sachin R. Shah, PharmD, BCOP, FCCP Background: Venous thromboembolism (VTE) is a major cause of morbidity and mortality in patients with cancer. Bevacizumab is approved for the treatment of several types of cancer.

Although VTE has been documented with the use of bevacizumab, it remains controversial whether the drug itself contributes to increased VTE risk, or if specific patient characteristics such as acquired or congenital risk factors, increase the patients’ risk for venous thrombosis.

Objective: The primary purpose of this study was to evaluate the risk of VTE in patients with a history of VTE who were receiving chemotherapy with or without bevacizumab.

Methods: Patients with documented advanced or metastatic colorectal cancer (CRC) or non–small-cell lung cancer (NSCLC) who received chemotherapy between January 2002 and September 2011 were retrospectively reviewed. Data were collected for patients who met the inclusion criteria, including age ≥18 years, advanced or metastatic CRC or NSCLC treated with first-line combination chemotherapy, and an Eastern Cooperative Oncology Group performance status of 0 to 2. Patients aged ≥89 years or who had received previous vascular endothelial growth factor inhibitor treatment were excluded from the analysis.

Results: A total of 209 patients met the inclusion criteria. Of these, 173 patients without a history of VTE received bevacizumab therapy, 13 patients with a history of VTE received bevacizumab therapy, and 23 patients who had a history of VTE received chemotherapy alone. Overall, 60.8% of patients had CRC and 39.2% had NSCLC. Patients with a history of VTE who received bevacizumab had a significantly higher incidence of VTE compared with patients without a history of VTE (23.1% vs 5.2%, respectively; P = .040). In addition, the inciJ Hematol Oncol Pharm. dence of recurrent VTE was higher in patients receiving bevacizumab compared with patients 2014;4(3):75-81 receiving chemotherapy alone (23.1% vs 8.7%, respectively; P = .328). www.JHOPonline.com Conclusion: The use of bevacizumab in patients with a history of VTE may be associated Disclosures are at end of text with increased risk for a subsequent VTE.

A

ngiogenesis, the development of new blood vessels from preexisting vessels, is considered to be one of the central “hallmarks” in most malignancies.1 A tumor must develop an independent blood supply to have the ability to grow beyond 1 to 2

mm in diameter.2 Vascular endothelial growth factor (VEGF) has been identified as the predominant regulator involved in tumor angiogenesis and has become a target of many new antineoplastic drugs, such as bevacizumab.3 Bevacizumab, a recombinant humanized mono-

Dr Welch is Medical Intensive Care Unit Clinical Pharmacist, University Medical Center, Lubbock, TX, and was a Pharmacy Practice Resident, Veterans Affairs North Texas Health Care System, and adjunct faculty, Texas Tech University Health Sciences Center School of Pharmacy, Dallas, TX, during the time of this research; Dr Gressett Ussery was Hematology/Oncology Advanced Practice Pharmacist, Veterans Affairs North Texas Health Care System, Dallas, TX, during the time of research, and is Medical Science Liaison Hematology, Celgene Corporation, Dallas, TX; Dr Kelly is Advanced Clinical Pharmacist, Veterans Affairs North Texas Health Care System, Dallas, TX; Dr Dowell is Chief, Hematology/Oncology Services, Veterans Affairs North Texas Health Care System, and Associate Professor, University of Texas Southwestern Medical Center, Dallas, TX; Dr Shah is Hematology/ Oncology Advanced Practice Pharmacist, Veterans Affairs North Texas Health Care System, and Associate Professor of Pharmacy Practice, Associate Dean for Assessment and Accreditation, and Hematology/Oncology Clinical Pharmacist, Texas Tech University Health Sciences Center School of Pharmacy, Dallas, TX.

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clonal antibody, neutralizes VEGF, thereby preventing VEGF from binding to its receptor and subsequently inhibiting the angiogenic process.4 Bevacizumab has been approved for, and has been shown to be effective in, the treatment of advanced or metastatic colorectal cancer (CRC), advanced or metastatic non–small-cell lung cancer (NSCLC), glioblastoma, and renal-cell carcinoma.5-8 Several unique and severe adverse effects are associated with the use of bevacizumab, including, but not limited to, hypertensive crisis, nephrotic syndrome, gastrointestinal tract perforation, wound dehiscence, hemorrhage, arterial thromboembolic events, neutropenia, infection, and congestive heart failure.4,9 Although venous thromboembolism (VTE) has been documented with the use of bevacizumab, it remains controversial whether the drug itself contributes to increased risk for VTE or if specific patient characteristics, such as acquired or congenital risk factors, increase the patients’ risk for venous thrombosis.10,11 VTE is a major cause of morbidity and mortality in patients with cancer. The etiologies of VTE in cancer include the inherent hypercoagulable state, vessel wall trauma, and vessel stasis.1 The frequency of cancerassociated VTE is increased further by the presence of additional risk factors, such as acquired or congenital thrombophilia, prolonged immobilization, surgical procedures, cancer type and disease burden, chemotherapy regimen and duration, comorbid conditions, and concomitant medications. It has been reported that VTE increases the likelihood of death by 2- to 8-fold in patients with cancer.12 The overall incidence of VTE in patients with metastatic or advanced CRC or NSCLC who receive treatment with bevacizumab varies considerably among phase 2 and 3 randomized controlled trials (RCTs; range, 3%-17.6%).13-16 To date, there have been 2 meta-analyses examining the incidence of VTE in patients treated with chemotherapy plus bevacizumab. However, the conclusions of these 2 studies are conflicting. Nalluri and colleagues determined that patients treated with bevacizumab had a significantly increased risk of VTE, relative risk of 1.33 (95% confidence interval [CI], 1.13-1.56; P <.001) compared with the risk in the control groups.10 Alternatively, Hurwitz and colleagues concluded that there was no significant increased risk for VTE in patients receiving bevacizumab versus controls (odds ratio, 1.14; 95% CI, 0.96-1.35; P = .13).11 Because of the conflicting results of these meta-analyses, a wide variation in results in previous RCTs, and limited current literature, it is uncertain whether the addition of bevacizumab to chemotherapy increases patients’ risk for VTE. Furthermore, there are no studies directly evaluating the risk for recurrent VTE in

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patients with a history of VTE who are treated with bevacizumab. In clinical practice, a history of VTE has typically not precluded the use of bevacizumab in patients with cancer.

The purpose of this study is to evaluate the risk for recurrent VTE in patients receiving chemotherapy plus bevacizumab.

Methods This retrospective cohort chart review included patient data from January 1, 2002, through September 31, 2011. Patients were eligible for inclusion if they were aged ≥18 years, had an Eastern Cooperative Oncology Group (ECOG) performance status of ≤2, and had a diagnosis of advanced or metastatic CRC or NSCLC and were receiving first-line combination chemotherapy. Patients with previous VEGF inhibitor treatment were excluded.

Patients were identified with the use of International Classification of Diseases, Ninth Revision (ICD-9) codes for NSCLC (162.00) and CRC (153.00). Demographic information collected included age, sex, body mass index (BMI), and baseline ECOG performance status.

Risk factors at baseline were also collected, including VTE history and location; baseline medication history, including hormonal therapy; erythropoietin stimulating agents; or megesterol. In addition, medical history of congestive heart failure, myocardial infarction or cerebrovascular accident, platelets ≥350,000, and major or minor surgery within 30 days or while receiving treatment were recorded.

Surgery was defined as major if the surgery lasted at least 1 hour with anesthesia and/or surgery with extensive tissue injury (ie, abdominal, thoracic, or orthopedic surgery, or reconstructive plastic surgery). Minor surgery was defined as a procedure lasting <1 hour.17 In addition, baseline use of anticoagulants or antiplatelets, cancer diagnosis, use of a chemotherapy regimen (initiation date and discontinuation date), dose of bevacizumab (if included in a regimen), total number of chemotherapy cycles received, and incidence and location of VTE while receiving treatment and up to 60 days after discontinuation of treatment were collected. The incidence of VTE was further delineated as inpatient or outpatient; inpatient was defined as a patient being admitted to the hospital for >3 days and outpatient for ≤3 days.

Computerized progress notes, pharmacy records, and imaging reports were reviewed. The study was conducted in compliance with the Institutional Review Board and the research and development committee of the Veterans Affairs North Texas Health Care System and Texas Tech University Health Sciences Center.

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Results A total of 1422 patients were initially identified using ICD-9 codes for CRC and NSCLC; of these, 1213 patients were excluded. Of the 209 patients who met the inclusion criteria, 186 patients were treated with chemotherapy plus bevacizumab. Of those 186 patients, 173 had no history of VTE (Group A) and 13 had a history of VTE (Group B). The third group, considered the control group (Group C), included 23 patients with a history of VTE who were treated with chemotherapy, without bevacizumab. Overall, 60.8% of patients had CRC and 39.2% had NSCLC. Baseline characteristics are reported in Table 1. There were no significant differences in baseline characteristics among all 3 groups. The mean age was 62 years, and the

The primary objective of the study was to evaluate the incidence of recurrent VTE in patients receiving bevacizumab. In addition, the incidence of recurrent VTE in patients receiving chemotherapy without bevacizumab exposure and primary incidence of VTE in patients receiving bevacizumab were evaluated and compared with the primary objective. Group comparison for categorical variables was performed using chi-square or Fisher exact test. Mann-Whitney U test was used to evaluate continuous variables. A multivariate regression model was used to test the relationship between the incidence of VTE and potential confounding factors.

All data were analyzed using the Minitab 15 Statistical Software (State College, PA). Statistical significance was defined as P ≤.05.

Table 1 Patients’ Baseline Characteristics

Bevacizumab

No Bevacizumab

No VTE history Group A

VTE history Group B

VTE history Group C

62.5 (± 8.5)

60.5 (± 7.5)

62.04 (± 8.9)

Male, N (%)

171 (99)

13 (100)

21 (91)

BMI ≥25 kg/mg2, N (%)

96 (55)

9 (69)

9 (39)

0

48 (28)

3 (23)

3 (13)

1

87 (50)

7 (54)

8 (35)

2

38 (22)

3 (23)

12 (52)

CRC, N (%)

113 (65)

8 (62)

6 (26)

NSCLC, N (%)

60 (35)

5 (38)

17 (74)

Lower DVT, N (%)

NA

6 (46)

11 (48)a

Upper DVT, N (%)

NA

3 (23)

3 (13)

PE, N (%)

NA

4 (31)

7 (30)a

ther (ie, mesenteric vein, splenic vein, O superior vena cava, brachiocephalic, portal vein), N (%)

NA

—

4 (17)

4 (2)

9 (69)

13 (57)b

Warfarin, N (%)

4 (100)

4 (44)

6 (46)

LMWH, N (%)

NA

5 (56)

8 (61)

Characteristics Age, mean, yrs (± SD)

(N = 173)

(N = 13)

(N = 23)

ECOG performance status, N (%)

Tumor site

History of VTE

Concurrent anticoagulation, N (%)

NOTE: None of these data were statistically significant. a One patient had both lower DVT and PE. b One patient was on both warfarin and LMWH. BMI indicates body mass index; CRC, colorectal cancer; DVT, deep vein thrombosis; ECOG, Eastern Cooperative Oncology Group; LMWH, low-molecular-weight heparin; NA, not applicable; NSCLC, non–small-cell lung cancer; PE, pulmonary embolism; SD, standard deviation; VTE, venous thromboembolism.

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Table 2 Patients’ VTE Risk Factors at Baseline Bevacizumab

No bevacizumab

No VTE history Group A

VTE history Group B

VTE history Group C

CHF, N (%)

3 (2)

—

2 (9)

Previous CVA, N (%)

6 (3)

1 (8)

3 (13)

Previous MI, N (%)

14 (8)

—

3 (13)

ESA, N (%)

22 (13)

2 (15)

2 (9)

1 (1)

—

—

—

—

1 (4)

Megesterol, N (%)

28 (16)

1 (8)

4 (17)

Platelets ≥350,000, N (%)

40 (23)

3 (23)

4 (17)

Surgery within 30 days of, or while receiving treatment, N (%)

22 (13)

3 (23)

2 (9)

Major, N (%)

3 (14)

1 (33)

1 (50)

Minor, N (%)

19 (86)

2 (67)

1 (50)

Risk factors

(N = 173)

Hormonal therapy, N (%) Acquired/congenital thrombophilia

(N = 13)

(N = 23)

CHF indicates congestive heart failure; CVA, cerebrovascular accident; ESA, erythropoietin-stimulating agent; MI, myocardial infarction; VTE, venous thromboembolism.

Table 3 Chemotherapy Characteristics Chemotherapy plus bevacizumab

Chemotherapy and no bevacizumab

No VTE history Group A

VTE history Group B

VTE history Group C

5 mg/kg

48 (28)

6 (46)

—

7.5 mg/kg

70 (40)

3 (23)

—

15 mg/kg

55 (32)

4 (31)

—

17.7

15.7

9.4a

6.8 (± 5.7)

7.6 (± 5.7)

3.3 (± 2.4)

FOLFOX/XELOX

78 (45)

7 (54)

1 (4)

FOLFIRI/XELIRI

13 (8)

1 (8)

NA

IFL

23 (13)

1 (8)

NA

Platinum doubletb

55 (32)

4 (31)

15 (65)

4 (2)

—

7 (30)

Treatment regimen

(N = 173)

(N = 13)

(N = 23)

Dose of bevacizumab, N (%)

Weeks on treatment, median Number of cycles, mean (± SD) Regimen, N (%)

Otherc

P = .0297.

Platinum doublet = carboplatin/gemcitabine, carboplatin/docetaxel, carboplatin/paclitaxel, cisplatin/pemetrexed. c Other = docetaxel alone, capecitabine alone, fluorouracil/leucovorin (5-FU/LV).

FOLFIRI indicates fluorouracil/leucovorin/irinotecan; FOLFOX, fluorouracil/leucovorin/oxaliplatin; IFL, irinotecan/5-fluorouracil/leucovorin; NA, not applicable; SD, standard deviation; VTE, venous thromboembolism; XELIRI, capecitabine/irinotecan; XELOX, capecitabine/oxaliplatin. a

b

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Figure

Venous Thromboembolism Incidence while Receiving Treatment, by Study Group

25 Incidence of VTE, %

majority of the patients were male (98%). The majority of the patients in the bevacizumab-treated groups (Groups A and B) were overweight, with a BMI of ≥25 kg/mg2 compared with those in Group C. The majority of patients in Groups A and B had an ECOG performance status of 1 (50% and 54%, respectively) compared with patients in Group C; 52% of these patients had an ECOG performance status of 2.

In Groups A and B, CRC was more common (65% and 62%, respectively) compared with Group C, in which NSCLC was more common (74%). Considering the 2 groups with a history of VTE (Groups B and C), the most common type of VTE was lower extremity deep vein thrombosis (DVT). These patients were most often treated with a low-molecular-weight heparin (LMWH) and 1 patient in Group C was treated with LMWH and with warfarin at baseline.

Table 2 reports the VTE risk factors at baseline among the study groups. Very few patients in any of the groups had surgery 30 days before or while receiving treatment. A total of 22 patients had minor surgeries, including mediport placement (19), cystoscopy (2), and incision and drainage (1); 5 patients had major surgeries, including exploratory laparotomy (2), hemicolectomy (2), and lower abdominal resection (1). Several patients had additional VTE risk factors at baseline; however, a multivariate analysis revealed no significant difference between the bevacizumab-treated and the control group on the effect of these risk factors.

Considering the chemotherapy characteristics, specifically in the bevacizumab-receiving groups, Group A most often (40.5%) received the 7.5-mg/kg dose compared with Group B, in which the most common (46%)

23.1%a

20 15 8.7%

10 5.2%a

5 0

No VTE history: VTE history: Group A Group B Bevacizumab

VTE history: Group C No bevacizumab

Treatment group P = .040 (Group A vs Group B).

VTE indicates venous thromboembolism. a

dose was the 5-mg/kg dose. Additional chemotherapy characteristics are listed in Table 3.

The patients in Group C received the shortest duration of treatment and subsequently the fewest number of chemotherapy cycles compared with the bevacizumabtreated groups. This difference was significant when comparing the median weeks of treatment between patients in Group B and patients in Group C—15.7 weeks versus 9.4 weeks, respectively (P = .0297).

The most common combination chemotherapy regimen used in all 3 groups was the platinum-based regimens (ie, FOLFOX [fluorouracil, leucovorin, and oxaliplatin], XELOX [capecitabine and oxaliplatin], and platinum doublets).

Table 4 Incidence of Venous Thromboembolism, by Group Chemotherapy plus bevacizumab

Chemotherapy and no bevacizumab

No VTE history Group A

VTE history Group B

VTE history Group C

a

9 (5.2)

3 (23.1)

2 (8.7)

Lower DVT, N (%)

3 (1.7)

1 (7.6)b

2 (8.7)b

Upper DVT, N (%)

2 (1.2)

—

—

PE, N (%)

4 (2.3)

3 (23.1)b

2 (8.7)b

9 (100)

2 (66.7)

2 (100)

—

1 (33.3)

—

VTE incidence VTE while receiving treatment, N (%)

(N = 173)

(N = 13) a

(N = 23)

Type of VTE

Outpatient VTE, N (%) Inpatient VTE, N (%)

P = .040.

One patient had both lower DVT and PE. DVT indicates deep vein thrombosis; PE, pulmonary embolism; VTE, venous thromboembolism. a

b

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Among the patients treated with bevacizumab, the incidence of VTE was 5.2% (9 of 173 patients) for Group A versus 23.1% (3 of 13) for Group B (P = .040). The incidence was still higher in Group B compared with patients in Group Câ&#x20AC;&#x201D;23.1% versus 8.7% (2 of 23), respectively; however, this was not significant (P = .328; Figure).

The most common on-treatment VTE manifestation among Groups A and B was pulmonary embolism (PE); in Group C, an equal number of patients had lower DVT and PE. One patient in Group B and 1 in Group C had both a PE and lower DVT. All the on-treatment VTE cases were in the outpatient setting, with the exception of 1 patient in Group B who was classified as inpatient.

The incidence of VTE is summarized in Table 4.

Discussion In patients with cancer, VTE can diminish quality of life and can even result in death. VTE has been reported in patients receiving bevacizumab. We used 2 different comparator groups to better understand the clinical impact of bevacizumab therapy on the incidence of recurrent VTE. The first group (Group A) included patients without a history of VTE who received bevacizumab. This group provided a baseline for the incidence of VTE in patients receiving bevacizumab.

The comparator group (Group C) was comprised of patients with a history of VTE who received chemotherapy but not bevacizumab. This group provided the baseline risk for recurrent VTE in patients receiving chemotherapy only.

This study used a cutoff period of 60 days to consider at least 3 half-lives of bevacizumab to account for any residual effects of the drug. Our study suggests that the risk for VTE was significantly higher in patients with a history of VTE compared with patients without a history of VTE who were receiving bevacizumab. Furthermore, the risk for VTE remains high, although not significantly, even when compared with the patients with a history of VTE who were receiving chemotherapy without bevacizumab.

Overall, 69% of patients were receiving active anticoagulation therapy while taking bevacizumab. Our study suggests that there is a consistent increased risk for recurrent VTE in patients receiving bevacizumab.

All 3 patients who had recurrent VTE while receiving bevacizumab were also taking therapeutically targeted anticoagulation agents.

We did not detect any significant differences between the group demographics at baseline. However, variations in ECOG performance status and types of cancers were observed between Groups B and C. The majority of the patients in Groups A and B

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had a performance status <1, whereas the majority of patients in Group C had performance status 2.

In addition, 62% of the patients in Groups A and B had CRC compared with 26% in Group C. Based on these differences of ECOG performance status and cancer type distributions at baseline between the 2 groups (ie, bevacizumab-treated vs no bevacizumab), patients in Group C should have had a higher incidence of VTE. According to the VTE predictive model, patients with lung cancer are at 50% increased risk of having VTE compared with those with CRC.18 No significant difference was noted among the 3 groups regarding the VTE risk factors at baseline (Table 2). There was a higher percentage (23%) of patients with recent surgery in Group B, but the majority of the surgeries were minor. In addition, the surgeries reported occurred within 30 days of chemotherapy or chemotherapy plus bevacizumab administration and did not occur before the incidence of VTE. Patients in Group B had significantly longer duration of cancer treatment (15.7 vs 9.4 weeks; P = .0297) compared with Group C. This difference could be explained by the cancer type distribution and chemotherapy regimen administered in these 2 groups. The majority of patients in Group C had NSCLC and received platinum-based chemotherapy. A typical patient with NSCLC might have received 4 cycles of platinum-based chemotherapy and then might have been followed for observation.

By contrast, a typical patient with CRC might have received 5-fluorouracilâ&#x20AC;&#x201C;based chemotherapy until the progression of cancer.

The increase in incidence of VTE in patients treated with bevacizumab may be attributed to the anti-VEGF mechanism of bevacizumab. Our study revealed a 5.2% incidence of primary VTE in patients with CRC or NSCLC who were treated with bevacizumab (Group A), which is consistent with what is reported in previous studies (incidence range, 3%-17.6%).13-16 The risk for VTE was significantly higher when bevacizumab was administered to patients with a history of VTE (23.1%) in our study compared with those without a history of VTE (5.2%). In addition, the risk for recurrent VTE was higher in patients receiving chemotherapy plus bevacizumab compared with chemotherapy alone (23.1% vs 8.7%; P = .328).

These results are consistent with the results of a 4-arm prospective RCT by Saltz and colleagues that included 1401 patients with metastatic CRC, in which the incidence of primary VTE was 13.5% in the bevacizumab arms.4,5 Among the 116 patients treated with anticoagulation after an initial VTE (73 in the bevacizumab plus chemotherapy arms and 43 in the chemotherapy-alone arms), the bevacizumab arms had

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higher incidence of recurrent VTE compared with the control arms (31.5% vs 25.6%, respectively).4 Another pivotal first-line trial in patients with metastatic CRC (AVF2107g) evaluated the incidence of recurrent VTE in patients receiving bolus IFL (irinotecan, 5-fluoroucil, and leucovorin) with or without bevacizumab.4,19 In this trial, patients with an incidence of primary VTE received full-dose warfarin therapy.

The recurrent VTE occurred in 21% (11 of 53 patients) of patients receiving bolus IFL plus bevacizumab compared with 3% (1 of 30 patients) of patients receiving bolus IFL alone.4,9 The key difference between these 2 trials and this present study is that these 2 trials did not evaluate the incidence of recurrent VTE in patients without previous exposure to bevacizumab.

Limitations This study has limitations that should be considered when interpreting the results. First, the results of this study are primarily applicable to male patients with cancer, because 98% of the patients were males. Another limitation was the relatively small sample size, which might have contributed to the nonstatistical differences between the groups at baseline, and for the VTE outcomes.

Conclusion Regardless of the study limitations, this study evaluates an important question, which to our knowledge has not been investigated, that is, the risk of recurrent VTE in patients receiving bevacizumab.

The results of this study suggest that patients with CRC or NSCLC who are receiving bevcizumab are at increased risk for recurrent VTE. This risk may be higher compared with patients receiving chemotherapy without bevacizumab. There are many clinical questions that cannot be answered by the available literature, such as the optimal timing of bevacizumab initiation after a VTE, whether the risk of VTE can be mitigated by appropriate anticoagulation, or if there is a difference in risk of recurrent VTE if patients have a provoked versus an unprovoked VTE. These are questions that still need to be answered to make concrete recommendations in the use of bevacizumab in the setting of a previous VTE. In practice, careful evaluation of risk versus benefit with the use of bevacizumab-based therapy should be considered in the setting of limited literature evaluating the risk of recurrent VTE. n

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Author Disclosure Statement Dr Gressett Ussery is an employee of Celgene Corporation; Dr Dowell has received research support from Verastem and MedImmune; Dr Welch, Dr Kelly, and Dr Shah reported no conflicts of interest.

References

1. Hanahan D, Weinberg RA. The hallmarks of cancer. Cell. 2000;100:57-70.

2. O’Byrne KJ, Steward WP. Tumour angiogenesis: a novel therapeutic target in patients with malignant disease. Expert Opin Emerg Drugs. 2001;6:155-174.

3. Hicklin DJ, Ellis LM. Role of the vascular endothelial growth factor pathway in tumor growth and angiogenesis. J Clin Oncol. 2005;23:1011-1027.

4. Avastin (bevacizumab) [prescribing information]. South San Francisco, CA: Genentech, Inc; August 2014.

5. Saltz LB, Clarke S, Díaz-Rubio E, et al. Bevacizumab in combination with oxaliplatin-based chemotherapy as first-line therapy in metastatic colorectal cancer: a randomized phase III study. J Clin Oncol. 2008;26:2013-2019. Erratum in: J Clin Oncol.

2008;26:3110; and J Clin Oncol. 2009;27:653.

6. Johnson BE, Kabbinavar F, Fehrenbacher L, et al. ATLAS: randomized, double-blind, placebo-controlled, phase IIIB trial comparing bevacizumab therapy with or without erlotinib, after completion of chemotherapy, with bevacizumab for first-line treatment of advanced non–small-cell lung cancer. J Clin Oncol. 2013;31:3926-3934.

7. Friedman HS, Prados MD, Wen PY, et al. Bevacizumab alone and in combination with irinotecan in recurrent glioblastoma. J Clin Oncol. 2009;27:4733-4740.

8. Rini BI, Bellmunt J, Clancy J, et al. Randomized phase III trial of temsirolimus and bevacizumab versus interferon alfa and bevacizumab in metastatic renal cell carcinoma: INTORACT trial. J Clin Oncol. 2014;32:752-759.

9. Gordon MS, Cunningham D. Managing patients treated with bevacizumab combination therapy. Oncology. 2005;69(suppl 3):25-33.

10. Nalluri SR, Chu D, Keresztes R, et al. Risk of venous thromboembolism with the angiogenesis inhibitor bevacizumab in cancer patients: a meta-analysis. JAMA. 2008;300:2277-2285.

11. Hurwitz HI, Saltz LB, Van Cutsem E, et al. Venous thromboembolic events with chemotherapy plus bevacizumab: a pooled analysis of patients in randomized phase II and III studies. J Clin Oncol. 2011;29:1757-1764.

12. Heit JA. Cancer and venous thromboembolism: scope of the problem. Cancer Control. 2005;12(suppl 1):5-10.

13. Kabbinavar FF, Schulz J, McCleod M, et al. Addition of bevacizumab to bolus fluorouracil and leucovorin in first-line metastatic colorectal cancer: results of a randomized phase II trial. J Clin Oncol. 2005;23:3697-3705.

14. Allegra CJ, Yothers G, O’Connell MJ, et al. Initial safety report of NSABP C-08: a randomized phase III study of modified FOLFOX6 with or without bevacizumab for the adjuvant treatment of patients with stage II or III colon cancer. J Clin Oncol.

2009;27:3385-3390.

15. Reck M, von Pawel J, Zatloukal P, et al. Phase III trial of cisplatin plus gemcitabine with either placebo or bevacizumab as first-line therapy for nonsquamous non–smallcell lung cancer: AVAiL. J Clin Oncol. 2009;27:1227-1234. Erratum in: J Clin Oncol.

2009;27:2415.

16. Johnson DH, Fehrenbacher L, Novotny WF, et al. Randomized phase II trial comparing bevacizumab plus carboplatin and paclitaxel with carboplatin and paclitaxel alone in previously untreated locally advanced or metastatic non–small-cell lung cancer. J Clin Oncol. 2004;22:2184-2191.

17. Douketis JD, Spyropoulos AC, Spencer FA, et al; for the American College of Chest Physicians. Perioperative management of antithrombotic therapy: Antithrombotic Therapy and Prevention of Thrombosis, 9th ed: American College of Chest Physicians Evidence-Based Clinical Practice Guidelines. Chest. 2012;141(2 suppl):e326S-e350S. Erratum in: Chest. 2012;141:1129.

18. Khorana AA, Kuderer NM, Culakova E, et al. Development and validation of a predictive model for chemotherapy-associated thrombosis. Blood. 2008;111:49024907.

19. Hurwitz H, Fehrenbacher L, Novotny W, et al. Bevacizumab plus irinotecan, fluorouracil, and leucovorin for metastatic colorectal cancer. N Engl J Med. 2004; 350:2335-2342.

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THIRD ANNUAL

WORLD CUTANEOUS MALIGNANCIES CONGRESS

™

October 29 – October 31, 2014 • Marriott Marquis • San Francisco, CA A 2-day congress dedicated to informing, educating, and fostering the exchange of clinically relevant information in the field of cutaneous malignancies on topics in melanoma, basal cell carcinoma, squamous cell carcinoma, Merkel cell carcinoma, and cutaneous T-cell lymphoma.

CONFERENCE CHAIR

WORLD CUTANEOUS MALIGNANCIES CONGRESS

Sanjiv S. Agarwala, MD Bethlehem, PA

PROGRAM COMMITTEE

Axel Hauschild, MD Kiel, Germany

Paul Nghiem, MD, PhD Seattle, WA

Pierluigi Porcu, MD Columbus, OH

Aleksandar Sekulic, MD, PhD Scottsdale, AZ

™

TARGET AUDIENCE

This educational initiative is directed toward medical and surgical oncologists, dermatologists, and radiation oncologists involved in the treatment of patients with cutaneous malignancies. Fellows, nurse practitioners, nurses, physician assistants, pharmacists, researchers, and other healthcare professionals interested in the treatment of cutaneous malignancies are also invited to participate.

EDUCATIONAL OBJECTIVES

After completing this activity, the participant should be better able to: • Review the molecular biology and pathogenesis of malignant melanoma, CTCL, BCC, and MCC, including how they relate to targeted therapy • Describe how to tailor therapeutic options and optimal sequencing for individual patients with melanoma, CTCL, BCC, and MCC • Utilize emerging data and recent advances with new molecular targets for the treatment of patients with metastatic melanoma, CTCL, BCC, and MCC into clinical practice • Identify new technologies for the prevention and early detection of cutaneous malignancies

PHYSICIAN CONTINUING MEDICAL EDUCATION

Accreditation Statement This activity has been planned and implemented in accordance with the accreditation requirements and policies of the Accreditation Council for Continuing Medical Education (ACCME) through the joint providership of Postgraduate Institute for Medicine and Center of Excellence Media. The Postgraduate Institute for Medicine is accredited by the ACCME to provide continuing medical education for physicians.

CREDIT DESIGNATION*

The Postgraduate Institute for Medicine designates this live activity for a maximum of 9.25 AMA PRA Category 1 Credit(s)™. Physicians should claim only the credit commensurate with the extent of their participation in the activity. *This CME/CE activity complies with all requirements of the federal Physician Payment Sunshine Act. If a reportable event is associated with this activity, the accredited provider managing the program will provide the appropriate physician data to the Open Payments database.

DISCLOSURE OF CONFLICTS OF INTEREST

Postgraduate Institute for Medicine (PIM) requires instructors, planners, managers, and other individuals who are in a position to control the content of this activity to disclose any real or apparent conflict of interest (COI) they may have as related to the content of this activity. All identified COIs are thoroughly vetted and resolved according to PIM policy.

The existence or absence of COIs for everyone in a position to control content will be disclosed to participants prior to the start of each activity.

AMERICANS WITH DISABILITIES ACT

Event staff will be glad to assist you with any special needs (ie, physical, dietary, etc). Please contact Linda Sangenito prior to the live event at 732-992-1520.

This activity is jointly provided by Postgraduate Institute for Medicine and Center of Excellence Media, LLC.

For more information please visit www.CutaneousMalignancies.com

AGENDA*

WEDNESDAY, OCTOBER 29 3:00 pm - 7:00 pm

Registration

5:30 pm - 7:30 pm

Welcome Reception/Exhibits

THURSDAY, OCTOBER 30 6:45 am - 9:15 am

Breakfast Product Theaters

9:15 am - 9:30 am

Break

9:30 am - 9:45 am Welcome to the Third Annual World Cutaneous Malignancies Congress - Setting the Stage for the Meeting – Sanjiv S. Agarwala, MD 9:45 am - 11:45 am General Session I The Molecular Biology of Cutaneous Malignancies Implications for Personalized Therapy • Understanding the molecular biology of malignant melanoma: a clinical perspective – Antoni Ribas, MD • The molecular basis of basal cell carcinoma (BCC) – James MacDonald • Cutaneous T-cell lymphoma (CTCL): molecular aspects of disease development and response to targeted agents – Anjali Mishra, PhD • Immunologic characterization of tumor cells in CTCL: application to clinical practice – Rachel Clark, MD, PhD • Virus-positive and virus-negative Merkel cell carcinoma (MCC): implications for the clinician – Isaac Brownell, MD, PhD Question & Answer Panel Discussion

• Ongoing clinical studies in BCC – Aleksandar Sekulic, MD, PhD • New systemic therapies in CTCL: beyond the old paradigms – Steve Horowitz • Emerging treatment options in MCC: chemotherapy and alternative approaches for metastatic disease – Shailender Bhatia, MD Question & Answer Session 4:35 pm - 5:15 pm Tumor Board Breakout Sessions • Attendee cases in malignant melanoma • Attendee cases in BCC • Attendee cases in CTCL and MCC 5:15 pm - 7:00 pm

FRIDAY, OCTOBER 31

Cocktail Reception/Exhibits

7:00 am - 8:00 am

Breakfast

8:00 am - 8:15 am

Break

8:15 am - 8:30 am Review of Thursday’s Presentations and Preview of Today’s Sessions – Sanjiv S. Agarwala, MD

11:45 am - 12:00 pm Break

8:30 am - 9:30 am General Session IV Prevention and Early Detection • Early detection of primary tumors in melanoma – Susan M. Swetter, MD • A new serologic assay for early detection of recurrent MCC – Paul Nghiem, MD, PhD • An update on the SCREEN trial: skin cancer screening in Germany – Axel Hauschild, MD Question & Answer Session

12:00 pm - 1:00 pm

9:30 am - 9:45 am

Meet the Experts/Lunch in the Exhibit Hall

1:00 pm - 2:15 pm General Session II Current Treatment Algorithms in Cutaneous Malignancies • Current approaches to therapy in malignant melanoma: the US perspective – Antoni Ribas, MD • Current approaches to therapy in malignant melanoma: the EU perspective – Axel Hauschild, MD • Current treatment options for advanced BCC – Karl Lewis, MD • Current treatment options in CTCL – Pierluigi Porcu, MD • Update on NCCN guidelines for the management of MCC – Christopher K. Bichakjian, MD 2:15 pm - 2:30 pm

Break

2:30 pm - 2:50 pm Keynote Debate International Focus on Melanoma: Case Presentation Followed by US vs EU vs Latin America Debate on Therapy – Sanjiv S. Agarwala, MD; Héctor Martínez Saíd, MD; Axel Hauschild, MD 2:50 pm - 4:35 pm General Session III Emerging Therapies, Combos, and Targeted Agents • Changing arena of adjuvant therapy in malignant melanoma – Reinhard Dummer, MD, PhD

Break

9:45 am - 11:10 am General Session V What’s Hot in New Drugs and Clinical Trial Data • Anti–PD-1 antibodies ± ipilimumab in melanoma – Caroline Robert, MD, PhD • Real-world management of BCC: the RegiSONIC study – Jean Tang, MD, PhD • New data on lymphoma biology with applications to CTCL – Leandro Cerchietti, MD • Rationale and status of immune targeted therapies for MCC – Isaac Brownell, MD, PhD Question & Answer Session 11:10 am - 11:25 am Keynote Panel Discussion Is There a Role for “Conventional Therapies” for Cutaneous Malignancies in the Era of Targeted Agents? – Sanjiv S. Agarwala, MD; Axel Hauschild, MD; Paul Nghiem, MD, PhD; Pierluigi Porcu, MD; Aleksandar Sekulic, MD, PhD 11:25 am - 11:30 am

Closing Remarks – Sanjiv S. Agarwala, MD

*Agenda subject to change.

For full faculty information please visit www.CutaneousMalignancies.com

WCMC2014ConfAd Asize_60914

REGISTER TODAY! www.regonline.com/wcmc2014

SYMPTOM MANAGEMENT OVERVIEW

INTRODUCING

SYMPTOM MANAGEMENT OVERVIEW Section Editor: Joseph Bubalo, PharmD, BCPS, BCOP

SUBMIT YOUR

SYMPTOM MANAGEMENT UPDATE Readers are invited to submit brief updates with practice insights on the care of a specific symptom or a cluster of symptoms associated with a condition that is often seen in patients with cancer—to be presented in the form of a “How I Treat” type of article.

The goal of this new section is to provide a quick background to enhance providers’ understanding of the symptoms associated with a specific condition and their characteristic presentation(s) and etiology. The emphasis should be on a concise description of available treatments and current course of therapy.

WHAT IS SYMPTOM MANAGEMENT OVERVIEW? Each review should provide a brief description of the symptom(s) associated with a common condition in oncology and its evidence-based management ARTICLE FORMAT • Length of article: 800-1200 words • Tables: 1-3 • Describe the symptom(s) • Etiology • Treatment options: dose(s), frequency, titration parameters • Course of therapy: time to effect/symptom resolution, expected effects, special or target populations for specific therapies, side effects and their management, as appropriate • References: minimum 5; maximum 15

HOW TO SUBMIT

Submit a Word file of your article at

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This new section provides a quick update of symptomatic conditions in oncology and their management. Readers are invited to submit brief updates following the guidelines provided on page 84.

Chemotherapy-Induced Peripheral Neuropathy

By Joseph Bubalo, PharmD, BCPS, BCOP Assistant Professor of Medicine, Division of Hematology and Medical Oncology, Oncology Clinical Pharmacy Specialist, Oregon Health and Science University Hospital, OHSU Hospital and Clinics, Portland, OR

SYMPTOM OVERVIEW Damage to motor, sensory, or autonomic nerves secondary to antineoplastic chemotherapy can result in varying degrees of dysfunction and/or pain, which can lead to significant morbidity and diminished quality of life for affected patients, with up to 70% of patients having some element of chemotherapy-induced peripheral neuropathy (CIPN) after chemotherapy.1,2 A variety of chemotherapy classes, with varying effects by agent within a class, are known neurotoxins with a different affinity for nerves (Table 1).

The effects of CIPN are generally symmetrical, distal, in a stocking-glove distribution, and primarily affect the upper and lower extremities. These are usually sensory effects (burning, freezing, electroshock-like); however, there are more agent-specific neuropathies, such as constipation seen with vincristine; orthostasis with bortezomib; or temperaturerelated effects with oxaliplatin.3,4 In general, these effects are cumulative, dose-dependent, variable by

Table 1 C hemotherapy Classes that May Cause Peripheral Neuropathya Dolastatin derivatives Epothilones Eribulin Immunomodulatory drugs Platinums Proteasome inhibitors Taxanes Vinca alkaloids These effects may relate to the individual dose size and to the cumulative dose.

Sources: References 1, 6, 8. a

agent, and attenuate to different levels once therapy is discontinued.

ETIOLOGY Although not fully understood, the mechanisms of nerve damage vary by agents, with symptoms seen on nerve-cell microtubules or their axonal transport systems, mitochondria, or dorsal root ganglia, all of which can ultimately result in neuronal degradation. Additional neurologic dysfunction can occur, depending on the underlying disease, especially diseases that may result in mechanical compression of nerves or nerve roots. Several patient attributes and conditions are also known to increase the risk for CIPN (Table 2).

The symptoms of CIPN frequently attenuate after therapy, but they can be dose-limiting and result in suboptimal chemotherapy dosing.5 Treatment goals include the prevention or attenuation of neuropathies associated with therapy, the relief of symptoms, improv-

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Table 2 P atient Risk Factors that Increase CIPN Risk Alcohol use Concomitant use of CYP3A4-inhibiting medications and vincristine Diabetes Increasing age Paraproteinemias Preexisting neuropathies CIPN indicates chemotherapy-induced peripheral neuropathy.

Sources: References 2, 3, 6, 9.

ing patient quality of life, and maintaining optimal chemotherapy dosing.

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TREATMENT OPTIONS A recent review of CIPN showed that no medications have enough evidence to suggest that they should be used to prevent CIPN, and there was adequate evidence to suggest that a variety of agents should not be used for that purpose, because of lack of efficacy, risk for harm, or both.7 The medications that should not be used for the prevention of CIPN include2,7: • Acetyl-L-carnitine • Amifostine • Amitriptyline • Calcium and magnesium for oxaliplatin-based chemotherapies • Diethyldithiocarbamate • Glutamine for taxanes • Glutathione for paclitaxel/carboplatin chemotherapies • Nimodipine • Org 2766 • Recombinant human leukemia inhibitor factor • All-transretinoic acid • Venlafaxine ±, may affect antitumor effects of platinums • Vitamin E.

Once neuropathy is present, the best approach to management is chemotherapy dose interruption. If chemotherapy interruption is not possible, then the addition of pharmacologic and/or nonpharmacologic therapies is common. Antidepressants, anticonvulsants, analgesics, antioxidants, nutritional supplements, and other agents have been used in attempts to prevent or ameliorate the symptoms of CIPN. Several medications may be helpful for the treatment of CIPN, as has been shown in placebo-controlled trials (Table 3)1,2,7,10-15; however, because of the risk for adverse events, the potential benefit from each agent should be matched to the individual patient’s neuropathy profile.

Titration to target dose, as tolerated by the patient, is required for most medications. For compounded pharmaceutical agents, the concern is regarding nonstandardization of agents and the minimal long-term safety data.

The duration of use of each agent is unclear, with most studies evaluating the treatment of CIPN over periods ranging from <2 weeks to as much as 12 weeks.1,4 Effects of therapy are often seen within days of initiating treatment and may take days to weeks for the full benefit to be seen.

Table 3 M edications Used for the Treatment of CIPN Drug

Dose

Comments

Amitriptyline

10 mg daily, titrate to normal dose 25-100 mg, maximum dose 200 mg daily

Significant improvement in pain, but not in depression, sleep, or QOL CYP2D6 substrate

Desipramine

10-25 mg daily, titrate to 25-100 mg, maximum dose 150 mg daily

CYP2D6 substrate

Duloxetine

30 mg daily × 1 week, then 60 mg daily

Decrease in average pain, numbness, and tingling CYP2D6 and CYP1A2 substrate and moderate CYP2D6 inhibitor

Gabapentin

300-900 mg initially, titrate to target dose of 2700 mg daily, dosed 3 times daily, maximum 3600 mg daily

No significant change in pain, neuropathy scores, or analgesic use

Lamotrigine

25 mg daily × 2 weeks, 25 mg twice daily × 2 weeks, 50 mg twice daily × 2 weeks, 100 mg twice daily × 2 weeks, then 150 mg twice daily × 2 weeks

No significant difference in average pain or global impression of change

Nortriptyline

25 mg daily, increase weekly to usual dose of 50-75 mg, maximum dose 100 mg daily

No significant improvement in pain, paresthesias, or QOL CYP2D6 substrate

Pregabalin

150 mg daily, increase weekly to maximum 600 mg daily

Caution with other sedating medications Peripheral edema and weight gain seen

Topical gel (baclofen 10 mg, amitriptyline 40 mg, ketamine 20 mg/dose)

Apply twice daily

Significant improvement in motor effects but not pain, mood, sensory, or autonomic effects

Venlafaxine

Start with 37.5-mg ER tablet, increase to twice daily at 3-7 days, maximum 225 mg daily

CYP2D6 substrate and weak inhibitor

CIPN indicates chemotherapy-induced peripheral neuropathy; ER, extended release; QOL, quality of life.

Sources: References 1, 2, 7, 10-15.

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Although these therapies can lessen the effects of CIPN, they rarely cure it, and the patient’s need is frequently longer than most study periods. As a result, the clinician is often left to evaluate the safety of the extended use of specific agents based on experiences from managing other disease states with the same agent. Therefore, longer-term use is common, with each patient’s duration of therapy customized based on the individual response. Therapy is frequently continued until the neuropathy wanes, until the patient has serious therapy-related side effects, or until there is an indication to stop the medication.

At the time of medication discontinuation, accepted guidelines for the discontinuation of antidepressants or other medications should be followed to reduce the risk for a discontinuation syndrome. Many potentially beneficial agents are currently in early-phase clinical trials or are reported by anecdotal experience. In addition, work is ongoing to identify genetic markers for patients with increased risk for developing CIPN to identify agents that would not be likely to cause neuropathy in individual patients.16 It is hoped that useful agents for the prevention and management of neuropathies can be found, and that patients with increased risk for neuropathies could be offered alternative therapies. n

References

1. Aziz MT, Good BL, Lowe DK. Serotonin-norepinephrine reuptake inhibitors for the management of chemotherapy-induced peripheral neuropathy. Ann Pharmacother. 2014;48:626-632.

2. Piccolo J, Kolesar JM. Prevention and treatment of chemotherapy-induced peripheral neuropathy. Am J Health Syst Pharm. 2014;71:19-25.

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3. Delforge M, Bladé J, Dimopoulos MA, et al. Treatment-related peripheral neuropathy in multiple myeloma: the challenge continues. Lancet Oncol. 2010;11:10861095.

4. Durand JP, Deplanque G, Montheil V, et al. Efficacy of venlafaxine for the prevention and relief of oxaliplatin-induced acute neurotoxicity: results of EFFOX, a randomized, double-blind, placebo-controlled phase III trial. Ann Oncol.

2012;23:200-205.

5. Speck RM, Sammel MD, Farrar JT, et al. Impact of chemotherapy-induced peripheral neuropathy on treatment delivery in nonmetastatic breast cancer.

J Oncol Pract. 2013;9:e234-e240.

6. Okada N, Hanafusa T, Sakurada T, et al. Risk factors for early-onset peripheral neuropathy caused by vincristine in patients with a first administration of R-CHOP or R-CHOP-like chemotherapy. J Clin Med Res. 2014;6:252-260.

7. Hershman DL, Lacchetti C, Dworkin RH, et al. Prevention and management of chemotherapy-induced peripheral neuropathy in survivors of adult cancers: American Society of Clinical Oncology clinical practice guideline. J Clin Oncol.

2014;32:1941-1967.

8. Quasthoff S, Hartung HP. Chemotherapy-induced peripheral neuropathy.

J Neurol. 2002;249:9-17.

9. Harnicar S, Adel N, Jurcic J. Modification of vincristine dosing during concomitant azole therapy in adult acute lymphoblastic leukemia patients. J Oncol Pharm Pract. 2009;15:175-182.

10. Barton DL, Wos EJ, Qin R, et al. A double-blind, placebo-controlled trial of a topical treatment for chemotherapy-induced peripheral neuropathy: NCCTG trial N06CA. Support Care Cancer. 2011;19:833-841.

11. Hammack JE, Michalak JC, Loprinzi CL, et al. Phase III evaluation of nortriptyline for alleviation of symptoms of cis-platinum-induced peripheral neuropathy.

Pain. 2002;98:195-203.

12. Kautio A-L, Haanpää M, Saarto T, Kalso E. Amitriptyline in the treatment of chemotherapy-induced neuropathic symptoms. J Pain Symptom Manage. 2008;35:31-39.

13. Rao RD, Michalak JC, Sloan JA, et al; for the North Central Cancer Treatment Group. Efficacy of gabapentin in the management of chemotherapyinduced peripheral neuropathy: a phase 3 randomized, double-blind, placebocontrolled, crossover trial (N00C3). Cancer. 2007;110:2110-2118.

14. Rao RD, Flynn PJ, Sloan JA, et al. Efficacy of lamotrigine in the management of chemotherapy-induced peripheral neuropathy: a phase 3 randomized, double-blind, placebo-controlled trial, N01C3. Cancer. 2008;112:2802-2808.

15. Lavoie Smith EM, Pang H, Cirrincione C, et al; for the Alliance for Clinical Trials in Oncology. Effect of duloxetine on pain, function, and quality of life among patients with chemotherapy-induced painful peripheral neuropathy: a randomized clinical trial. JAMA. 2013;309:1359-1367.

16. de Graan A-J, Elens L, Sprowl JA, et al. CYP3A4*22 genotype and systemic exposure affect paclitaxel-induced neurotoxicity. Clin Cancer Res. 2013;19:3316-3324.

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Improving Patient Care and Medication Safety: Standardizing Antiemetic Agents in Chemotherapy Order Sets in a Large Healthcare System Maria Zarambo, PharmD, BCOP; Elizabeth A. Brenner, PharmD; Ann E. Sather, RPh, BCOP Background: Chemotherapy-induced nausea and vomiting can significantly affect a patient’s quality of life. Optimizing antiemetic therapy during chemotherapy can affect the quality of patient care and patient satisfaction. Nausea and vomiting often rank highly among patients’ reported unwanted side effects. Using appropriate standardized antiemetic medications may potentially alleviate some of these unwanted side effects.

Objective: To evaluate the impact of antiemetic medication standardization in select chemotherapy order sets on a patient’s incidence of nausea complaints, episodes of vomiting, and use of as-needed (PRN) medications for nausea and vomiting.

Methods: Inpatient chemotherapy regimens within our healthcare system were stratified as highly emetogenic or moderately emetogenic using the National Comprehensive Cancer Network antiemetic clinical practice guidelines, version 1.2012. A universal, standardized antiemetic order set was created and was incorporated into the select chemotherapy regimens. The electronic medical records of a randomly selected sample of 50 patient encounters between November 2011 and December 2012 were included in the prestandardization group.

A total of 32 patient encounters between March 5, 2013, and June 6, 2013, were included in the poststandardization group. Pharmacists at our healthcare system, as well as other providers from an affiliated organization, were educated about the order set changes. The frequency of PRN antiemetic medication use, the number of nausea complaints, and the number of vomiting events were evaluated in the prestandardized and the poststandardized order sets. In addition, antiemetic medication prescribing habits were evaluated in the prestandardized and the poststandardized order sets.

Results: The analysis of the poststandardized order sets shows that the number of nausea complaints decreased from the prestandardization period, provider compliance with guideline-based antiemetic regimens increased, and the overall use of PRN antiemetic medications decreased as a result of education and adherence to order set standardization. In addition, the prescribing of PRN medications with different mechanisms of action increased from prestandardization to poststandardization. This study did not identify any barriers to adherence J Hematol Oncol Pharm. to order sets or order set standardization.

2014;4(3):88-92 Conclusion: Standardizing antiemetic therapy on chemotherapy order sets based on the www.JHOPonline.com emetogenicity of the regimen has a positive impact on the incidence of nausea complaints, Disclosures are at end of text episodes of vomiting, and need for PRN medication use for nausea and vomiting.

T

he Multinational Association of Supportive Care in Cancer, the American Society of Clinical Oncology, and the National Comprehensive

Cancer Network (NCCN) each publish antiemetic and supportive care guidelines for patients who are undergoing chemotherapy treatment.1-3 These guidelines serve

Dr Zarambo is Clinical Pharmacy Coordinator, Abbott Northwestern Hospital, part of Allina Health, Minneapolis, MN; Dr Brenner is Clinical Pharmacist, University of Kansas Hospital and Westwood Cancer Center, Kansas City, KS; Ms Sather is Staff Pharmacist, Abbott Northwestern Hospital, part of Allina Health, Minneapolis, MN.

The views expressed in this article are the authors’ own and do not represent an official position of Allina Health.

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as resources for evidence-based antiemetic decisions.

Antiemetic therapy is based on the emetogenic potential of the chemotherapy agents used in the regimen.

For single-day highly emetogenic chemotherapy regimens (eg, high-dose cisplatin, high-dose doxorubicin), a 5-hydroxytryptamine (5-HT3) receptor antagonist, steroid, and neurokinin 1 (NK1) receptor antagonist are recommended on day 1 of chemotherapy use. In addition, steroids are recommended on day 2 through day 4 of the regimen.3 If the NK1 receptor antagonist chosen on day 1 is oral aprepitant, continuation of aprepitant through day 3 is recommended. Patients who receive intravenous (IV) fosaprepitant on day 1 should not receive an NK1 receptor antagonist on days 2 and 3.3 When administering a single-day, moderately emetogenic chemotherapy regimen (eg, IV melphalan or cyclophosphamide ≤1500 mg/m2), a 5-HT3 receptor antagonist and a steroid (with or without an NK1 receptor antagonist) should be administered on day 1 of initiating chemotherapy.3 On day 2 and day 3, monotherapy with a 5-HT3 receptor antagonist or a steroid is recommended. If an NK1 receptor antagonist is used on day 1, its use should continue on days 2 and 3 only if oral aprepitant is the selected therapy.3 When administering multiday chemotherapy regimens, it is difficult to recommend a specific antiemetic regimen for each day, especially because acute and delayed emesis may overlap after the initial day of chemotherapy through the last day of chemotherapy.3 With multiday regimens, dexamethasone (oral or IV) should be administered once daily on the days of chemotherapy and for 2 to 3 days after chemotherapy with regimens that are likely to cause significant delayed emesis. In addition, a serotonin antagonist should be administered before the first dose and the subsequent doses of moderately or highly emetogenic chemotherapy.3 For the treatment of breakthrough nausea and vomiting, as-needed (PRN) antiemetic medications should be available. Ideally, these medications would act via a different mechanism from those of the scheduled antiemetic regimens. If the PRN medication is effective for the patient, it should be scheduled and considered in future chemotherapy cycles.3 If the PRN medication is ineffective, a different dose, or a different antiemetic medication, should be considered. When a patient experiences substantial nausea and vomiting despite the scheduled antiemetic medications, increasing to a regimen with a higher emetogenicity profile may be warranted (ie, using the highly emetogenic regimen for a patient who did not respond to the moderately emetogenic antiemetic regimen).2 Within the Allina Health system, standardized paper chemotherapy order sets are used for medication ordering

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and prescribing. Before the standardization of antiemetic medications, antiemetic agents were ordered and prescribed inconsistently for patients receiving chemotherapy. In addition, the antiemetic regimens and agents used were not stratified based on the emetogenic potential of the chemotherapy regimen.

The study was based on the assumption that optimizing the prescribing of antiemetic medications may reduce the potential for nausea and vomiting events associated with chemotherapy.

The study was based on the assumption that optimizing the prescribing of antiemetic medications may reduce the potential for nausea and vomiting events associated with chemotherapy. The purpose of this study was therefore to evaluate the impact of standardizing antiemetic medications on select chemotherapy order sets within a large healthcare system, such as Allina Health. The elements evaluated include (1) the appropriateness of antiemetic therapy compared with the NCCN guideline recommendations, (2) the number of nausea complaints, (3) the frequency of PRN antiemetic use, and (4) the number of vomiting events in the prestandardization group (ie, prestandardized order sets) and in the poststandardization group (ie, poststandardized order sets). This study also sought to identify potential barriers and limitations to provider’s compliance with guideline-based ordering of antiemetic medications.

Methods For this study, inpatient chemotherapy regimens were stratified as highly emetogenic or moderately emetogenic using the NCCN antiemetic guidelines, version 1.2012.3 A group of oncology pharmacists created universal antiemetic order sets—1 antiemetic order set for highly emetogenic regimens and 1 antiemetic order set for moderately emetogenic regimens––based on the NCCN clinical practice guidelines.3 Standardized antiemetics were integrated into select order sets on March 5, 2013. The highly emetogenic order sets included DHAP (dexamethasone, high-dose cytarabine, and cisplatin); CHOP (cyclophosphamide, doxorubicin, vincristine, and prednisone), with or without rituximab; and cisplatin plus lomustine.

The moderately emetogenic order sets included ICE (ifosfamide, carboplatin, and etoposide) for lymphoma; CVAD (cyclophosphamide, vincristine, doxorubicin, and dexamethasone), course A and B; and the acute myeloid leukemia (AML) induction regimen known as “7 + 3.”

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The health systemâ&#x20AC;&#x2122;s electronic medical records (EMRs) were utilized to identify patients for study inclusion who received inpatient chemotherapy from the predetermined order sets between November 2011 and December 2012. Data were retrospectively collected from 3 of the metro area hospitals within this health system. The EMRs of a randomly selected sample of 50 patient encounters between November 2011 and December 2012 were included in the prestandardization group. A total of 32 patient encounters between March 5, 2013, and June 6, 2013, were included in the poststandardization group.

The patient encounters were compared in the preand poststandardization periods to identify whether a decreased use of PRN antiemetics, decreased incidence Table 1 D istribution of Treatment Regimens, by Study Group

Treatment regimen

Prestandardization group, N (N = 50)

Poststandardization group, N (N = 32)

AML induction

15

6

Hyper-CVAD

10

12

CHOP Âą rituximab

11

5

ICE for lymphoma

8

6

DHAP

3

0

Cisplatin + lomustine

3

3

AML indicates acute myeloid leukemia; CHOP, cyclophosphamide, doxorubicin, vincristine, prednisone; CVAD, cyclophosphamide, vincristine, doxorubicin, dexamethasone; DHAP, dexamethasone, high-dose cytarabine, cisplatin; ICE, ifosfamide, carboplatin, etoposide.

of nausea complaints, and/or decreased incidence of vomiting occurred as a reflection of standardizing the antiemetic therapy. Nausea complaints and vomiting events were evaluated based on nursing documentation in the EMRs. This study involved retrospective data extraction, and it was exempt from review by the Allina Institutional Review Board.

Results The treatment regimens of the 50 patient encounters in the prestandardization group and the 32 patient encounters in the poststandardization group were compared. Table 1 outlines the patient distribution of the treatment regimens for the pre- and poststandardization phases of the study.

The most frequently administered regimen in the prestandardization group was the AML induction regimen (categorized as moderately emetogenic, days 1-3), with 15 of the 50 patients receiving this therapy. The most frequently administered regimen in the poststandardization group was hyper-CVAD, course A and B (categorized as moderately emetogenic), with 12 of the 32 patients receiving this regimen.

The baseline patient characteristics (ie, age and sex distribution) were similar between the 2 groups (Table 2). Overall, patients whose antiemetic agents were ordered and prescribed from the poststandardized order sets required fewer PRN medications and complained of nausea less frequently than patients in the prestandardization group (Table 2). The average use of PRN medications for breakthrough nausea and vomiting was 12.8 events (range, 0-115) in the prestandardization group compared with 5.9 events (range, 0-44) in the poststandardization group.

Table 2 P atient Characteristics Characteristics

Prestandardization group (N = 50)

Poststandardization group (N = 32)

55.6 (31-85)

53.75 (29-81)

Female, 19 (38)

Female, 9 (28)

Male, 31 (62)

Male, 23 (72)

85.8 (54-124.059)

97.8 (61.6-165.7)

85.1 (47.8-126.1)

97.2 (64.2-150.1)

Frequency of PRN use, average (range), N

12.8 (0-115)

5.9 (0-44)

Frequency of PRN use (minus lorazepam), average (range), N

7.16 (0-52)

4.35 (0-35)

5 (0-45)

2.2 (0-22)

0.54 (0-7)

1.03 (0-18)

Baseline age, average (range), yrs Baseline sex, N (%) Preadmission weight, average (range), kg Discharge weight, average (range), kg

Nausea complaints, average (range), N Vomiting events, average (range), N PRN indicates as needed.

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Discussion The NCCN clinical practice guidelines were chosen as the main resource for order set standardization, because these guidelines are updated annually and are consensus based.

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Patients receiving therapy, %

Figure 1 P restandardization Antiemetic Agents Used with Moderately Emetogenic Chemotherapy Regimens Day 1 Day 2 Day 3

120 100 100 96.9

100

96.9 96.9

90.6

80

71.9 72.7 65.6

60 40 20

3.1

0

5-HT3 receptor Steroid NK1 receptor antagonist antagonist Type of antiemetic agent, by day (32 patients in each day)

PRN medication

5-HT3 indicates 5-hydroxytryptamine; NK1, neurokinin 1; PRN, as needed.

Figure 2 P oststandardization Antiemetic Agents Used with Moderately Emetogenic Chemotherapy Regimens

Patients receiving therapy, %

In addition, the average number of nausea complaints as documented in the EMR system was 2.2 events (range, 0-22) in the poststandardization group compared with 5 events (range, 0-45) in the prestandardization group. The average number of vomiting events was 1.03 in the poststandardization group compared with 0.54 in the prestandardization group. This was thought to be the result of 1 specific patient; this patient stayed in the hospital for 34 days, and the nausea and vomiting did not occur until well after chemotherapy had been completed (ie, day 10 of chemotherapy).

Excluding this patient, vomiting events averaged 0.47 per patient hospital stay in the poststandardization group. This is slightly less than 0.54 events in the prestandardization group.

The results for the moderately emetogenic regimens are presented in Figure 1 and Figure 2. The prescribing of NK1 receptor antagonists increased from 3% in the prestandardization group to 40% in the poststandardization group. The use of NK1 receptor antagonists is optional for moderately emetogenic chemotherapy, according to the NCCN guidelines.3 In addition, the prescribing of PRN medications with different mechanisms of action increased from 69% (range, 65.6%72.7%) in the prestandardization group to 88% in the poststandardization group.

The NCCN guidelines recommend the use of a 5-HT3 receptor antagonist and a steroid on every day of a highly emetogenic chemotherapy regimen and an oral NK1 receptor antagonist on day 1 through day 3, or an NK1 receptor antagonist administered intravenously on day 1.3 The results for the highly emetogenic regimens in this study are presented in Figure 3 and Figure 4.

The use of scheduled 5-HT3 receptor antagonists on day 1 decreased from 94% in the prestandardization group to 75% in the poststandardization group. In this study, steroid prescribing for highly emetogenic regimens on day 1 and day 2 was similar between the prestandardization and the poststandardization groups.

The use of NK1 receptor antagonists on day 1 of highly emetogenic regimens increased from 35% in the prestandardization group to 75% in the poststandardization group. The prescribing of PRN medications with different mechanisms of action increased from 60% (range, 45.5%-75%) in the prestandardization group to 87% (range, 75%-100%) in the poststandardization group.

Day 1 Day 2 Day 3

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Type of antiemetic agent, by day (25 patients in each day) 5-HT3 indicates 5-hydroxytryptamine; NK1, neurokinin 1; PRN, as needed.

Overall, the establishment of antiemetic medication standardization of chemotherapy order sets at Allina Health reduced the average number of nausea complaints and the need for PRN antiemetic medications during inpatient chemotherapy days.

In addition, there was a marked improvement in the use of NK1 receptor antagonists during the administration of highly emetogenic chemotherapy regimens.

Furthermore, the prescribing of PRN breakthrough medications improved in patients receiving moderately emetogenic and highly emetogenic chemotherapy regimens. Although breakthrough nausea and vomiting are often difficult to manage and control, it is important

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Figure 3 P restandardization Antiemetic Agents Used with Highly Emetogenic Chemotherapy Regimens

100

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90 Patients receiving therapy, %

5-HT3 receptor antagonist Steroid NK1 receptor antagonist PRN medication

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80

75

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60 50

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20

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18.8 9.1

10 0

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Day 2 (N = 16)

Day 3 (N = 11)

Day 4 (N = 11)

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Patients receiving therapy, %

Figure 4 P oststandardization Antiemetic Agents Used with Highly Emetogenic Chemotherapy Regimens 5-HT3 receptor antagonist Steroid NK1 receptor antagonist PRN medication

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for antiemetic medications to be available, should the need arise.

There are still opportunities for improvement and reeducation of the standardized antiemetic order sets.

After standardization of the antiemetic agents on the order sets, there was a slight decrease in the use of 5-HT3 receptor antagonists on day 1 of administering the highly emetogenic regimens. Because nausea and

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vomiting are often very individualized, achieving 100% adherence with prescribing based on the NCCN guidelines is unlikely.

This study did not identify any barriers to adherence to the order sets or the order set standardization. Before the standardized order sets were released, the oncology providers in this study were educated on the change.

The providers were encouraged to use the standardized antiemetic agents on the order sets.

Limitations This analysis has several limitations. Because the study includes data from multiple hospital sites within the Allina Health system, one potential limitation is that the sample groups are not evenly matched.

In addition, the increased number of vomiting events seen in the poststandardization group was largely attributed to a single patient who experienced substantial nausea and vomiting. Furthermore, the sample size for patient encounters for patients who received highly emetogenic chemotherapy regimens in the poststandardization phase was small, with only 8 patients.

Excluding this patient would reduce the rate of vomiting events poststandardization.

Conclusion The results of this study suggest that standardizing antiemetic medication use on oncology order sets based on the emetogenic potential of the chemotherapy regimen used can reduce the use of PRN medications and decrease the number of nausea events associated with the administration of chemotherapy. These changes can provide benefits to patients with cancer and improve quality of life. The results of this study further indicate that monitoring order set adherence and updating chemotherapy order sets periodically based on changes in treatment guidelines is imperative.

It is important to provide patients with effective, evidence-based antiemetic therapy to control the nausea and vomiting associated with chemotherapy. n Author Disclosure Statement Dr Zarambo, Dr Brenner, and Ms Sather reported no conflicts of interest.

References

1. Roila F, Herrstedt J, Aapro M, et al; for the ESMO/MASCC Guidelines Working Group. Guideline update for MASCC and ESMO in the prevention of chemotherapy- and radiotherapy-induced nausea and vomiting: results of the Perugia consensus conference. Ann Oncol. 2010;21(suppl 5):v232-v243.

2. Basch E, Prestrud AA, Hesketh PJ, et al. Antiemetics: American Society of Clinical Oncology clinical practice guideline update. J Clin Oncol. 2011;29:4189-4198.

3. National Comprehensive Cancer Network. NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelinesâ&#x201E;˘): antiemesis. Version 1.2012. July 20, 2011. www5.medicine.wisc.edu/~williams/antiemesis.pdf. Accessed March 3, 2013.

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FROM THE LITERATURE

Concise Reviews of Studies Relevant to Hematology Oncology Pharmacy With Commentaries by Robert J. Ignoffo, PharmD, FASHP, FCSHP Clinical Professor Emeritus, University of California, San Francisco; Professor of Pharmacy, College of Pharmacy, Touro University–California, Mare Island, Vallejo, CA

nE nzalutamide

Improves Outcomes in Metastatic Prostate Cancer

BACKGROUND: Prostate cancer is the sixth most common cause of cancer-related death among men worldwide. Androgen receptor overexpression is common in patients with advanced prostate cancer.

Suppressing androgen receptor signaling has been shown to be a successful strategy for the treatment of prostate cancer. The recently published PREVAIL trial investigated the benefit of enzalutamide, an oral androgen receptor inhibitor, in patients with metastatic castration-resistant prostate cancer (mCRPC) who had not received chemotherapy.

METHODS: PREVAIL was a multinational, doubleblind, placebo-controlled, phase 3 clinical trial. Between September 2010 and September 2012, PREVAIL included 1717 chemotherapy-naïve patients with asymptomatic or with mildly symptomatic mCRPC that progressed with androgen deprivation therapy. The patients were randomly assigned to receive 160 mg daily of enzalutamide (N = 872) or placebo (N = 845); 1715 patients received at least 1 dose of a study drug. The coprimary end points were radiographic progression-free survival (PFS) and overall survival (OS). The secondary end points included the time until initiation of cytotoxic chemotherapy, the time until first skeletal-related event, the best overall soft-tissue response, the time until prostate-specific antigen (PSA) progression, and a decline in PSA of ≥50% from baseline.

RESULTS: Enzalutamide significantly reduced the risks for radiographic progression of disease and improved OS. The study was stopped after a planned interim analysis ––which was conducted when 540 deaths had been reported––showed a benefit of the active treatment.

The findings showed an 81% reduction in the risk for radiographic progression in the enzalutamide group (hazard ratio [HR], 0.19; P <.001). At the planned interim analysis of OS, the median follow-up time was approximately 22 months. Treatment with enzalutamide compared with placebo resulted in a 29% decrease in the risk of death (HR, 0.71; P <.001). The median OS was an estimated 32.4 months in the enzalutamide group and 30.2 months in the placebo group.

The benefit of enzalutamide was shown with respect to all of the secondary end points. For example, in patients with measurable soft-tissue disease, 59% of the patients receiving enzalutamide (20% of whom achieved complete response and 39% of whom achieved partial response) versus only 5% of patients in the placebo group had an objective response (P <.001). The researchers found that enzalutamide delayed the median time to chemotherapy initiation by 17 months; patients receiving enzalutamide did not need to initiate chemotherapy until a median of 28 months versus 10.8 months in the placebo arm (HR, 0.35; P <.001).

Enzalutamide also exhibited a favorable safety profile.

The grade ≥3 adverse event rates were similar between the enzalutamide and the placebo arms (43% vs 37%, respectively), although the safety observation period was 3 times longer with enzalutamide than with placebo (17.1 months vs 5.4 months, respectively). Fatigue and hypertension were the most common clinically relevant adverse events associated with enzalutamide.

In this phase 3 clinical trial, enzalutamide provided a clinically meaningful benefit for men with mCRPC when factoring in its reduced risk of radiographic progression of disease, improved OS, delayed initiation of chemotherapy, and excellent side-effect profile.

Source: Beer TM, Rathkopf DE, Loriot CN, et al. Enzalutamide in metastatic prostate cancer before chemotherapy. N Engl J Med. 2014;371:424-433.

COMMENTARY BY ROBERT J. IGNOFFO

Enzalutamide was approved August 31, 2012, for the treatment of metastatic prostate cancer in patients who had previously received docetaxel. Beer and colleagues report their results in patients with metastatic disease who have not been previously treated with chemotherapy. The results were very impressive in that not only did survival improve, but the objective responses improved as well. For example, complete tumor shrinkage and partial tumor shrinkage were significantly better with enzalutamide than with placebo. This is a major advance in the treatment of metastatic prostate cancer, with enzalutamide delaying the use of systemic chemotherapy while increasing the duration of a patient’s Continued

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quality of life. This orally administered drug appears to be comparable, if not preferable, to the use of abiraterone, which necessitates the use of the systemic corticosteroid prednisone and its attendant adverse effects.

Enzalutamide was very well tolerated and did not produce any extraordinary side effects.

The package insert for enzalutamide warns of significant drug interactions and recommends that the coadministration of enzalutamide with strong cytochrome (CY)P3A4 and CYP2CB inducers be avoided if possible. n

I brutinib Outperforms Ofatumumab, Extends Survival in Patients with CLL

BACKGROUND: A head-to-head randomized study compared 2 recently approved therapies, ibrutinib and ofatumumab, for the second-line treatment of patients with relapsed or refractory chronic lymphocytic leukemia (CLL) or with small lymphocytic lymphoma (SLL).

Ibrutinib is a first-in-class, oral covalent inhibitor of Bruton’s tyrosine kinase, whereas ofatumumab is a monoclonal antibody that binds to the CD20 antigen on the CLL or SLL cells.

METHODS: In RESONATE, a multicenter, open-label, phase 3 clinical trial, 391 patients with relapsed or refractory CLL or SLL in whom ≥1 therapies had failed were randomized in a 1:1 ratio to receive ibrutinib (N = 195) 420 mg once daily or ofatumumab (N = 196) 300 mg intravenously at week 1, followed by 2000 mg weekly for 7 weeks and then every 4 weeks for 16 weeks. The primary end point was progression-free survival (PFS), with secondary end points evaluating overall survival (OS) and response rate. The median follow-up time was 9.4 months.

RESULTS: Ibrutinib significantly improved PFS time, OS, as well as response rate. Ibrutinib significantly extended PFS, with the median not reached (88% at 6 months) at the follow-up compared with a median PFS of 8.1 months in the ofatumumab group (hazard ratio [HR], 0.22; 95% confidence interval [CI], 0.15-0.32; P <.001).

Furthermore, ibrutinib significantly improved the duration of OS (HR for death, 0.43; 95 CI, 0.24-0.79; P = 005), with the risk of death reduced by 57%. The OS rate was 90% at 12 months in the ibrutinib group versus 81% in the ofatumumab group.

Overall, 57 patients in the ofatumumab group whose disease had progressed had crossed over and began receiving treatment with ibrutinib at the time this analysis was conducted. The partial response rate was much higher for patients in the ibrutinib group (43%) than for patients in the ofatumumab group (4%). In the ibrutinib group, 20% of the patients showed a partial response with lymphocytosis; if these patients are included, the

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resulting response rate is 63%. Similar effects were observed in patients with chromosome 17p13.1 deletion or those with resistance to purine analogs.

More patients in the ibrutinib group than in the ofatumumab group had at least 1 adverse event of grade ≥3 (57% vs 47%, respectively). Adverse events (grade ≥3) that occurred more often in the ibrutinib group than in the ofatumumab group included diarrhea (4% vs 2%, respectively) and atrial fibrillation (3% vs 0%, respectively). Bleeding-related adverse events of any grade were also more common in the ibrutinib group (44%) than in the ofatumumab group (12%).

These results support ibrutinib as an effective single-agent therapy for difficult-to-treat patients with CLL or SLL given its positive effect on PFS, OS, and response rate. The improvement in survival was observed across all subgroups that were examined. Phase 3 trials examining the effect of ibrutinib in patients with previously untreated CLL or SLL are ongoing.

Source: Byrd JC, Brown SR, O’Brien S, et al. Ibrutinib versus ofatumumab in previously treated chronic lymphoid leukemia. N Engl J Med. 2014;371:213-223.

COMMENTARY BY ROBERT J. IGNOFFO

This study reports a major advance for ibrutinib, an oral covalent inhibitor of Bruton’s tyrosine kinase, over ofatumumab, an inhibitor of an essential enzyme in the B-cell receptor pathway. The response parameters of PFS and overall response rate are improved over the comparator. However, adverse effects were more common with ibrutinib than with ofatumumab, especially petechiae, rash, and blurred vision. This study confirms that ibrutinib is superior to ofatumumab in patients with relapsed or refractory CLL or SLL without chromosome 11q or 17p deletions. The National Comprehensive Cancer Network guidelines recommend ibrutinib as the preferred agent for relapsed or refractory CLL or SLL without chromosome 11q or 17p deletions.

Caution must be exercised with the concomitant use of ibrutinib and strong cytochrome P3A4 inhibitors.

The use of ibrutinib with ketoconazole, itraconazole, voriconazole, or posaconazole should be avoided. n

P anitumumab and Cetuximab Show Comparable Survival Benefit in Patients with Metastatic Colorectal Cancer

BACKGROUND: Panitumumab proved noninferior to cetuximab in overall survival (OS) in patients with chemotherapy-refractory wild-type KRAS exon 2 meta-

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FROM THE LITERATURE

static colorectal cancer (mCRC), according to the results of ASPECCT (A Study of Panitumumab Efficacy and Safety Compared to Cetuximab). ASPECCT is the first head-to-head, open-label, randomized, multicenter, international, phase 3 clinical study designed to determine if the 2 epidermal growth factor receptor (EGFR)targeted monoclonal antibodies provide a comparable survival benefit in patients with mCRC. METHODS: From February 2010 to July 2012, researchers enrolled patients aged ≥18 years with chemotherapyrefractory mCRC, an Eastern Cooperative Oncology Group performance status of ≤2, and wild-type KRAS exon 2 status. Of the 1010 patients enrolled, 999 began receiving the study treatment. Patients were randomized in a 1:1 ratio to receive panitumumab (N = 499) 6 mg/kg intravenously once every 2 weeks or cetuximab (N = 500) 400 mg/m2 intravenously followed by 250 mg/m2 weekly.

The primary end point was OS. Noninferiority was determined if panitumumab preserved ≥50% of cetuximab’s OS effect compared with best supportive care. The median durations of treatment were 14.3 weeks for panitumumab and 14.1 weeks for cetuximab.

RESULTS: At a median follow-up of >9 months, the findings showed that panitumumab was noninferior to cetuximab. The median OS times were 10.4 months with panitumumab and 10 months with cetuximab (hazard ratio [HR], 0.97; 95% confidence interval [CI], 0.841.11; P = .007). The Z score was −3.19, meeting the criteria of noninferiority of less than −1.96. The median progression-free survival (PFS) times were also similar between panitumumab and cetuximab (4.1 months and 4.4 months, respectively; HR, 1; 95% CI, 0.88-1.14).

The incidence of adverse events of any grade was consistent across the treatment groups. Serious adverse events were reported in 30% of patients in the panitumumab group and in 34% of patients in the cetuximab group, with 35% and 36% of patients, respectively, needing dose reductions as a result of adverse events. Grade 3 or 4 skin toxicity was more common with panitumumab than with cetuximab (13% vs 10%, respectively), as was hypomagnesemia (7% vs 3%, respectively). However, infusion reactions were more common with cetuximab than with panitumumab (2% vs <0.5%, respectively). Considering the consistencies of efficacy and toxicity that were observed, small but meaningful differences in the rate of

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grade 3 or 4 infusion reactions and the differences in dose scheduling can guide clinician choice of anti-EGFR therapy for this patient population, concluded the researchers.

Source: Price TJ, Peeters M, Kim TW, et al. Panitumumab versus cetuximab in patients with chemotherapy-refractory wild-type KRAS exon 2 metastatic colorectal cancer (ASPECCT): a randomised, multicentre, open-label, non-inferiority phase 3 study.

Lancet Oncol. 2014;15:569-579.

COMMENTARY BY ROBERT J. IGNOFFO

This is the first comparative trial of 2 first-line targeted agents, panitumumab and cetuximab, in patients with chemotherapy-refractory wild-type KRAS exon 2 mCRC. The response rates, OS, PFS, and toxicities are almost identical between these 2 agents. So, which drug is preferable? Factors that may affect drug selection include the drug cost, insurance coverage, time spent in the clinic receiving therapy, and convenience.

With regard to drug cost, the average wholesale price of panitumumab is $38,900 for 420 mg (average weight, 70 kg), administered every 2 weeks; the average wholesale price of cetuximab is $26,531 for 680 mg, followed by 425 mg (average body surface area, 1.7 m2), administered weekly for 14 weeks. Cetuximab would require twice as many clinic visits as well as twice the cost for supplies and nursing care, thus making it more inconvenient for the patient. Medicare and private insurance beneficiaries are likely to have access to either drug, whereas patients with limited insurance may opt for a less expensive treatment.

The discussion by the study’s authors and the accompanying editorial in the same issue by Waddell1 bring up the topic of known resistance to EGFR inhibitors in patients with KRAS exon 2, 3, and 4 mutations. This study evaluated patient tumors for only exon 2 mutations, but not exon 3 and 4 mutations.

Therefore, the results of this study are somewhat blurred by the lack of important biomarker data. At this time, the selection of 1 of these EGFR inhibitors may be made on the basis of the factors mentioned above, as well as on physician and patient preferences.

1. Waddell T. Targeting EGFR in colorectal cancer: beyond KRAS exon 2. Lancet Oncol. 2014;15:540-541.

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P ositive Outcomes for Diffuse Large B-Cell Lymphoma with Lenalidomide plus R-CHOP

BACKGROUND: Intensive high-dose chemotherapy can be used as salvage therapy for some patients with relapsed or refractory diffuse large B-cell lymphoma (DLBCL). The majority of patients will die from this cancer; therefore, the development of a more effective initial therapy is crucial to improving outcomes. A recent study investigated the potential benefits of adding lenalidomide to the R-CHOP (rituximab, cyclophosphamide, doxorubicin hydrochloride, vincristine sulfate, and prednisone) regimen (ie, R2CHOP) in patients with newly diagnosed DLBCL and the nongerminal center B-cell (GCB) phenotype. Lenalidomide has previously shown activity in patients with relapsed or refractory DLBCL with the non-GCB subtype.

METHODS: Researchers from the Mayo Clinic conducted a phase 2, open-label, single-arm study of 64 patients with newly diagnosed, untreated, stage II to stage IV CD20-positive DLBCL. For comparison, 87 patients with DLBCL who had received treatment with conventional R-CHOP were selected from the Mayo Clinic lymphoma database. This control group was treated during a similar time frame and met the same inclusion criteria as the patients in the active study group. The DLBCL molecular subtypes were determined by tumor immunohistochemistry and were classified as GCB or non-GCB. Of the 64 patients enrolled, 60 patients were eligible for response evaluation. The treatment consisted of 25-mg lenalidomide daily on day 1 to day 10 with standard R-CHOP every 3 weeks for 6 cycles. All patients received a subcutaneous injection of pegfilgrastim 6 mg on day 2 of each cycle and aspirin prophylaxis throughout the treatment period. The primary end point was event-free survival (EFS), and the secondary end points were progression-free survival (PFS) and overall survival (OS).

RESULTS: Among the 60 evaluable patients, the overall response rate was 98%, with 80% of the patients achieving a complete response. At a median follow-up of 23.5 months, the median duration of response had not yet been reached. In patients receiving the R2CHOP treatment regimen, the 24-month EFS rate was 59%.

Because no patients received subsequent treatment for lymphoma before disease progression, the results for EFS and PFS were identical. The 24-month OS rate was 78%. In the patients receiving the R-CHOP regimen, the 24-month PFS and OS rates were 64% and 28%, respectively, in patients with non-GCB DLBCL versus 46% and 78%, respectively, in patients with GCB DLBCL. Conversely, no significant differences were observed in the 24-month PFS or OS rates in patients receiving the R2CHOP regimen between the non-GCB and GCB subtypes.

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The R2CHOP treatment regimen was well tolerated.

The most common grade ≥3 adverse events were neutropenia (88%), leukopenia (80%), and thrombocytopenia (44%). One patient had grade 5 sepsis after the first cycle of therapy.

Overall, the addition of lenalidomide to the conventional R-CHOP regimen resulted in similar PFS rates and OS rates between the non-GCB and GCB subtypes.

Typically, patients with the non-GCB phenotype have poorer outcomes.

Source: Nowakowski GS, LaPlant B, Macon WR, et al.

Lenalidomide combined with R-CHOP overcomes prognostic impact of non–germinal center B-cell phenotype in newly diagnosed diffuse large B-cell lymphoma: a phase II study. J Clin Oncol.

2014 Aug 18 [Epub ahead of print].

COMMENTARY BY ROBERT J. IGNOFFO

This study investigated the addition of lenalidomide to R-CHOP in patients with DLBCL. The comparator group was based on a data set of patients from the Mayo Clinic who had received the R-CHOP treatment regimen in previous trials. Improvements in the PFS and OS rates were observed primarily in patients with nonGCB DLBCL when lenalidomide was added to R-CHOP, suggesting that lenalidomide prevents resistance to R-CHOP therapy. Lenalidomide is not approved for use in patients with DLBCL, and a randomized, phase 2 trial is ongoing to confirm these results.

It is important to note that neurologic toxicity was not worse with lenalidomide plus R-CHOP than with R-CHOP alone. Furthermore, the risk for thrombosis (approximately 6% in patients with non-Hodgkin’s lymphoma) was minimal (1.6%) with the addition of low-dose aspirin.

Only a few drug interactions with lenalidomide are well documented. Lenalidomide should not be administered concurrently with itraconazole or other cytochrome P3A4 inhibitors.

HOLD for next month

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FDA UPDATE

Recent Cancer Drugs Approved by the FDA

T

his section provides information on recent drug approvals by the US Food and Drug Administration (FDA) to provide oncology/hematology pharmacists up-to-date information on new therapies and new combination therapies reaching the market, or expanded indications for older drugs already on the

First Anti–PD-1 Immunotherapy, Pembrolizumab, Receives Accelerated FDA Approval for Advanced Melanoma On September 4, 2014, the FDA approved the first anti–programmed death receptor (PD)-1 therapy pembrolizumab (Keytruda; Merck) for the treatment of patients with unresectable or metastatic melanoma and disease progression after therapy with ipilimumab, or, for a patient with BRAF V600 mutation, after a BRAF inhibitor therapy. The approved dosing schedule for pembrolizumab is 2 mg/kg every 3 weeks.

The FDA applied its accelerated process for this approval based on early clinical data showing tumor reductions and durability of response. Ongoing phase 2 and 3 clinical trials are expected to provide confirmatory information to demonstrate clinically meaningful benefits, including potential improvement in survival and/or reduction in disease progression.

Pembrolizumab is a humanized monoclonal antibody that blocks the interaction between PD-1 and its ligands, PD-L1 and PD-L2. It is the first ever anti–PD-1 therapy to receive FDA approval. The FDA granted pembrolizumab a breakthrough therapy designation for advanced melanoma based on the early results from the ongoing multicenter, open-label, randomized, dose-comparative study of the KEYNOTE-001 phase 1b trial with 173 patients with unresectable or metastatic melanoma and progression of disease.

All patients had received previous treatment with ipilimumab and a BRAF or a MEK inhibitor for patients who had a BRAF V600 mutation. The patients were randomized to 2 mg/kg (N = 89) or to 10 mg/kg (N = 84) of pembrolizumab every 3 weeks until unacceptable toxicity or disease progression.

Early results in the 89 patients who received pembrolizumab 2 mg/kg every 3 weeks showed an overall response rate of 24% (95% confidence interval [CI], 15-34), including 1 complete response and 20 partial responses.

At the time of the analysis, 86% (N = 18) of patients with objective responses had ongoing responses, with duration of response ranging between 1.4 and 8.5 months. Most patients showed continued response after that.

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market, that can improve the management of patients with a variety of cancers, including solid tumors and hematologic malignancies.

The following news briefs are intended to help pharmacists keep up with new information related to cancer management.

Severe immune-mediated adverse events were uncommon. Pembrolizumab was discontinued because of adverse events in 6% of 89 patients receiving the recommended dose and in 9% of 411 patients across all doses. Serious adverse reactions occurred in 36% of patients receiving pembrolizumab. The most common serious adverse events reported in ≥2% of patients included renal failure, dyspnea, pneumonia, and cellulitis. The most common (≥20% of patients) adverse events were fatigue, cough, nausea, pruritus, rash, decreased appetite, constipation, arthralgia, and diarrhea.

Ibrutinib Received Expanded Indication for Patients with CLL and 17p Deletion On July 28, 2014, the FDA issued an expanded indication for ibrutinib (Imbruvica; Pharmacyclics) for the treatment of patients with chronic lymphocytic leukemia (CLL) who have a deletion in chromosome 17 (17p deletion), which results in poor response to standard CLL therapies. Earlier in the year, the FDA approved ibrutinib for all patients with CLL, after having designated it as a breakthrough therapy.

With this new indication, the FDA also approved new labeling for the drug to reflect that the clinical benefit of ibrutinib for the treatment of CLL has been verified based on new clinical trial results. These results confirmed the progression-free survival (PFS) and overall survival (OS) benefits associated with ibrutinib.

The expanded indication for patients with 17p deletion is based on results from a clinical trial of 391 previously treated patients with CLL; of these, 127 patients had CLL with 17p deletion. Patients were randomized to ibrutinib or to ofatumumab until disease progression or until side effects became intolerable.

The trial was stopped early after a preplanned interim analysis showed that patients receiving ibrutinib had a 78% PFS improvement and a 57% OS benefit.

Among the 127 patients with CLL plus 17p deletion, those receiving ibrutinib had a 75% improvement in PFS.

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The most common side effects associated with ibrutinib were thrombocytopenia, neutropenia, diarrhea, anemia, fatigue, musculoskeletal pain, upper respiratory tract infection, rash, nausea, and fever.

This new indication was approved under the FDA’s accelerated approval and was reviewed under the agency’s priority review program.

FDA Approved Idelalisib for Three Types of Hematologic Cancers On July 23, 2014, the FDA approved idelalisib (Zydelig; Gilead Sciences) for the treatment of patients with relapsed chronic CLL to be used in combination with rituximab (Rituxan). Idelalisib is recommended for use in this patient population in those for whom rituximab alone would be considered inappropriate therapy because of potential comorbidities. The drug received a breakthrough therapy designation for CLL earlier this year.

On the same day, the FDA granted idelalisib an accelerated approval for the treatment of patients with relapsed follicular B-cell non-Hodgkin lymphoma (FL), as well as relapsed small lymphocytic lymphoma (SLL).

Idelalisib is intended to be used in patients who have received at least 2 previous systemic therapies.

Idelalisib’s safety and effectiveness for relapsed CLL were established in a clinical trial of 220 patients with this condition who were randomized to receive idelalisib plus rituximab or to placebo plus rituximab. The trial was stopped after the first prespecified interim analysis point, which showed that the active combination resulted in a PFS of 10.7 months compared with approximately 5.5 months with rituximab plus placebo.

Results from a second interim analysis continued to show a statistically significant improvement for the active combination.

The safety and effectiveness of idelalisib in the treatment of FL and relapsed SLL were established in a clinical trial with 123 patients with indolent non-Hodgkin lymphomas. All patients received idelalisib and were evaluated for objective response rate (ORR). Results showed a 54% ORR in patients with relapsed FL and a 58% ORR for patients with SLL. Idelalisib carries a Boxed Warning regarding the risk of fatal and serious toxicities, including liver toxicity, colitis, pneumonitis, and intestinal perforation. The drug was also approved with a REMS (Risk Evaluation and Mitigation Strategy) program.

Common side effects with idelalisib include diarrhea, fever, fatigue, nausea, cough, pneumonia, abdominal pain, chills, and rash. Common laboratory abnormalities include neutropenia, hypertriglyceridemia, hyperglycemia, and elevated levels of liver enzymes.

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September 2014

Belinostat Approved for Peripheral T-Cell Lymphoma, an Aggressive Form of NHL The FDA approved belinostat (Beleodaq; Spectrum Pharmaceuticals) on July 3, 2014, for the treatment of patients with relapsed or refractory peripheral T-cell lymphoma (PTCL), a rare and fast-growing type of non-Hodgkin lymphoma (NHL). The approval was done under the agency’s accelerated approval program. PTCL comprises a diverse group of rare diseases in which lymph nodes become cancerous. PTCL represents approximately 10% to 15% of NHL cases in North America.

Belinostat works by preventing the development of T-cells from becoming cancerous. According to Richard Pazdur, MD, Director of the Office of Hematology and Oncology Products in the FDA’s Center for Drug Evaluation and Research, “This is the third drug that has been approved since 2009 for the treatment of peripheral T-cell lymphoma.”

The safety and effectiveness of belinostat were evaluated in a clinical trial involving 129 patients with relapsed or refractory PTCL. All patients received belinostat until disease progression or until their side effects became unacceptable. In all, 25.8% of the patients showed complete or partial response after treatment with belinostat.

The most common side effects seen with belinostat were nausea, fatigue, fever, anemia, and vomiting.

Belinostat was designated by the FDA as an orphan drug, because it is intended for the treatment of patients with PTCL, which is a rare disease.

Lymphoseek Injection Received Expanded Indication for Head and Neck Cancer SLN Biopsy Technetium Tc 99m tilmanocept (Lymphoseek Injection; Navidea Biopharmaceuticals) received an expanded indication by the FDA on June 13, 2014, for guiding sentinel lymph node (SLN) biopsy in patients with head and neck cancers with squamous-cell carcinoma of the oral cavity. This is the first approval for a radiopharmaceutical agent for the diagnosis of SLN. The approval was done under the agency’s priority review process.

In 2013, the FDA approved Tc 99m for lymphatic mapping in patients with breast cancer or with melanoma. The new indication was approved based on data from a prospective phase 3 study showing that Tc 99m had a significantly greater ability to correctly identify patients with pathology-positive SLN compared with lymph node dissections or pathologic evaluations.

In addition, the use of multiple levels of lymph node dissection in the trial resulted in the removal of 38 lymph nodes per patient compared with only 4 lymph nodes, on average, with Tc 99m, which represents a substantial reduction in potential morbidity in patients undergoing SLN biopsy. n

www.JHOPonline.com

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Journal of Hematology Oncology Pharmacy

97

THIRD ANNUAL CONFERENCE

October 31November 1, 2014 Marriott Marquis San Francisco, CA

CONFERENCE CHAIRS Jorge E. Cortes, MD

Chair, CML and AML Sections D.B. Lane Cancer Research Distinguished Professor for Leukemia Research Department of Leukemia, Division of Cancer Medicine The University of Texas MD Anderson Cancer Center Houston, TX

Roy S. Herbst, MD, PhD

Ensign Professor of Medicine Professor of Pharmacology Chief of Medical Oncology Director, Thoracic Oncology Research Program Associate Director for Translational Research Yale Cancer Center, New Haven, CT

CONFERENCE OVERVIEW

The only global meeting dedicated to advancing the understanding of value and clinical impact of biomarker and immunotherapy research in oncology. Guided by the expertise of leaders in this field, participants will receive a thorough understanding of the current and future landscape of the relevance of tumor biomarkers and how to effectively personalize cancer care in the clinical setting.

TARGET AUDIENCE

This activity has been designed to meet the educational needs of medical oncologists and hematologists, pathologists, geneticists, advanced practice oncology/hematology nurses, research nurses, clinical oncology pharmacists, and genetic counselors involved in the management of patients with solid cancers or hematologic malignancies, and interested in the use of molecular biomarkers to help optimize patient care. Research scientists interested in the field of molecular biomarkers in oncology are also invited to participate.

DESIGNATION OF CREDIT STATEMENTS ACCREDITATION STATEMENT

This activity has been planned and implemented in accordance with the accreditation requirements and policies of the Accreditation Council for Continuing Medical Education (ACCME) through the joint providership of the Postgraduate Institute for Medicine and Center of Excellence Media, LLC. The Postgraduate Institute for Medicine is accredited by the ACCME to provide continuing medical education for physicians.

CREDIT DESIGNATION

The Postgraduate Institute for Medicine designates this live activity for a maximum of 9.5 AMA PRA Category 1 Credit(s)™. Physicians should claim only the credit commensurate with the extent of their participation in the activity.

AMERICANS WITH DISABILITIES ACT

Event staff will be glad to assist you with any special needs (ie, physical, dietary, etc). Please contact Linda Sangenito prior to the live event at 732-992-1520.

DISCLOSURE OF CONFLICTS OF INTEREST

The Postgraduate Institute for Medicine (PIM) requires instructors, planners, managers, and other individuals who are in a position to control the content of this activity to disclose any real or apparent conflict of interest (COI) they may have as related to the content of this activity. All identified COI are thoroughly vetted and resolved according to PIM policy. The existence or absence of COI for everyone in a position to control content will be disclosed to participants prior to the start of each activity.

Jointly provided by Postgraduate Institute for Medicine and Center of Excellence Media, LLC

EDUCATIONAL OBJECTIVES

After completing this activity, the participant should be better able to: • Assess emerging data and recent advances in the discovery of molecular biomarkers on the management of patients with solid tumors and hematologic malignancies •

Discuss the role of molecular biomarkers in designing personalized therapy for patients with solid tumors and hematologic malignancies

•

Outline the practical aspects and value-based considerations of integrating molecular biomarkers into everyday clinical practice in the treatment of patients with cancer

REGISTER TODAY! www.PMO-Live.com

This activity is supported, in part, by independent educational grants from Lilly USA. For further information concerning Lilly grant funding, visit www.lillygrantoffice.com.

This activity is also supported, in part, by an educational grant from Prometheus.

Current at time of printing.

SUBMIT AN ABSTRACT BY OCTOBER 3, 2014 Submit an abstract for the Third Annual PMO Live Conference.

This is an opportunity to share research, programs, and results with your peers. This session will facilitate communication among the various professionals and programs to advance the knowledge of all our members and those in attendance.

www.pmo-live.com/conference/abstracts

AGENDA*

FRIDAY, OCTOBER 31 7:00 am - 12:00 pm Registration 11:45 am - 2:15 pm Product Theaters 2:15 pm - 2:30 pm

Break

2:30 pm - 2:40 pm

Welcome to the Third Annual PMO Live Conference, a Global Biomarkers Consortium — Opening Remarks – Jorge E. Cortes, MD – Roy S. Herbst, MD, PhD

2:40 pm - 4:15 pm

General Session I: Cancer Care in the Era of Molecular Biomarkers • Personalized medicine in oncology: therapeutic advances from cytotoxic chemotherapy to molecularly targeted agents – Razelle Kurzrock, MD • Understanding cancer at the molecular level – Caroline Robert, MD, PhD • Standardization of molecular biomarker testing – Mark Sausen, MD • Implications of molecular diagnostics on clinical trial design – John J. Wright, MD, PhD Question & Answer Session

4:15 pm - 4:30 pm

Break

4:30 pm - 5:30 pm

General Session II - Part 1: Incorporating Molecular Biomarkers into the Therapy of Solid Tumors — Case Studies on “How I Treat” • Melanoma – Sanjiv S. Agarwala, MD • Breast cancer – Hope Rugo, MD Question & Answer Session

5:30 pm - 7:00 pm

Welcome Reception and Exhibits

SATURDAY, NOVEMBER 1 7:00 am - 8:00 am

Product Theater

8:00 am - 8:15 am

Break

8:15 am - 8:30 am

Review of Friday’s Presentations and Preview of Today

8:30 am - 9:30 am

General Session II - Part 2: Incorporating Molecular Biomarkers into the Therapy of Solid Tumors — Case Studies on “How I Treat” • Melanoma – Sanjiv S. Agarwala, MD • Colorectal cancer – Axel Grothey, MD Question & Answer Session

9:30 am - 9:45 am

9:45 am - 11:05 am General Session III: Incorporating Molecular Biomarkers into the Therapy of Hematologic Malignancies — Case Studies on “How I Treat” • Myeloid hematologic malignancies – Jorge E. Cortes, MD • Chronic lymphocytic leukemia – William Wierda, MD, PhD • Multiple myeloma – Sagar Lonial, MD • Lymphoma – Anas Younes, MD 11:05 am - 12:00 pm Keynote Lecture: Markers of Resistance to Targeted Therapies – Alberto Bardelli, PhD Question & Answer Session 12:00 pm - 1:00 pm Meet the Experts and Lunch in the Exhibit Hall 1:00 pm - 1:15 pm

Break

1:15 pm - 2:00 pm

Tumor Board Breakout Sessions • Attendee cases in solid tumors • Attendee cases in hematologic malignancies

2:00 pm - 2:15 pm

Break

2:15 pm - 3:30 pm

General Session IV: Molecular Biomarkers for the Early Detection of Cancer: Are They Ready for Prime Time?

• Developing and validating biomarkers via the Early Detection Research Network (EDRN-NCI) – Sudhir Srivastava, PhD, MPH • Beyond PSA: novel molecular biomarkers for prostate cancer – Mark Rubin, MD • Airway biomarkers for lung cancer detection in the post-NLST era – Avi Spira, MD, MSc • Early detection biomarkers for breast cancer – Karen Anderson, MD, PhD Question & Answer Session

3:30 pm - 3:45 pm

Break

3:45 pm - 4:00 pm

Keynote Lecture: Actionable Genomic Alterations in Oncology – Phil Stephens, PhD

4:00 pm - 4:50 pm

General Session V: Regulatory and Economic Aspects of Personalized Medicine in Oncology • Understanding the regulatory aspects of personalized medicine in oncology – Andrew Stainthorpe, PhD • A debate on health economics and molecular biomarkers: can we afford personalized medicine in oncology?

– Gary Johnson, MD, MS, MBA, and Ken Schaecher, MD, FACP, CPC Question & Answer Session

4:50 pm - 5:00 pm

Closing Remarks – Jorge E. Cortes, MD – Roy S. Herbst, MD, PhD

Break *Agenda subject to change.

GBC2014ConfAd Asize_91014

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.