Jhop june2013 issue web by The Oncology Pharmacist

June 2013 Vol 3 I No 2

Journal OF

hematology Oncology ™ Pharmacy The Peer-Reviewed Forum for Oncology Pharmacy Practice

ORIGINAL RESEARCH

The Effect of Atazanavir on Doxorubicin Pharmacokinetics: A Case Report Neha Umesh Sheth, PharmD, AAHIVP, BCPS; Steven Gilmore, PharmD, BCOP; Kenneth S. Bauer Jr, PharmD, PhD; Saranya Chumsri, MD

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In the newly metastatic CRPC patient who is asymptomatic or minimally symptomatic

STARTS THE FIGHT

AND HELPS HIS IMMUNE SYSTEM SUSTAIN* IT 1

• Targets and attacks prostate cancer cells • Statistically significant overall survival advantage1,2 • Sustained* immune response *A sustained immune response was seen out to 26 weeks in the pivotal study (the last time point measured).1 INDICATION: PROVENGE® (sipuleucel-T) is an autologous cellular immunotherapy indicated for the treatment of asymptomatic or minimally symptomatic metastatic castrate resistant (hormone refractory) prostate cancer. IMPORTANT SAFETY INFORMATION: PROVENGE is intended solely for autologous use and is not routinely tested for transmissible infectious diseases. In controlled clinical trials, serious adverse events reported in the PROVENGE group included acute infusion reactions (occurring within 1 day of infusion) and cerebrovascular events. Severe (Grade 3) acute infusion reactions were reported in 3.5% of patients in the PROVENGE group. Reactions included chills, fever, fatigue, asthenia, dyspnea, hypoxia, bronchospasm, dizziness, headache, hypertension, muscle ache, nausea, and vomiting. No Grade 4 or 5 acute infusion reactions were reported in patients in the PROVENGE group. The most common adverse events (incidence ≥15%) reported in the PROVENGE group were chills, fatigue, fever, back pain, nausea, joint ache, and headache. For more information on PROVENGE, please see Brief Summary of Prescribing Information on adjacent pages. www.PROVENGEHCP.com

PROVENGE® (sipuleucel-T) Suspension for Intravenous Infusion

Rx Only

BRIEF SUMMARY — See full Prescribing Information for complete product information

INDICATIONS AND USAGE: PROVENGE® (sipuleucel-T) is an autologous cellular immunotherapy indicated for the treatment of asymptomatic or minimally symptomatic metastatic castrate resistant (hormone refractory) prostate cancer. DOSAGE AND ADMINISTRATION • For Autologous Use Only. • The recommended course of therapy for PROVENGE is 3 complete doses, given at approximately 2-week intervals. • Premedicate patients with oral acetaminophen and an antihistamine such as diphenhydramine. • Before infusion, confirm that the patient’s identity matches the patient identifiers on the infusion bag. • Do Not Initiate Infusion of Expired Product. • Infuse PROVENGE intravenously over a period of approximately 60 minutes. Do Not Use a Cell Filter. • Interrupt or slow infusion as necessary for acute infusion reactions, depending on the severity of the reaction. (See Dosage and Administration [2] of full Prescribing Information.) CONTRAINDICATIONS: None. WARNINGS AND PRECAUTIONS • PROVENGE is intended solely for autologous use. • Acute infusion reactions (reported within 1 day of infusion) included, but were not limited to, fever, chills, respiratory events (dyspnea, hypoxia, and bronchospasm), nausea, vomiting, fatigue, hypertension, and tachycardia. In controlled clinical trials, 71.2% of patients in the PROVENGE group developed an acute infusion reaction. In controlled clinical trials, severe (Grade 3) acute infusion reactions were reported in 3.5% of patients in the PROVENGE group. Reactions included chills, fever, fatigue, asthenia, dyspnea, hypoxia, bronchospasm, dizziness, headache, hypertension, muscle ache, nausea, and vomiting. The incidence of severe events was greater following the second infusion (2.1% vs 0.8% following the first infusion), and decreased to 1.3% following the third infusion. Some (1.2%) patients in the PROVENGE group were hospitalized within 1 day of infusion for management of acute infusion reactions. No Grade 4 or 5 acute infusion reactions were reported in patients in the PROVENGE group. Closely monitor patients with cardiac or pulmonary conditions. In the event of an acute infusion reaction, the infusion rate may be decreased, or the infusion stopped, depending on the severity of the reaction. Appropriate medical therapy should be administered as needed. • Handling Precautions for Control of Infectious Disease. PROVENGE is not routinely tested for transmissible infectious diseases. Therefore, patient leukapheresis material and PROVENGE may carry the risk of transmitting infectious diseases to health care professionals handling the product. Universal precautions should be followed. • Concomitant Chemotherapy or Immunosuppressive Therapy. Use of either chemotherapy or immunosuppressive agents (such as systemic corticosteroids) given concurrently with the leukapheresis procedure or PROVENGE has not been studied. PROVENGE is designed to stimulate the immune system, and concurrent use of immunosuppressive agents may alter the efficacy and/or safety of PROVENGE. Therefore, patients should be carefully evaluated to determine whether it is medically appropriate to reduce or discontinue immunosuppressive agents prior to treatment with PROVENGE. • Product Safety Testing. PROVENGE is released for infusion based on the microbial and sterility results from several tests: microbial contamination determination by Gram stain, endotoxin content, and in-process sterility with a 2-day incubation to determine absence of microbial growth. The final (7-day incubation) sterility test results are not available at the time of infusion. If the sterility results become positive for microbial contamination after PROVENGE has been approved for infusion, Dendreon will notify the treating physician. Dendreon will attempt to identify the microorganism, perform antibiotic sensitivity testing on recovered microorganisms, and communicate the results to the treating physician. Dendreon may request additional information from the physician in order to determine the source of contamination. (See Warnings and Precautions [5] of full Prescribing Information.) ADVERSE REACTIONS Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice.

The safety evaluation of PROVENGE is based on 601 prostate cancer patients in the PROVENGE group who underwent at least 1 leukapheresis procedure in four randomized, controlled clinical trials. The control was non-activated autologous peripheral blood mononuclear cells. The most common adverse events, reported in patients in the PROVENGE group at a rate ≥15%, were chills, fatigue, fever, back pain, nausea, joint ache, and headache. Severe (Grade 3) and life-threatening (Grade 4) adverse events were reported in 23.6% and 4.0% of patients in the PROVENGE group compared with 25.1% and 3.3% of patients in the control group. Fatal (Grade 5) adverse events were reported in 3.3% of patients in the PROVENGE group compared with 3.6% of patients in the control group. Serious adverse events were reported in 24.0% of patients in the PROVENGE group and 25.1% of patients in the control group. Serious adverse events in the PROVENGE group included acute infusion reactions (see Warnings and Precautions), cerebrovascular events, and single case reports of eosinophilia, rhabdomyolysis, myasthenia gravis, myositis, and tumor flare. PROVENGE was discontinued in 1.5% of patients in Study 1 (PROVENGE group n=341; Control group n=171) due to adverse events. Some patients who required central venous catheters for treatment with PROVENGE developed infections, including sepsis. A small number of these patients discontinued treatment as a result. Monitoring for infectious sequelae in patients with central venous catheters is recommended. Each dose of PROVENGE requires a standard leukapheresis procedure approximately 3 days prior to the infusion. Adverse events that were reported ≤1 day following a leukapheresis procedure in ≥5% of patients in controlled clinical trials included citrate toxicity (14.2%), oral paresthesia (12.6%), paresthesia (11.4%), and fatigue (8.3%). Table 1 provides the frequency and severity of adverse events reported in ≥5% of patients in the PROVENGE group of randomized, controlled trials of men with prostate cancer. The population included 485 patients with metastatic castrate resistant prostate cancer and 116 patients with non-metastatic androgen dependent prostate cancer who were scheduled to receive 3 infusions of PROVENGE at approximately 2-week intervals. The population was age 40 to 91 years (median 70 years), and 90.6% of patients were Caucasian. Table 1 Incidence of Adverse Events Occurring in ≥5% of Patients Randomized to PROVENGE PROVENGE (N = 601)

Any Adverse Event Chills Fatigue Fever Back pain Nausea Joint ache Headache Citrate toxicity Paresthesia Vomiting Anemia Constipation Pain Paresthesia oral Pain in extremity Dizziness Muscle ache Asthenia Diarrhea Influenza-like illness Musculoskeletal pain Dyspnea Edema peripheral Hot flush Hematuria Muscle spasms

Control* (N = 303)

All Grades n (%)

Grade 3-5 n (%)

All Grades n (%)

591 (98.3) 319 (53.1) 247 (41.1) 188 (31.3) 178 (29.6) 129 (21.5) 118 (19.6) 109 (18.1) 89 (14.8) 85 (14.1) 80 (13.3) 75 (12.5) 74 (12.3) 74 (12.3) 74 (12.3) 73 (12.1) 71 (11.8) 71 (11.8) 65 (10.8) 60 (10.0) 58 (9.7) 54 (9.0) 52 (8.7) 50 (8.3) 49 (8.2) 46 (7.7) 46 (7.7)

186 (30.9) 13 (2.2) 6 (1.0) 6 (1.0) 18 (3.0) 3 (0.5) 11 (1.8) 4 (0.7) 0 (0.0) 1 (0.2) 2 (0.3) 11 (1.8) 1 (0.2) 7 (1.2) 0 (0.0) 5 (0.8) 2 (0.3) 3 (0.5) 6 (1.0) 1 (0.2) 0 (0.0) 3 (0.5) 11 (1.8) 1 (0.2) 2 (0.3) 6 (1.0) 2 (0.3)

291 (96.0) 33 (10.9) 105 (34.7) 29 (9.6) 87 (28.7) 45 (14.9) 62 (20.5) 20 (6.6) 43 (14.2) 43 (14.2) 23 (7.6) 34 (11.2) 40 (13.2) 20 (6.6) 43 (14.2) 40 (13.2) 34 (11.2) 17 (5.6) 20 (6.6) 34 (11.2) 11 (3.6) 31 (10.2) 14 (4.6) 31 (10.2) 29 (9.6) 18 (5.9) 17 (5.6)

Grade 3-5 n (%) 97 (32.0) 0 (0.0) 4 (1.3) 3 (1.0) 9 (3.0) 0 (0.0) 5 (1.7) 0 (0.0) 0 (0.0) 0 (0.0) 0 (0.0) 7 (2.3) 3 (1.0) 3 (1.0) 0 (0.0) 1 (0.3) 0 (0.0) 0 (0.0) 2 (0.7) 3 (1.0) 0 (0.0) 3 (1.0) 3 (1.0) 1 (0.3) 1 (0.3) 3 (1.0) 0 (0.0)

(Table 1 continued on next page.)

Table 1 Incidence of Adverse Events Occurring in ≥5% of Patients Randomized to PROVENGE PROVENGE (N = 601)

Hypertension Anorexia Bone pain Upper respiratory tract infection Insomnia Musculoskeletal chest pain Cough Neck pain Weight decreased Urinary tract infection Rash Sweating Tremor

Control* (N = 303)

All Grades n (%)

Grade 3-5 n (%)

All Grades n (%)

Grade 3-5 n (%)

45 (7.5) 39 (6.5) 38 (6.3) 38 (6.3)

3 (0.5) 1 (0.2) 4 (0.7) 0 (0.0)

14 (4.6) 33 (10.9) 22 (7.3) 18 (5.9)

0 (0.0) 3 (1.0) 3 (1.0) 0 (0.0)

37 (6.2) 36 (6.0)

0 (0.0) 2 (0.3)

22 (7.3) 23 (7.6)

1 (0.3) 2 (0.7)

35 (5.8) 34 (5.7) 34 (5.7) 33 (5.5) 31 (5.2) 30 (5.0) 30 (5.0)

0 (0.0) 3 (0.5) 2 (0.3) 1 (0.2) 0 (0.0) 1 (0.2) 0 (0.0)

17 (5.6) 14 (4.6) 24 (7.9) 18 (5.9) 10 (3.3) 3 (1.0) 9 (3.0)

0 (0.0) 2 (0.7) 1 (0.3) 2 (0.7) 0 (0.0) 0 (0.0) 0 (0.0)

*Control was non-activated autologous peripheral blood mononuclear cells.

Cerebrovascular Events. In controlled clinical trials, cerebrovascular events, including hemorrhagic and ischemic strokes, were reported in 3.5% of patients in the PROVENGE group compared with 2.6% of patients in the control group. (See Adverse Reactions [6] of full Prescribing Information.) To report SUSPECTED ADVERSE REACTIONS, contact Dendreon Corporation at 1-877-336-3736 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch.

Dendreon Corporation Seattle, Washington 98101

Journal of Hematology Oncology Pharmacy

Information for Authors

Manuscripts submitted to the Journal of Hematology Oncology Pharmacy (JHOP) must be original and must not have been published previously, either in print or in electronic form. Manuscripts cannot be submitted elsewhere while under consideration by JHOP, and must adhere to the format described in the full Guidelines for Authors available at www.JHOPonline.com. All manuscripts undergo peer review, and acceptance is based on that review. If accepted, authors will be notified of any recommended revisions.

COPYRIGHT/DISCLOSURE Authors must sign a Copyright Transfer Form, assigning all copyrights to Green Hill Healthcare Communications, LLC, publisher of JHOP, as well as a Financial Disclosure Form, disclosing any financial interests or potential conflict of interest involving the materials discussed in the manuscript. MANUSCRIPT FORMAT • Title page: provide a proper title for the article; list names, degrees, titles, and affiliations for all authors, as well as contact information for the corresponding author • Abstract: 150-250 words • Tables and Figures: cite these in the text, but place graphic elements after the references; type all tables in a Word format • References: 30-40 current, post-1990 references, cited in the text but listed at the end of the manuscript; avoid automatic numbering, footnotes, endnotes

REFERENCES: 1. PROVENGE [package insert]. Dendreon Corporation; June 2011. 2. Kantoff PW, Higano CS, Shore ND, et al; for the IMPACT Study Investigators. Sipuleucel-T immunotherapy for castration-resistant prostate cancer. N Engl J Med. 2010;363:411-422.

• Length of article: 3000-4000 words, plus tables and figures • Provide all Figures as PDF, jpg, PowerPoint files, saved at 300 dpi

PERMISSIONS Authors must secure written permission from the original publisher for any previously published (online or in print) Table or Figure. Provide the source with each element. ©2013 Dendreon Corporation. All rights reserved. January 2013. Printed in the U.S.A. Dendreon, the Dendreon logo, and PROVENGE are registered trademarks of Dendreon Corporation. P-A-01.13-002.00

Submit the manuscript electronically to: editorial@ greenhillhc.com. For assistance call 732-992-1536.

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

Section Editors Clinical Controversies

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

Original Research

R. Donald Harvey, PharmD, FCCP, BCPS, BCOP Assistant Professor, Hematology/Medical Oncology Department of Hematology/Medical Oncology Director, Phase 1 Unit Winship Cancer Institute Emory University, Atlanta, GA

Review Articles

Scott Soefje, PharmD, BCOP Associate Director, Oncology Pharmacy Smilow Cancer Hospital at Yale-New Haven Yale-New Haven Hospital New Haven, CT

Practical Issues in Pharmacy Management

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 Universityâ&#x20AC;&#x201C;California Mare Island, Vallejo, CA

editors-At-Large Joseph Bubalo, PharmD, BCPS, BCOP Assistant Professor of Medicine Oncology Clinical Specialist and Oncology Lead OHSU Hospital and Clinics Portland, OR

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

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

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 University of Texas M. D. Anderson Cancer Center Houston, TX

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Journal of Hematology Oncology Pharmacy

This is the biologic medicine That the patient counts on That the nurse trusts That the pharmacist has confidence in That the doctor relies on Because it was manufactured knowing the patient’s treatment depends on it. Building confidence in the quality and supply of biologic medicines starts with a deeper understanding of how these medicines are made. After all, there’s so much at stake.

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June 2013

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Publishing Staff

hematology Oncology Pharmacy™

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Table of Contents

Editorial Director Dalia Buffery dalia@greenhillhc.com

ORIGINAL RESEARCH 41 The Effect of Atazanavir on Doxorubicin Pharmacokinetics: A Case Report Neha Umesh Sheth, PharmD, AAHIVP, BCPS; Steven Gilmore, PharmD, BCOP; Kenneth S. Bauer Jr, PharmD, PhD; Saranya Chumsri, MD

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Complimentary CE 58 Considerations in Multiple Myeloma—Ask the Experts: Maintenance Settings From the Literature 68 Concise Reviews of Studies Relevant to Hematology Oncology Pharmacy

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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.

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Journal of Hematology Oncology Pharmacy™, ISSN applied for (print); ISSN applied for (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 ©2013 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.

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Original ARTICLE

Case Study

The Effect of Atazanavir on Doxorubicin Pharmacokinetics: A Case Report Neha Umesh Sheth, PharmD, AAHIVP, BCPS; Steven Gilmore, PharmD, BCOP; Kenneth S. Bauer Jr, PharmD, PhD; Saranya Chumsri, MD Background: With the increasing incidence of cancers in the HIV-infected population, a better understanding of the clinical effects of the coadministration of chemotherapy and antiretroviral medications needs to be known. Doxorubicin is a common chemotherapy agent and atazanavir is a common antiretroviral agent. Atazanavir can cause hyperbilirubinemia. Doxorubicin is dosed by total bilirubin levels as a result of its metabolism. If prescribers follow the recommended dose adjustment for doxorubicin and hyperbilirubinemia, it can result in subtherapeutic doses of doxorubicin and potentially unsuccessful therapeutic results. Objectives: The goal of this case report was to determine the clinical and pharmacokinetic effects of the coadministration of atazanavir and doxorubicin in 1 patient. Discussion: We examined a patient undergoing chemotherapy for breast cancer with doxorubicin and cyclophosphamide while also receiving antiretroviral therapy, including atazanavir, darunavir, ritonavir, tenofovir, and emtricitabine for her HIV infection. The pharmacokinetics of doxorubicin and the clinical outcomes for the patient were monitored. The patient had an increase in total bilirubin secondary to atazanavir, suggesting a 75% dose reduction of doxorubicin. Because she showed no other signs of hepatotoxicity, she was given a full dose of doxorubicin. The patient quickly developed febrile neutropenia, requiring a 10% reduction for subsequent cycles. She continued to have episodes of febrile neutropenia. The pharmacokinetic evaluation was performed on day 1 of cycle 3. The doxorubicin area under the curve (AUC) 0-12 for this patient was between 616 µg*hr/L and 691 µg*hr/L compared with a previously reported AUC 0-12 of 673 ± 205 µg*hr/L. Conclusion: This is the first case report to assess the pharmacokinetic profile of doxorubicin coadministered with atazanavir in the setting of hyperbilirubinemia. The recommended dose reduction of doxorubicin based on total bilirubin was not necessary in this case, based on the associated pharmacokinetics and clinical outcomes.

IDS-defining cancers, such as Kaposi’s sarcoma and non-Hodgkin’s lymphoma, have always disproportionately affected individuals infected with HIV. Since the introduction of antiretroviral therapy in 1996, the incidence of these cancers has decreased dramatically. However, with this decline, there seemed to be an increase in non–AIDs-defining cancers, such as cancers of the anus, liver, and lung, and Hodgkin’s lymphoma.1 Many studies have shown that by administering antiretroviral therapy to patients with AIDS-defining cancers, survival and response to chemotherapy can be improved.2,3 Despite the increasing risk of non–AIDSdefining cancers and the need to use antiretroviral

J Hematol Oncol Pharm. 2013;3(2):41-47 www.JHOPonline.com Disclosures are at end of text

therapy with chemotherapy to improve outcomes, little is still known about the drug–drug interactions between these 2 classes of medications. Many clinical decisions are centered on theoretical outcomes that are based on the pharmacology of each agent; however, very limited clinical data are available regarding the concomitant use of these medications.4-7 One drug–drug interaction in particular involves the anthracycline, doxorubicin, and the frequently prescribed antiretroviral protease inhibitor, atazanavir. Atazanavir is known to increase total bilirubin levels, but the drug rarely causes hepatotoxicity. Doxorubicin is dosed based on the elevation of total bilirubin because

Dr Sheth is Assistant Professor, Department of Pharmacy Practice and Science, University of Maryland School of Pharmacy, Baltimore; Dr Gilmore is Clinical Specialist, Hematology/Oncology, University of Maryland Medical Center; Dr Bauer is Associate Professor, Department of Pharmacy Practice and Science, University of Maryland School of Pharmacy; and Dr Chumsri is Assistant Professor, Department of Medicine, University of Maryland Greenebaum Cancer Center.

Vol 3, No 2

June 2013

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Journal of Hematology Oncology Pharmacy

Original ARTICLE

of hepatic elimination. The concomitant use of these medications could result in subtherapeutic doses of doxorubicin, leading to poor chemotherapy treatment outcomes. There are currently no pharmacokinetic or clinical studies on the coadministration of doxorubicin and atazanavir. We report the case of a woman infected with HIV who was diagnosed with breast cancer and was initiated therapy with a doxorubicin-based chemotherapy regimen in conjunction with her antiretroviral therapy, which included atazanavir. This case report discusses the drug–drug interaction between doxorubicin and atazanavir using pharmacologic and pharmacokinetic data for both medications.

Case Report A 46-year-old white woman presented to our hospital with a palpable right breast mass. Her medical history included HIV, which was diagnosed in 1997. The patient presented with no pain or nipple discharge associated with the breast mass. Her physical examination was remarkable for a 1.8-cm × 1.7-cm mobile right breast mass, with no skin changes or palpable axillary lymphadenopathy. A diagnostic mammography demonstrated a medium- to high-density, 24-mm, round mass at the 12:00 to 1:00 position of the right breast. An ultrasound of the breast and right axilla showed a 20-mm, round cystic mass (Figure, Panel A) and a nonspecific 18-mm lymph node with cortical thickening (Figure, Panel B).

The concomitant use of these medications could result in subtherapeutic doses of doxorubicin, leading to poor chemotherapy treatment outcomes. There are currently no pharmacokinetic or clinical studies on the coadministration of doxorubicin and atazanavir. A biopsy revealed invasive grade III ductal carcinoma, and immunohistochemical (IHC) staining showed no expression of estrogen or progesterone receptors. HER2 was 2+ by IHC staining, but it was negative for gene amplification. Our patient had a family history of breast cancer, including her mother, 2 sisters, and a maternal aunt, all of whom were diagnosed in their 30s or early 40s. After genetic counseling, the patient tested positive for the BRCA1 mutation. A bilateral mastectomy and sentinel lymph node biopsy were performed, which were consistent with stage Ia cancer (ie, TNM stage pT1c N0 M0).

Journal of Hematology Oncology Pharmacy

Adjuvant systemic chemotherapy was initiated 5 weeks after an uneventful surgery. Taxanes, such as docetaxel, were avoided, because of the significant drug–drug interactions with antiretroviral therapy, specifically inhibitors of the cytochrome (CY) P450 3A4 (CYP3A4) enzyme, which metabolizes docetaxel. When docetaxel is administered with CYP3A4 inhibitors, such as antiretroviral protease inhibitors, increases in docetaxel concentrations can be seen, resulting in myelosuppression. Furthermore, although taxane-containing regimens, such as docetaxel and cyclophosphamide, showed superiority in the adjuvant setting compared with standard doxorubicin and cyclophosphamide given every 3 weeks, currently no data are available comparing the docetaxel plus cyclophosphamide regimen (given every 3 weeks) and the dose-dense doxorubicin plus cyclophosphamide regimen (given every 2 weeks).8,9 Based on the Cancer and Leukemia Group B (CALGB) 9741 clinical trial, doxorubicin plus cyclophosphamide, given in a dose-dense fashion with growth factor support, has been shown to be superior to an every-3-week schedule.10 After considering all of the data, dose-dense doxorubicin plus cyclophosphamide, given every 2 weeks for 4 cycles, was chosen for this patient. Our patient had not had antiretroviral therapy for approximately 7 years before her malignancy diagnosis. After her diagnosis, it was determined that antiretroviral therapy would help optimize her chemotherapy, based on higher response and survival rates seen in patients with lymphoma when a combination of chemotherapy and antiretroviral therapy were given.2,3,7,11 Although the same has not clearly been seen in patients with breast cancer, it is known that chemotherapy can be cytotoxic and can cause more immunosuppression. To prevent the worsening of immune function with cytotoxic agents, the use of antiretroviral therapy can help boost a patient’s immune function before the initiation of chemotherapy.12 The patient’s previous antiretroviral therapy exposure included zidovudine, lamivudine, tenofovir, abacavir, indinavir, saquinavir, nelfinavir, nevirapine, and efavirenz. Only 1 genotypic resistance test was performed, which showed pan sensitivity to all antiretroviral medications; however, this test was performed while the patient was not taking any medications, and it was therefore unclear if mutations were hidden because of a lack of drug pressure. Because of the patient’s extensive antiretroviral medication exposure since her 1997 HIV diagnosis, she was prescribed a regimen accounting for common mutations, such as the M184V, that may have occurred but were not found on her previous genotype testing.

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Shortly after her malig- Figure Ultrasound of the Patient’s Breast Mass nancy diagnosis, the patient was prescribed antiretroviral Panel B Panel A therapy with atazanavir 300 mg, darunavir 800 mg, ritonavir 100 mg, and tenofovir/emtricitabine 300/200 mg administered orally and daily. Before starting the antiretroviral therapy, the patient’s CD4 cell count was 634 (28%) cells/mm3, her HIV RNA level was 356,571 copies/mL, her total bilirubin was 0.9 mg/dL, her aspartate aminotransferase (AST) was 100 U/L, and her alanine aminotransferase (ALT) was 73 U/L. After 3 months of antiretroviral therapy, her total bilirubin increased, secondary to atazanavir, to 3.8 mg/dL, whereas her AST and This ultrasound of the breast and right axilla shows (A) a 20-mm, round cystic mass ALT levels normalized to 27 (arrow), and (B) a nonspecific 18-mm lymph node with cortical thickening. U/L and 14 U/L, respectively. Our patient was supposed to begin chemotherapy after these laboratory data became Given that (1) the duration of severe neutropenia available; however, the increase in total bilirubin suggested after treatment with pegfilgrastim during breast cancer a reduction in doxorubicin dose by 75% (15 mg/m2).13 treatment with docetaxel and cyclophosphamide is 1.8 Knowing that atazanavir can increase unconjugated days, (2) the incidence of severe neutropenia ranges and total bilirubin, but not conjugated bilirubin, we evalfrom 30% to 50% during doxorubicin and cyclophosuated our patient’s conjugated bilirubin concentrations phamide therapy, and (3) the incidence of febrile neuand found that they were within normal limits (ie, 0.2 tropenia ranges from 1% to 7% during treatment with mg/dL to 0.5 mg/dL). We determined that the increase in total bilirubin could have resulted from atazanavir and Because of her febrile neutropenia, a 10% was not a true representation of the patient’s liver funcreduction in doxorubicin dose was used in tion. Therefore, we gave her the standard doses of doxo2 2 rubicin (60 mg/m ) and cyclophosphamide (600 mg/m ). subsequent chemotherapy cycles; however, Growth factor support was given on day 2 of chemothe febrile neutropenia continued after each therapy, and, on day 9, the patient developed febrile cycle. After cycle 4, her nadir was 0 cells/mcL, neutropenia that required hospitalization. Her absolute neutrophil count (ANC) nadir after this cycle was 250 with a total duration of 84 hours of cells/mcL for less than 12 hours, and her ANC was up ANC <1000 cells/mcL. to 900 cells/mcL within 24 hours. The total duration of severe neutropenia was 24 hours after cycle 1. Because of her febrile neutropenia, a 10% reduction in doxorubicin and cyclophosphamide, it was determined doxorubicin dose was used in subsequent chemotherapy that our patient’s neutropenia was within the range of cycles; however, the febrile neutropenia continued after acceptability for normal chemotherapy effects.14,15 In addition, these previously reported results do not indicate each cycle. After cycle 2, the patient’s ANC nadir was the number of patients infected with HIV; therefore, 800 cells/mcL, and, after cycle 3, the nadir was 150 cells/ our patient may have had a more profound hematologic mcL, with a 36-hour duration of ANC <1000 cells/mcL. response to the myelosuppressive therapy because of her After cycle 4, her nadir was 0 cells/mcL, with a total underlying immune suppression. duration of 84 hours of ANC <1000 cells/mcL.

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Journal of Hematology Oncology Pharmacy

Original ARTICLE

Additional toxicities (other than febrile neutropenia) identified in this patient included nausea, vomiting, and stomatitis; these were all grade ≥3 toxicities and were all manageable and consistent with a dose-dense doxorubicin plus cyclophosphamide regimen. It should be noted that in addition to the chemotherapy, the patient received aprepitant 125 mg, ondansetron 16 mg, and dexamethasone 12 mg on the days of chemotherapy. She also received pegfilgrastim 1 to 2 days after each cycle of chemotherapy. Aprepitant is a weak inhibitor of the CYP450 2C19 and CYP450 2C9 enzymes, and a moderate inhibitor of the CYP450 3A4 enzyme, but it is not expected to alter the metabolism of doxorubicin, cyclophosphamide, or antiretroviral therapy; it is indicated before this chemotherapy administration.16 Dexamethasone and ondansetron are also not expected to alter chemotherapy or antiretroviral therapy metabolism, and are indicated as part of the chemotherapy regimen.17,18

Gilbert’s syndrome is an inherited disorder that causes unconjugated hyperbilirubinemia. This hyperbilirubinemia is similar to that seen in patients with atazanavir-induced direct hyperbilirubinemia. Pharmacokinetic Analysis of Doxorubicin For further evaluation of the interaction between atazanavir and doxorubicin clearance, a pharmacokinetic study of doxorubicin was performed on day 1 of cycle 3. It should be noted that even during the third cycle, the patient’s CD4 cell count was 487 (48%) cells/mm3, her HIV RNA level was 128 copies/mL, her total bilirubin was 1.3 mg/dL, her AST was 27 U/L, and her ALT was 19 U/L. The conjugated bilirubin remained normal (at 0.4 mg/dL) 6 days after the initiation of the third cycle of chemotherapy. All samples obtained from the patient for pharmacokinetic analysis were drawn during routine clinical care visits with her oncologist. With the samples obtained, only limited pharmacokinetic analyses were able to be made. For the doxorubicin analysis, 5 mL of blood were drawn in sodium heparin–coated tubes at 0.25 hours, 0.5 hours, and 3 hours after administration once informed patient consent was obtained. The blood was immediately centrifuged for 15 minutes and stored at approximately –80˚C until the time of the analysis. Doxorubicin concentrations were determined using a high-performance reverse-phase chromatographic method based on a previously described method.19

Journal of Hematology Oncology Pharmacy

The assay was linear and validated using the range of 10 ng/mL to 500 ng/mL. Because increased doxorubicin area under the curve (AUC) has been linked to toxicities, such as myelosuppression, we calculated the AUC for our patient using a linear trapezoidal algorithm with WinNonlin v5.2. Using the range of previously reported gamma half-lives of 13 to 50 hours, the AUC0-12 for our patient was predicted to be between 616 µg*hr/L and 691 µg*hr/L.20,21 The previously reported estimated doxorubicin AUC0-12 is 673 ± 205 µg*hr/L.13 Previous studies have shown that the concentrations of doxorubicin after a 20-minute infusion at doses of 50 mg/m2 and 60 mg/m2 were 109 ± 14 ng/mL, and 135 ± 34 ng/mL at 0.5 hours after the infusion.22 Although our patient’s concentration of 94.2 ng/mL is slightly lower than previously reported, we believe that this may be a result of the lower concentrations expected after a 30-minute infusion, which our patient received, versus a 20-minute infusion. Another study showed that doxorubicin administered 0.5 hours and 24 hours before paclitaxel resulted in doxorubicin concentrations of 66.0 ± 18.7 ng/mL and 40.9 ± 13.6 ng/mL, respectively, 3 hours after administration.19 The concentrations observed in our patient were similar (54 mg/m2) to those previously reported for patients who were administered doxorubicin 50 mg/m2 or 60 mg/m2 (Table). Six months after our patient’s last chemotherapy cycle, she presented for her follow-up visit doing well and without any evidence of breast cancer recurrence.

Pharmacology of Doxorubicin Doxorubicin is a first-generation anthracycline that has been in use for more than 40 years. It is effective in the treatment of a variety of tumors and AIDS-defining cancers.23-25 The clearance of anthracyclines relies primarily on the liver for metabolism and for excretion of the active compound and metabolites. Metabolism of doxorubicin occurs by a CYP-mediated pathway. Doxorubicin is metabolized to a doxorubicinol and to aglycones. The doxorubicin and doxorubicinol components are cytotoxic, unlike the aglycone metabolites, which can be cardiotoxic.11,20,25 Doxorubicin is eliminated primarily through biliary and fecal routes. Approximately 40% to 50% of a dose appears in the bile after 5 days.11 The pharmacokinetics of doxorubicin are linear.20 Elevated total bilirubin levels and aminotransaminases have been reported to predict doxorubicin toxicity. The guidelines for doxorubicin dose reduction based on elevated total bilirubin levels were proposed in the 1970s.13 Since then, several studies have shown

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Table Doxorubicin Pharmacokinetics: Our Patient versus Reports in the Literature Our patient, 54 mg/m2 Sample time, hr

Hirte, et al22 50 mg/m2

Hirte, et al22 60 mg/m2

Doxorubicin, ng/mL

0.25

176.9

0.5

94.2

3.0

51.7

Cmax, ng/mL

176.9

AUC0-3, µg*hr/mL

260.5

AUC0-12, µg*hr/mL

Moreira, et al23 60 mg/m2

Doxorubicin, ng/mL 109.3 ± 14

135.34 ± 34 40.9 ± 13.6

673 ± 205

1110 ± 306

AUC indicates area under the curve; Cmax, maximum plasma concentration.

an inconsistent relationship between liver function and doxorubicin metabolism.26,27 Twelves and colleagues conducted a doxorubicin pharmacokinetic study in 24 patients with abnormal liver chemistries.28 Patients with an increased total bilirubin level between 1.75 mg/dL and 17.3 mg/dL did in fact have decreased doxorubicin clearance, but no clear relationship was established between the elevation in bilirubin and the extent of doxorubicin clearance reduction.28 This study, in addition to other studies that assess doxorubicin pharmacokinetics with liver function, used total bilirubin, AST, and ALT, but the studies do not mention the conjugated and unconjugated bilirubin levels and often already-assessed patients with known liver function abnormalities.26-28 Gilbert’s syndrome is an inherited disorder that causes unconjugated hyperbilirubinemia. This hyperbilirubinemia is similar to that seen in patients with atazanavir-induced direct hyperbilirubinemia. A case report of a 62-year-old man with large-cell non-Hodgkin’s lymphoma and Gilbert’s syndrome who received doxorubicin treatment showed that, at the time of doxorubicin initiation, the patient had a total bilirubin level of 2.1 mg/dL and an unconjugated bilirubin level of 1.9 mg/dL. According to the doxorubicin dosing guidelines, the dose should have been decreased by 50% because of the total bilirubin, but the patient was subsequently given full-dose doxorubicin with no secondary complications of neutropenia or mucosal toxicities.29

Pharmacology of Protease Inhibitors Atazanavir and darunavir are recommended as preferred protease inhibitors for initial therapy in the treatment of HIV infection.30 Our patient was prescribed a dual protease inhibitor antiretroviral regimen, which included atazanavir and darunavir. These 2

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medications were given in conjunction with ritonavir, which is known to enhance the effects of the active protease inhibitors by inhibiting metabolism of these medications, causing elevated concentrations of the active protease inhibitors. The use of protease inhibitors with chemotherapy can be difficult because of the complex drug–drug interactions with the 2 classes of medications. The major mechanisms of interaction between atazanavir, darunavir, and ritonavir with the patient’s doxorubicin include uridine diphosphate glucuronyltransferase 1A1 (UGT1A1) and P-glycoprotein (P-gp). The protease inhibitors are rapidly absorbed and are metabolized primarily through the liver, utilizing the CYP3A4; however, they can also inhibit CYP3A4 and UGT1A1. Protease inhibitors also serve as a substrate and inhibitor of P-gp.

The use of protease inhibitors with chemotherapy can be difficult because of the complex drug–drug interactions with the 2 classes of medications. The major mechanisms of interaction between atazanavir, darunavir, and ritonavir with the patient’s doxorubicin include uridine diphosphate glucuronyltransferase and P-glycoprotein. The Role of UGT1A1 UGT1A1 facilitates the excretion of bilirubin from the body. Unconjugated bilirubin is a product of the metabolism of heme from hemoglobin. This bilirubin is not water soluble, which prevents its elimination into bile. Unconjugated bilirubin is bound to albumin and transported to the liver for conjugation to facili-

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Original ARTICLE

tate elimination. Unconjugated bilirubin is bound to glucuronic acid through esterification catalyzed by UGT1A1, causing conjugation and subsequently elimination.31 Because atazanavir inhibits UGT1A1, increases of unconjugated bilirubin are frequently seen in patients who have no signs of liver dysfunction. Total levels of bilirubin of more than 2.5 times the upper limit of normal can be seen in 22% to 49% of patients receiving atazanavir.32

The Role of P-glycoprotein P-gp has many functions, depending on the site of these proteins. Its major role in our patient’s case includes the effects of HIV-1 infection on P-gp, the potential drug–drug interactions through P-gp, and the effects of P-gp on this patient’s chemotherapy and cancer. P-gp is a protein that is most often found on the mucosal surface of the gastrointestinal (GI) tract. Its function is to prevent uptake of toxic substances and to help eliminate those substances across the mucosa of the GI tract.33

To our knowledge, this is the first case report to discuss the interaction between doxorubicin and atazanavir. The pharmacokinetics performed in this study show that further evaluation of liver dysfunction beyond total bilirubin may be necessary in patients concomitantly taking medications that could inhibit UGT1A1. P-gp has long been studied in cancer, because this protein is highly expressed in certain human cancers, such as breast cancer. As a drug efflux pump, P-gp plays a vital role in the ability of chemotherapy to access the cells needed for these cancers. Various studies have been performed to provide patients with chemotherapy and P-gp inhibitors to enhance chemotherapy sensitivity; however, mixed outcomes of this drug–drug interaction have led to controversy, and no consensus can been made. Patel and Tannock discovered that the use of P-gp inhibitors with doxorubicin only increased doxorubicin’s uptake in cells close to the blood vessels but might have decreased doxorubicin uptake in distal cells.34 As noted earlier, most protease inhibitors serve as a P-gp substrate and inhibitor. This could lead to erratic uptake of doxorubicin in patients receiving chemotherapy. Ritonavir is the most potent P-gp inhibitor,

Journal of Hematology Oncology Pharmacy

which our patient was receiving. Although previous studies that have evaluated the use of doxorubicin with P-gp inhibitors do not clarify the drug–drug interaction potential for our patient at this time, it may be considered a confounding factor.

Conclusions It is generally understood that patients infected with HIV have an elevated risk of AIDS-defining cancers. Although the increase in effectiveness of antiretroviral therapy has resulted in a significant decline in AIDS-defining cancers, we have seen an increase in non–AIDS-defining cancers, such as breast cancer. Despite the known risk of malignancies in the HIVinfected population, little is known about the clinical effects of chemotherapy with concomitant antiretroviral therapy. To our knowledge, this is the first case report to discuss the interaction between doxorubicin and atazanavir. The pharmacokinetics performed in this study show that further evaluation of liver dysfunction beyond total bilirubin may be necessary in patients concomitantly taking medications that could inhibit UGT1A1 and subsequently increase total bilirubin concentrations, such as atazanavir. Furthermore, dose reduction of doxorubicin according to the total bilirubin level may not be appropriate when used in combination with inhibitors of both UGT1A1 and P-gp. n Acknowledgment The authors would like to thank Nancy Tait, BSN, from the University of Maryland Greenebaum Cancer Center, and Lisa Gresiman, MD, for their contribution to patient care. Author Disclosure Statement Dr Chumsri has received grant support from GlaxoSmithKline, Merck, and Novartis. Dr Sheth, Dr Gilmore, and Dr Bauer reported no conflicts of interest.

References

1. Simard EP, Pfeiffer RM, Engels EA. Cumulative incidence of cancer among individuals with acquired immunodeficiency syndrome in the United States. Cancer. 2011;117:1089-1096. 2. Antinori A, Cingolani A, Alba L, et al. Better response to chemotherapy and prolonged survival in AIDS-related lymphomas responding to highly active antiretroviral therapy. AIDS. 2001;15:1483-1491. 3. Diamond C, Taylor TH, Im T, et al. Improved survival and chemotherapy response among patients with AIDS-related non-Hodgkin’s lymphoma receiving highly active antiretroviral therapy. Hematol Oncol. 2006;24:139-145. 4. Rudek MA, Flexner C, Ambinder RF. Use of antineoplastic agents in patients with cancer who have HIV/AIDS. Lancet Oncol. 2011;12:905-912. 5. Makinson A, Pujol J, Moing VL, et al. Interactions between cytotoxic chemotherapy and antiretroviral treatment in human immunodeficiency virus-infected patients with lung cancer. J Thorac Oncol. 2010;5:562-571. 6. Mounier N, Katlama C, Costagliola D, et al. Drug interactions between antineoplastic and antiretroviral therapies: implications and management for clinical practice. Crit Rev Oncol Hematol. 2009;72:10-20.

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7. Antoniou T, Tseng AL. Interactions between antiretrovirals and antineoplastic drug therapy. Clin Pharmacokinet. 2005;44:111-145. 8. Jones SE, Savin MA, Holmes FA, et al. Phase III trial comparing doxorubicin plus cyclophosphamide with docetaxel plus cyclophosphamide as adjuvant therapy for operable breast cancer. J Clin Oncol. 2006;24:5381-5387. 9. Jones S, Holmes FA, O’Shaughnessy J, et al. Docetaxel with cyclophosphamide is associated with an overall survival benefit compared with doxorubicin and cyclophosphamide: 7-year follow-up of US Oncology Research Trial 9735. J Clin Oncol. 2009;27:1177-1183. 10. Citron ML, Berry DA, Cirrincione C, et al. Randomized trial of dose-dense versus conventionally scheduled and sequential versus concurrent combination chemotherapy as postoperative adjuvant treatment of node-positive primary breast cancer: First Report of Intergroup Trial C9741/Cancer and Leukemia Group B Trial 9741. J Clin Oncol. 2003;21:1431-1439. 11. Danesi R, Fogli S, Gennari A, et al. Pharmacokinetic-pharmacodynamic relationships of the anthracycline anticancer drugs. Clin Pharmacokinet. 2002;41:431-444. 12. Latif N, Rana F, Guthrie T. Breast cancer and HIV in the era of highly active antiretroviral therapy: two case reports and review of the literature. Breast J. 2001;17:87-92. 13. Benjamin RS. A practical approach to Adriamycin (NSC-123127) toxicology. Cancer Chemother Rep. 1975;6:191-194. 14. Robert N, Krekow L, Stokoe C, et al. Adjuvant dose-dense doxorubicin plus cyclophosphamide followed by dose-dense nab-paclitaxel is safe in women with early-stage breast cancer: a pilot study. Breast Cancer Res Treat. 2011;125:115-120. 15. Dang C, Lin N, Moy B, et al. Dose-dense doxorubicin and cyclophosphamide followed by weekly paclitaxel with trastuzumab and lapatinib in HER2/neu-overexpressed/amplified breast cancer is not feasible because of excessive diarrhea. J Clin Oncol. 2010;28:2982-2988. 16. Emend [package insert]. Whitehouse Station, NJ: Merck and Co; 2012. 17. Dexamethasone [package insert]. Columbus, OH: Roxane Laboratories; 2007. 18. Zofran [package insert]. Research Triangle, NC: GlaxoSmithKline; 2012. 19. Camaggi CM, Comparsi R, Strocchi E, et al. HPLC analysis of doxorubicin, epirubicin and fluorescent metabolites in biological fluids. Cancer Chemother Pharmacol. 1988;21:216-220. 20. Speth PA, van Hoesel QG, Haanen C. Clinical pharmacokinetics of doxorubicin. Clin Pharmacokinet. 1988;15:15-31. 21. Mross K, Maessen P, van der Vijgh WJ, et al. Pharmacokinetics and metabolism of epidoxorubicin and doxorubicin in humans. J Clin Oncol. 1988;6:517-526.

22. Hirte H, Stewart D, Goel R, et al. An NCIC-CTG phase I dose escalation pharmacokinetic study of the matrix metalloproteinase inhibitor BAY 12-9566 in combination with doxorubicin. Invest New Drugs. 2005;23:437-443. 23. Moreira A, Lobato R, Morais J, et al. Influence of the interval between the administration of doxorubicin and paclitaxel on the pharmacokinetics of these drugs in patients with locally advanced breast cancer. Cancer Chemother Pharmacol. 2001;48:333-337. 24. Gewirtz DA. A critical evaluation of the mechanism of action proposed for the antitumor effects of the anthracycline antibiotics Adriamycin and daunorubicin. Biochem Pharmacol. 1999;57:727-741. 25. Joerger M, Huitema AD, Meenhorst PL, et al. Pharmacokinetics of low dose doxorubicin and metabolites in patients with AIDS-related Kaposi sarcoma. Cancer Chemother Pharmacol. 2005;55:488-496. 26. Sulkes A, Collins JM. Reappraisal of some dosage adjustment guidelines. Cancer Treat Rep. 1987;71:229-233. 27. Johnson PJ, Dobbs N, Kalayci C, et al. Clinical efficacy and toxicity of standard dose Adriamycin in hyperbilirubinaemic patients with hepatocellular carcinoma: relation to liver tests and pharmacokinetic parameters. Br J Cancer. 1992;65:751-755. 28. Twelves CJ, Dobbs NA, Gillies HC, et al. Doxorubicin pharmacokinetics: the effect of abnormal liver biochemistry tests. Cancer Chemother Pharmacol. 1998;42:229-234. 29. Cupp MJ, Higa GM. Doxorubicin dosage guidelines in a patient with hyperbilirubinemia of Gilbert’s syndrome. Ann Pharmacother. 1998;32:1026-1029. 30. Panel on Antiretroviral Guidelines for Adults and Adolescents. Guidelines for the use of antiretroviral agents in HIV-1-infected adults and adolescents. Department of Health and Human Services. http://aidsinfo.nih.gov/contentfiles/ lvguidelines/AdultandAdolescentGL.pdf. Accessed September 1, 2012. 31. Kamisako T, Kobayashi Y, Takeuchi K, et al. Recent advances in bilirubin metabolism research: the molecular mechanism of hepatocyte bilirubin transport and its clinical relevance. J Gastroenterol. 2000;35:659-664. 32. Orrick JJ, Steinhart CR. Atazanavir. Ann Pharmacother. 2004;38:1664-1674. 33. Sankatsing SUC, Beijnen JH, Schinkel AH, et al. P glycoprotein in human immunodeficiency virus type 1 infection and therapy. Antimicrob Agents Chemother. 2004;48:1073-1081. 34. Patel KJ, Tannock IF. The influence of P-glycoprotein expression and its inhibitors on the distribution of doxorubicin in breast tumors. BMC Cancer. 2009;9:356-365.

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2013 WORLD CUTANEOUS MALIGNANCIES CONGRESS

• Melanoma • Basal Cell Carcinoma • Cutaneous T-Cell Lymphoma • Squamous Cell Carcinoma

July 26-28, 2013

• Merkel Cell Carcinoma

Hyatt Regency La Jolla • San Diego, California PROGRAM OVERVIEW

CONFERENCE CO-CHAIRS

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, cutaneous T-cell lymphoma, squamous cell carcinoma, and Merkel cell carcinoma, including: • Epidemiology and genetic/environmental factors • Molecular biology and cytogenetics related to the pathogenesis of cutaneous malignancies • Risk stratification based on patient and tumor characteristics • Principles of cancer prevention of melanoma and basal cell carcinoma • Current treatment guidelines • Emerging treatment options for personalized therapy • Future strategies in management based on translational data from current clinical trials and basic research

LEARNING OBJECTIVES

Sanjiv S. Agarwala, MD Professor of Medicine Temple University School of Medicine Chief, Oncology & Hematology St. Luke’s Cancer Center Bethlehem, Pennsylvania

Upon completion of this activity, the participant will be able to: • Review the molecular biology and pathogenesis of cutaneous malignancies as they relate to the treatment of cutaneous T-cell lymphoma, basal cell carcinoma, Merkel cell tumors, and malignant melanoma • Compare risk stratification of patients with cutaneous malignancies, and how to tailor treatment based on patient and tumor characteristics • Summarize a personalized treatment strategy that incorporates current standards of care and emerging treatment options for therapy of patients with cutaneous malignancies

TARGET AUDIENCE This activity was developed for medical and surgical oncologists, dermatologists, radiation oncologists, and pathologists actively involved in the treatment of cutaneous malignancies. Advanced practice oncology or dermatololgy nurses, oncology pharmacists, and researchers interested in the molecular biology and management of cutaneous malignancies are also encouraged to participate.

DESIGNATION OF CREDIT STATEMENTS SPONSORS

FRIDAY, JULY 26, 2013 3:00 pm – 7:00 pm

Registration

5:30 pm – 7:30 pm

Welcome Reception/Exhibits

SATURDAY, JULY 27, 2013 7:00 am – 8:00 am

Symposium/Product Theater/Exhibits (non–CME-certified activity)

8:00 am – 8:15 am

BREAK

8:15 am – 8:30 am

Welcome to the Second Annual World Cutaneous Malignancies Congress — Setting the Stage for the Meeting - Sanjiv S. Agarwala, MD

8:30 am – 11:45 am General Session I: A Clinician’s Primer on the Molecular Biology of Cutaneous Malignancies • Keynote Lecture Understanding the Basic Biology and Clinical Implications of the Hedgehog Pathway • Keynote Lecture Pathogenesis of Merkel Cell Carcinoma: An Infectious Etiology? - Paul Nghiem, MD, PhD 12:00 pm – 1:00 pm Lunch Symposium/Product Theater/Exhibits (non–CME-certified activity) 1:00 pm – 1:15 pm

BREAK

1:15 pm – 4:30 pm

General Session II: Current Treatment Guidelines in Cutaneous Malignancies • Case Studies Optimal, Value-Based Therapy of Cutaneous Malignancies: The Expert’s Perspective on How I Treat My Patients • Panel Discussion Management Controversies and Accepted Guidelines for the Personalized Management of Cutaneous Malignancies • Keynote Lecture New Combinations in Melanoma: A Role for MEK + BRAF and Anti–PD-1

4:30 pm – 6:30 pm

Meet the Experts/Networking/Exhibits

COMMERCIAL SUPPORT ACKNOWLEDGMENT Grant requests are currently being reviewed by numerous supporters. Support will be acknowledged prior to the start of the educational activities.

The Medical Learning Institute Inc designates this live activity for a maximum of 13.0 AMA PRA Category 1 Credits ™. Physicians should claim only the credit commensurate with the extent of their participation in the activity. This activity has been planned and implemented in accordance with the Essential Areas and policies of the Accreditation Council for Continuing Medical Education through the joint sponsorship of the Medical Learning Institute Inc and the Center of Excellence Media, LLC. The Medical Learning Institute Inc is accredited by the Accreditation Council for Continuing Medical Education to provide continuing medical education for physicians.

www.CutaneousMalignancies.com WCMC2013ConferenceA_Ad_60313

Professor Dr. Med. Axel Hauschild Professor, Department of Dermatology University of Kiel Kiel, Germany

AGENDA*

This activity is jointly sponsored by Medical Learning Institute Inc, Center of Excellence Media, LLC, and Core Principle Solutions, LLC.

PHYSICIAN CREDIT DESIGNATION

Steven J. O’Day, MD Hematology/Oncology Director of Clinical Research Director of Los Angeles Skin Cancer Institute at Beverly Hills Cancer Center Clinical Associate Professor of Medicine USC Keck School of Medicine Los Angeles, California

SUNDAY, JULY 28, 2013 7:00 am – 8:00 am

Breakfast Symposium/Product Theater/Exhibits (non–CME-certified activity)

8:00 am – 8:15 am

BREAK

8:15 am – 8:30 am

Review of Saturday’s Presentations and Preview of Today’s Sessions

8:30 am – 11:45 am General Session III: Review of Emerging Treatment Options for Cutaneous Malignancies General Session IV: Challenges for the Cutaneous Malignancies Clinician • Panel Discussion How Can the Healthcare Team Work Best Together to Deliver Value-Based Care in Cutaneous Malignancies? 12:00 pm – 1:00 pm Lunch Symposium/Product Theater/Exhibits (non–CME-certified activity) 1:00 pm – 1:15 pm

BREAK

1:15 pm – 2:45 pm

General Session V: “Hot Data” — What I Learned at Recent Meetings: Focus on Cutaneous Malignancies

2:45 pm – 3:00 pm

Closing Remarks - Steven J. O’Day, MD

*Agenda is subject to change.

For complete agenda please visit www.CutaneousMalignancies.com

Call for Papers The Journal of Hematology Oncology Pharmacy is the nation’s first peer-reviewed clinical journal for oncology pharmacists. As pharmacy practice and research become integral to improving both the clinical care of cancer patients as well as expanding the research literature in contemporary oncology pharmacy, new avenues are necessary to ensure this information gets disseminated to the profession. Launched in March 2011, the Journal of Hematology Oncology Pharmacy provides a new venue for the publication of peer-reviewed, high-quality pharmacy reviews and original research to help oncology pharmacy practitioners and other hematology oncology professionals optimize drug therapy for patients with cancer. Readers are invited to submit articles addressing new research, clinical, and practice management issues in oncology pharmacy. All articles will undergo a blind peer-review process, and acceptance is based on that review.

Original Research

REVIEW ARTICLES

• Clinical • Basic science • Translational • Practice-based • Case reports • Case series

• New drug classes • Disease states • Basic science • Pharmacology • Pathways and the drugs targeting them

CLINICAL CONTROVERSIES

PRACTICAL ISSUES IN PHARMACY MANAGEMENT

• Point and counterpoint • Roundtable discussions • “How I treat”

• Logistics • Economics • Practice-influencing issues

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2ND ANNUAL

se V Jh rie iew op s o th On nli e lin ne e. at co m

CONQUERING THE CANCER CARE CONTINUUM

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CONQUERING THE CANCER CARE CONTINUUM CONQUERING CANCER CARTHE C E CONT I

A 6-part series

The publishers of The Oncology Nurse-APN/PA, The Oncology Pharmacist, and Personalized Medicine in Oncology are proud to present our 2nd annual Conquering the Cancer Care Continuum series. Upcoming topics include:

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Challenges Patients Face in Cancer Care: Implications for the Healthcare Team Lea Ann Hansen, PharmD, BCOP Associate Professor, Virginia Commonwealth University

cancer.1 More than half are living well beyond 5 years ancer is an illness associated with substantial physical, emotional, social, and financial ramafter diagnosis. Women comprise a majority of longifications for affected individuals and their term survivors due to the favorable outcomes with families. In a significant number of cases, the diagnosis breast, cervical, and uterine cancers.2 The number of of cancer is either preceded by a period people living with a history of cancer of gradual, nonspecific symptoms or is projected to grow considerably over discovered by routine screening, and the next 20 years for 2 major reasons. individuals are then thrust into a First, the number of Americans over whirlwind of diagnostic testing, inage 65 is predicted to double between vasive procedures, and complicated the years 2000 and 2030.3 Consetreatments with very little warning or Lea Ann Han quently, as a disease primarily of older sen, Pha Associate opportunity to assimilate their circumProfessor, rmD, BCOP adults, cancer will also increase. SecVirginia Commond, stances. Frequently, a multidisciplinary as the effectiveness of cancer onweal versity â&#x201E;˘ th Uni approach to treatment is necessary, retreatments improves, the number of he past dec ade has seen quiring patients to engage with numerthe utilizat a drapatients matic upscured of the disease will inion of spe urgan e in ous medical teams comprising several crease, and even larger percentage cialty pha types of Medic rmacies for are Moder Lea Annthe Hansen, rapeutic all nization Ac different specialties, often in different those for can will be living longer with the disease mo dal as cer. ities, inc â&#x20AC;&#x153;a t D PharmD, t defined The BCOP cost of can luding multiple par a specialty locations. 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THE QUERING N O C ANCER CARE C

â&#x20AC;˘ Palliation â&#x20AC;˘ Pain management â&#x20AC;˘ Hospice care â&#x20AC;˘ Treatment planning â&#x20AC;˘ Survivorship care â&#x20AC;˘ Biosimilars in supportive care

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Conveni ence, C The Imp halleng es a Patient ct of Specialty , and Cost Con Care Pharma cies on tainment:

TU U M CONTIN

SECOND ISSU Therapy E IN THE 2013 SE to Cancer RIES ce en er SE C O N dh Nona of ct D ANN pa Im UAL

CONQUERING T CANCER CAREHE CONTI

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Introduc tion to O ncology Pain Ma nageme nt

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fe to bite e his teeth. Iâ&#x20AC;&#x2122;m betwee age pain ass viders effectively ma of ociated wit nwas how peo sure back in the day n its treatm h cancer and this ent quor to numple coped with pain provide you . The following art â&#x20AC;&#x201C; icle hard to bite b them and someth liwit s h a wealth mation ass ing on. This is of inf oci orfar ate Today all from ide d with the and guidel se too ine hospital env patients who ent al. that though s. They also promo ls er a tful care be an inpatie ironment, whether te sure that nt it taken to enLillie D. Sho all their doctor unit or a clinic visit be ckney, RN cancer pat of us address with wit , , BS, MAS our ients the pain measu are asked to comple h experienci pai rement too te ng and imp n they are of whether l that provid a to relieve the it. Pain ste lement ways gree. Patien y are presently in es some expression als away soc pai physical end time, psycholog ial what to circ ts have trouble, how n, and to what deica le tually absent urance and can ma l well-being, and pain was bad (a happy face or a ever, interpreting ke quality ver of life virand adequa for some patients. cause they in the morning but y sad face) if their Accur te treatment too not so bad ment nee for effectiv ate assessment doctor. Fur k a pain pill before now bed to be pri e pain ma thermore, orities for the cancer nageis this info coming to see the viewed by all fiel of us worki d. any rma I feel confide ng in and sometim one during their visi tion actually rent you wil t? Sometim es provoking es it is, Certainly it is not. and contain l find these article s thought will assist ing valuab cer patien one of the greatest fea you le information ts is the fea rs well as dev in reassessing you that r of pain and expressed by canr current pat elo suffering and future patien ping more effectiv ients as e the fectively ma ts have quality of life ways to help your naged. Q by having pain efÂŠ 2013 Gre en Hill Hea lthcare Com munication s, LLC

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Case Study

Palifermin Use for the Prevention of Chemotherapy-Induced Oral Mucositis in Anal Cancer: A Case Report Amanda Brahim, PharmD, BCPS; William Kernan, PharmD, BCPS; Mohammed Ibrahim, RPh, BCOP, BCPS, BCACP; Tim Nguyen, MD; Zahava Ohana, PharmD Background: Mucositis is a significant adverse effect of chemotherapy that often leads to treatment delays or to dose reductions. Palifermin is a human keratinocyte growth factor that is indicated to decrease the incidence and the duration of severe oral mucositis in patients with hematologic malignancies who are receiving myelotoxic therapy requiring hematopoietic stemcell support. Limited data are available concerning the efficacy and the safety of palifermin in the setting of solid tumors. Objectives: To describe the use of palifermin outside of its US Food and Drug Administrationâ&#x20AC;&#x201C; approved indication in a 70-year-old patient with stage IIIc squamous-cell anal carcinoma for the secondary prevention of oral mucositis when using fluorouracil plus mitomycin concurrent with radiation therapy. Discussion: This patient was treated according to the Nigro protocol, and he experienced severe mucositis associated with his first 4 days of treatment (World Health Organization grade 3) with significant pain for more than 2 weeks. On day 32, a single dose of palifermin 180 mcg was administered as an intravenous bolus. The patient was able to receive fulldose chemotherapy and radiation and did not experience adverse effects related to taking palifermin. Mucositis was minimal, with no pain reported by the patient and only 2 small superficial ulcers noted on physical examination. Conclusion: To our knowledge, there are no other case reports of the use of palifermin to prevent oral mucositis in a patient receiving high-dose fluorouracil plus mitomycin concurrent with radiation therapy. Although our patient experienced great benefit from treatment with no adverse effects, the use of palifermin in nonhematologic malignancies remains controversial because of the potential concern of tumor growth stimulation and of interference with clinical outcomes.

ucositis is the inflammation of oral mucosa resulting from chemotherapeutic agents or ionizing radiation and is a significant adverse effect of cancer chemotherapy, as reported by patients.1-4 It typically manifests as erythema, which may progress to erosion and to severe ulcerations involving the oral cavity, oropharynx, and hypopharynx. The frequency of oral mucositis is estimated to be between 5% and 40% in patients receiving myelosuppressive chemotherapy for solid malignancies.1-4 It can lead to significant pain, requirement of total parenteral nutrition, systemic infections, increased number of hospitalizations, and increased length of stay.1-4 Mucositis is estimated to result in a dose reduction

J Hematol Oncol Pharm. 2013;3(2):51-57 www.JHOPonline.com Disclosures are at end of text

in approximately 23% to 28% of chemotherapy cycles.5 The risk for the development of oral mucositis may vary according to patient age, chemotherapy regimen, comorbidities, type of malignancy, and baseline oral condition. A variety of assessment scales have been developed. These scales consider mucosal changes, symptoms, and functional assessments. The World Health Organization (WHO) scale is one of the most widely used scales, and it grades mucositis from grades 1 to 4, with 4 being the most severe (Table 1).6 For patients who are at risk of developing oral mucositis, prevention and treatment options are limited. Effective oral hygiene (using soft toothbrushes, flossing, and using bland rinses, such as 0.9% saline, sodium

Dr Brahim is Clinical Pharmacist, Dr Kernan is Assistant Pharmacy Director and Pharmacy Residency Director, Mr Ibrahim is Pharmaceutical Care Manager, Dr Nguyen is an associate staff member in oncology, and Dr Ohana is Pharmacist; all at Cleveland Clinic Florida, Weston.

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Table 1 WHO Grading Scale for Assessment of Oral Mucositis Grade

Description

None

Soreness ± erythema, no ulceration

Erythema, ulcers; patients can swallow solid diet

Ulcers, extensive erythema; patients cannot swallow solid diet

Oral mucositis to the extent that alimentation is not possible

WHO indicates World Health Organization. Source: Reference 6.

bicarbonate, and water) and topical therapies, including topical anesthetics and mucosal-coating agents, are recommended by the Multinational Association of Supportive Care in Cancer and in the European Society for Medical Oncology clinical practice guidelines.1,2 Preventive oral cryotherapy is the application of ice chips to the oral cavity before and up to 30 minutes during the administration of antineoplastic agents.1,2 Cryotherapy may be useful in preventing the oral mucositis that is associated with chemotherapeutic agents administered as an intravenous (IV) bolus, such as 5-fluorouracil (5-FU).1,2,7 However, cryotherapy is not practical for continuous infusion chemotherapy.7

Palifermin is indicated to decrease the incidence and the duration of severe oral mucositis in patients with hematologic malignancies who are receiving myelotoxic therapy that requires hematopoietic stemcell support. The efficacy of palifermin has not been established in patients with nonhematologic malignancies. Palifermin is a human keratinocyte growth factor (KGF) produced by recombinant DNA technology in Escherichia coli.8-11 Endogenous KGF is a protein produced by mesenchymal cells in response to epithelial tissue injury. KGF binds to the KGF receptors and may result in the proliferation, differentiation, and migration of epithelial cells. KGF receptors have been detected in multiple tissues (eg, on the tongue, buccal mucosa, esophagus, stomach, and intestine).8-11

Journal of Hematology Oncology Pharmacy

Palifermin is indicated to decrease the incidence and the duration of severe oral mucositis in patients with hematologic malignancies who are receiving myelotoxic therapy that requires hematopoietic stem-cell support.7 Palifermin’s mechanism of action is multifactorial. Palifermin increases the thickness of mucosal epithelium through its mitogenic effect, upregulates gene encoding for scavenging enzymes, and stimulates interleukin-13, which reduces tumor necrosis factor.1 In addition, palifermin exerts antiapoptotic effects and reduces angiogenesis.1,2 The recommended dose of palifermin is 60 mcg/kg administered as an IV bolus daily for 3 days before conditioning treatment and for 3 days after myelotoxic therapy, thereby totaling 6 doses.2,8 The efficacy of palifermin has not been established in patients with nonhematologic malignancies.8 The following case report describes the off-label use of palifermin to prevent oral mucositis in a patient receiving fluorouracil, mitomycin, and radiation for anal cancer.

Case Report A 70-year-old man was diagnosed with anal cancer after a biopsy revealed invasive, moderately differentiated stage IIIc squamous-cell carcinoma. A positron emission tomography scan showed positive anal lesion and bilateral inguinal lymph nodes. The patient’s medical history was significant for obstructed sleep apnea, osteoarthritis, and hyperlipidemia. His social history included smoking of 60 pack-years and consumption of approximately 15 oz to 18 oz of alcohol weekly (10-12 mixed drinks weekly). His home medications included fluticasone 50-mcg nasal spray at bedtime, atorvastatin 10 mg daily at bedtime, diazepam 10 mg daily at bedtime, hydrochlorothiazide 12.5 mg daily, transdermal testosterone daily, vitamin E 100 U daily, and oxycodone plus acetaminophen 10/650 mg every 6 hours as needed for pain. Three weeks after his diagnosis, the patient was initiated on concurrent chemoradiation according to the Nigro regimen. The regimen consisted of 5-FU 1000 mg/m2 daily (actual dose, 2100 mg over 24 hours) continuous IV infusion on days 1 to 4 and on days 29 to 32, and mitomycin 10 mg/m2 (actual dose, 21 mg) as an IV bolus on days 1 and 29, concurrent with radiation therapy of 1.8 Gy daily, 5 days weekly for 5 weeks (total, 45 Gy). Before the first treatment, the review of systems and the patient’s physical examination were normal. His only complaint was some perianal discomfort and infrequent bleeding. The patient was otherwise healthy with an Eastern Cooperative Oncology Group Performance Status grade of 0.12 On day 6, the patient was seen by the oncologist and

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Palifermin for Prevention of Chemotherapy-Induced Mucositis in Anal Cancer

was found to have developed WHO grade 3 mucositis; oral mucosa was noted to be red with ulcer lesions and fissures at the corners of the lips. The patient described the pain as a 10 (on a scale of 0-10), with a burning, constant pain and the inability to swallow solid food, which started on day 3. The patient was still able to swallow liquids and medications. Pain management was initiated with oxycodone plus acetaminophen 10/325 mg every 4 hours as needed for pain, and fentanyl 25-mcg transdermal patch applied every 72 hours. Oral rinses every 4 hours with 5 mL to 10 mL of magic mouthwash (antacid, 30 mL; viscous lidocaine 2%, 50 mL; nystatin oral suspension 100,000 U/mL, 30 mL) and saline solution were started as well. On day 10, the patient developed grade 3 neutropenia, and his laboratory values showed a white blood cell count of 1.1 K/µL and an absolute neutrophil count of 0.5 K/µL. The patient reported a pain level of 8 (scale, 0-10) despite taking pain medications as prescribed. The oral cavity was described as having moist oral mucosa, erythema of the tongue with small visible ulcers, and generalized redness. The decision was made to hold radiation from day 10 and to restart it on day 15 because of mucositis and neutropenia, and to start the patient on filgrastim 480 mcg daily subcutaneously for 3 days. The patient was instructed to continue using oral rinses (ie, magic mouthwash, baking soda, and salt solution). On day 14, a physical examination revealed partial recovery of mucous membranes, although the patient still verbalized a pain level in the mouth of 8 and trouble swallowing. On day 17, a physical examination revealed moist oral mucosa without lesions, and the pain was rated as 4 on a scale of 0 to 10. On day 23, a physical examination revealed moist oral mucosa with erythema with no ulcer, and the patient rated his pain level as 0. When the patient experienced 13 days of mucositis after chemotherapy treatment days 1 to 4, he refused further treatment out of fear of developing mucositis, despite several patient–provider discussions. The patient’s refusal led to a treatment delay. To address his concerns and to minimize subsequent toxicities, a number of options were evaluated, including a 25% dose reduction of the overall regimen and/or the omission of mitomycin from the regimen. However, these alternatives could possibly compromise the treatment’s effectiveness. The option of a one-time dose of palifermin was presented to the physician and to the patient, although evidence of use in this setting was lacking. The decision was made to use palifermin off label as a single dose 3 days before the initiation of chemotherapy on day 35. The patient consented with this plan. At 72 hours before receiving chemotherapy, the patient was administered palifermin 180 mcg/kg as an IV

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bolus in a single dose in the outpatient clinic, which the patient tolerated well. He was monitored in the infusion center for 2 hours postadministration and then discharged home. He also received filgrastim 480 mcg daily subcutaneously for 2 days on days 33 and 34 as prophylaxis for neutropenia. The patient was given education about the importance of good oral hygiene and about smoking cessation, but he never stopped smoking. Chemotherapy was started on day 35. The patient received a full dose of fluorouracil 1000 mg/m2 daily (actual dose, 2100 mg over 24 hours) in a continuous IV infusion on days 35 to 39 and mitomycin 10 mg/m2 (actual dose, 21 mg) as an IV bolus on day 35. During a follow-up visit on day 39, the patient reported to be pain free, and a physical examination revealed moist oral mucosa without lesions. In an interview with the patient, he stated that he did not experience any mucositis-related pain. On day 46, the patient came to the emergency department with a chief complaint of fever and chills and was admitted (temperature, 100°F; white blood cell count, 0.4 K/µL; absolute neutrophil count, 0.2 K/µL), where he received IV vancomycin and piperacillin plus tazobactam. On physical examination during this admission, the patient was noted as having pink mucous membranes, except for 2 small superficial ulcers. The patient was discharged on day 49. Blood cultures that were taken on day 46 showed no growth at 5 days. During a follow-up visit on day 50, the physical examination revealed moist oral mucosa with 2 superficial oral ulcers and no mouth pain. The patient denied dysphagia and odynophagia. On day 66, he had no change of appetite, energy, or weight, and his oral mucosa was noted to be moist without lesions. During a follow-up interview with the patient approximately 1 month after completion of the chemoradiation therapy, he stated that he experienced no mucositis-related pain. One year after completing treatment, he has no evidence of new soft tissue masses seen on computed tomography scan at 3 months, 6 months, 12 months, and 18 months posttreatment. The patient follows up regularly with the oncologist and with the colorectal surgeon.

Discussion Patients may experience increased toxicities associated with their cancer treatments now that more intensive cancer therapies, including radiation, cytotoxic chemotherapy, and biologic-targeted therapies, are being used. One of the most significant of these toxicities is mucositis. Oral mucositis oftentimes is a dose-limiting toxicity.5 The development and evaluation of supportive agents that improve patients’ quality of life, as well as clinical

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Original ARTICLE

outcomes, are critical. By stimulating epithelial-cell proliferative activity, palifermin has a unique mechanism of action that is useful for the prevention of mucositis. The use of palifermin in hematologic malignancies and stem-cell transplants has been established, but its efficacy in nonhematologic malignancies has yet to be conclusively determined.13 Several clinical trials have evaluated the use of palifermin in the prevention of mucositis in patients with solid tumors.14-19 A PubMed search for clinical trials that was limited to the past 15 years using the key words “palifermin,” “solid tumors,” and “mucositis” yielded several articles, as listed below and in Table 2.

Patients may experience increased toxicities associated with their cancer treatments now that more intensive cancer therapies, including radiation, cytotoxic chemotherapy, and biologic-targeted therapies, are being used. One of the most significant of these toxicities is mucositis. A phase 1/2 randomized, double-blind, placebo-controlled study was conducted of patients with metastatic colorectal cancer who were receiving fluorouracil-based chemotherapy.16 Patients received leucovorin 20 mg/m2 administered by IV injection, immediately followed by an IV bolus of fluorouracil 425 mg/m2 once daily for 5 consecutive days. Patients received 2 chemotherapy cycles. The patients in the treatment arm received IV palifermin 40 mcg/kg daily for 3 consecutive days before chemotherapy. The efficacy outcomes included incidence, duration, and severity of mucositis (WHO grades 2-4). Safety evaluations included adverse events, clinical laboratory values, and the development of antipalifermin antibodies. The incidence of WHO grade 2 or higher mucositis was significantly lower in the palifermin group versus in the group receiving placebo (29% vs 61%; P = .016). The overall incidence of adverse events was comparable between the study groups. One patient in the study developed antipalifermin antibodies; titers were below the quantitation limit. Of note, fewer patients in the palifermin group required a chemotherapy dose reduction during cycle 2 than patients in the placebo group. Vadhan-Raj and colleagues conducted a randomized, double-blind, placebo-controlled trial to evaluate the efficacy of palifermin when it is given as a single dose before each cycle of chemotherapy in 48 patients with sarcoma who had already experienced severe mucositis.15

Journal of Hematology Oncology Pharmacy

Patients were given palifermin 180 mcg/kg or placebo intravenously as a single dose 3 days before chemotherapy with doxorubicin and ifosfamide in each cycle. The primary end point was the incidence of moderate-to-severe mucositis (≥grade 2). Patients in the palifermin group experienced a lower incidence of grade 2 or higher mucositis versus the placebo group (44% vs 88%, respectively; P <.001). Common adverse events included patient-reported sensation of increased thickness of oral mucosa, altered taste, and a film coating in the mouth. A phase 2 trial evaluated the efficacy of palifermin in patients receiving concurrent chemoradiotherapy for advanced head and neck squamous-cell carcinoma.14 Patients in the treatment arm were given 60 mcg/kg of palifermin once weekly for 10 doses. The primary outcome of median duration of grade 2 or greater mucositis was shorter for palifermin than for placebo (6.5 and 8.1 weeks, respectively), but the difference was not significant (P = .157). The proportion of patients who still had grade 2 mucositis at week 12 was 47% in the palifermin group and 42% in the placebo group. The authors noted that the palifermin dose may have been too low to show a significant difference, because the study was powered to detect a mean difference of 30%, based on results from a previous trial.14 Le and colleagues conducted a multicenter, double-blind study of 188 patients receiving postoperative concurrent chemoradiotherapy (2.0 Gy daily, 5 days weekly, to 70 Gy) with cisplatin (100 mg/m2 on days 1, 22, and 43) for locally advanced head and neck squamous-cell carcinoma.19 The patients in the study arm received palifermin 120 mcg/kg 3 days before treatment and then weekly for 7 weeks. The primary end point was the incidence of severe mucositis (WHO grades 3-4), in which significance was reached (54% vs 69%, respectively; P = .041). Overall survival and progression-free survival were similar between the 2 arms after a median follow-up of almost 26 months. Henke and colleagues studied the efficacy of palifermin in patients who were undergoing postoperative radiochemotherapy for head and neck cancer.20 This multicenter, double-blind, randomized trial enrolled 92 patients in the palifermin arm and 94 patients in the placebo arm. Patients received 60 Gy or 66 Gy of radiochemotherapy after complete (R0) or incomplete (R1) resection, respectively, at 2 Gy per fraction and 5 fractions weekly. Cisplatin 100 mg/m2 was administered on days 1 and 22 (and on day 43 with R1 resection). Patients were randomly assigned to receive weekly palifermin 120 mcg/kg or placebo from 3 days before radiochemotherapy and continuing throughout radiochemotherapy.

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Palifermin for Prevention of Chemotherapy-Induced Mucositis in Anal Cancer

Table 2 Recent Clinical Trials Using Palifermin for Solid Tumors and Mucositis Cancer type

Study Brizel, et al

Locally advanced head and neck

Patients, N Placebo, 32 Palifermin, 69

WHO criteria for Palifermin dose mucositis

Chemotherapy regimen Cisplatin 20 mg/m daily

Results

60 mcg/kg weekly for 10 weeks

≥Grade 2

Median duration, 6.5 weeks (palifermin) vs 8.1 weeks (placebo), P = .157

Doxorubicin 90 mg/m2 CIVI over 72 hours and ifosfamide 10 g/m2 day for 4 days, or cisplatin 120 mg/m2 intraarterially for osteosarcoma

180 mcg/kg as a single dose 3 days before chemotherapy cycle

≥Grade 2

Palifermin 44% vs placebo 88%, P<.001

Fluorouracil 425 mg/m2 day IV for 5 days

40 mcg/kg for 3 days before chemotherapy

≥Grade 2

Palifermin vs placebo, 29% vs 61%, respectively, P = .016 for cycle 1; 11% vs 47%, P = .003 for cycle 2

180 mcg/kg before starting chemotherapy and then once weekly for 7 weeks

Primary Palifermin 54% vs end point, placebo 69%, grades 3-4 P = .041

Fluorouracil 1000 mg/m2 daily CIVI for 4 days on weeks 1 and 5 Radiotherapy for 7 weeks

Vadhan-Raj, et al15 Sarcoma

Rosen, et al16

Placebo, 16 Palifermin, 32

Metastatic Placebo, 36 colorectal Palifermin, 28

Leucovorin 20 mg/m2 day for 5 days for 2 cycles Le, et al19

Henke, et al20

Locally advanced head and neck

Placebo, 94 Palifermin, 94

Locally advanced head and neck

Placebo, 94 Palifermin, 92

Cisplatin 100 mg/m2 on days 1, 22, and 43 of radiotherapy Fractionated radiotherapy (2.0 Gy, 5 days weekly to 70 Gy)

Primary Palifermin 51% vs Cisplatin 100 mg/m2 120 mcg/kg on days 1 and 22 (day weekly through- end point, placebo 67%, out radiochemo- grades 3-4 P = .027 43 for R1) therapy starting Radiation 60 or 66 3 days earlier Gy after complete (R0) or incomplete resection (R1), respectively, at 2 Gy/fraction and 5 fractions weekly

CIVI indicates continuous intravenous infusion; IV, intravenous; WHO, World Health Organization.

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Original ARTICLE

The primary end point was the incidence of severe oral mucositis (WHO grades 3-4). Patients in the palifermin group experienced severe oral mucositis at a significantly lower rate (51% vs 67%, respectively; P = .027) than in the placebo group. Adverse effects were similar between the 2 groups. Survival times for the palifermin and the placebo arms were nearly identical after a median follow-up of almost 33 months. The investigators cautioned against generalization of these results because of their small sample size.

A concern of using palifermin for multiple doses up to the day before chemotherapy for repeated cycles is that because mucosal tissue is rapidly proliferating, it may be more sensitive to chemotherapy-induced injury. In addition, if tumors were to express the KGF receptors, the administration of palifermin could theoretically lead to the stimulation of tumor growth. The use of palifermin in the setting of solid tumors raises questions that are not applicable to the treatment of patients with hematologic malignancies, because epithelial cells express KGF receptors, whereas blood cells do not.17 A concern of using palifermin for multiple doses up to the day before chemotherapy for repeated cycles is that because mucosal tissue is rapidly proliferating, it may be more sensitive to chemotherapy-induced injury. In addition, if tumors were to express the KGF receptors, the administration of palifermin could theoretically lead to the stimulation of tumor growth and therefore interfere with disease outcomes, although in vitro and in vivo studies do not indicate a definitive role for KGF in tumor genesis.17 However, if the medication is given as a single dose, this issue may be avoided. Clinical studies that were conducted in patients with hematologic and solid tumor cancer did not show adverse clinical outcomes.14-16,18-20 Furthermore, in a phase 2 study of patients with head and neck squamous-cell carcinoma, mucosal cells in patients who were given a single dose of palifermin were shown to express cyclin E, a putative G1 marker, thereby suggesting that most of the mucosal cells were not actively dividing.15 In light of the experiences with erythropoietin-stimulating agents and their effect on tumor growth, it is important to assess the long-term safety of this KGF.

Journal of Hematology Oncology Pharmacy

The patient described in this case report had several risk factors for the development of oral mucositis. Fluorouracil is known to be one of the agents with the highest risk of developing mucositis, and the addition of radiation to chemotherapy further increases this risk.1,2 Delaying radiation treatment, as was done during the first cycle, has been documented to lead to poorer outcomes.21 Additional patient-specific risk factors included his continued alcohol consumption and his tobacco use. The patient received a dose of 180 mcg/kg of palifermin, corresponding to the dose that was used in the above-mentioned clinical trial by Vadhan-Raj and colleagues, which was available at the time.15 The study by Vadhan-Raj and colleagues also established the efficacy of palifermin as prophylaxis in patients who already experienced severe mucositis, as our patient did. Subsequent trials that were conducted in patients with head and neck cancer have been published with alternative dosing regimens with varying results. However, no data were available about the use of palifermin in a regimen of fluorouracil 1000 mg/m2 plus mitomycin 100 mg/m2 concurrent with radiation. Our patient tolerated palifermin very well, with no complaints of adverse effects, which is consistent with experiences in the literature. The side effects tend to be mild for most patients, including altered taste and dry mouth. To date, the patient described in this case report did not suffer any adverse clinical outcomes that could possibly be linked to his use of palifermin. However, we still have limited data on the use of palifermin in multiple doses for repeated cycles on clinical outcomes, such as survival rate and time to disease progression. Our decision to use palifermin was made after other therapies (ie, oral rinses, cryotherapy) had failed to relieve the patientâ&#x20AC;&#x2122;s symptoms. Furthermore, our patient was refusing the continuation of chemoradiation, even though his disease was very curable. The positive experience from this case report cannot necessarily be extrapolated to patients with solid tumors, who are at a lower risk for developing mucositis.

Conclusion Clinical trials of palifermin use in patients with solid tumors show promise, but there is little consistency across studies concerning dosing and primary end points. No clinical trials have evaluated the use of palifermin in high-dose fluorouracil therapy combined with radiation, such as the Nigro regimen. To our knowledge this is the first report of palifermin being used in a patient with anal cancer for the prevention of mucositis. Further research

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Palifermin for Prevention of Chemotherapy-Induced Mucositis in Anal Cancer

for the long-term safety and efficacy of palifermin in patients with nonhematologic malignancies is warranted. Palifermin may only be an option once other therapies are exhausted because of its possible effects on patient outcomes, especially in early-stage solid-tumor cancers. An extensive patient-specific risk-versus-benefit analysis needs to be conducted before using palifermin in this setting. n Author Disclosure Statement Dr Brahim, Dr Kernan, Mr Ibrahim, Dr Nguyen, and Dr Ohana reported no conflicts of interest.

References

1. Keefe DM, Schubert MM, Elting LS, et al; Mucositis Study Section of the Multinational Association of Supportive Care in Cancer and the International Society for Oral Oncology. Updated clinical practice guidelines for the prevention and treatment of mucositis. Cancer. 2007;109:820-831. 2. Peterson DE, Bensadoun RJ, Roila F; ESMO Guidelines Working Group. Management of oral and gastrointestinal mucositis: ESMO clinical recommendations. Ann Oncol. 2009;20(suppl 4):174-177. 3. Treister NS, Woo S-B. Chemotherapy-induced oral mucositis. MedScape. Updated April 23, 2013. http://emedicine.medscape.com/article/1079570-over view. Accessed April 25, 2013. 4. Borbasi S, Cameron K, Quested B, et al. More than a sore mouth: patientsâ&#x20AC;&#x2122; experience of oral mucositis. Oncol Nurs Forum. 2002;29:1051-1057. 5. Elting LS, Cooksley C, Chambers M, et al. The burdens of cancer therapy: clinical and economic outcomes of chemotherapy-induced mucositis. Cancer. 2003;98:1531-1539. 6. World Health Organization. WHO Handbook for Reporting Results of Cancer Treatment. Geneva, Switzerland: World Health Organization. 1979. http://whqlib doc.who.int/offset/WHO_OFFSET_48.pdf. Accessed April 2, 2013. 7. Rubenstein EB, Peterson DE, Schubert M, et al; Mucositis Study Section of the Multinational Association for Supportive Care in Cancer, International Society for Oral Oncology. Clinical practice guidelines for the prevention and treatment

of cancer therapy-induced oral and gastrointestinal mucositis. Cancer. 2004;100(9 suppl):2026-2046. 8. Kepivance (palifermin) [prescribing information]. Stockholm, Sweden: Swedish Orphan Biovitrum AB; November 2011. 9. Osslund TD, Syed R, Singer E, et al. Correlation between the 1.6 A crystal structure and mutational analysis of keratinocyte growth factor. Protein Sci. 1998;7:1681-1690. 10. Danilenko DM. Preclinical and early clinical development of keratinocyte growth factor, an epithelial-specific tissue growth factor. Toxicol Pathol. 1999;27:64-71. 11. Werner S. Keratinocyte growth factor: a unique player in epithelial repair processes. Cytokine Growth Factor Rev. 1998;9:153-165. 12. Oken MM, Creech RH, Tormey DC, et al. Toxicity and response criteria of the Eastern Cooperative Oncology Group. Am J Clin Oncol. 1982;5:649-655. 13. Spielberger R, Emmanouilides C, Stiff P, et al. Use of recombinant human keratinocyte growth factor (palifermin) can reduce severe oral mucositis in patients with hematologic malignancies undergoing autologous peripheral blood progenitor cell transplantation after radiation-based conditioning. J Support Oncol. 2004;2(suppl 2):73-74. 14. Brizel DM, Murphy BA, Rosenthal DI, et al. Phase II study of palifermin and concurrent chemoradiation in head and neck squamous cell carcinoma. J Clin Oncol. 2008;26:2489-2496. 15. Vadhan-Raj S, Trent J, Patel S, et al. Single-dose palifermin prevents severe oral mucositis during multicycle chemotherapy in patients with cancer: a randomized trial. Ann Intern Med. 2010;153:358-367. 16. Rosen LS, Abdi E, Davis ID, et al. Palifermin reduces the incidence of oral mucositis in patients with metastatic colorectal cancer treated with fluorouracil-based chemotherapy. J Clin Oncol. 2006;24:5194-5200. 17. Finch PW, Rubin JS. Keratinocyte growth factor expression and activity in cancer: implications for use in patients with solid tumors. J Natl Cancer Inst. 2006;98:812-824. 18. Bossi P, Locati LD, Licitra L. Palifermin in prevention of head and neck cancer radiation-induced mucositis: not yet a definitive word on safety and efficacy profile. J Clin Oncol. 2012;30:564-565. 19. Le QT, Kim HE, Schneider CJ, et al. Palifermin reduces severe mucositis in definitive chemoradiotherapy of locally advanced head and neck cancer: a randomized, placebo-controlled study. J Clin Oncol. 2011;29:2808-2814. 20. Henke M, Alfonsi M, Foa P, et al. Palifermin decreases severe oral mucositis of patients undergoing postoperative radiochemotherapy for head and neck cancer: a randomized, placebo-controlled trial. J Clin Oncol. 2011;29:2815-2820. 21. Pepek JM, Willet CG, Czito BG. Radiation therapy advances for treatment of anal cancer. J Natl Compr Canc Netw. 2010;8:123-129.

4th AnnuAl ConferenCe

MAy 7-9, 2014 loews hollywood hotel los Angeles, CA www.AvbCConline.org Vol 3, No 2

June 2013

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Journal of Hematology Oncology Pharmacy

CONTINUING EDUCATION 6th Annual

MAY 2013 • VOLUME 6 • NUMBER 2

CONSIDERATIONS in

Multiple Myeloma

™

ASK THE EXPERTS: Maintenance Settings PUBLISHING STAFF Group Director, Sales & Marketing John W. Hennessy john@greenhillhc.com Editorial Director Susan A. Berry susan@coexm.com Senior Copy Editor BJ Hansen Copy Editors Dana Delibovi Rosemary Hansen Grants/Project Associate Susan Yeager The Lynx Group President/CEO Brian Tyburski

LETTER

FROM THE

EDITOR-IN-CHIEF

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

Chief Operating Officer Pam Rattanonont Ferris

Sagar Lonial, MD Professor Vice Chair of Clinical Affairs Department of Hematology and Medical Oncology Winship Cancer Institute Emory University School of Medicine Atlanta, GA

Vice President of Finance Andrea Kelly Director, Human Resources Blanche Marchitto Associate Editorial Director, Projects Division Terri Moore Director, Quality Control Barbara Marino Director, Production & Manufacturing Alaina Pede Director, Creative & Design Robyn Jacobs Creative & Design Assistant Lora LaRocca Director, Digital Media Anthony Romano Web Content Managers David Maldonado Anthony Travean

FACULTY Kenneth C. Anderson, MD Director, Jerome Lipper Multiple Myeloma Center and LeBow Institute for Myeloma Therapeutics Kraft Family Professor of Medicine Harvard Medical School Dana-Farber Cancer Institute, Boston, MA

Tina Flaherty, ANP-BC, AOCN Nurse Practitioner Division of Hematologic Malignancies Dana-Farber Cancer Institute Boston, MA

Houry Leblebjian, PharmD, BCOP Clinical Pharmacy Specialist in Hematology/Oncology Dana-Farber Cancer Institute Boston, MA

Digital Programmer Michael Amundsen Senior Project Manager Andrea Boylston Project Coordinators Deanna Martinez Jackie Luma

Supported by educational grants from Onyx Pharmaceuticals and Millennium: The Takeda Oncology Company.

Executive Administrator Rachael Baranoski Office Coordinator Robert Sorensen

This activity is jointly sponsored by Medical Learning Institute Inc and Center of Excellence Media, LLC.

Center of Excellence Media, LLC 1249 South River Road - Ste 202A Cranbury, NJ 08512

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CONSIDERATIONS IN MULTIPLE MYELOMA Sponsors This activity is jointly sponsored by Medical Learning Institute Inc and Center of Excellence Media, LLC. Commercial Support Acknowledgment This activity is supported by educational grants from Onyx Pharmaceuticals and Millennium: The Takeda Oncology Company. Target Audience The activity was developed for physicians, nurses, and pharmacists involved in the treatment of patients with multiple myeloma (MM). Purpose Statement The purpose of this activity is to enhance competence of physicians, nurses, and pharmacists concerning the treatment of MM. Physician Credit Designation The Medical Learning Institute Inc designates this enduring material for a maximum of 1.0 AMA PRA Category 1 Credits™. Physicians should claim only the credit commensurate with the extent of their participation in the activity. This activity has been planned and implemented in accordance with the Essential Areas and policies of the Accreditation Council for Continuing Medical Education through the joint sponsorship of the Medical Learning Institute Inc and the Center of Excellence Media, LLC. The Medical Learning Institute Inc is accredited by the Accreditation Council for Continuing Medical Education to provide continuing medical education for physicians. Registered Nurse Designation Medical Learning Institute Inc Provider approved by the California Board of Registered Nursing, Provider Number 15106, for 1.0 contact hour. Registered Pharmacy Designation The Medical Learning Institute Inc is accredited by the Accreditation Council for Pharmacy Education as a provider of continuing pharmacy education. Completion of this application-based activity provides for 1.0 contact hour (0.1 CEU) of continuing pharmacy education credit. The Universal Activity Number for this activity is 0468-9999-13-012-H01-P. Learning Objectives Upon completion of this activity, the participant will be able to: • Discuss existing and emerging therapeutic options for patients with newly diagnosed or relapsed/refractory MM and how to tailor therapy for individual patients

• Describe the pharmacokinetics and pharmacodynamics of novel agents when integrating these agents into treatment regimens for MM • Evaluate adverse event management strategies for patients with MM receiving novel therapies and multidrug regimens Disclosures Before the activity, all faculty and anyone who is in a position to have control over the content of this activity and their spouse/life partner will disclose the existence of any financial interest and/or relationship(s) they might have with any commercial interest producing healthcare goods/services to be discussed during their presentation(s): honoraria, expenses, grants, consulting roles, speakers’ bureau membership, stock ownership, or other special relationships. Presenters will inform participants of any off-label discussions. All identified conflicts of interest are thoroughly vetted by Medical Learning Institute Inc for fair balance, scientific objectivity of studies mentioned in the materials or used as the basis for content, and appropriateness of patient care recommendations. The associates of Medical Learning Institute Inc, the accredited provider for this activity, and Center of Excellence Media, LLC, do not have any financial relationships or relationships to products or devices with any commercial interest related to the content of this CME/CPE/CE activity for any amount during the past 12 months. Planners’ and Managers’ Disclosures William J. Wong, MD, MLI Reviewer, has nothing to disclose. Bobbie Perrin, RN, OCN, MLI Reviewer, has nothing to disclose. Shelly Chun, PharmD, MLI Reviewer, has nothing to disclose. Faculty Disclosures Sagar Lonial, MD, is on the Advisory Board for and is a Consultant to Bristol-Myers Squibb, Celgene Corporation, Millennium: the Takeda Oncology Company, Novartis, Onyx Pharmaceuticals, and sanofi-aventis. He does not intend to discuss any non-FDA-approved or investigational use for any products/devices. Kenneth C. Anderson, MD, is on the Advisory Boards for Celgene Corporation, Gilead, Onyx Pharmaceuticals, and sanofi-aventis, and is a Scientific Founder for Acetylon Pharmaceuticals, Inc., and OncoPep, Inc. He does not intend to discuss any non-FDA-approved or investigational use for any products/devices. Tina Flaherty, ANP-BC, AOCN, has nothing to disclose. She does not intend to discuss any non-FDA-approved or investigational use for any products/devices. Houry Leblebjian, PharmD, BCOP, is on the Advisory Board for Teva Pharmaceuticals Industries, Ltd. She does not intend to

discuss any non-FDA-approved or investigational use for any products/devices. Disclaimer The information provided in this CME/CPE/CE activity is for continuing education purposes only and is not meant to substitute for the independent medical judgment of a healthcare provider relative to diagnostic and treatment options of a specific patient’s medical condition. Recommendations for the use of particular therapeutic agents are based on the best available scientific evidence and current clinical guidelines. No bias towards or promotion for any agent discussed in this program should be inferred. Instructions for Credit There is no fee for this activity. To receive credit after reading this CME/CPE/CE activity in its entirety, participants must complete the pretest, posttest, and evaluation. The pretest, posttest, and evaluation can be completed online at www.mlicme.org/P13008B. html. Upon completion of the evaluation and scoring 70% or better on the posttest, you will immediately receive your certificate online. If you do not achieve a score of 70% or better on the posttest, you will be asked to take it again. Please retain a copy of the certificate for your records. For questions regarding the accreditation of this activity, please contact Medical Learning Institute Inc at 609-333-1693 or cgusack@mlicme.org. For pharmacists, Medical Learning Institute Inc will report your participation in this educational activity to the NABP only if you provide your NABP e-Profile number and date of birth. For more information regarding this process or to get your NABP e-Profile number, go to www.mycpemonitor.net. Estimated time to complete activity: 1.0 hour Date of initial release: May 14, 2013 Valid for CME/CPE/CE credit through: May 14, 2014

SCAN HERE to Download the PDF or Apply for Credit. To use 2D barcodes, download the ScanLife app: • Text “scan” to 43588 • Go to www.getscanlife.com on your smartphone’s Web browser, and select “Download” • Visit the app store for your smartphone

The Role of Consolidation and Maintenance Therapies for Improving Myeloma Care Kenneth C. Anderson, MD

Director, Jerome Lipper Multiple Myeloma Center and LeBow Institute for Myeloma Therapeutics Kraft Family Professor of Medicine, Harvard Medical School Dana-Farber Cancer Institute, Boston, MA

Introduction With the advent of novel, targeted agents, consolidation and maintenance therapies have become a key component of care in multiple myeloma (MM). Lenalidomide, thalidomide, and bortezomib can consolidate response after stem cell transplantation and provide ongoing maintenance to prolong response duration. Improved outcomes result, but the efficacy of these agents must be weighed against the potential risks of additional treatment. In this article, Kenneth C. Anderson, MD, shares insights and best practices in the use of consolidation and maintenance in the age of molecularly targeted antimyeloma therapies.

How is maintenance therapy different from consolidation? Consolidation therapy is given to increase the depth of response following treatment. As the term consolidation implies, this therapy is commonly used

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after high-dose melphalan therapy and autologous stem cell transplantation (HDT/ASCT).1 Novel therapies—thalidomide, lenalidomide, or bortezomib—are currently used for consolidation, alone or in combination, for 1 or 2 cycles.2 Evidence shows that such consolidation does increase the depth of response,3 with a significant proportion of patients achieving a molecular complete response (CR).4 Maintenance therapy, in contrast, aims to prolong the duration of response. In the patient who has received HDT/ASCT, maintenance helps extend the response that has been previously achieved through induction, transplantation, and consolidation. Maintenance therapy can also be utilized to prolong response to initial therapy in the elderly population and others ineligible for transplant. Early explorations of maintenance therapy in MM began with interferon alfa-2 and then corticosteroids.5 More recently, thalidomide, lenalidomide, and bortezomib have all been explored and accepted as maintenance therapies.6-10 For example, lenalidomide maintenance has been shown to increase progression-free survival (PFS) in transplant candidates9,10 and in elderly patients with newly diagnosed MM.7 In a US trial of patients receiving HDT/ASCT, the use of lenalidomide as posttransplant maintenance therapy prolonged both PFS and overall survival (OS; Figure).10 In the HOVON-65/GMMG-HD4 trial, bortezomib-based induction (bortezomib/doxorubicin/dexamethasone) plus posttransplant maintenance with bortezomib improved CR, PFS, and OS compared with vincristine-based induction (vincristine/doxorubicin/dexamethasone) followed by thalidomide maintenance.8

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CONTINUING EDUCATION

Figure. Three-year survival rates in the US randomized trial of lenalidomide maintenance post-HDT/ASCT (N=460).10

Placebo, n (%)

Attal 2012 (N=608)9

n=306

n=302

➢Hematologic malignancies

13 (4)

5 (2)

➢Solid tumors

10 (3)

4 (1)

McCarthy 2012 (N=460)10

n=231

n=229

➢Hematologic malignancies

8 (3.5)

1 (0.4)

➢Solid tumors

10 (4.3)

5 (2.2)

80%

Patients (%)

Lenalidomide Maintenance, n (%)

88%

Table 1. Second Primary Cancers in Patients Receiving Lenalidomide Maintenance in Randomized, PlaceboControlled Trials9,10

Lenalidomide maintenance (n=231) Placebo (n=229)

66%

60 50

39%

40 30 20 10 0

PFS*

*Deﬁned as freedom from progression or death. ASCT indicates autologous stem cell transplantation; HDT, high-dose therapy; OS, overall survival; PFS, progression-free survival.

Which factors must be considered when recommending maintenance and choosing a specific agent? Multiple clinical factors affect the decision to use maintenance therapy and the choice of agent. The first thing to consider is the patient’s response history. Trials have generally shown that patients with stable disease (SD), partial response, very good partial response (VGPR), or even CR all have benefited from maintenance therapy.6-10 This evidence suggests that patients who have at least SD as a result of initial treatment enjoy an advantage from maintenance treatment. So, the question that must be asked is: How likely is the patient to benefit, given his or her response to date? A second factor to consider is risk stratification, as determined by cytogenetic abnormalities. To date, the best-studied agent in the maintenance setting is lenalidomide, which has been compared with placebo in 2 randomized trials posttransplant (IFM 2005-02 and CALGB 100104)9,10; in both of these trials, lenalidomide maintenance extended PFS, and in the CALGB trial, OS was prolonged as well.10 This advantage, however, was not evident among the subgroup of patients with high-risk cytogenetics, especially in those with del(17p). For this reason, high-risk patients require more than lenalidomide for maintenance. At our center, these patients receive bortezomib maintenance, often in combination with lenalidomide or thalidomide. This decision is based on recent data suggesting that bortezomib may improve the adverse outcomes usually associated with cytogenetic abnormalities.8,11,12 A third factor in decision-making is the patient’s prior therapy. For instance, if an individual has already received thalidomide in the induction regimen, one might consider using an alternative such as lenalidomide for maintenance. This approach anticipates the potential for development of resistance to the prior therapy. It is also a strategy to use when there is concern about exacerbating an adverse event (AE) seen with prior therapy, such as peripheral neuropathy with thalidomide. Patients may now receive 2 or more novel agents during initial therapy before transplantation. The standard of care is becoming a 3-drug initial regimen, often combinations of targeted therapies. For example, high extent and frequency of response have been documented with lenalidomide/bortezomib/ dexamethasone (RVD)13 or cyclophosphamide/bortezomib/dexamethasone14 for induction in the transplant-eligible population. Regimens like this achieve very high overall response (OR) rates. After these patients receive a transplant, they may get consolidation therapy, often with the same combination of targeted therapies as they received during induction, then go on to receive maintenance therapy with lenalidomide or bortezomib. Similarly, in elderly patients and others who are ineligible for transplant, melphalan plus prednisone may be combined with novel agents (thalidomide, lenalidomide, or bortezomib), followed by maintenance with the same agents—an approach that appears to be effective.7,15,16

Journal of Hematology Oncology Pharmacy

In this context, it may be worth mentioning that, in the United States, the selection of thalidomide for initial therapy or maintenance is less common than in Europe. The United Kingdom’s Medical Research Council conducted a large trial (MRC IX) in patients who received initial therapy with thalidomide-containing regimens, with or without subsequent transplant, followed by thalidomide maintenance or no maintenance. In this trial, thalidomide maintenance enhanced survival outcomes compared with no maintenance—although this benefit did not fully extend to patients with adverse cytogenetics.17 The difference between the United States and Europe in the use of novel agents probably boils down to our ability, in the United States, to use drugs off-label. Lenalidomide, for example, is approved for treatment of relapsed and relapsed/refractory myeloma in the United States.18 Yet, we use lenalidomide commonly in the newly diagnosed patient, in consolidation, and in maintenance. In Europe, however, clinicians are required to use drugs on-label only. This helps explain the greater use in Europe of the older immunomodulatory drug thalidomide. How often do you recommend maintenance for your patients? I routinely recommend maintenance therapy to my patients. My main reason is the knowledge that, in the absence of this therapy, the disease is destined to relapse. My second reason for using maintenance is that randomized trials have demonstrated its value. As described above, lenalidomide maintenance posttransplant, as well as in elderly, nontransplant candidates, has been shown to prolong PFS and, in one major study, OS.7,9,10 Bortezomibbased maintenance has also been associated with longer PFS and OS in these settings,8,15,16 although maintenance with this agent is not as well studied as lenalidomide maintenance. I feel there is an overwhelming benefit to maintenance that outweighs the risks. Lenalidomide is well tolerated; its common AEs in the maintenance setting include neutropenia, diarrhea, upper respiratory infections, and fatigue.9,10 One noteworthy effect is a 2- to 3-fold increased risk of second primary cancers among patients who receive HDT/ASCT plus lenalidomide maintenance treatment (Table 1).9,10 It is important to point out, however, that there are additional risk factors for developing second primary cancer posttransplant when using lenalidomide, including male gender, advanced stage III International Staging System myeloma, and, most importantly, the use of a regimen of dexamethasone/cyclophosphamide/etoposide/cisplatin (DCEP) before transplant.9 The DCEP regimen contains multiple alkylating or DNAdamaging chemotherapeutic agents, so it stands to reason that the avoidance of this combination as induction would markedly reduce the risk of second primary cancers. In our patients, however, I believe that the risk of developing progressive myeloma and dying rapidly from the disease is far greater than any potential risk of a second primary cancer after lenalidomide maintenance. The use of bortezomib as maintenance also has a favorable benefit-to-risk ratio, especially in patients with high-risk cytogenetics. Bortezomib significantly improved PFS and OS in patients with del(13) and del(17p) in the HOVON-65/GMMG-HD4 trial (Table 2),8 identifying a potentially effective treatment option in these types of patients. Therefore, when cytogenetic risk is high, I think adding bortezomib to lenalidomide is a useful approach. The efficacy with less toxicity of subcutaneous bortezomib19 makes this drug more readily applied in the maintenance setting.

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Table 2. Efficacy Results: HOVON-65/GMMG-HD48 VAD (n=414)

PAD (n=413)

P value

All patients

.002

Subgroup with del(17p)

.01

Not reached

N/A

at 66 mo

Not reached

Median PFS,* mo

Median OS,* mo All patients Subgroup with del(17p)

.003

at 54 mo *Median follow-up of 41 months. N/A indicates not available; OS, overall survival; PAD, bortezomib/doxorubicin/dexamethasone; PFS, progression-free survival; VAD, vincristine/doxorubicin/dexamethasone.

How will maintenance therapy for MM continue to evolve? An exciting development that may affect maintenance therapy is the advent of newer targeted agents, most notably, newer proteasome inhibitors such as carfilzomib and MLN9708 (ixazomib). These drugs represent alternative options to combine with lenalidomide in high-risk patients. Carfilzomib is now approved by the US Food and Drug Administration for use in the relapsed/refractory setting,20 and it is being used and evaluated as frontline treatment as well.21,22 Carfilzomib/lenalidomide/dexamethasone (CRd) is a promising combination,21 as well as a potential successor to the very effective induction regimen, RVD.13 For example, in a seminal trial, RVD induction in newly diagnosed MM attained 100% OR, with 67% to 74% of patients achieving VGPR or better.13 A comparable universal response was seen with CRd induction in newly diagnosed patients, with 78% enjoying CR or near CR.21 A clinical trial is currently evaluating CRd both as induction and as posttransplant consolidation therapy and maintenance.23 Another novel proteasome inhibitor, the oral agent MLN9708, can also be combined with lenalidomide and dexamethasone upfront to achieve high response rates.24 This is an all-oral regimen, which is appealing to patients and clinicians alike. An oral proteasome inhibitor would also be a useful option in the maintenance setting. In the near future, maintenance therapy may enable us to delay transplantation. A clinical trial is looking at RVD induction, collection of stem cells after 3 to 4 cycles, and then randomizing patients to receive either HDT/ ASCT plus lenalidomide maintenance or lenalidomide maintenance with no transplant.25 Our favorable experience with novel agents in initial therapy, consolidation, and maintenance has begun to shift the timing of ASCT away from the current standard of early transplant toward delayed transplant. We are gathering clinical evidence on the relative efficacy and safety of novelagent induction followed by early ASCT versus novel-agent induction with ASCT reserved until progression. Maintenance therapy is also becoming more crucial in our efforts to sustain the profound responses we now achieve with these newer drugs. The increasing depth, duration, and frequency of responses have made us more stringent in the way we assess response. We can now regularly attain molecular CR with novel targeted agents, as measured by polymerase chain reaction for the immunoglobulin gene rearrangement or multicolor flow cytometry. A further degree of stringency is evolving from the use of positron emission tomography/computed tomography (PET/CT) in MM. It is now incumbent on us to utilize maintenance therapy in an attempt to prolong the response stringently defined by molecular CR and PET/CT. In summary, novel agents will continue to help us achieve good rates of high-quality response that were never before possible in MM. Consolidation with combination targeted treatments will continue to increase the depth of response, producing molecular CR in a significant fraction of patients. Finally, maintenance therapies with novel agents will continue to prolong PFS and even OS. We will see more gains from ongoing trends. First, building upon 3-drug

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combinations such as RVD, we will see new combinations of immunomodulators, proteasome inhibitors, and steroids, with the addition of monoclonal antibodies, histone deacetylase inhibitors, and other targeted agents. As in other malignancies, a combination of 4 or 5 agents is likely to achieve CR in the majority of patients, if not all. Second, we will advance our ability to measure minimal residual disease and molecular CR, and we can use these metrics to determine the optimal duration of maintenance therapy in MM. Although we have already seen tremendous progress over the past few decades, I believe the best is yet to come in the care of the disease. ♦ References

1. Spencer A, Prince HM, Roberts AW, et al. Consolidation therapy with low-dose thalidomide and prednisolone prolongs the survival of multiple myeloma patients undergoing a single autologous stem-cell transplantation procedure. J Clin Oncol. 2009;27:1788-1793. 2. San-Miguel JF. Consolidation therapy in myeloma: a consolidated approach? Blood. 2012; 120:2-3. 3. Cavo M, Pantani L, Petrucci MT, et al; for the GIMEMA Italian Myeloma Network. Bortezomib-thalidomide-dexamethasone is superior to thalidomide-dexamethasone as consolidation therapy after autologous hematopoietic stem cell transplantation in patients with newly diagnosed multiple myeloma. Blood. 2012;120:9-19. 4. Ladetto M, Pagliano G, Ferrero S, et al. Major tumor shrinking and persistent molecular remissions after consolidation with bortezomib, thalidomide, and dexamethasone in patients with autografted myeloma. J Clin Oncol. 2010;28:2077-2084. 5. National Comprehensive Cancer Network (NCCN). NCCN Clinical Practice Guidelines in Oncology®: Multiple Myeloma. Version 1.2013. http://www.nccn.org. Accessed March 8, 2013. 6. Attal M, Harousseau J-L, Leyvraz S, et al; for the Inter-Groupe Francophone du Myélome (IFM). Maintenance therapy with thalidomide improves survival in patients with multiple myeloma. Blood. 2006;108:3289-3294. 7. Palumbo A, Hajek R, Delforge M, et al; MM-015 Investigators. Continuous lenalidomide treatment for newly diagnosed multiple myeloma. N Engl J Med. 2012;366:1759-1769. 8. Sonneveld P, Schmidt-Wolf IGH, van der Holt B, et al. Bortezomib induction and maintenance treatment in patients with newly diagnosed multiple myeloma: results of the randomized phase III HOVON-65/GMMG-HD4 trial. J Clin Oncol. 2012;30:2946-2955. 9. Attal M, Lauwers-Cances V, Marit G, et al. Lenalidomide maintenance after stem-cell transplantation for multiple myeloma. N Engl J Med. 2012;366:1782-1791. 10. McCarthy PL, Owzar K, Hofmeister CC, et al. Lenalidomide after stem-cell transplantation for multiple myeloma. N Engl J Med. 2012;366:1770-1781. 11. Jagannath S, Richardson PG, Sonneveld P, et al. Bortezomib appears to overcome the poor prognosis conferred by chromosome 13 deletion in phase 2 and 3 trials. Leukemia. 2007; 21:151-157. 12. Neben K, Lokhorst HM, Jauch A, et al. Administration of bortezomib before and after autologous stem cell transplantation improves outcome in multiple myeloma patients with deletion 17p. Blood. 2012;119:940-948. 13. Richardson PG, Weller E, Lonial S, et al. Lenalidomide, bortezomib, and dexamethasone combination therapy in patients with newly diagnosed multiple myeloma. Blood. 2010; 116:679-686. 14. Reeder CB, Reece DE, Kukreti V, et al. Once- versus twice-weekly bortezomib induction therapy with CyBorD in newly diagnosed multiple myeloma. Blood. 2010;115:3416-3417. 15. Palumbo A, Bringhen S, Rossi D, et al. Bortezomib-melphalan-prednisone-thalidomide followed by maintenance with bortezomib-thalidomide compared with bortezomib-melphalan-prednisone for initial treatment of multiple myeloma: a randomized controlled trial. J Clin Oncol. 2010;28:5101-5109. 16. Niesvizky R, Flinn IW, Rifkin RM, et al. Phase 3b UPFRONT study: safety and efficacy of weekly bortezomib maintenance therapy after bortezomib-based induction regimens in elderly, newly diagnosed multiple myeloma patients. Blood (ASH Annual Meeting Abstracts). 2010;116:Abstract 619. 17. Morgan GJ, Gregory WM, Davies FE, et al; on behalf of the National Cancer Research Institute Haematological Oncology Clinical Studies Group. The role of maintenance thalidomide therapy in multiple myeloma: MRC Myeloma IX results and meta-analysis. Blood. 2012;119:7-15. 18. Revlimid [package insert]. Summit, NJ: Celgene Corporation; May 2012. 19. Moreau P, Pylypenko H, Grosicki S, et al. Subcutaneous versus intravenous administration of bortezomib in patients with relapsed multiple myeloma: a randomised, phase 3, non-inferiority study. Lancet Oncol. 2011;12:431-440. 20. Kyprolis [package insert]. South San Francisco, CA: Onyx Pharmaceuticals; July 2012. 21. Jakubowiak AJ, Dytfeld D, Griffith KA, et al. A phase 1/2 study of carfilzomib in combination with lenalidomide and low-dose dexamethasone as a frontline treatment for multiple myeloma. Blood. 2012;120:1801-1809. 22. Palumbo A, Bringhen S, Villani O, et al. Carfilzomib, cyclophosphamide and dexamethasone (CCd) for newly diagnosed multiple myeloma (MM) patients. Blood (ASH Annual Meeting Abstracts). 2012;120:Abstract 730. 23. Carfilzomib, lenalidomide, and dexamethasone before and after stem cell transplant in treating patients with newly diagnosed multiple myeloma, NCT01816971. http://www. clinicaltrials.gov. Accessed April 24, 2013. 24. Kumar SK, Berdeja JG, Niesvizky R, et al. A phase 1/2 study of weekly MLN9708, an investigational oral proteasome inhibitor, in combination with lenalidomide and dexamethasone in patients with previously untreated multiple myeloma (MM). Blood (ASH Annual Meeting Abstracts). 2012;120:Abstract 332. 25. Study comparing conventional dose combination RVD to high-dose treatment with ASCT in the initial myeloma up to 65 years (IFM/DFCI2009), NCT01191060. http://www. clinicaltrials.gov. Accessed April 24, 2013.

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Journal of Hematology Oncology Pharmacy

CONTINUING EDUCATION

Nursing Considerations in the Maintenance Setting for Multiple Myeloma Tina Flaherty, ANP-BC, AOCN

Nurse Practitioner Division of Hematologic Malignancies Dana-Farber Cancer Institute, Boston, MA

Introduction Maintenance therapy is becoming a well-accepted recommendation for patients with multiple myeloma (MM), in both the transplant and nontransplant settings. However, there are several factors that must be considered when deciding which specific drugs, doses, and schedules should be used for this line of treatment, including age, performance status, prior response to therapy, patient preferences, and comorbidities. Elderly patients tend to be at greater risk for age-related diabetes or organ dysfunction (eg, cardiovascular disease, renal impairment) than younger patients, which may make disease management especially challenging.1,2 In this article, Tina Flaherty, ANP-BC, AOCN, answers questions related to the use of novel agents as maintenance and discusses the monitoring and management of treatment-related adverse events (AEs), including myelosuppression, neurotoxicity, and thromboembolic events.

How do you monitor for and treat myelosuppression in the maintenance setting? We tend to see less hematologic toxicity in the maintenance setting than we do in the frontline and relapsed/refractory settings. This is because the novel agents being used are usually given at reduced doses and schedules. In addition, most patients have already achieved a complete or very good partial response when maintenance therapy begins; therefore, their disease is less likely to be causing myelosuppression. That being said, some patients will still be predisposed to hematologic toxicities due to age, preexisting conditions, or cumulative toxicities from previous treatments, and they will require appropriate management strategies to maintain safety and preserve quality of life. To effectively manage such hematologic AEs as neutropenia, thrombocytopenia, and anemia, it is important to monitor patient blood counts on a regular basis, especially in the first and second cycles of therapy. When lenalidomide is used as maintenance, we typically check blood counts every 2 weeks during cycles 1 and 2. When bortezomib is used, counts are checked every 2 weeks prior to each administration of the drug. The interventions to use will depend on the grade or severity of the specific hematologic AEs (Table 1).3,4 The most common hematologic toxicity associated with lenalidomide is neutropenia.3 Grade 1 neutropenia usually does not require an adjustment in dose or schedule, but we do continue to monitor blood counts carefully. Conversely, grade 4 neutropenia would prompt us to hold lenalidomide therapy until either the neutropenia returns to grade 1 or the absolute neutrophil count is in the normal range.2 If neutropenia continues at grade 2 or higher for 2 or more cycles, we typically reduce the dose of lenalidomide to 5 mg and may consider adjusting the schedule in certain patient populations. For example, we may administer lenalidomide 5 mg every Monday, Wednesday, and Friday. In patients with standard- to high-risk disease, it is important to try to at least maintain the customary dose of lenalidomide maintenance (10 mg every 21 days of a 28-day cycle) to ensure optimal benefit. In these individuals, granulocyte colony-stimulating factors such as filgrastim can be utilized in a once-weekly or once-monthly schedule, depending on the grade of neutropenia. In the maintenance setting, hematologic toxicity rates tend to be low with bortezomib because this agent is administered every other week. However,

Journal of Hematology Oncology Pharmacy

some patients may still develop thrombocytopenia. With grade 1 thrombocytopenia, there is typically no need to adjust the dose or schedule of bortezomib; however, careful monitoring of blood counts is recommended.3 Grade 4 thrombocytopenia usually necessitates holding treatment until the toxicity resolves. We may also consider a transfusion of platelets if there is an increased risk of bleeding. With grade 2 or 3 thrombocytopenia, we may consider holding the bortezomib dose, and if there is a continued trend of toxicity, we many change the dose from 1.3 mg/m2 to 1.0 mg/m2. If the patient has been receiving this drug intravenously, we will also consider switching to the subcutaneous (SC) mode of administration if possible. Anemia may also occur with the use of novel agents in the maintenance setting. Some individuals are predisposed to this toxicity, especially if they have renal impairment from the myeloma itself, earlier therapy, or a preexisting condition.5 Management of anemia should take into account that some patients can tolerate a greater degree of this condition than others can.3 In addition to testing the numeric values of hemoglobin and hematocrit, quality of life should also be routinely assessed. A provider should ask questions concerning performance status, shortness of breath, and fatigue, which will assist in determining the need for transfusion versus erythropoietin-stimulating agents, such as darbepoetin alfa. With grade 1 or 2 anemia, depending on clinical circumstances, a patient may benefit from these agents, especially if he or she has concomitant renal dysfunction.5 With grade 4 anemia (and in certain scenarios, grade 2 or 3), the decision to transfuse must be balanced with the associated risks.3 In patients receiving lenalidomide maintenance, if grade 2 or 3 anemia is present for 2 or more cycles of therapy, we typically reduce the dose to 5 mg, especially in patients with renal impairment. What other toxicities are commonly associated with newer agents used as maintenance? Peripheral neuropathy (PN) is a well-known AE associated with the use of certain novel drugs, including bortezomib.6 This fact must be considered when choosing a maintenance therapy that individuals might be treated with for up to 2 years. In patients who already have grade 4 PN, we typically do not consider bortezomib for maintenance. If bortezomib is the drug of choice for a particular patient, then we frequently recommend the SC route of administration to decrease the incidence of neuropathy; fortunately, the

Grade 1 neutropenia usually does not require an adjustment in dose or schedule, but we do continue to monitor blood counts carefully. majority of our patients do not experience an increase in PN if they receive biweekly dosing of SC bortezomib. However, monitoring for signs and symptoms of this toxicity at the beginning of maintenance therapy and throughout the course of treatment remains essential.3 When bortezomib-related PN develops, the goal is to alleviate symptoms and prevent progression. We may consider holding the dose if grade 2 or 3 PN develops, and if painful symptoms continue, we may also reduce the dose from 1.3 mg/m2 to 1.0 mg/ m2 (given every other week). Thromboembolic events, including deep-vein thrombosis (DVT) and pulmonary embolism (PE) are also seen in patients with MM in the maintenance setting.7 Patients can be at risk for these life-threatening events due to their disease, individual risk factors (eg, obesity, diabetes, blood-clotting disorders), and specific medications.7 The development of DVT and/or PE can permanently affect the lives of patients and their families, as well as interfere with

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CONSIDERATIONS IN MULTIPLE MYELOMA

Table 1. NCI CTCAE: Hematologic Toxicity Grades3,4 Toxicity

Unit of Measure

Grade 1

Grade 2

Grade 3

Grade 4

ANC, ×109/L

<LLN to 1.5

<1.5-1.0

<1.0-0.5

<0.5

Platelet count, ×109/L

<LLN to 75

<75-50

<50-25

<25

Hb, g/dL

<LLN to 10.0

<10.0-8.0

<8.0-6.5

<6.5

Neutropenia Thrombocytopenia Anemia

ANC indicates absolute neutrophil count; Hb, hemoglobin; LLN, lower limit of normal; NCI CTCAE, National Cancer Institute Common Terminology Criteria for Adverse Events.

minimizing chronic diarrhea that patients may experience during treatment. For this reason, we offer probiotics to our patients, being sure to recommend products that contain strains of bacteria that are considered very safe for the general population.13

Table 2. Symptoms of Venous Thromboembolic Event7 Pulmonary Embolism Anxiety Discomfort in the chest area Electrocardiogram right axis deviation or new right bundle branch block Low-grade fever

What additional factors are important to consider in the maintenance setting?

Positive Homan’s sign (pain in the calf and popliteal area on passive dorsiflexion of the foot)a

To provide optimal care and adherence during maintenance, providers must consider prior response to therapy, cumulative toxicities, patient preferences, and psychosocial factors. Some patients may prefer oral lenalidomide, so that they do not have to travel back and forth to the clinic every other week for treatment. If we determine that a patient can be compliant with an oral regimen and that there are no contraindications, we will most likely use lenalidomide. For other individuals, bortezomib may be a better option, based on individual patient- and disease-related factors, such as a poor response to previous lenalidomide therapy or specific cytogenetic abnormalities. Regardless of which agent is used, nurses play an important role in improving patient compliance and outcomes. This requires good communication with patients and caregivers, careful monitoring for signs and symptoms of toxicities, and the prompt initiation of supportive or corrective strategies when necessary. ♦

Tachycardia

References

Sudden onset dyspnea Tachypnea or tachycardia Deep-Vein Thrombosis Cyanosis and cool skin in the presence of venous obstruction Distention of superficial venous collateral vessels Dull pain or tight feeling over area and with palpation Low-grade fever Obvious swelling (may not be present early)

Unilateral swollen, erythematous, warm extremity a

Present in approximately 35% of patients; high false-positive rate.

future treatment.7 Therefore, it is critical that patients are assessed for specific signs and symptoms that may indicate these events (Table 2). Venous thromboembolism (VTE) has been reported in patients receiving treatment with bortezomib, but at a much lower rate than in patients receiving treatment with lenalidomide (with or without dexamethasone).7 Recommendations for prevention and prophylaxis of thromboembolic events in MM depend on institutional practices, drug combinations being used, and factors specific to each patient. Typically, if patients have no prior history of VTE and do not have individual factors that predispose them to clot, either baby aspirin or standard-dose aspirin can be considered when they are receiving lenalidomide maintenance.7-9 However, if patients do have an increased risk of clot or have had past thromboembolic events, low-molecular-weight heparin or warfarin should be utilized. It is important to remember that some antithrombotic agents may be contraindicated in the presence of thrombocytopenia, renal impairment, or other comorbidities, due to the MM itself or to specific antimyeloma therapy.7 A common but less-addressed AE that occurs during maintenance—especially with lenalidomide—is chronic diarrhea.10 This toxicity can directly affect adherence to therapy and can have a negative impact on a patient’s quality of life. Although the direct mechanism of action is not clearly understood, it may be a direct or indirect cumulative effect of lenalidomide on the intestinal microflora (population of microscopic organisms) of the gut. Over the past several years, we have seen emerging data on the importance of gastrointestinal (GI) and immune health.11,12 Recently, probiotics have been promoted as an aid to enhance GI health by regulating the digestive system and

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1. Mehta J, Cavo M, Singhal S. How I treat elderly patients with myeloma. Blood. 2010; 116:2215-2223. 2. Palumbo A, Gay F. How to treat elderly patients with multiple myeloma: combination of therapy or sequencing. Hematology Am Soc Hematol Educ Program. 2009:566-577. 3. Miceli T, Colson K, Gavino M, Lilleby K; IMF Nurse Leadership Board. Myelosuppression associated with novel therapies in patients with multiple myeloma: consensus statement of the IMF Nurse Leadership Board. Clin J Oncol Nurs. 2008;12(suppl 3):13-20. 4. National Cancer Institute. Common Terminology Criteria for Adverse Events v.3.0 (CTCAE). http://ctep.cancer.gov/protocolDevelopment/electronic_applications/docs/ctcaev3.pdf. Published August 9, 2006. Accessed May 3, 2013. 5. Birgegård G. Managing anemia in lymphoma and multiple myeloma. Ther Clin Risk Manag. 2008;4:527-539. 6. Tariman JD, Love G, McCullagh E, Sandifer S; IMF Nurse Leadership Board. Peripheral neuropathy associated with novel therapies in patients with multiple myeloma: consensus statement of the IMF Nurse Leadership Board. Clin J Oncol Nurs. 2008;12(suppl 3): 29-36. 7. Rome S, Doss D, Miller K, Westphal J; IMF Nurse Leadership Board. Thromboembolic events associated with novel therapies in patients with multiple myeloma: consensus statement of the IMF Nurse Leadership Board. Clin J Oncol Nurs. 2008;12(suppl 3):21-28. 8. Palumbo A, Rajkumar SV, Dimopoulos MA, et al; International Myeloma Working Group. Prevention of thalidomide- and lenalidomide-associated thrombosis in myeloma. Leukemia. 2008;22:414-423. 9. Klein U, Kosely F, Hillengass J, et al. Effective prophylaxis of thromboembolic complications with low molecular weight heparin in relapsed multiple myeloma patients treated with lenalidomide and dexamethasone. Ann Hematol. 2009;88:67-71. 10. Smith LC, Bertolotti P, Curran K, Jenkins B; IMF Nurse Leadership Board. Gastrointestinal side effects associated with novel therapies in patients with multiple myeloma: consensus statement of the IMF Nurse Leadership Board. Clin J Oncol Nurs. 2008; 12(suppl 3):37-52. 11. Cummings JH, Antoine JM, Azpiroz F, et al. PASSCLAIM—gut health and immunity. Eur J Nutr. 2004;43(suppl 2):ii118-ii173. 12. Fooks LJ, Gibson GR. Probiotics as modulators of the gut flora. Br J Nutr. 2002;88(suppl 1): S39-S49. 13. Piascik M, Sanders ME. Probiotic supplementation: what nurse practitioners need to know to recommend safe and effective formulations. Postgraduate Healthcare Education Web site. http://www.powerpak.com/course/preamble/108730. Accessed May 4, 2013.

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CONTINUING EDUCATION

Pharmacologic Perspectives on Maintenance Therapy in the Era of Novel Agents Houry Leblebjian, PharmD, BCOP

Clinical Pharmacy Specialist in Hematology/Oncology Dana-Farber Cancer Institute Boston, MA

Introduction Recently, maintenance therapy with novel antimyeloma agents has been shown to be effective for prolonging duration of response following initial therapy, consolidation, or autologous stem cell transplantation (ASCT). This approach to myeloma treatment not only has the potential to improve quality of life, but may also extend survival. In this article, Houry Leblebjian, PharmD, BCOP, responds to frequently asked questions regarding the safety and efficacy of novel drugs as maintenance, and discusses administration issues that must be considered when using these therapies in the clinical setting.

How is the dose and schedule of lenalidomide adjusted in the maintenance setting? In multiple myeloma (MM), the dose of lenalidomide used in the maintenance setting differs from that used in other lines of treatment. As initial therapy or consolidation, this drug is typically used at a dose of 25 mg, given daily on days 1 to 14 of therapy repeated every 21 days or at a dose of 25 mg given daily on days 1 to 21 of therapy repeated every 28 days. Of course, these doses sometimes need to be reduced in patients with specific comorbidities, such as renal dysfunction.1,2 In the maintenance setting, lenalidomide is usually given at a dose of 15 mg at the same schedule used for induction, or sometimes daily without any break from therapy, if tolerated. Again, in patients who may be having difficulty tolerating this therapy, we have the option of lowering the dose to 10 mg or 5 mg. Three phase 3 randomized trials have evaluated lenalidomide in the maintenance setting (2 in the posttransplant setting and 1 as consolidation in transplant-ineligible patients).3-5 In the IFM 2005-02 trial (N=614), following ASCT, patients were randomly assigned to receive either consolidation treatment with lenalidomide (25 mg per day, on days 1-21 of

each 28-day cycle, for 2 cycles), followed by maintenance therapy with lenalidomide (10 mg per day for the first 3 months, increased to 15 mg if tolerated), or the same consolidation treatment with lenalidomide, followed by maintenance therapy with placebo. At a median follow-up of 45 months, median progression-free survival (PFS) was 41 months in the lenalidomide maintenance group versus 23 months in the placebo group (P<.001). No improvement was seen in overall survival (OS).3 In the CALGB 100104 study (N=460), investigators also studied lenalidomide maintenance in the posttransplant setting. Patients were randomly assigned in a blinded manner to lenalidomide (10 mg per day, increased to 15 mg if tolerated) or placebo between day 100 and day 110 after ASCT. At a median follow-up of 34 months, median time to progression (TTP) was 46 months in the lenalidomide maintenance group versus 27 months in the observation group (P<.001). In this trial, an OS benefit was observed.4 In the MM-015 trial (N=459), transplant-ineligible patients were randomized to receive melphalan plus prednisone (MP), melphalan/prednisone/lenalidomide (MPR), or MPR followed by lenalidomide maintenance (MPR-R). At a median follow-up of 30 months, PFS was 13 months, 14 months, and 31 months with MP, MPR, and MPR-R, respectively (P<.001 for MPR-R vs MPR and MPR-R vs MP). No difference in OS was observed between the groups.5 As evidenced by these studies, maintenance lenalidomide improves PFS, although a consistent OS benefit has yet to be reported.

Another factor to consider when analyzing results from these studies is the other drugs that were used during treatment, as they can contribute to additional toxicity.

Adverse events (AEs) must be carefully considered when treating MM patients with long-term lenalidomide. The most common AEs seen with this agent are myelosuppression, venous thromboembolism, and gastrointestinal toxicities. Lenalidomide may cause both thrombocytopenia and neutropenia, which may require dose modifications or temporarily withholding treatment until symptoms subside. However, the incidence of these and other AEs tends to be lower when lenalidomide is used as maintenance, compared with when it is used as frontline therapy (Table 1).3-5 It should be noted that the rates of hematologic toxicities in the IFM and the CALGB trials seem high because the Table 1. Incidence of Select Adverse Events in Phase 3 Trials of Lenalidomide percentages reported included the AEs observed throughout Maintenance3-5 the whole study窶馬ot just during maintenance therapy. On Grade 3/4 Grade 3/4 Grade 3/4 the other hand, investigators in the MM-015 study reported Neutropenia, Thrombocytopenia, Venous Secondary the rates of neutropenia and thrombocytopenia for the mainClinical Trial % % Thromboembolism, % Cancers, % tenance portion of the study separately, and these percentages IFM 2005-0023 were much lower than what was reported during frontline 51 14 6 7.5 Lenalidomide therapy. Another factor to consider when analyzing results 18 7 2 2.9 Placebo from these studies is the other drugs that were used during CALGB 1001044 treatment, as they can contribute to additional toxicity.3-5 45 14 1 7.8 Lenalidomide Investigators have reported a higher incidence of secondary 15 4 0 2.6 Placebo cancers in the lenalidomide arms of maintenance studies.3-5 5 MM-015 This does not appear to be related to the dose of lenalidomide, 1 2 0 3 MP but rather to the duration of treatment, as well as the use of 0 2 1 7 MPR other alkylating agents during induction or conditioning prior 7 6 2 7 MPR-R to transplant. Additional follow-up is needed to continue assessing potential risk factors for secondary malignancies and MP indicates melphalan plus prednisone; MPR, melphalan/prednisone/lenalidomide; MPR-R, MPR followed by lenalidomide maintenance. to determine the optimal duration of treatment with lenalid-

Journal of Hematology Oncology Pharmacy

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Vol 3, No 2

CONSIDERATIONS IN MULTIPLE MYELOMA omide. Fortunately, many studies are under way to evaluate the safety and efficacy of long-term lenalidomide in the maintenance setting for myeloma. How is the recent approval of subcutaneous (SC) bortezomib impacting the use of this agent in the maintenance setting? Bortezomib has shown efficacy when used in the maintenance setting. The phase 3 HOVON-65/GMMG-HD4 trial compared bortezomib/doxorubicin/ dexamethasone plus posttransplant maintenance followed by bortezomib versus vincristine/doxorubicin/dexamethasone followed by thalidomide maintenance.6 The phase 3 GIMEMA trial compared bortezomib/melphalan/prednisone/thalidomide followed by bortezomib and thalidomide maintenance for 2 years versus bortezomib/melphalan/prednisone without maintenance.7 Both of these trials showed a PFS benefit with maintenance therapy. Peripheral neuropathy (PN), a common toxicity associated with bortezomib, occurs more frequently when patients receive this agent at a dose of 1.3 mg/m2 given intravenously on days 1, 4, 8, 11 every 21 days. Bortezomibinduced PN is often reversible with dose or schedule reductions or upon discontinuation of therapy. To reduce the incidence and severity of PN, we now have another option—SC bortezomib. A large phase 3 trial (N=222) randomized patients in a 2:1 ratio to receive intravenous (IV) or SC bortezomib at a dose of 1.3 mg/m2 on days 1, 4, 8, and 11 every 3 weeks for 12 weeks.8 Results from this study confirmed the noninferiority of SC bortezomib in terms of overall response rate after 4 cycles. In addition, after a median follow-up of 12 months, no significant differences in TTP or OS were observed between the 2 arms. Grade ≥3 PN was significantly lower in the SC arm compared with the IV arm (6% vs 16%; P=.026). Neuropathy of any grade was also lower in the SC arm (38% vs 53%; P=.044) (Table 2). Other AEs, including myelosuppression, fatigue, and GI toxicities, were comparable among treatment arms.8 Given these results, I think SC bortezomib will continue to be used more frequently in the maintenance setting. The use of SC bortezomib can cause local injection site reactions. Of the 159 patients in 2 trials of SC bortezomib, 60% reported at least 1 local SC injection site reaction during the study, with 56% having a reaction in the first cycle. Two patients (1%) experienced local reactions that were considered severe (1 case of pruritis and 1 case of redness). These reactions resolved in a median of 6 days. Local reaction led to study discontinuation in only 1 patient and reduction in dose concentration in another.8,9 The recommended concentration of bortezomib when administered intravenously is 1.0 mg/mL; with SC administration, the recommended concentration of bortezomib is 2.5 mg/mL. Because each route of administration has a different reconstituted concentration, caution must be used when calculating the volume to be administered. When the SC route is used, the site for each injection (thigh or abdomen) should be rotated. New injections should be given at least 1 inch from an old site and never into areas where the site is tender, bruised, erythematous, or indurated. Preparation times and administration for SC and IV bortezomib do not differ since both are prepared by reconstituting the vial of bortezomib with normal saline and administered to patients as a quick injection.10 How often is thalidomide being used in the maintenance setting for MM in 2013? For years, thalidomide appeared to be a good choice for maintenance therapy due to its efficacy and the convenience of being an oral agent. Eight phase 3 studies assessed thalidomide in the maintenance setting, and the use of this agent led to improvement in event-free survival (EFS) and/or PFS.11-18 However, only 2 studies showed improvement in OS. The first was the IFM 99-02 study (N=597) in which patients were randomized to receive 1 of the 3 treatment arms following double ASCT: (1) no maintenance, (2) pamidronate, or (3) thalidomide 400 mg daily plus pamidronate. Patients were to receive these treatments until progression. Increased EFS and OS was seen in patients in the thalidomide arm, but this benefit was observed only in patients who achieved less than a very good partial response after transplant and those without del(13) or high beta-2 microglobulin levels.11 A second trial, by Spencer and colleagues (N=269) randomized patients to receive thalidomide plus prednisone or prednisone alone following single

Table 2. Incidence of Peripheral Neuropathy in the Phase 3 MMY-3021 Trial8 SC Bortezomib (N=147)

IV Bortezomib (N=74)

n (%)

P Value

56 (38)

39 (53)

.044

Grade ≥2

35 (24)

30 (41)

0.12

Grade ≥3

9 (6)

12 (16)

0.26

Any peripheral neuropathy

IV indicates intravenous; SC, subcutaneous.

ASCT. Patients were to receive thalidomide for 12 months. There was improvement in 3-year PFS and OS in the thalidomide arm (P<.001 and P =.004, respectively).12 Thalidomide maintenance has fallen out of favor in most clinics in the United States because of the high rates of treatment-related toxicity (especially PN) and the inconsistent data regarding OS benefit. Lenalidomide and bortezomib are now being used as maintenance therapy for almost all of the patients at our institution, either as monotherapy or in combination. Newly approved drugs such as pomalidomide and carfilzomib are also undergoing investigation as maintenance in clinical trials and may provide additional options in the near future. ♦ References

1. Niesvizky R, Jayabalan DS, Christos PJ, et al. BiRD (Biaxin [clarithromycin]/Revlimid [lenalidomide]/dexamethasone) combination therapy results in high complete- and overall-response rates in treatment-naive symptomatic multiple myeloma. Blood. 2008;111:1101-1109. 2. Dimopoulos M, Spencer A, Attal M, et al. Lenalidomide plus dexamethasone for relapsed or refractory multiple myeloma. N Engl J Med. 2007;357:2123-2132. 3. Attal M, Lauwers-Cances V, Marit G, et al. Lenalidomide maintenance after stem-cell transplantation for multiple myeloma. N Engl J Med. 2012;366:1782-1791. 4. McCarthy PL, Owzar K, Hofmeister CC, et al. Lenalidomide after stem-cell transplantation for multiple myeloma. N Engl J Med. 2012;366:1770-1781. 5. Palumbo A, Hajek R, Delforge M, et al. Continuous lenalidomide treatment for newly diagnosed multiple myeloma. N Engl J Med. 2012;366:1759-1769. 6. Sonneveld P, Schmidt-Wolf IG, van der Holt B, et al. Bortezomib induction and maintenance treatment in patients with newly diagnosed multiple myeloma: results of the randomized phase III HOVON-65/GMMG-HD4 trial. J Clin Oncol. 2012;30:2946-2955. 7. Palumbo A, Bringhen S, Rossi D, et al. Bortezomib-melphalan-prednisone-thalidomide followed by maintenance with bortezomib-thalidomide compared with bortezomib-melphalan-prednisone for initial treatment of multiple myeloma: a randomized controlled trial. J Clin Oncol. 2010;28:5101-5109. 8. Moreau P, Pylypenko H, Grosicki S, et al. Subcutaneous versus intravenous administration of bortezomib in patients with relapsed multiple myeloma: a randomised, phase 3, non-inferiority study. Lancet Oncol. 2011;12:431-440. 9. Moreau P, Coiteux V, Hulin C, et al. Prospective comparison of subcutaneous versus intravenous administration of bortezomib in patients with multiple myeloma. Haematologica. 2008; 93:1908-1911. 10. Velcade [package insert]. Cambridge, MA: Millennium Pharmaceuticals Inc; May 2013. 11. Attal M, Harousseau JL, Leyvraz S, et al. Maintenance therapy with thalidomide improves survival in patients with multiple myeloma. Blood. 2006;108:3289-3294. 12. Spencer A, Prince HM, Roberts AW, et al. Consolidation therapy with low-dose thalidomide and prednisolone prolongs the survival of multiple myeloma patients undergoing a single autologous stem-cell transplantation procedure. J Clin Oncol. 2009;27:1788-1793. 13. Morgan G, Jackson G, Davies F. Maintenance thalidomide may improve progression free but not overall survival: results from the Myeloma IX Maintenance Randomisation. Blood (ASH Annual Meeting Abstracts). 2008;Abstract 656. 14. Barlogie B, Tricot G, Anaissie E, et al. Thalidomide and hematopoietic-cell transplantation for multiple myeloma. N Engl J Med. 2006;354:1021-1030. 15. Lokhorst HM, van der Holt B, Zweegman S, et al. A randomized phase 3 study on the effect of thalidomide combined with adriamycin, dexamethasone, and high-dose melphalan, followed by thalidomide maintenance in patients with multiple myeloma. Blood. 2010;115:1113-1120. 16. Stewart AK, Trudel S, Bahlis NJ, et al. A randomized phase III trial of thalidomide and prednisone as maintenance therapy following autologous stem cell transplantation (ASCT) in patients with multiple myeloma (MM): the NCIC CTG MY.10 trial. Blood (ASH Annual Meeting Abstracts). 2010;116:Abstract 39. 17. Ludwig H, Adam Z, Tothova E, et al. Thalidomide maintenance treatment increases progression-free but not overall survival in elderly patients with myeloma. Haematologica. 2010; 95:1548-1554. 18. Maiolino A, Hungria VT, Garnica M, et al. Thalidomide plus dexamethasone as a maintenance therapy after autologous hematopoietic stem cell transplantation improves progression-free survival in multiple myeloma. Am J Hematol. 2012;87:948-952.

COE106-2

Vol 3, No 2

June 2013

www.JHOPonline.com

Journal of Hematology Oncology Pharmacy

Fourth Annual Navigation and

November 15-17, 2013 • The Peabo PRELIMINARY AGENDA* FRIDAY, NOVEMBER 15 12:00 pm - 12:30 pm Welcome • Conference Co-Chairs: Sharon Gentry, RN, MSN, AOCN, CBCN Lillie D. Shockney, RN, BS, MAS 12:30 pm - 2:00 pm PRE-CONFERENCE WORKSHOPS Basic Navigation Track • Tricia Strusowski, MS, RN • Nicole Messier, RN, BSN OR Advanced Navigation Track • Elaine Sein, RN, BSN, OCN, CBCN • Danelle Johnston, RN, MSN, OCN, CBCN 2:00 pm - 2:45 pm BREAK IN THE EXHIBIT HALL 2:45 pm - 3:30 pm General Session 1: Top 10 Best Practices • Moderators – Conference Co-Chairs: Sharon Gentry, RN, MSN, AOCN, CBCN Lillie D. Shockney, RN, BS, MAS 3:30 pm - 5:00 pm Administrator’s Track • Mandi Pratt-Chapman, MA • Michele O’Brien, MSN, ACNS-BC, RN, BA OR

5:00 pm - 6:00 pm 6:00 pm - 8:00 pm

Case Manager’s Track FREE TIME Welcome Reception/Posters in the Exhibit Hall

SATURDAY, NOVEMBER 16 6:30 am - 7:30 am

Breakfast/Product Theater (non–CME-certified activity) 7:45 am - 8:00 am Welcome and Introductions • Conference Co-Chairs: Sharon Gentry, RN, MSN, AOCN, CBCN Lillie D. Shockney, RN, BS, MAS 8:00 am - 8:30 am General Session 2: The Future of AONN (The AONN Business Meeting) • Sharon Gentry, RN, MSN, AOCN, CBCN • Lillie D. Shockney, RN, BS, MAS 8:30 am - 9:15 am General Session 3: Community Needs and Navigation • Lillie D. Shockney, RN, BS, MAS, on behalf of the Global Breast Health Initiative • Jennifer Klemp, PhD, MPH, MS 9:15 am - 10:00 am General Session 4: Development and Application of Evidence-Based Guidelines in Cancer Care: The NCCN Perspective • Liz Danielson, MHA 10:00 am - 10:45 am BREAK IN THE EXHIBIT HALL 10:45 am - 11:30 am Keynote: Update on Guidelines • Linda Ferris, PhD 11:45 am - 12:45 pm Lunch/Product Theater (non–CME-certified activity) 1:00 pm - 1:45 pm General Session 5: Onco-Politic Barriers • Dan O’Connor 1:45 pm - 2:30 pm General Session 6: Addressing Disparities of Care • Swann Arp Adams, PhD, MS • Michelle Weaver Knowles, RNC, BSN

2:30 pm - 3:15 pm 3:15 pm - 3:45 pm 3:50 pm - 4:35 pm

4:35 pm - 5:20 pm 5:30 pm - 7:30 pm

General Session 7: Oncology Medical Home BREAK IN THE EXHIBIT HALL General Session 8: Meeting the Needs of the Adult and Child Survivor Throughout the Life Span • Christy Roberts, RN, BSN, OCN General Session 9: The Role of Complementary Therapies in Navigation • Linda Lee, MD, AGAF Poster Award Reception

SUNDAY, NOVEMBER 17 6:30 am - 7:30 am

Breakfast/Product Theater (non–CME-certified activity) 7:45 am - 8:00 am Welcome and Introductions • Conference Co-Chairs: Sharon Gentry, RN, MSN, AOCN, CBCN Lillie D. Shockney, RN, BS, MAS 8:30 am - 8:45 am General Session 10: Navigator’s Role in Tumor Boards • Laurie Mathis, RN, BS, MAS 8:45 am - 10:30 am DISEASE SITE–SPECIFIC BREAKOUTS • Breast Cancer Navigation & Survivorship • Karen Dow Meneses, PhD, RN, FAAN • Vinnie Myers • Thoracic Oncology Navigation • Gean Brown, RN, OCN • GI & Colorectal Cancer Navigation • Darcy Doege, RN, BSN • Kristen Vogel, MS, CGC • GYN Cancers Navigation • Penny Daugherty, BSN, RN, OCN • Prostate Cancer Navigation • Head, Neck, & Neuro Navigation • Tamara Bowen, RN, BSN, MHA • Pediatric Oncology • Kathy Ruble, RN, CPNP, PhD • Hematology/Oncology Navigation • Melanoma Navigation • Sherry Riggins, RN, BSN, OCN 10:30 am - 11:15 am BREAK IN THE EXHIBIT HALL 11:15 am - 12:00 pm General Session 11: Understanding the Role of the Primary Care Physician • Michael Kolodziej, MD 12:15 pm - 1:15 pm Lunch/Product Theater (non–CME-certified activity) 1:30 pm - 2:15 pm General Session 12: Navigator’s Role in End-of-Life Care • Lillie D. Shockney, RN, BS, MAS 2:15 pm - 3:00 pm General Session 13: Music & Medicine: A Dynamic Partnership • Deforia Lane, PhD, MT-BC 3:00 pm - 3:15 pm Conclusion of the Conference/Final Remarks • Conference Co-Chairs: Sharon Gentry, RN, MSN, AOCN, CBCN Lillie D. Shockney, RN, BS, MAS *Preliminary agenda, subject to change.

Survivorship Conference

ody Memphis • Memphis, Tennessee CONFERENCE CO-CHAIRS Program Director: Lillie D. Shockney, RN, BS, MAS University Distinguished Service Associate Professor of Breast Cancer Depts of Surgery and Oncology Adm Director, Johns Hopkins Breast Center Adm Director, Johns Hopkins Cancer Survivorship Programs Associate Professor, JHU School of Medicine Depts of Surgery, Oncology & Gynecology and Obstetrics Associate Professor, JHU School of Nursing Baltimore, MD

FACULTY* Swann Arp Adams, PhD, MS Tamara Bowen, RN, BSN, MHA Gean Brown, RN, OCN

Penny Daugherty, BSN, RN, OCN Darcy Doege, RN, BSN Karen Dow Meneses, PhD, RN, FAAN Linda Ferris, PhD Sharon Gentry, RN, MSN, AOCN, CBCN

Jennifer Klemp, PhD, MPH, MS Michael Kolodziej, MD Deforia Lane, PhD, MT-BC Linda Lee, MD, AGAF

CONFERENCE OVERVIEW

AONN’s Fourth Annual Conference will continue to advance the navigation profession by expanding the scope of educational sessions, networking opportunities, and poster presentations. In addition, this year’s conference will address the evolving challenges of program improvement, the role of personalized medicine, and implementing best practices in navigation, survivorship, and psychosocial care.

TARGET AUDIENCE

This activity was developed for oncology nurse navigators, patient navigators, social workers, and case managers.

CONTINUING EDUCATION INFORMATION

Learning Objectives Upon completion of this activity, the participant will be able to: • Discuss the evolution of the role of navigation in healthcare. • Assess strategies for navigating diverse patient populations by cancer type and environmental factors. • Define methods for providing patient support and guidance in the age of personalized cancer care. • Evaluate best practices regarding survivorship and psychosocial care.

Nicole Messier, RN, BSN Vinnie Myers Michele O’Brien, MSN, ACNS-BC, RN, BA

Liz Danielson, MHA

Danelle Johnston, RN, MSN, OCN, CBCN

Sharon Gentry, RN, MSN, AOCN, CBCN Breast Nurse Navigator Derrick L. Davis Forsyth Regional Cancer Center Winston-Salem, NC

Laurie Mathis, RN, CBCN, OCN

Dan O’Connor Mandi Pratt-Chapman, MA Sherry Riggens, RN, BSN, OCN Christy Roberts, RN, BSN, OCN Kathy Ruble, RN, CPNP, PhD Elaine Sein, RN, BSN, OCN, CBCN Lillie D. Shockney, RN, BS, MAS Tricia Strusowski, MS, RN Kristen Vogel, MS, CGC Michelle Weaver Knowles, RNC, BSN *For full information visit www.aonnonline.org