Top may2013 issue web

May 2013

www.TheOncologyPharmacist.com

Vol 6, No 2

COMPLIMENTARY CE Considerations in Multiple Myeloma—Ask the Experts: Frontline and Retreatment Settings

see page 22

Oncology Pharmacy Safety

Cancer Center Profile

Kimmel Cancer Center at Thomas Jefferson University Hospital

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

Chemotherapy and Pharmacy: A Toxic Mix?

The Role of the Oncology Pharmacist Alice Goodman

Thomas H. Connor, PhD, Research Biologist, National Institute for Occupational Safety and Health Cincinnati, Ohio

Christine Roussel, PharmD, BCOP Directory of Pharmacy, OncoMed Crum Lynne, Pennsylvania

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harmacists and nurses know that chemotherapy can be dangerous, but many are unfamiliar with the large body of research documenting the magnitude of workplace contamination, extent of chemical absorption (work-

er exposure), and downstream effects these chemicals may exert on healthcare workers. While oncology pharmacists are good at discussing new trial data, rarely do they chat about the recent urinary Continued on page 32

Side Effects Management

The oncology pharmacy team at the Kimmel Cancer Center (left to right): Bruce Park, PharmD; Renata Dul, PharmD; Trish Clifford, PharmD; William O’Hara, PharmD, BCOP; Justine Chung, PharmD; Jae Ryu, PharmD, BCOP; Sarah Shockley, PharmD; and Anne Marie Valorie-Oberle, PharmD, BCOP. Not pictured, but also part of the team, Christine Cote, PharmD; Kelly Miskovsky, PharmD; Judith Alberto, PharmD; Phil Maher, PharmD; Ginah Nightingale, PharmD, BCOP; and Gina Hemmert, PharmD.

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he Kimmel Cancer Center (KCC) at the Thomas Jefferson University Hospital in Philadelphia, Pennsylvania, is a National Cancer Institute (NCI)-designated clinical cancer center. The center, founded in 1991, received the NCI designation in 1996, confirming KCC’s position as a leader in treatment, research, and education.

Continued on page 34

Conference News

Highlights From the American Association for Cancer Research Annual Meeting Alice Goodman

T

he annual meeting of the American Association for Cancer Research (AACR) focuses on preliminary studies with promising findings for the treatment of cancer. This year’s conference was held in Washington, DC, from April 6-10,

2013. Selected highlights of early studies presented at the annual meeting follow. It is hoped that these encouraging preliminary findings will be confirmed by larger studies and lead to advances in cancer care.

New Developments in the Management of Hand-Foot Syndrome Associated With Oral Anti-VEGF Tyrosine Kinase Inhibitor–Targeted Anticancer Therapies Joanna Schwartz, PharmD, BCOP, and Shannon Hogan, PharmD Albany College of Pharmacy and Health Sciences—Vermont Campus Colchester, Vermont

H

and-foot skin reaction (HFSR), also known as hand-foot syndrome or palmar-plantar erythrodysesthesia (PPE), is an adverse effect of several chemotherapeutic agents. The syndrome is characterized by redness, swelling, pain,

and tingling in the palms of the hands and the soles of the feet. Other symptoms may include sensitivity or intolerance to hot or warm objects or fluids, hyperkeratosis (callus), blistering, and dry skin.

Continued on page 16

inside Best Practices . . . . . . . . . . . . . . . . . .

8

Mandatory Oncology Clinical Pathways Can Enhance Value Helping Patients Overcome Obstacles to Oral Chemo Is Part of Anticancer Drug Management Side Effects Management . .

Preventing Methotrexate Toxicity: Know How to Use Leucovorin, Glucarpidase

Continued on page 19 ©2013 Green Hill Healthcare Communications, LLC

18

Personalized Medicine

. . . . .

18

Gene Analysis Allows for Personalization of 5-FU to Reduce Risk of Toxicity

You Voted For The 2013

T.O.P. Award Find out who won on page 30

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.

PROF35855_Provenge_VBCC_DR.indd 2

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.)

3/12/13 4:00 PM

COLORECTAL CANCER

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

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.

©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

Regorafenib Benefit in Colorectal Cancer Not Dependent on Mutations

By Wayne Kuznar

T

he clinical response to regorafenib does not depend on tumor mutations. Among patients with metastatic colorectal cancer who participated in the phase 3 CORRECT (Colorectal Cancer Treated With Regorafenib or Placebo After Failure of Standard Therapy) study, an analysis of tumor specimens for KRAS and PIK3CA mutations did not predict clinical benefit in the patients assigned to regorafenib compared with placebo, said Michael Jeffers, PhD. He presented the results of the study at the 2013 Gastrointestinal Cancers Symposium.

“There was a trend toward regorafenib benefit regardless of KRAS mutational status,” said Jeffers, lead investigator of the analysis. “We found the same thing when we looked at PIK3CA mutations.”

He and colleagues conducted a retrospective biomarker analysis on DNA isolated from baseline plasma and archival tumor tissue specimens to determine if a correlation existed between mutational status and the clinical response to regorafenib in the CORRECT trial.

The KRAS, PIK3CA, and BRAF genes were analyzed.

Mutational analysis of plasma showed mutant KRAS in 69% of samples and mutant PIK3CA in 17%.

Mutational analysis of tumor tissue demonstrated mutant KRAS in 59% of specimens and mutant PIK3CA in 12%. The concordance in KRAS results between archival tissue versus fresh plasma was 79%. Concordance of PIK3CA results was 88%.

The small percentage of patients who had wild-type KRAS in archival tumor tissue but mutated KRAS in fresh tumor tissue “may have acquired KRAS-mutant tumor cells following therapy with anti-epidermal growth

factor receptor, a phenomenon that has been described in colorectal cancer,” said Jeffers, associate director of Clinical Oncology Biomarkers at Bayer HealthCare Pharmaceuticals, Montville, New Jersey. Mutational analysis of fresh plasma may therefore be a more accurate reflection of current mutational status, he indicated.

“The study overall showed that regardless of biomarker subgroup, regorafenib seems to have benefit,” he said. The hazard ratio for overall survival favored regorafenib in patients with mutant and wildtype KRAS and PIK3CA, consistent with the overall study population. In addition, the hazard ratio for progression-free survival was <1.0 in all biomarker subgroups that were assigned to regorafenib compared with placebo.

Owing to low patient numbers, subgroups based on BRAF mutational status were not analyzed. BRAF mutations were detected in 3.4% of the plasma samples and 1.5% of the tumor tissue samples analyzed.

“Colorectal cancer has a high prevalence of KRAS mutations as well as PIK3CA mutations as part of this disease.

Since the low-hanging fruit didn’t seem to work, we’ll go on to other things,” said Jeffers. Thus far, “we haven’t come across anything to differentiate responders from nonresponders. We have the tumor samples; we can do immunohistochemistry and run expression analysis. We haven’t done either of those yet. We have looked at plasma proteins but haven’t published those data yet.” l Reference

Jeffers M, Van Cutsem E, Sobrero AF, et al.

Mutational analysis of biomarker samples from the CORRECT study: correlating mutation status with clinical response to regorafenib. Presented at: 2013 Gastrointestinal Cancers Symposium; January 24-26, 2013; San Francisco, CA. Abstract 381/ Poster A49.

Get involved: have you ever wanted to write an article for TOP ?

We’re interested in articles about the everyday issues that affect pharmacists.

PROF35855_Provenge_VBCC_DR.indd 3

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MAy 2013 I VOL 6, NO 2

Contact editorial@greenhillhc.com for information.

3/12/13 4:00 PM

www.TheOncologyPharmacist.com

Editorial Board EDITOR-IN-CHIEF

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

Anjana Elefante, PharmD, BSc, BSc Pharm, RPh

Dwight Kloth, PharmD, FCCP, BCOP

Timothy G. Tyler, PharmD, FCSHP

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

Jim Koeller, MS

John M. Valgus, PharmD, BCOP

Christopher Fausel, PharmD

Christopher J. Lowe, PharmD

Roswell Park Cancer Institute Buffalo, NY

Fox Chase Cancer Center Philadelphia, PA

Desert Regional Medical Center Palm Springs, CA

ASSOCIATE EDITOR-IN-CHIEF

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

John F. Aforismo, BSc Pharm, RPh, FASCP RJ Health Systems International, LLC Wethersfield, CT

University of Texas at Austin San Antonio, TX

Cleveland Clinic Taussig Cancer Institute Cleveland, OH

Indiana University Simon Cancer Center Indianapolis, IN

Indiana University Hospital Indianapolis, IN

David Baribeault, RPh, BCOP

Rebecca S. Finley, PharmD, MS

Emily Mackler, PharmD, BCOP

Betty M. Chan, PharmD, BCOP

David C. Gammon, BSPh

Laura Boehnke Michaud, PharmD, BCOP, FASHP

Boston Medical Center Boston, MA

USC/Norris Cancer Hospital Los Angeles, CA

Jefferson School of Pharmacy Philadelphia, PA

OncologyPharmacist.net Warwick, RI

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

The University of Texas MD Anderson Cancer Center Houston, TX

University of North Carolina Hospitals and Clinics Chapel Hill, NC

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

Burt Zweigenhaft, BS

OncoMed Onco360 Great Neck, NY

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

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

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

www.TheOncologyPharmacist.com

Lew Iacovelli, BS, PharmD, BCOP, CPP

Moses H. Cone Health System Greensboro, NC

LeAnn Best Norris, PharmD, BCPS, BCOP

South Carolina College of Pharmacy Columbia, SC

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

May 2013 I VOL 6, NO 2

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From The EditorS PUBLISHING STAFF Senior Vice President, Sales & Marketing Nicholas Englezos nick@engagehc.com Vice President/Director of Sales & Marketing Joe Chanley joe@greenhillhc.com Group Director, Sales & Marketing John W. Hennessy john@greenhillhc.com Publisher Cristopher Pires cris@engagehc.com Editorial Director Kristin Siyahian kristin@greenhillhc.com Managing Editor Kristen Olafson kristen@greenhillhc.com Copy Editors Mollie Friedman Peggy Roeske Editorial Assistant Jennifer Brandt Production Manager Stephanie Laudien

President/CEO Brian Tyburski Chief Operating Officer Pam Rattananont Ferris Vice President of Finance Andrea Kelly Associate Editorial Director, Projects Division Terri Moore Director, Quality Control Barbara Marino

Patrick Medina, PharmD, BCOP Editor-in-Chief

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

his issue of The Oncology Pharmacist (TOP) offers the first in a series of articles about oncology pharmacy safety and issues related to hazardous materials in the workplace. Christine Roussel, PharmD, BCOP, and Thomas H. Connor, PhD, discuss the research documenting the magnitude of workplace contamination, extent of chemical absorption (worker exposure), and downstream effects these chemicals may exert on healthcare workers. Roussel and Connor emphasize how important it is for oncology pharmacists to be aware of, and to adhere to, existing safe handling guidelines in addition to keeping up-to-date on training and the latest improvements in safety equipment.

In this month’s issue, we present our coverage of the news from the Hematology/Oncology Pharmacy Association 9th Annual Conference. TOP was there, and we highlight

presentations about oncology clinical pathways, how a comprehensive analysis of the DPYD gene can be used to personalize a patient’s 5-FU/capecitabine therapy, the role of the pharmacist in helping overcome patients’ financial and personal obstacles to oral chemotherapy, and how pharmacists can help expand patient access to compassionate-use drugs.

Be sure to read about Jill Drury, this year’s winner of the T.O.P. Pharmacist Award. Jill says that oncology pharmacy is a field that encourages creativity in its mixture of science and clinical care and she relishes her interaction with patients.

Please visit our website, www.TheOncologyPharmacist. com. Tell us what topics you want to see covered in TOP. We appreciate your feedback—positive and negative— about what you see in print and on the website. l

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VISIT THE NEW ONLINE RESOURCE FOR THE ENTIRE MULTIPLE MYELOMA CARE TEAM

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Value-Based Care in Myeloma delivers exclusive interviews and perspectives related to cost, quality, and access issues.

Special sections for VA-based clinicians, advanced practice nurses, and pharmacists will also focus on the unique challenges in the management of multiple myeloma.

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Best Practices

Mandatory Oncology Clinical Pathways Can Enhance Value

By Wayne Kuznar

S

ystematic application of oncology clinical pathways can reduce variation in cancer disease management and result in significant overall savings, said Jim Koeller, MS, at the Hematology/ Oncology Pharmacy Association 9th Annual Conference.1 A pathway is a tool for standardizing a specific disease care plan, or “a method to control the application of resources.” The need for clinical pathways in oncology is evident when one considers that variations in cancer disease management can exceed 100%, said Koeller, a professor of pharmacy at the University of Texas at Austin and the Health Science Center, San Antonio.

Although criticism of clinical pathways as “cookbook” medicine has been levied, “if the pathway is created properly, it can build in variations for patients who don’t fit the mold, the outlier patient,” he said.

A Cochrane systematic review of 27 studies of pathway use within a hospital found that by employing a resource management tool, hospital length of stay declined significantly by more than 1 day and cost decreased significantly.2 To date, most active pathways have focused on the disease treatment phase of cancer care, in which a set of regimens to be used as the standard of care, including

Table US Oncology’s “Level 1” Metastatic Non-Small Cell Lung Cancer Pathway (Squamous)3 First line

Carboplatin/paclitaxel Vinorelbine (if poor performance status) Best supportive care

Second line

Docetaxel Erlotinib Best supportive care

Third line

Erlotinib Best supportive care

regimens for chemotherapy and supportive care, is established. “Once you have the regimens locked, a pathway is putting regimens in order by line of therapy,” said Koeller. In lung cancer, the main cost driver of cancer care is not chemotherapy but hospitalization, which accounts for about 60% of the costs.

End-of-life care also is in need of standards, as 20% of patients with lung cancer receive chemotherapy in the last 14 days of life, and 40% receive it in the last 30 days. “That’s where a lot of the variations in treatment can come,” he said.

Oncology clinical pathways should combine evidence-based medicine, supported by nationally recognized guidelines, and practicing physician consensus to develop the best approach, he said. The pathways should be designed to narrow

treatment options and guide physicians to preferred treatment strategies. “When managed properly, pathways should maintain or enhance health outcomes and bring down the cost,” said Koeller.

Stakeholders should consider a variety of inputs when selecting regimens for a specific pathway. At his institution in the past, physicians were insulated from the economics of selecting regimens for pathways. “In hindsight, it was a mistake,” he said. “Moving forward, it’s a necessity.”

The American Society of Clinical Oncology (ASCO) is expected to include value and quality as elements of cancer care, “which means you’ll be making value calculations for regimens and treatments coming up relatively quickly, so physicians can start to see what those numbers look like for care,” he said.

Pathways are currently available from the National Comprehensive Cancer Network (NCCN), McKesson/ US Oncology, University of Pittsburgh Medical Center/Via Oncology (implemented by Horizon Blue Cross Blue Shield), and Cardinal Health/P4 Healthcare (utilized by CareFirst). The NCCN pathways include clinical judgment when the evidence is insufficient to answer a question, unlike ASCO guidelines, which only consider evidence and do not take cost into consideration.

A retrospective analysis of US Oncology’s Level 1 Pathway (the most restrictive pathway; see Table) for the management of non–small cell lung cancer in 1409 patients revealed that managing chemotherapy and supportive care drugs accounted for 22% and 23%, respectively, of a reduction in costs over 12 months compared with off-pathway management.3 Total cumulative costs were 35% lower with on-pathway care, with no detriment to survival. Chemotherapy cost savings came from a reduction in cost during the first line of on-pathway therapy (29% savings). l References

1. Koeller J. Oncology pathways: what’s the endgame? Presented at: Hematology/Oncology Pharmacy Association 9th Annual Conference; March 20, 2013; Los Angeles, CA. 2. Rotter T, Kinsman L, James EL, et al. Clinical pathways: effects on professional practice, patient outcomes, length of stay and hospital costs. Cochrane Database Syst Rev. 2010;17(3):CD006632.

3. Neubauer MA, Hoverman JR, Kolodziej M, et al. Cost effectiveness of evidence-based treatment guidelines for the treatment of non-small-cell lung cancer in the community setting. J Oncol Pract. 2010;6(1):12-18.

Helping Patients Overcome Obstacles to Oral Chemo Is Part of Anticancer Drug Management

P

harmacists can play a role in overcoming patients’ financial and personal obstacles to oral chemotherapy. In addition to appealing to the insurer for coverage, pharmacists can determine available assistance for patients, said Sarah Hudson-DiSalle, PharmD, RPh, at the Hematology/Oncology Pharmacy Association 9th Annual Conference.

Patients prescribed oral chemotherapy agents are often faced with large copays because these agents tend to be placed on specialty tiers. Underinsured patients may lack the financial ability to cover these out-of-pocket expenses. “We worry about these folks because they take on the characteristics of the uninsured patient,” said Hudson-DiSalle, specialty practice pharmacist at the Arthur G. James Cancer Hospital and Richard J. Solove Research Institute, Columbus, Ohio. “They start to skip doses at the end of therapy, they may split tablets.”

Most at risk are Medicare patients who do not qualify for low-income subsidies

8

MAy 2013 I VOL 6, NO 2

and have high copays that are in the coverage gap, and patients who have commercial insurance with high deductibles or limited coverage.

“You need to ask your patients what their prescription drug copayments are and [if the copayments are] drug specific [a high copay for only one medication or across-the-board high copays],” she said. If copayments are drug specific, the pharmacist can attempt to work with the insurer to get the oral chemotherapy agent on a different tier, such as a letter of medical necessity with supporting literature.

If the patient has a generally high copay, the cost may be ameliorated with manufacturer copay cards.

Disease-based assistance, such as grants provided by nonprofit foundations, also may be available. Manufacturer patient assistance programs, which are medication specific, can be tapped as well.

“When you launch a new medication, it’s important to take a proactive

approach,” she advised. “Meet with the pharmaceutical manufacturer representatives ahead of time” for coverage resources, patient assistance program forms, and discount cards. Gather information from clinics (ie, patient lists, prescriber and dosage information) and contact patients to find out which specialty pharmacy they use, with whom they are contracted, and their income level.

A structured program offers a longterm solution for patient medication needs. It has the potential to improve medication access, adherence, and continuity of care, said Hudson-DiSalle.

It also offers the opportunity “to be a patient advocate on a state and national level to make a positive change for your patients,” she said. One such positive change is supporting legislative efforts for oral chemotherapy parity, which ensures equal coverage at equitable rates for oral and intravenous chemotherapy drugs. The Cancer Drug

Coverage Parity Act (HR 2746) is expected to be introduced into the US House of Representatives soon.

Oral chemotherapy requires educating patients about the effects of food on the pharmacokinetics of the agent, said Robert Mancini, PharmD, BCOP, postgraduate year 2 oncology residency director at St. Luke’s Mountain States Tumor Institute, Boise, Idaho.

“It’s our job as pharmacists to assess the patient’s ability to handle these oral agents,” he said. Adhering to instructions may be especially difficult when patients are on combination drugs given with different instructions with regard to meals. In such instances, helping patients set up their food schedule may be as important as setting up their medication schedule.

“For those who work with dietitians, you may want to consider immediate referrals so they can step in and provide additional assistance,” said Mancini.

—WK l

www.TheOncologyPharmacist.com

For indolent B-cell non-Hodgkin lymphoma (NHL) that has progressed during or within 6 months of treatment with rituximab or a rituximab-containing regimen

Established treatment, demonstrated results Single-agent TREANDA® (bendamustine HCl) for Injection provided durable responses that lasted a median of 9 months Median DR

9.2 months

All responders (n=74)

(95% CI: 7.1, 10.8)

Patients who achieved a CR/CRu

10.4 months

1

(95% CI: 9.3, 13.6)

8.3 months

Patients who achieved a PR

1

(95% CI: 6.3, 10.8)

0

2

4

6

Months

8

10

12

The efficacy of TREANDA was evaluated in a single-arm study of 100 patients with indolent B-cell NHL that had progressed during or within six months of treatment with rituximab or a rituximab-containing regimen.

In 2 single-arm studies of patients with indolent B-cell NHL that had progressed (N=176), the most common non-hematologic adverse reactions (frequency ≥30%) were nausea (75%), fatigue (57%), vomiting (40%), diarrhea (37%), and pyrexia (34%).

The most common hematologic abnormalities (frequency ≥15%) were lymphopenia (99%), leukopenia (94%), anemia (88%), neutropenia (86%), and thrombocytopenia (86%).

TREANDA is indicated for the treatment of patients with indolent B-cell non-Hodgkin lymphoma (NHL) that has progressed during or within 6 months of treatment with rituximab or a rituximab-containing regimen.

• TREANDA is administered with a convenient dosing schedule – The recommended dose is 120 mg/m² administered intravenously over 60 minutes on Days 1 and 2 of a 21-day treatment cycle, up to 8 cycles Important Safety Information • Serious adverse reactions, including myelosuppression, infections, infusion reactions and anaphylaxis, tumor lysis syndrome, skin reactions including SJS/TEN, other malignancies, and extravasation, have been associated with TREANDA. Some reactions, such as myelosuppression, infections, and SJS/TEN (when TREANDA was administered concomitantly with allopurinol and other medications known to cause SJS/TEN), have been fatal. Patients should be monitored closely for these reactions and treated promptly if any occur • Adverse reactions may require interventions such as decreasing the dose of TREANDA, or withholding or delaying treatment • TREANDA is contraindicated in patients with a known hypersensitivity to bendamustine or mannitol.

Women should be advised to avoid becoming pregnant while using TREANDA • The most common non-hematologic adverse reactions for NHL (frequency ≥15%) are nausea, fatigue, vomiting, diarrhea, pyrexia, constipation, anorexia, cough, headache, weight decreased, dyspnea, rash, and stomatitis. The most common hematologic abnormalities (frequency ≥15%) are lymphopenia, leukopenia, anemia, neutropenia, and thrombocytopenia Learn more www.TREANDAHCP.com Learnatmore at www.TREANDAHCP.com Please see accompanying brief summary of full Prescribing Information. ©2013 Cephalon, Inc., a wholly owned subsidiary Reference: 1. Data on file. Teva Pharmaceuticals.

of Teva Pharmaceutical Industries Ltd. All rights reserved. TRE-2577c January 2013

ASH Highlights

Abstracts of Interest From the 54th Annual Meeting of the American Society of Hematology

By Caroline Helwick

Modified Dosing of Pegaspargase Proposed for ALL Induction In the treatment of adults with newly diagnosed acute lymphoblastic leuke-

mia (ALL), a pharmacokinetic-based intravenous dosing of pegaspargase,

Brief Summary of Prescribing Information for Indolent B-cell Non-Hodgkin Lymphoma That Has Progressed INDICATION AND USAGE: TREANDA for Injection is indicated for the treatment of patients with indolent B-cell non-Hodgkin lymphoma (NHL) that has progressed during or within six months of treatment with rituximab or a rituximab-containing regimen.

CONTRAINDICATIONS: TREANDA is contraindicated in patients with a known hypersensitivity (eg, anaphylactic and anaphylactoid reactions) to bendamustine or mannitol. [See Warnings and Precautions] WARNINGS AND PRECAUTIONS: Myelosuppression. Patients treated with TREANDA are likely to experience myelosuppression. In the two NHL studies, 98% of patients had Grade 3-4 myelosuppression (see Table 2). Three patients (2%) died from myelosuppression-related adverse reactions; one each from neutropenic sepsis, diffuse alveolar hemorrhage with Grade 3 thrombocytopenia, and pneumonia from an opportunistic infection (CMV). In the event of treatment-related myelosuppression, monitor leukocytes, platelets, hemoglobin (Hgb), and neutrophils closely. In the clinical trials, blood counts were monitored every week initially. Hematologic nadirs were observed predominantly in the third week of therapy. Hematologic nadirs may require dose delays if recovery to the recommended values have not occurred by the first day of the next scheduled cycle. Prior to the initiation of the next cycle of therapy, the ANC should be ≥ 1 x 109/L and the platelet count should be ≥ 75 x 109/L. [See Dosage and Administration]. Infections. Infection, including pneumonia and sepsis, has been reported in patients in clinical trials and in post-marketing reports.

Infection has been associated with hospitalization, septic shock and death. Patients with myelosuppression following treatment with TREANDA are more susceptible to infections. Patients with myelosuppression following TREANDA treatment should be advised to contact a physician if they have symptoms or signs of infection. Infusion Reactions and Anaphylaxis. Infusion reactions to TREANDA have occurred commonly in clinical trials. Symptoms include fever, chills, pruritus and rash. In rare instances severe anaphylactic and anaphylactoid reactions have occurred, particularly in the second and subsequent cycles of therapy. Monitor clinically and discontinue drug for severe reactions. Patients should be asked about symptoms suggestive of infusion reactions after their first cycle of therapy. Patients who experienced Grade 3 or worse allergic-type reactions were not typically rechallenged. Measures to prevent severe reactions, including antihistamines, antipyretics and corticosteroids should be considered in subsequent cycles in patients who have previously experienced Grade 1 or 2 infusion reactions. Discontinuation should be considered in patients with Grade 3 or 4 infusion reactions. Tumor Lysis Syndrome. Tumor lysis syndrome associated with TREANDA treatment has been reported in patients in clinical trials and in post-marketing reports. The onset tends to be within the first treatment cycle of TREANDA and, without intervention, may lead to acute renal failure and death.

Preventive measures include maintaining adequate volume status, and close monitoring of blood chemistry, particularly potassium and uric acid levels. Allopurinol has also been used during the beginning of TREANDA therapy. However, there may be an increased risk of severe skin toxicity when TREANDA and allopurinol are administered concomitantly. Skin Reactions. A number of skin reactions have been reported in clinical trials and post-marketing safety reports. These events have included rash, toxic skin reactions and bullous exanthema. Some events occurred when TREANDA was given in combination with other anticancer agents, so the precise relationship to TREANDA is uncertain. In a study of TREANDA (90 mg/m2) in combination with rituximab, one case of toxic epidermal necrolysis (TEN) occurred. TEN has been reported for rituximab (see rituximab package insert). Cases of Stevens-Johnson syndrome (SJS) and TEN, some fatal, have been reported when TREANDA was administered concomitantly with allopurinol and other medications known to cause these syndromes. The relationship to TREANDA cannot be determined. Where skin reactions occur, they may be progressive and increase in severity with further treatment. Therefore, patients with skin reactions should be monitored closely. If skin reactions are severe or progressive, TREANDA should be withheld or discontinued. Other Malignancies. There are reports of pre-malignant and malignant diseases that have developed in patients who have been treated with TREANDA, including myelodysplastic syndrome, myeloproliferative disorders, acute myeloid leukemia and bronchial carcinoma. The association with TREANDA therapy has not been determined. Extravasation. There are postmarketing reports of bendamustine extravasations resulting in hospitalizations from erythema, marked swelling, and pain.

Precautions should be taken to avoid extravasations, including monitoring of the intravenous infusion site for redness, swelling, pain, infection, and necrosis during and after administration of TREANDA. Use in Pregnancy. TREANDA can cause fetal harm when administered to a pregnant woman. Single intraperitoneal doses of bendamustine in mice and rats administered during organogenesis caused an increase in resorptions, skeletal and visceral malformations, and decreased fetal body weights.

ADVERSE REACTIONS: The data described below reflect exposure to TREANDA in 176 patients who participated in two single-arm trials for the treatment of indolent B-cell NHL. 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 following serious adverse reactions have been associated with TREANDA in clinical trials and are discussed in greater detail in other sections [See Warnings and Precautions] of the label: Myelosuppression; Infections; Infusion Reactions and Anaphylaxis; Tumor Lysis Syndrome; Skin Reactions; Other Malignancies. Clinical Trials Experience in NHL. The data described below reflect exposure to TREANDA in 176 patients with indolent B-cell NHL treated in two single-arm studies. The population was 31-84 years of age, 60% male, and 40% female. The race distribution was 89% White, 7% Black, 3% Hispanic, 1% other, and <1% Asian. These patients received TREANDA at a dose of 120 mg/m2 intravenously on Days 1 and 2 for up to 8 21-day cycles.

The adverse reactions occurring in at least 5% of the NHL patients, regardless of severity, are shown in Table 1. The most common non-hematologic adverse reactions (≥30%) were nausea (75%), fatigue (57%), vomiting (40%), diarrhea (37%) and pyrexia (34%). The most common non-hematologic Grade 3 or 4 adverse reactions (≥5%) were fatigue (11%), febrile neutropenia (6%), and pneumonia, hypokalemia and dehydration, each reported in 5% of patients.

Table 1: Non-Hematologic Adverse Reactions Occurring in at Least 5% of NHL Patients Treated With TREANDA by System Organ Class and Preferred Term (N=176).

System organ class, preferred term, and number (%) of patients* are shown.

Total number of patients with at least 1 adverse reaction— All Grades: 176 (100); Grade 3/4: 94 (53).

Cardiac disorders, All Grades and Grade 3/4—Tachycardia: 13 (7), 0.

Gastrointestinal disorders, All Grades and Grade 3/4—Nausea: 132 (75), 7 (4); Vomiting: 71 (40), 5 (3); Diarrhea: 65 (37), 6 (3); Constipation: 51 (29), 1 (<1); Stomatitis: 27 (15), 1 (<1); Abdominal pain: 22 (13), 2 (1); Dyspepsia: 20 (11), 0; Gastroesophageal reflux disease: 18 (10), 0; Dry mouth: 15 (9), 1 (<1); Abdominal pain upper: 8 (5), 0; Abdominal distension: 8 (5), 0.

General disorders and administration site conditions, All Grades and Grade 3/4—Fatigue: 101 (57), 19 (11); Pyrexia: 59 (34), 3 (2); Chills: 24 (14), 0; Edema peripheral: 23 (13), 1 (<1); Asthenia: 19 (11), 4 (2); Chest pain: 11 (6), 1 (<1); Infusion site pain: 11 (6), 0; Pain: 10 (6), 0; Catheter site pain: 8 (5), 0.

Infections and infestations, All Grades and Grade 3/4—Herpes zoster: 18 (10), 5 (3); Upper respiratory tract infection: 18 (10), 0; Urinary tract infection: 17 (10), 4 (2); Sinusitis: 15 (9), 0; Pneumonia: 14 (8), 9 (5); Febrile Neutropenia: 11 (6), 11 (6); Oral Candidiasis: 11 (6), 2 (1); Nasopharyngitis: 11 (6), 0.

Investigations, All Grades and Grade 3/4—Weight decreased: 31 (18), 3 (2).

Metabolism and nutrition disorders, All Grades and Grade 3/4—Anorexia: 40 (23), 3 (2); Dehydration: 24 (14), 8 (5); Decreased appetite: 22 (13), 1 (<1); Hypokalemia: 15 (9), 9 (5).

Musculoskeletal and connective tissue disorders, All Grades and Grade 3/4—Back pain: 25 (14), 5 (3); Arthralgia: 11 (6), 0; Pain in extremity: 8 (5), 2 (1); Bone pain: 8 (5), 0.

Nervous system disorders, All Grades and Grade 3/4—Headache: 36 (21), 0; Dizziness: 25 (14), 0; Dysgeusia: 13 (7), 0.

Psychiatric disorders, All Grades and Grade 3/4—Insomnia: 23 (13), 0; Anxiety: 14 (8), 1 (<1); Depression: 10 (6), 0.

Respiratory, thoracic and mediastinal disorders, All Grades and Grade 3/4—Cough: 38 (22), 1 (<1); Dyspnea: 28 (16), 3 (2); Pharyngolaryngeal pain: 14 (8), 1 (<1); Wheezing: 8 (5), 0; Nasal congestion: 8 (5), 0.

Skin and subcutaneous tissue disorders, All Grades and Grade 3/4—Rash: 28 (16), 1 (<1); Pruritus: 11 (6), 0; Dry skin: 9 (5), 0; Night sweats: 9 (5), 0; Hyperhidrosis: 8 (5), 0.

Vascular disorders, All Grades and Grade 3/4—Hypotension: 10 (6), 2 (1). *Patients may have reported more than 1 adverse reaction.

NOTE: Patients counted only once in each preferred term category and once in each system organ class category.

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MAy 2013 I VOL 6, NO 2

rationally synchronized with other chemotherapy drugs in a pediatric-in-

Hematologic toxicities, based on laboratory values and CTC grade, in NHL patients treated in both single arm studies combined are described in Table 2. Clinically important chemistry laboratory values that were new or worsened from baseline and occurred in >1% of patients at Grade 3 or 4, in NHL patients treated in both single arm studies combined were hyperglycemia (3%), elevated creatinine (2%), hyponatremia (2%), and hypocalcemia (2%).

Table 2: Incidence of Hematology Laboratory Abnormalities in Patients Who Received TREANDA in the NHL Studies Percent of patients Hematology Variable All Grades Grade 3/4 Lymphocytes Decreased 99 94 Leukocytes Decreased 94 56 Hemoglobin Decreased 88 11 Neutrophils Decreased 86 60 Platelets Decreased 86 25 In both studies, serious adverse reactions, regardless of causality, were reported in 37% of patients receiving TREANDA. The most common serious adverse reactions occurring in ≥ 5% of patients were febrile neutropenia and pneumonia. Other important serious adverse reactions reported in clinical trials and/or post-marketing experience were acute renal failure, cardiac failure, hypersensitivity, skin reactions, pulmonary fibrosis, and myelodysplastic syndrome. Serious drug-related adverse reactions reported in clinical trials included myelosuppression, infection, pneumonia, tumor lysis syndrome, and infusion reactions. [See Warnings and Precautions] Adverse reactions occurring less frequently but possibly related to TREANDA treatment were hemolysis, dysgeusia/taste disorder, atypical pneumonia, sepsis, herpes zoster, erythema, dermatitis, and skin necrosis. Post-Marketing Experience. The following adverse reactions have been identified during post-approval use of TREANDA. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure: anaphylaxis; and injection or infusion site reactions including phlebitis, pruritus, irritation, pain, and swelling. Skin reactions including SJS and TEN have occurred when TREANDA was administered concomitantly with allopurinol and other medications known to cause these syndromes. [See Warnings and Precautions] OVERDOSAGE: The intravenous LD of bendamustine HCl is 240 mg/m2 in the mouse and rat.

Toxicities included sedation, tremor, ataxia, convulsions and respiratory distress. Across all clinical experience, the reported maximum single dose received was 280 mg/m2. Three of four patients treated at this dose showed ECG changes considered dose-limiting at 7 and 21 days post-dosing. These changes included QT prolongation (one patient), sinus tachycardia (one patient), ST and T wave deviations (two patients), and left anterior fascicular block (one patient). Cardiac enzymes and ejection fractions remained normal in all patients. No specific antidote for TREANDA overdose is known.

Management of overdosage should include general supportive measures, including monitoring of hematologic parameters and ECGs. DOSAGE AND ADMINISTRATION: Dosing Instructions for NHL. Recommended Dosage: The recommended dose is 120 mg/m2 administered intravenously over 60 minutes on Days 1 and 2 of a 21-day cycle, up to 8 cycles. Dose Delays, Dose Modifications and Reinitiation of Therapy for NHL: TREANDA administration should be delayed in the event of a Grade 4 hematologic toxicity or clinically significant ≥ Grade 2 non-hematologic toxicity. Once non-hematologic toxicity has recovered to ≤ Grade 1 and/or the blood counts have improved [Absolute Neutrophil Count (ANC) ≥ 1 x 109/L, platelets ≥ 75 x 109/L], TREANDA can be reinitiated at the discretion of the treating physician. In addition, dose reduction may be warranted. [See Warnings and Precautions] Dose modifications for hematologic toxicity: for Grade 4 toxicity, reduce the dose to 90 mg/m2 on Days 1 and 2 of each cycle; if Grade 4 toxicity recurs, reduce the dose to 60 mg/m2 on Days 1 and 2 of each cycle. Dose modifications for non-hematologic toxicity: for Grade 3 or greater toxicity, reduce the dose to 90 mg/m2 on Days 1 and 2 of each cycle; if Grade 3 or greater toxicity recurs, reduce the dose to 60 mg/m2 on Days 1 and 2 of each cycle. Reconstitution/Preparation for Intravenous Administration.

• Aseptically reconstitute each TREANDA vial as follows: • 25 mg TREANDA vial: Add 5 mL of only Sterile Water for Injection, USP. • 100 mg TREANDA vial: Add 20 mL of only Sterile Water for Injection, USP. Shake well to yield a clear, colorless to a pale yellow solution with a bendamustine HCl concentration of 5 mg/mL. The lyophilized powder should completely dissolve in 5 minutes.

If particulate matter is observed, the reconstituted product should not be used.

• Aseptically withdraw the volume needed for the required dose (based on 5 mg/mL concentration) and immediately transfer to a 500 mL infusion bag of 0.9% Sodium Chloride Injection, USP (normal saline). As an alternative to 0.9% Sodium Chloride Injection, USP (normal saline), a 500 mL infusion bag of 2.5% Dextrose/0.45% Sodium Chloride Injection, USP, may be considered. The resulting final concentration of bendamustine HCl in the infusion bag should be within 0.2–0.6 mg/mL. The reconstituted solution must be transferred to the infusion bag within 30 minutes of reconstitution.

After transferring, thoroughly mix the contents of the infusion bag. The admixture should be a clear and colorless to slightly yellow solution. • Use Sterile Water for Injection, USP, for reconstitution and then either 0.9% Sodium Chloride Injection, USP, or 2.5% Dextrose/0.45% Sodium Chloride Injection, USP, for dilution, as outlined above. No other diluents have been shown to be compatible. • Parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration whenever solution and container permit. Any unused solution should be discarded according to institutional procedures for antineoplastics. Admixture Stability. TREANDA contains no antimicrobial preservative. The admixture should be prepared as close as possible to the time of patient administration. Once diluted with either 0.9% Sodium Chloride Injection, USP, or 2.5% Dextrose/0.45% Sodium Chloride Injection, USP, the final admixture is stable for 24 hours when stored refrigerated (2-8°C or 36-47°F) or for 3 hours when stored at room temperature (15-30°C or 59-86°F) and room light.

Administration of TREANDA must be completed within this period.

DOSAGE FORMS AND STRENGTHS: TREANDA for Injection single-use vial containing either 25 mg or 100 mg of bendamustine HCl as white to off-white lyophilized powder.

HOW SUPPLIED/STORAGE AND HANDLING: Safe Handling and Disposal. As with other potentially toxic anticancer agents, care should be exercised in the handling and preparation of solutions prepared from TREANDA. The use of gloves and safety glasses is recommended to avoid exposure in case of breakage of the vial or other accidental spillage. If a solution of TREANDA contacts the skin, wash the skin immediately and thoroughly with soap and water. If TREANDA contacts the mucous membranes, flush thoroughly with water. Procedures for the proper handling and disposal of anticancer drugs should be considered. Several guidelines on the subject have been published. There is no general agreement that all of the procedures recommended in the guidelines are necessary or appropriate. How Supplied. TREANDA (bendamustine hydrochloride) for Injection is supplied in individual cartons as follows: NDC 63459-390-08 TREANDA (bendamustine hydrochloride) for Injection, 25 mg in 8 mL amber single-use vial and NDC 63459-391-20 TREANDA (bendamustine hydrochloride) for Injection, 100 mg in 20 mL amber single-use vial. Storage. TREANDA may be stored up to 25°C (77°F) with excursions permitted up to 30°C (86°F) (see USP Controlled Room Temperature). Retain in original package until time of use to protect from light.

50

Distributed by: Cephalon, Inc. Frazer, PA 19355 TREANDA is a trademark of Cephalon, Inc., or its affiliates. All rights reserved. ©2008-2012 Cephalon, Inc., or its affiliates.

TRE-2486c November 2012 (Label Code: 00016287.06) This brief summary is based on TRE-2527 TREANDA full Prescribing Information.

spired regimen, provides a safer induction with no detriment to clinical outcomes, compared with standard dosing.

The results of the multicenter study were reported by Dan Douer, MD, of Memorial Sloan-Kettering Cancer Center, New York, at the ASH annual meeting.

“Prolonged asparaginase (ASP) use is standard in all pediatric ALL regimens. In adults, ASP is either not used or is given for much shorter duration. Recently, several adult ALL protocols adopted pediatric regimens, with long duration of ASP, with better outcomes than historically reported. However, the optimal implementation of pediatric regimens to adults, especially ASP dosing, has not been studied, considering its potentially higher toxicity,” Douer noted.

He and his colleagues adopted the augmented Berlin-Frankfurt-Munster pediatric protocol, replacing the native E coli ASP with 6 doses of long-acting pegaspargase (PEG-ASP). While pediatric and most pediatric-inspired adult protocols use 2500 IU/m2 PEGASP at 2-week intervals, the researchers reduced the dose to 2000 IU/m2 at intervals no shorter than 4 weeks.

They also synchronized the PEGASP doses with the timing of myelosuppressive drugs to avoid “coinciding toxicities,” he said. In addition, they replaced the escalated methotrexate dosing plus E coli ASP with 4 fixed high doses of methotrexate, timing PEG-ASP to avoid its overlapping long enzymatic activity with methotrexate activity. Hydrocortisone premedication and steroids were administered for 7 to 14 days after each dose.

Outcomes for the 51 patients included a 96% complete response rate (98% at 4 weeks), 7-year overall survival of 51%, and disease-free survival of 58%. Median days to absolute neutrophil count >500/ dL as well as platelets >50,000/dL were 17, and 83% of patients achieved these landmarks by day 21.

Fifty percent of patients received all 6 PEG-ASP doses. All toxicities were manageable and reversible, only 19% discontinued treatment due to toxicity, and there were no deaths at 30 days.

“Our study implies that the standard PEG-ASP adult dose can be 2000 IU/ m2, which is lower than the FDAapproved dose, at intervals no less than 4 weeks, without impairing overall outcomes,” Douer said. “This is safer induction. Low blood counts do not coincide with ASP toxicity.”

Reference

Douer D, Aldoss I, Lunning MA, et al. Pharmacokineticsbased modification of intravenous pegylated asparaginase dosing in the context of “pediatric-inspired” protocol in adults with newly diagnosed acute lymphoblastic leukemia (ALL). Presented at: 54th American Society of Hematology Annual Meeting; December 8-11, 2012; Atlanta, GA. Abstract 1495.

www.TheOncologyPharmacist.com

ASH Highlights Eliminating Chemotherapy in Acute Promyelocytic Leukemia At the ASH plenary session, investigators showed that acute promyelocytic leukemia (APL), traditionally one of the deadliest hematologic malignancies, can be treated without chemotherapy.

Outcomes in the APL0406 study were just as good with a combination of alltrans retinoic acid (ATRA) and arsenic trioxide (ATO), compounds that have long been used in traditional Chinese medicine. The 2-year event-free survival was 97% in the ATRA/ATO arm versus 86.7% in the ATRA/chemotherapy arm, while overall survival was 98.7% and 91.1%, respectively.

The phase 3 trial, conducted in Italy and Germany, involved 162 patients with newly diagnosed APL. Patients received the noncytotoxic regimen of ATO plus ATRA daily until a complete response was achieved, then ATO for 5 days a week for 4 weeks on,

Rivaroxaban Comparable to Enoxaparin for Anticoagulation A pooled analysis of the EINSTEIN-DVT and EINSTEIN-PE studies showed rivaroxaban to be as effective in preventing recurrences of venous thromboembolism as enoxaparin followed by a vitamin-K antagonist, with perhaps less risk for bleeding. Subgroup analyses found the drug to be safe and effective in specific high-risk populations, such as elderly fragile patients and patients with cancer or large clots. The studies had noninferiority designs and compared oral rivaroxaban (15 mg twice daily for 3 weeks, then 20 mg once daily for up to 12 months) with enoxaparin for 5 to 10 days followed by an oral vitamin-K antagonist.

Among the 8282 patients enrolled in the 2 trials, thromboembolism recurred in 2.1% receiving rivaroxaban and 2.3% receiving enoxaparin/vitamin-K antagonist; major or nonmajor clinically relevant bleeding was observed in 9.4% and 10.0%, and major bleeding in 1.0% and 1.7%, respectively.

In patients with cancer, recurrence was observed in 2.6% and 4.0%, and major bleeding in 2.6% and 4.1%, respectively.

Reference

Buller HR. Oral rivaroxaban for the treatment of symptomatic venous thromboembolism: a pooled analysis of the EINSTEIN DVT and EINSTEIN PE studies. Presented at: 54th American Society of Hematology Annual Meeting; December 8-11, 2012; Atlanta, GA. Abstract 20.

www.TheOncologyPharmacist.com

Investigators showed that APL, traditionally one of the deadliest hematologic malignancies, can be treated without chemotherapy.

4 weeks off (4 courses), and ATRA 2 weeks on, 2 weeks off (7 courses).

Patients in the control arm received

standard ATRA plus idarubicin induction, followed by 3 cycles of anthracycline-based chemotherapy plus

ATRA consolidation, followed by ATRA and low-dose chemotherapy for maintenance.

Reference

Lo-Coco F, Avvisati G, Orlando SM, et al. ATRA and arsenic trioxide (ATO) versus ATRA and idarubicin (AIDA) for newly diagnosed, non high-risk acute promyelocytic leukemia (APL): results of the phase III prospective, randomized, intergroup APL0406 study by the Italian-German Cooperative Groups GimemaSAL-AMLSG. Presented at: 54th American Society of Hematology Annual Meeting; December 8-11, 2012; Atlanta, GA. Abstract 6.

ONCOLOGY

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THAT’S OUR COMMITMENT IN ACTION. Reference: 1. Data on file. Fresenius Kabi USA, LLC, June 2011.

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A PROVEN RECORD OF RESPONSE. APP® and are trademarks of Fresenius Kabi USA, LLC. ©2013, Fresenius Kabi USA, LLC. All Rights Reserved. 0513-APPF-05-01/13

May 2013 I VOL 6, NO 2

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ASH Highlights Meta-Analysis Examines Adverse Effects of Rituximab Maintenance in Lymphoma Rituximab has improved outcomes of clinical trials of maintenance therapy to patients with follicular lymphoma and determine rates of grade 3 and 4 toxicities. mantle cell lymphoma. Treatment schedThe study found that maintenance ules have varied between a single infusion rituximab given every 6 months as 4 given every 2 or 3 months to 4 weekly weekly infusions for 2 years was assoinfusions every 6 months, all given for a ciated with fewer grade 3 or 4 toxictotal of 2 years. This systematic review ities compared with a single infusion and meta-analysis analyzedAd prospective every COEAsizeCE_fish_71112_House 7/11/12 11:47 AM Page 12 months: 10% versus 28%

FREE

(P = .035). The study was not able to compare the 3-month infusion schedule to other schedules, owing to the limited number of studies. Toxicities in patients receiving treatment in the frontline setting appeared lower than those treated for relapsed disease, but the difference was not statistically significant. Toxicities

Continuing Education

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MULTIPLE MYELOMA BREAST CANCER LUNG CANCER LYMPHOMAS CINV BIOMARKERS MYELOFIBROSIS SUPPORTIVE CARE PATIENT NAVIGATION MULTIPLE SCLEROSIS CUTANEOUS MALIGNANCIES VALUE-BASED CANCER CARE PERSONALIZED CANCER CARE

were lower when rituximab was given alone compared with chemotherapy in the induction program: 12% versus 35% (P = .031).

Reference

Nabhan C, Villines MA, Chiu B C-H, et al. Meta analysis of grade 3 and/or 4 toxicities in follicular (FL) and mantle cell (MCL) non-Hodgkin lymphoma (NHL) patients receiving maintenance rituximab (MR): impact of schedule, histology, and induction regimen. Presented at: 54th American Society of Hematology Annual Meeting; December 8-11, 2012; Atlanta, GA. Abstract 3654.

Cyclophosphamide Reduces Risk of GVHD After Transplant Investigators from the MD Anderson Cancer Center advised against using pulse doses of cyclophosphamide on days +3 and +4 after hematopoietic stem cell transplant as sole prophylaxis for graft-versus-host disease (GVHD). They previously reported that this practice was associated with lower rates of chronic GVHD than were traditional prophylaxis regimens in bone marrow transplant recipients undergoing ablative conditioning regimens.

Using a matched-control design, the researchers assessed 37 patients to determine whether posttransplant cyclophosphamide would also be effective after a reduced-intensity conditioning regimen, compared with tacrolimus and minidose methotrexate (conventional regimen).

The incidence of acute GVHD grades 2 to 4 was 51% with cyclophosphamide as sole prophylaxis compared with 19% with the conventional regimen, for a hazard ratio of 3.2 (P = .009) favoring tacrolimus/methotrexate. Grades 3 and 4 acute GVHD occurred in 14% for cyclophosphamide and 0% for the conventional regimen (P = .02), but no significant differences were seen in chronic GVHD, 14% and 21%, respectively (P = .8). The experimental regimen was also associated with a trend toward higher nonrelapse mortality.

Reference

REGISTER TODAY AT www.COEXM.com ©iStockphoto.com/altaykaya

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MAy 2013 I VOL 6, NO 2

COEKsize71112CE

Alousi AM, Saliba RN, Chen J, et al. A matched controlled analysis of post-transplant cyclophosphamide (CY) versus tacrolimus and mini-dose methotrexate in matched sibling and unrelated donor transplant recipients receiving reduced-intensity conditioning: post-transplant CY is associated with higher rates of acute Gvhd. Presented at: 54th American Society of Hematology Annual Meeting; December 8-11, 2012; Atlanta, GA. Abstract 4200.

www.TheOncologyPharmacist.com

ASH Highlights VRE Bacteremia in AML Signals Worse Survival Bacteremia caused by vancomycinresistant enterococcus (VRE) is an independent risk factor for worse overall survival (OS) in patients undergoing induction chemotherapy for acute myeloid leukemia (AML), Cleveland Clinic investigators reported at ASH. “Patients with AML are more susceptible to VRE than other hospitalized patients, but the impact of VRE bacteremia on outcomes after induction chemotherapy has not been established,” said Moshe Ornstein, MD, MA, of the Taussig Cancer Institute, Cleveland, Ohio.

Patients who had VRE infections during induction had significantly worse OS than did patients without infection.

The retrospective study of 350 patients with AML who received cytarabine-based induction chemotherapy between 2000 and 2008 determined VRE rates and their effect on complete remission and OS. The overall complete remission rate was 73%, including 70% in patients who had VRE and 73% in patients who did not.

At a median follow-up of 72 months, the unadjusted median OS was 12.8 months overall, including 7.1 months for patients who developed VRE and 13.1 months for the others, a numerical but not statistically significant difference (P = .13).

In a multivariable analysis that adjusted for important factors including VRE infection as a time-varying covariate, patients who had VRE infections during induction had significantly worse OS than did patients without infection. VRE infection was associated with a 77% increase in mortality (P = .022), Ornstein reported. “Consideration should therefore be given to escalating VRE-appropriate antibiotics in these patients sooner and in the postremission setting,” he said.

Reference

Ornstein M, Mukherjee S, King MK, et al.

Vancomycin-resistant enterococcus (VRE) bacteremia during acute myeloid leukemia (AML) induction therapy is an independent predictor of poor outcome.

Presented at: 54th American Society of Hematology Annual Meeting; December 8-11, 2012; Atlanta, GA. Abstract 1487.

www.TheOncologyPharmacist.com

Should NCI Toxicity Criteria in AML Be Revisited?

The common toxicity criteria established by the National Cancer Institute (NCI) is not necessarily an accurate treatment guide for acute myeloid leukemia (AML), according to a study from the University of Washington and the Fred Hutchinson Cancer Research Center, Seattle, presented by Joshua R. Veatch, MD, PhD, at the ASH annual meeting.

“Our data suggest that if the principal purpose of toxicity grading is to guide subsequent dose reduction to prevent death, the NCI toxicity criteria should be revisited,” Veatch proposed.

NCI grade 3 toxicity leads to changes in disease management, but it is not known how these toxicity criteria relate to treatment-associated mortality. To provide a more empiric basis for deci-

sions, the researchers analyzed the relationship between mortality and grades of NCI toxicity for bilirubin, creatinine, alanine aminotransferase (ALT), and aspartate aminotransferase (AST) after chemotherapy for AML. They examined 714 courses of chemotherapy in 509 patients with newly diagnosed or relapsed/refractory AML. At 28 days, the mortality rate was 5.6% for treatments and 7.7% for patients.

Maximum laboratory values for creatinine were strongly related to mortality. Grade 0 had a 1.0% mortality rate, and each increasing grade was associated with a significant increase over the preceding toxicity level: 5.1% for grade 1, 23% for grade 2, and 50% for grade 3 or 4. Relative to grade 0, bilirubin was

significantly associated with mortality at grade 2 (11%) and grade 3 or 4 (17%), as was AST at grade 2 (10.2%) and grade 3 or 4 (15.6%). ALT, on the other hand, was not correlated with mortality, even at grade 3 or 4 (9.8% vs 5.6% at grade 0), Veatch reported.

“Creatinine was more highly correlated to mortality than liver function tests, and ALT did not significantly correlate,” he noted. “These correlations certainly do not imply causation, but suggest the common toxicity criteria be revised.” l Reference

Veatch JR, Sandhu RK, Shannon-Dorcy K, et al. NCI common toxicity criteria and mortality after chemotherapy for acute myeloid leukemia (AML). Presented at: 54th American Society of Hematology Annual Meeting; December 8-11, 2012; Atlanta, GA. Abstract 1479.

Breast Cancer

Two-Thirds of Women Experience Musculoskeletal Toxicity on Aromatase Inhibitors and 22.9% Discontinue Therapy

By Phoebe Starr

S

tudies have suggested that musculoskeletal toxicity associated with aromatase inhibitor therapy can lead to noncompliance in up to one-third of women with breast cancer. A large, single-center, cohort study at a regional cancer center found that the rate of musculoskeletal toxicity in women with early breast cancer treated with endocrine therapy was 64%. Patients taking aromatase inhibitors experienced almost twice the frequency of musculoskeletal toxicity as those taking tamoxifen: 64% versus 36%, respectively. These findings are similar to a report in the literature, showing that 61% of women receiving aromatase inhibitors experienced musculoskeletal toxicity in clinical trials.1 The findings were presented at the 2012 CTRC-AACR San Antonio Breast Cancer Symposium.2 “Despite the high incidence of musculoskeletal toxicity observed in patients taking aromatase inhibitors, the majority continued treatment, with only 22.9% of women discontinuing therapy for this reason,” stated lead author Susan F. Dent, MD, of the Ottawa Hospital Cancer Centre, the University of Ottawa, Ontario, Canada. This is also similar to the report in the literature, where Gaillard and colleagues found that 20% discontinued aromatase inhibitor therapy due to musculoskeletal toxicity in clinical trials.

The study was based on a retrospec-

tive chart review at the Ottawa Hospital Cancer Centre between January 1999 and December 2006. The population included 626 postmenopausal women with hormone receptor–positive early breast cancer treated with endocrine therapy, including at least 1 aromatase inhibitor.

The most common musculoskeletal toxicities were arthralgias (41%), myalgias (25%), osteoporosis/ osteopenia (23%), and arthritis (19%).

Mean age was 59 years. Median follow-up was 98 months, and median duration of treatment with an aromatase inhibitor was 59 months. The women had a total of 1117 prescriptions that included letrozole, anastrozole, exemestane, and tamoxifen.

Musculoskeletal toxicity developed in 68% of those taking letrozole, 47.6% of those taking exemestane, 63.9% of those taking anastrozole, and 36% of those taking tamoxifen. Median time to developing musculoskeletal toxicity

was 21 months, 9 months, 23 months, and 23 months, respectively.

The most common musculoskeletal toxicities were arthralgias (41%), myalgias (25%), osteoporosis/osteopenia (23%), and arthritis (19%).

Treatment was discontinued for these toxicities significantly more often with any aromastase inhibitor than with tamoxifen: 14.6% versus 4.8%, respectively (P <.0001). Treatment strategies for musculoskeletal toxicity did not significantly impact adherence to therapy, except in the case of exemestane. Among the group treated with exemestane, adherence rate with no intervention was 33% and adherence increased to 80% with musculoskeletal toxicity intervention, including mediation and physiotherapy (P <.0001). Longer exposure to any endocrine therapy did not appear to increase the rate of musculoskeletal toxicity. Among this group of women, 51% completed 5 years of endocrine therapy as prescribed. l References

1. Gaillard S, Stearns V. Aromatase inhibitorassociated bone and musculoskeletal effects: new evidence defining etiology and strategies for management. Breast Cancer Res. 2011;13(2):205.

2. Dent SF, Campbell MM, Crawley FL, et al. The impact of musculoskeletal toxicity on adherence to endocrine therapy in women with early stage breast cancer—observations in a non-trial setting.

Presented at: 2012 CTRC-AACR San Antonio Breast Cancer Symposium; December 4-8, 2012; San Antonio, TX. Poster P1-05-06.

May 2013 I VOL 6, NO 2

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Side Effects Management

Monitor Adverse Events Early With Regorafenib, Especially After Initiation

drugs (INDs) were revised in 2009. The new regulations have a provision for charging for INDs, which must be approved by the US Food and Drug Administration (FDA) at the time of the IND submission.

To qualify for expanded access, the patient must have no other treatment options and there cannot be any clinical trials open for which the patient qualifies. In addition, the risks of treatment with the IND must outweigh the risks of the disease or the condition, and expanded access must not create an adverse impact on the development of the drug.

The advanced search field on www.clinicaltrials.gov can be used to identify available expanded-access programs. “These will only be the treatment INDs, the ones which are available and open for large numbers of patients,” said Redic. “If you don’t find anything, you can contact individual sponsors or individual companies that have these drugs in development and see if they are making them available for single patient access.”

Expanded access to a drug may be denied if the supply is limited, the regulatory work is deemed too costly, safety problems that may arise could jeopardize the FDA approval process, and the expanded access program may hinder enrollment in other clinical trials.

Redic reminds pharmacists to consider that providing a drug outside a clinical trial, in a patient population the drug hasn’t been tested in, may leave the patient worse off. “This is worth thinking about and reminding your team about as you’re wrestling with this idea of compassionate use,” she said. —WK l

given that side effects are strongest in the first cycle and then abate over time, but this is exactly what we saw in the study.”

Close monitoring of AEs in the days immediately following the start of regorafenib treatment will allow prompt intervention. Grothey recommends patients be contacted or seen in the office 1 week after starting treatment at the full 160 mg/day dosage, to allow for early dosage adjustment if necessary. Per the package insert, patients should be seen 2 weeks into treatment, at which time lab tests, including measurement of liver enzymes, should be obtained.

“At that point, most of the time we can either continue the dose or make any dose adjustments,” he said.

In the CORRECT study, AEs led to dose modification in 66.6% of patients assigned to regorafenib, but treatment had to be discontinued permanently in only 17.6%. The most frequent grade 3 AEs were hand-foot skin reaction (HFSR), fatigue, diarrhea, hypertension, and rash/ desquamation.

During cycle 1 of regorafenib, the incidence of fatigue was about 45% and the incidence of HFSR exceeded 30%. These incidence rates decreased to ≤25% during cycle 2 and remained relatively stable through cycle 6. The rates of fatigue and HFSR diminished further in cycles 7 and 8.

The incidences of hypertension and rash/desquamation were highest in cycle 1, at 20% to 25%, “and tapered to low or no incidence over cycles 2 to 8,” said Grothey. The incidence of diarrhea remained relatively constant from cycles 1 to 6, but was lower in cycles 7 and 8.

“The time course suggested an initial flare up of key side effects, in particular fatigue and HFSR, and then over time these side effects decreased in incidence but also in severity,” he said.

On average, the dose intensity was highest in cycle 1 and reached a lower, relatively stable dose by cycle 3.

Because it works by blocking multiple protein kinases, identifying the actions of regorafenib that contribute to toxicity and efficacy is difficult, said Grothey.

“There are so many different pathways that are being inhibited that it’s impossible to tease that out.”

“The critical issue now is no matter how thoughtfully and thoroughly we conduct a phase 3 trial, eventually when the drug is approved, it gets expanded to a larger patient population, sometimes patients that might not have met the eligibility criteria of a clinical trial,” he said. “As we get more experience, we will see side effects we have not seen before.” l

Reference

Reference

By Wayne Kuznar

A

dverse effects (AEs) with regorafenib tend to occur early— during the first treatment cycle— and then quickly taper off. Although dose modification as a result of AEs will be required in about two-thirds of patients, most can be maintained on treatment, said Axel Grothey, MD, at the 2013 Gastrointestinal Cancers Symposium.

Regorafenib was approved as second-line therapy for the treatment of patients with metastatic colorectal cancer in September 2012 on the basis of the phase 3 CORRECT (Colorectal Cancer Treated With Regorafenib or Placebo After Failure of Standard Therapy) study, in which

Because it works by blocking multiple protein kinases, identifying the actions of regorafenib that contribute to toxicity and efficacy is difficult. regorafenib improved overall and progression-free survival compared with placebo.

“As with other small-molecule kinase inhibitors, regorafenib has a toxicity profile that differs from those seen with cytotoxic chemotherapies,” said Grothey, a professor of oncology at the Mayo Clinic, Rochester, Minnesota.

The experience from the CORRECT

trial was that when AEs occurred with regorafenib, they occurred early “and then got better, even if you kept the dose constant,” he said. “This is not necessarily a given. When you look at some chemotherapy drugs, for instance, neuropathy or neurotoxicity on oxaliplatin gets worse over time. Often, the impact on neutrophils accumulates over time, so it is not a

Best Practices

Expanding Patient Access to Compassionate-Use Drugs: Pharmacists Can Play a Crucial Role

P

harmacists can serve as an important information portal for access to investigational drugs through clinical trials or via expanded-access mechanisms.

Unfortunately, less than 1% of patients say that they learn about clinical trials from pharmacists, with most relying on the media or their physicians, said Kimberly Redic, PharmD, BCPS, at the Hematology/Oncology Pharmacy Association 9th Annual Conference. Most patients, however, indicated that they are willing to hear about clinical trials from their pharmacists.

Clinical trials may take longer than expected to complete because of recruitment delays. “This is an area where we can play a part,” said Redic, manager, Research Pharmacy, University of Michigan Health System, Ann Arbor. Only 6% of clinical trials are completed on schedule, with three-fourths running over schedule by more than 1 month. Nearly one-fourth of cooperative group phase 3 trials fail to attain at least 90% of their recruitment goal.

Clinical trials can provide an opportunity for access to a treatment. Two government sources for open clinical trials are the National Institutes of Health (NIH) and the National Cancer Institute. Disease and foundation websites are another source of clinical trial information, and many institutions have websites that identify their open clinical trials. Of note, institutions that are not formal research sites can sometimes arrange to become a second institution; in these cases, patients are enrolled at another institution but receive doses at their home institution.

“The patients may start at NIH but get their doses closer to home,” Redic said. Guidance on criteria for becoming a second institution is available at http://www.fda.gov/ RegulatoryInformation/Guidances/ucm126432.htm.

Regulations for expanded access to investigational new

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MAy 2013 I VOL 6, NO 2

Redic K. Accessing drugs in development: an update to expanded access (compassionate use) and participation in clinical trials. Presented at: Hematology/Oncology Pharmacy Association 9th Annual Conference; March 22, 2013; Los Angeles, CA.

Grothey A, Van Cutsem E, Sobrero AF, et al. Time course of regorafenib-associated adverse events in the phase III CORRECT study. Presented at: 2013 Gastrointestinal Cancers Symposium; January 24-26, 2013; San Francisco, CA. Abstract 467/ Poster C23.

www.TheOncologyPharmacist.com

Renal Cell Carcinoma

Head to Head in Metastatic Renal Cell Carcinoma: Pazopanib Favored

By Caroline Helwick

I

n a head-to-head comparison for the treatment of metastatic renal cell carcinoma, pazopanib showed similar efficacy to sunitinib but was associated with fewer side effects and an increased quality of life, according to Robert Motzer, MD, of Memorial Sloan-Kettering Cancer Center, New York, who presented the COMPARZ trial at the European Society for Medical Oncology 2012 Congress, held in Vienna, Austria.

The choice of treatment is a “complicated situation” that requires individualization, “but in general this trial tips the scale for the preferred treatment from sunitinib to pazopanib, based on its better tolerability,” Motzer said at a press briefing.

The objective of the phase 3 randomized, open-label COMPARZ trial was to show noninferiority in progression-free survival (PFS). The noninferiority limits were set to exclude a more than 25% difference in the hazard for progression.

“We aimed this phase 3 trial to provide a direct comparison of the efficacy, safety, and tolerability for pazopanib and sunitinib,” Motzer said.

Among 1110 patients randomized to receive pazopanib or sunitinib, patients on pazopanib achieved a median PFS of 8.4 months, compared with 9.5 months for patients on sunitinib (hazard ratio = 1.047). This was a nonsignificant difference that fell within the prespecified statistical boundaries for noninferiority, Motzer reported.

Overall response rates were 31% and 25%, respectively.

But treatment with pazopanib was considered more tolerable. The drug was associated with significantly less fatigue (55% vs 63%), less hand-foot syndrome (29% vs 50%), less alteration in taste (26% vs 36%), and less thrombocytopenia (10% vs 34%), compared with sunitinib (P <.05).

But pazopanib was associated with significantly more transaminase elevation (31% vs 18%) and more hair color changes (30% vs 10%) (P <.05), Motzer reported.

The study also found a statistically significant outcome in favor of pazopanib for about a dozen quality-of-life domains, which included measurements of fatigue, mouth and throat soreness, and foot soreness, among other parameters. “All domains achieving a statistical significance favored pazopanib,” Motzer said.

www.TheOncologyPharmacist.com

Equal Efficacy, but Quality-of-Life assessment intervals at day 28 “favored Comparison Questionable pazopanib,” he maintained.

The invited discussant of the study at the “The quality-of-life data are not as Presidential Symposium, Tim Eisen, convincing as the efficacy data,” he conMD, of the University of Cambridge cluded. in the United Kingdom (UK), said A spokesperson for Pfizer, Robin that the study had “an acceptable Wiltshire, MD, of Tadworth, UK, comstatistical plan.” He suggested, “In the mented to The Oncology Pharmacist that context of other trials, I would say the the 2 drugs actually have “overlapping drugs are comparable in efficacy,” but side effects to some extent, and both he added that the new tyrosine kinase have some tolerability issues.” inhibitor tivozanib is superior to both He said that the elevation in liver pazopanib and sunitinib. enzymes with pazopanib can be serious.

Regarding toxicity, Eisen suggested “Patients don’t feel this, but it can be that “pazopanib does score” in terms of silent and life-threatening,” he said. side effects that “matter to patients.”

“There are tolerability issues with He questioned, however, the indica- either, and each patient has a differtion that quality of life was better with ent journey,” Wiltshire said. “Sunitinib pazopanib, suggesting that the timing has been around for 6 years, and physiof the assessment might have led to cians have gained experience in working the differences observed. Whereas pazo- through the side effects for an extremely panib is given continuously, sunitinib is positive outcome. This heritage of expegiven for 4 weeks on, then 2 weeks off, rience is very important, especially given and “patients can feel better in the ‘off’ the efficacy results with sunitinib.” weeks,” he said. The timing of the disease further that2 the nonWCMC_2013Conf_horizontalV491212_Layout 1He 9/13/12 4:32noted PM Page

inferiority design allows for a 25% difference between the agents, and he maintained that the “PFS difference [of 1 month favoring sunitinib] is important. With pazopanib, there is an unknown as to where it lies on the efficacy scale. The study does not demonstrate equivalent efficacy.” l Reference

Motzer RJ, Hutson TE, Reeves J, et al. Randomized, open label, phase III trial of pazopanib versus sunitinib in first-line treatment of patients with metastatic renal cell carcinoma (mRCC): results of the COMPARZ trial. Presented at: European Society for Medical Oncology 2012 Congress; October 1, 2012; Vienna, Austria. Abstract LBA8 PR.

For previous coverage of pazopanib and sunitinib, go to www.

TheOncologyPharmacist.com to see “Quality of Life Drives Patient Preference for Metastatic Renal Cell Carcinoma Drug” in the August 2012 issue.

SAVE THE DATE SECOND ANNUAL CONFERENCE

2013 WORLD CUTANEOUS MALIGNANCIES CONGRESS

TM

July 26-28, 2013 Hyatt Regency La Jolla at Aventine 3777 La Jolla Village Drive San Diego, California Melanoma • Basal Cell Carcinoma • Cutaneous T-Cell Lymphoma Squamous Cell Carcinoma • Merkel Cell Carcinoma

May 2013 I VOL 6, NO 2

15

Side Effects Management

New Developments in the Management... Continued from cover Callus-like thickened tender blisters with some surrounding erythema are most typically localized to areas of pressure or friction, such as the heel and forefoot. The National Cancer Institute has classified the clinical manifestations by grades, ranging from 1 to 3. Grade 1 is characterized by minimal skin changes and dermatitis without pain; grade 2 presents with some skin changes and pain; and grade 3 is characterized by pain, severe skin changes such as blistering and/or desquamation, and an inability to undertake adequate selfcare activities of daily living (ADL).1 Along with agents that are known to cause HFSR, such as liposomal doxorubicin and capecitabine, newer molecularly targeted oral anti–vascular endothelial growth factor receptor (VEGFr) tyrosine kinase inhibitor (TKI)-targeted therapies used in several cancers also have been found to cause HFSR. The syndrome begins within the first 2 to 4 weeks of therapy with TKIs, presenting with tender blisters, redness, and swelling, which can progress to thickened and painful lesions that may interfere with ADL such as walking or bathing.2-4 Although oral VEGFr-TKI agents are convenient to administer and generally well tolerated, with the most common adverse effects being diarrhea, rash, fatigue, and hypertension, the rates of HFSR can be significant. The incidence of HFSR syndrome with sorafenib, sunitinib, pazopanib, axitinib, vandetanib, cabozantinib, and regorafenib, and approved indications for their use, are shown in Table 1.3-7 The management of HFSR syndrome caused by these agents has only

Joanna Schwartz, PharmD, BCOP

Shannon Hogan, PharmD

recently been studied. The mechanism of action in HFSR is yet unknown, although some researchers propose that it is distinct from other agents, such as decreased repair mechanisms by endothelial cells to the vasculature after trauma to high-pressure areas such as the palms and soles. Moreover, because

Of note, the intravenous monoclonal antibody inhibitor of VEGF, bevacizumab, does not cause HFSR. HFSR with VEGFr TKIs does not predict drug efficacy, as has been shown with the acne-like skin rash caused by epidermal growth factor receptor inhibitors.2-4 Interest in the prevention and

Although oral VEGFr-TKI agents are convenient to administer and generally well tolerated, with the most common adverse effects being diarrhea, rash, fatigue, and hypertension, the rates of HFSR can be significant.

most of these agents are multitargeted and affect several receptor TKIs, the HFSR mechanism may be related to other repair functions, such as platelet-derived growth factor receptor.

Table 1 Rates of HFSR Oral AntiVEGFr TKI

FDA-Approved Indications

All Grades Grades 3-4 HFSR (%) Severe HFSR (%)

Sorafenib

Renal cell carcinoma, hepatocellular carcinoma

33

6

Sunitinib

Renal cell carcinoma, GIST, PNET

29

9

Pazopanib

Renal cell carcinoma, advanced soft-tissue sarcoma

6

1

Axitinib

Renal cell carcinoma

27

5

Vandetanib

Advanced medullary thyroid cancer

17

2

Cabozantinib

Advanced medullary thyroid cancer

50

13

Regorafenib

Metastatic colon cancer, GIST

45

17

Abbreviations: FDA, US Food and Drug Administration; HFSR, hand-foot skin reaction; GIST, gastrointestinal stromal tumor; PNET, pancreatic neuroendocrine tumor; TKI, tyrosine kinase inhibitor; VEGFr, vascular endothelial growth factor receptor.

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MAy 2013 I VOL 6, NO 2

treatment of HFSR syndrome is on the rise, as these therapies have become standards of care for advanced renal cell carcinoma, hepatocellular carcinoma, and medullary thyroid cancer. Prompt recognition and treatment will minimize the impact on patients’ quality of life and may prevent unnecessary treatment interruptions or dose reductions.

Trials of HFSR Prevention and Treatment Several recent trials have been published on the topic of HFSR, but with a number of limitations, notably that the majority of current studies explored HFSR caused by capecitabine; VEGFr TKIs were not included in several of these trials.

A study by Zhang and colleagues suggested the use of celecoxib to prevent HFSR in patients receiving capecitabine for colorectal cancer.8 The study concluded that celecoxib was beneficial for preventing HFSR in these patients; however, among other limitations, the recent warnings surrounding celecoxib’s cardiac adverse-event profile limits the generalizability of these results.9 Kang and colleagues assessed the benefit of pyridoxine for the preven-

tion of capecitabine-induced HFSR.10 The patients in this study, who were chemotherapy naive and being treated with a capecitabine-containing regimen, were randomized to receive 200 mg of pyridoxine or placebo daily.

Pyridoxine was not found to be an effective prophylactic therapy for HFSR caused by capecitabine.

Wolf and colleagues evaluated a urea/ lactic acid–based topical keratolytic agent in capecitabine-induced HFSR.11 This randomized, double-blind, phase 3 trial was conducted with 137 patients who were receiving their first cycle of capecitabine 2000 or 2500 mg/m2 daily for 14 days. Patients received either a urea/lactic acid–based topical keratolytic agent or a placebo cream, applied twice daily for 21 days after the start of capecitabine therapy. The study found no significant difference in the percentage of patients with moderate or severe HFSR between the 2 arms (P = .768); therefore, this cream with lactic acid should not be recommended.

While the previously mentioned studies have investigated prophylactic treatments for capecitabine-induced HFSR, few so far have investigated treatment and prevention in the oral anti–VEGF-TKI population, perhaps owing to the more recent approval dates of these therapies.

One such study was conducted using a Chinese herbal extract that is not available from community pharmacies in the United States and did not have statistically significant results; thus, this study was not included in the present review.12 A randomized, prospective, openlabel trial in Japan plans to enroll 100 patients receiving sorafenib 400 mg twice daily to determine the usefulness of high-slip skin care pads (Remois pads) in controlling pain and preventing skin damage in patients with HFSR. The study is comparing a high-slip skin care pad, changed every 2 to 3 days, with 10% urea cream, used 2 to 3 times a day. Progress will be monitored every 2 to 4 weeks, and the primary end point is the incidence of grade 2 or 3 HFSR during therapy. As of the 2011 abstract publication, 19 patients had been enrolled in the study. No results are currently available.13 The only other study on the subject of HFSR caused by VEGFr TKIs was presented at the 2012 Annual Meeting of the American Society of Clinical Oncology (ASCO). The large randomized study by Zhenggang and colleagues introduces a promising new treatment using a topical lowcost, over-the-counter (OTC) cream,

www.TheOncologyPharmacist.com

Side Effects Management

with a low risk of either systemic adverse effects or possible interactions with any chemotherapy agent.14 The prospective phase 3 study compared the prophylactic effect of urea-based cream, specifically Eucerin Intensive Repair Extra-Enriched Foot Crème (10% urea; Beiersdorf AG), and best supportive care.

The study followed up patients taking sorafenib 800 mg daily for advanced hepatocellular carcinoma; 868 patients with similar baseline characteristics were enrolled. Patients in arm A received urea-based cream twice a day starting on day 1 and continuing for up to 12 weeks, while those in arm B received best supportive care based on the practitioner’s preference, excluding urea-based creams. A significantly lower incidence of HFSRs of all grades was observed in arm A compared with arm B (P <.0001).

Furthermore, there was a trend toward a lower incidence of grade ≥2 HFSR in arm A compared with arm B, but it did not reach statistical significance (P = .1638).

The findings of this study indicate that urea-based creams may be effective in preventing HFSR caused by sorafenib and could be applicable to other related oral VEGF TKIs. One limitation is that the study results have not yet been published in a peer-reviewed journal.

The findings...indicate urea-based creams may be effective in preventing HFSR caused by sorafenib.

Treatment Guidelines While the study by Zhenggang and colleagues shows great promise for managing the adverse effects of VEGFinhibiting TKIs, randomized controlled trials in this area are lacking, and currently there are no ASCO or National Comprehensive Cancer Network guidelines on this topic. However, because these medications are self-administered, patients still need effective education on HFSR management. Mario Lacouture and Eugene Balagula, who research and write extensively on this topic, have published several excellent reviews of the data and evidence as well as consensus panel–based recommendations in journals and in the 2012 edition of The MASCC Textbook of Cancer Supportive Care and Survivorship (chapter 35, Dermatologic Toxicities).15 The Figure details the treatments recommended in the review by Lacouture and colleagues.16 The currently available OTC

www.TheOncologyPharmacist.com

Figure Currently Recommended Treatments Therapy Initiation -No HFSR (grade 0)

Maintain consistent communication with practitioner to diagnose HFSR early Proactive self-care: full-body skin exam, wear thick cotton gloves/ socks; avoid hot water, constrictive footwear, and unnecessary friction If symptoms develop within the first month, continue to the next step

Grade 1 -Numbness, tingling, dysesthesia, paresthesia, painless swelling, erythema, discomfort of hands or feet, no interference in ADL

Grade 2 -Painful erythema, swelling of hands/feet, interference in ADL

Grade 3 -Moist desquamation, ulceration, blistering, severe pain of hands/feet, patient unable to perform ADL

Continue current dose of TKI; watch for changes in severity Continue with self-care as above, use moisturizing creams and 20%-40% urea creams for relief If symptoms worsen after 2-week evaluation, continue to the next step

Reduce the dose of the TKI by 50% for 1-4 weeks Treat as grade 1 with the subsequent additions: clobetasol 0.05% ointment, 2% lidocaine, and codeine and pregabalin as necessary for pain

Discontinue treatment for 1 week until toxicity improves to grade 0 or 1 Continue treating toxicity as before in grades 1 and 2

Abbreviations: ADL, activities of daily living; HFSR, hand-foot skin reaction; TKI, tyrosine kinase inhibitor.

Table 2 Urea-Containing Creams and Lotions Brand

Ingredients

Eucerin (Beiersdorf AG, Hamburg, Germany) Intensive Repair – Very Dry Skin Lotion*

Urea 5%

Eucerin (Beiersdorf AG, Hamburg, Germany) Professional Repair – Extremely Dry Skin Lotion*

Urea 5%

Eucerin (Beiersdorf AG, Hamburg, Germany) Smoothing Repair – Dry Skin Lotion*

Urea 5%

Eucerin (Beiersdorf AG, Hamburg, Germany) Urea 5%/Lactic Acid 2.5% Intensive Repair – Extra-Enriched Hand Crème* Eucerin (Beiersdorf AG, Hamburg, Germany) Intensive Repair – Extra-Enriched Foot Crème*

Urea/Lactic Acid

Udderly Smooth (Redex Industries, Salem, Ohio) Extra Care with 10% Urea for Dry Skin

Urea 10%

Lespain Spray (DTR Dermal Therapy Research Inc., London, Ontario)

Urea 10%/Lidocaine 4%

Carmol 40 Cream (Groupe Parima Inc., Montreal, Quebec)

Urea 40%

Nutraplus Lotion (Galderma Laboratories LP, Fort Worth, Texas)

Urea 10%

tions/ctc.htm. Published June 14, 2010. Accessed March 17, 2013.

2. Rosen AC, Wu S, Damse A, et al. Risk of rash in cancer patients treated with vandetanib: systemic review and meta-analysis. J Clin Endocrinol Metab. 2012;97(4):11251133.

3. Chu D, Lacouture M, Fillos T, et al. Risk of hand-foot skin reaction with sorafenib: a systematic review and meta-analysis. Acta Oncol. 2008;47(2):176-186.

4. Chu D, Lacouture M, Weiner E, et al. Risk of handfoot skin reaction with the multitargeted kinase inhibitor sunitinib in patients with renal cell and non-renal cell carcinoma: a meta-analysis. Clin Genitourin Cancer.

2009;7(1):11-19.

5. Balagula Y, Wu S, Su X, et al. The risk of hand foot skin reaction to pazopanib, a novel multikinase inhibitor: a systematic review of literature and meta-analysis. Invest New Drugs. 2012;30(4):1773-1781.

6. Caprelsa [package insert]. Wilmington, DE: AstraZeneca; 2012.

7. Michaelson MD, Rini BI, Escudier BJ, et al. Phase III AXIS trial of axitinib versus sorafenib in metastatic renal cell carcinoma: updated results among cytokine-treated patients. J Clin Oncol. 2012;30(suppl):Abstract 4546.

8. Zhang RX, Wu XJ, Wan DS, et al. Celecoxib can prevent capecitabine-related hand-foot syndrome in stage II and III colorectal cancer patients: result of a single-center, prospective randomized phase III trial. Ann Oncol.

2012;23(5):1348-1353.

9. US Food and Drug Administration. Postmarket drug safety information for patients and providers. http:// www.fda.gov/Drugs/DrugSafety/PostmarketDrug SafetyInformationforPatientsandProviders/default.htm.

Updated March 8, 2012. Accessed March 17, 2013.

10. Kang YK, Lee SS, Yoon DH, et al. Pyridoxine is not effective to prevent hand-foot syndrome associated with capecitabine therapy: results of a randomized, double-blind, placebo-controlled study. J Clin Oncol.

2010;28(24):3824-3829.

11. Wolf SL, Qin R, Menon SP, et al. Placebo-controlled trial to determine the effectiveness of a urea/lactic acid-based topical keratolytic agent for prevention of capecitabine-induced hand-foot syndrome: North Central Cancer Treatment Group Study N05C5. J Clin Oncol.

2010;28(35):5182-5187.

12. Jia L, Lou Y, Tian A, et al. Randomized, multicenter, phase II trial of compound Chinese herbal extract LC09 versus placebo for external treatment of hand-foot syndrome induced by anticancer therapy. J Clin Oncol.

2011;29(suppl):Abstract 9049.

13. Shinohara N, Nonomura N, Kimura G, et al. A randomized multicenter phase II trial on efficacy of highslip skin care pad for hand-foot skin reaction caused by sorafenib in patients with renal cell carcinoma. J Clin Oncol. 2011;29(suppl):Abstract TPS233.

14. Zhenggang R, Kangshun Z, Kang H, et al. A randomized controlled phase II study of the prophylactic effect of urea-based cream on the hand-foot skin reaction associated with sorafenib in advanced hepatocellular carcinoma.

J Clin Oncol. 2012;30(suppl):Abstract 4008.

15. Balagula E, Lacouture ME. Dermatologic toxicities.

In: Olver IN, ed. The MASCC Textbook of Cancer Supportive Care and Survivorship. New York, NY: Springer; 2011:361-380.

16. Lacouture ME, Wu S, Robert C, et al. Evolving strategies for the management of hand-foot skin reaction associated with the multitargeted kinase inhibitors sorafenib and sunitinib. Oncologist. 2008;13(9):1001-1011.

Want to participate in TOP’s new poll?

* Generic may be available, ask your pharmacist to help select the correct product.

urea-containing creams and lotions are listed in Table 2.

Because HFSR associated with antiVEGF TKIs is widely considered to be one of the most clinically significant toxicities of these agents, additional

research into the prevention and treatment of HFSR is paramount. l References

1. National Cancer Institute. Common Terminology Criteria for Adverse Events, version 4.03. http://ctep. cancer.gov/protocolDevelopment/electronic_applica

©iStockphoto.com/Slobodan Vasic

See page 6 for details. www.TheOncologyPharmacist.com

May 2013 I VOL 6, NO 2

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Side Effects Management

Preventing Methotrexate Toxicity: Know How to Use Leucovorin, Glucarpidase

By Wayne Kuznar

E

xtremely high levels of methotrexate can lead to precipitation of the drug in the renal tubules, delayed drug clearance, and the potential for acute renal failure. Preventing high-dose methotrexate toxicity requires effective methotrexate monitoring and knowledge of the appropriate protocols for leucovorin rescue and the role of glucarpidase, said Katherine Mandock, PharmD, BCPS, at the Hematology/Oncology Pharmacy Association 9th Annual Conference.

Methotrexate toxicity is a function of both the concentration of the drug and duration of exposure. Acute consequences of high concentrations (>5-10 µM) of methotrexate include severe renal and hepatic dysfunction. Sustained, elevated plasma levels of methotrexate (>0.1 µM) can lead to life-threatening myelosuppression and mucositis.

The first step to managing high-dose methotrexate administration (>1000 mg/m2 requiring leucovorin rescue) is to check for potential drug interactions, said Mandock, clinical oncology pharmacist at Smilow Cancer Hospital at YaleNew Haven, Connecticut. Weak organic acids (ie, nonsteroidal anti-inflammatory drugs) compete with methotrexate for tubular secretion, resulting in decreased renal clearance of methotrexate. Highdose vitamin C will acidify the urine and cause crystallization of methotrexate in the kidney, interfering with clearance.

Proton pump inhibitors have been shown to cause methotrexate accumulation in the kidney.

Because methotrexate accumulates in third-space fluid, “in patients who have third-space fluid such as ascites or pleural effusion, you should think twice, if at

all, about using high-dose methotrexate,” Mandock said.

Poor hydration or dehydration, a urine pH <6.5, decreased creatinine clearance, and third spacing are all risk factors for methotrexate toxicity. “When plasma concentrations of methotrexate are >10 to 100 µM, high doses of leucovorin are unlikely to completely reverse the toxicity of methotrexate, leading to ineffective leucovorin rescue,” she said.

To prevent high-dose methotrexate toxicity, the urine should be alkalinized via administration of sodium bicarbonate.

“We keep the urine pH >7.5 because methotrexate and its metabolites are less soluble at lower urine pH’s,” Mandock reported.

To be effective, leucovorin rescue must be started within 24 to 48 hours of methotrexate initiation, or within 24 hours of

Personalized Medicine

Gene Analysis Allows for Personalization of 5-FU to Reduce Risk of Toxicity

A

bout 3% to 5% of the general population is believed to have a mutation in the gene that encodes a major 5-fluorouracil (5-FU) metabolizing enzyme.

This mutation can extend the half-life of 5-FU, leading to increased plasma concentrations and potential toxicities, said Colleen Rock, PharmD, PhD, at the Hematology/Oncology Pharmacy Association 9th Annual Conference, held in Los Angeles, California.

Comprehensive analysis of the gene—DPYD—can be used to personalize a patient’s 5-FU/capecitabine therapy, she said.

The rate-limiting enzyme in the metabolism of 5-FU (and its oral prodrug capecitabine) is dihydropyrimidine dehydrogenase (DPD), which is encoded by the DPYD gene.

“A mutation in the gene can lead to drug accumulation; approximately 80% of 5-FU is rapidly metabolized by DPYD in the liver,” said Rock, clinical research associate at Myriad Genetic Laboratories, Inc, Salt Lake City, Utah. “If there’s a mutation that affects the protein function, it’s not going to be metabolized. There’s going to be accumulation, and this can lead to toxicity.”

Analyzing the DPYD gene “can allow us to decide whether to potentially reduce the dose of 5-FU in a patient or even switch to a different drug,” she said.

The data she presented were from an analysis of full gene sequencing test results from 3083 patients. DPYD analysis was performed by polymerase chain reaction and DNA sequencing. Genetic variants were tested using multiple variant classification techniques, including comparison with a consensus wild-type DPYD sequence.

“Because of the large number of patients included in this analysis, we have good information regarding prevalence, and found that the prevalence for the common DPYD mutations in the testing population is 7.3%,” said Rock. The 3 common

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high-risk mutations were IVS14+1G>A (52.0%), D949V (40.5%), and 1560S (7.5%).

Full sequence analysis of the gene allowed for detection of a unique variant—E412E—that has been linked with a deleterious mutation in DPYD in some cases (N=12). “When we take the E412E variant into account, along with the common mutations, the potential exists for an almost 11% prevalence of gene mutation,” she reported. “These patients who have this mutation are at risk for toxicity. Only full gene sequencing allows for identification of both common and novel mutations that may be associated with 5-FU toxicity.”

In a subset of 24 patients who were tested for DPYD mutations in response to an elevated 5-FU plasma level, gene variants were identified in 7 of the 24. In this population, the E412E variant occurred with similar frequency as that of the common high-risk mutations.

DPYD mutations were found with greater frequency in patients who suffered a greater number of 5-FU toxicities prior to DPYD gene testing. While the majority of patients were tested after experiencing at least one 5-FU toxicity, among those without pretest toxicities, the prevalence of DPYD mutations was 4.7%, which increased to 31.6% in patients with 4 toxicities.

Among the 5-FU toxicities, the prevalence of mutations (18.5%) was greatest for hematopoietic events, followed by hand-foot syndrome and stomatitis (12.6% each).

Most providers choose to submit a sample for testing after a 5-FU toxicity has occurred, noted Rock. “I think that the preference would be to prevent toxicities and therefore test ahead of time, including for the E412E mutation,” she said.

The prevalence of mutations also varied by ancestry, with mutations most common among European and Latin American patients. —WK l

completion. It should be continued until the methotrexate level falls below 0.1 µM. The amount needed to reverse toxicity is proportional to the methotrexate concentration.

Essentials of Glucarpidase Rescue Glucarpidase is a methotrexate antidote that was approved by the US Food and Drug Administration on January 17, 2012. It metabolizes circulating methotrexate to 2,4-diamino-N10-methylpteroic acid (DAMPA). “In patients who have impaired renal function secondary to high levels of methotrexate, we’re now providing a nonrenal route of elimination for methotrexate in the form of DAMPA,” said Mandock.

It is indicated for the treatment of methotrexate concentrations >1 µmol/L (or plasma concentrations >2 standard deviations of the mean methotrexate concentration curve at least 12 hours following methotrexate administration) in patients with delayed methotrexate due to impaired renal function.

Plasma concentrations of methotrexate decrease by 99% on average within 15 minutes of glucarpidase administration. About 40% of patients given glucarpidase will experience a slight rebound in methotrexate concentrations, “but for most of these patients, the levels are decreased by >90% for a duration of 8 days,” she reported.

Glucarpidase will not reverse toxicities present prior to its administration, is most effective when given within 96 hours of methotrexate administration, and is not a substitute for leucovorin because glucarpidase does not gain entry into cells, Mandock cautioned. The schedule of leucovorin should be adjusted so that it is not administered 2 hours prior to or for 2 hours following glucarpidase. Other standard-of-care treatments (hydration, alkalization of urine) should be continued.

Serum levels interpretation should consider whether the laboratory uses high-performance liquid chromatography or immunoassays. Since glucarpidase converts circulating plasma methotrexate into DAMPA, and DAMPA interferes with the immunoassay measurement, use of immunoassays can result in methotrexate concentrations that are falsely elevated. “The half-life of DAMPA is 9 hours, so for 48 hours after the administration of glucarpidase, immunoassays are not reliable measures of methotrexate plasma concentrations,” she said.

“It’s also important that we base the leucovorin dose on pre-glucarpidase methotrexate levels for 48 hours post-glucarpidase” because leucovorin is a substrate for glucarpidase. l Reference

Mandock K. Monitoring methotrexate, leucovorin dose escalation, and the role of glucarpidase. Presented at: Hematology/Oncology Pharmacy Association 9th Annual Conference; March 20-23, 2013; Los Angeles, CA.

www.TheOncologyPharmacist.com

Conference News: AACR Antibody-Conjugate Encouraging in Platinum-Resistant Ovarian Cancer T-DM1 was the first antibody-drug conjugate to gain US Food and Drug Administration approval for HER2 (human epidermal growth factor 2)-positive metastatic breast cancer. A preliminary study suggests that a second antibody-drug conjugate is active in platinum-resistant ovarian cancer, and if the encouraging early results are confirmed by clinical trials, this would fulfill an unmet need for a difficult-to-treat cancer with limited treatment options.

The antibody-drug conjugate DMUC5754A includes a monoclonal antibody that recognizes the MUC16 protein expressed by ovarian cancer cells, which is linked to a potent antimitotic toxin called MMAE (monomethyl auri-

statin E). The antibody targets MUC16 and the toxin is released selectively into tumor cells that express MUC16, limiting the effects of the toxin on healthy tissues and organs.

MMAE is so potent that it could not be delivered directly to patients, explained lead author Joyce Liu, MD, Dana-Farber Cancer Institute and Harvard Medical School, Boston, Massachusetts.

The phase 1 study evaluated the safety, pharmacokinetics, and pharmacodynamics of DMUC5754A in 44 women with advanced, recurrent, platinum-resistant ovarian cancer. Among these heavily pretreated patients, 1 complete response and 4 partial responses were reported. All 5 of the responses were observed in patients

with high expression of MUC16 in their tumor cells.

The maximum tolerated dose was identified as 2.4 mg/kg, and the antibody-drug

Fatigue was the most common adverse event at all dose levels.

conjugate was given every 3 weeks.

Dose-limiting toxicities included one grade 4 neutropenia and one grade 4 uric acid increase, occurring at a higher dose level. Grade 3 adverse events

included fatigue in 9% of patients and neutropenia in 9%. Fatigue was the most common adverse event at all dose levels, occurring in 57% of patients.

Nausea, vomiting, decreased appetite, diarrhea, and peripheral neuropathy were also reported.

“If the activity of this drug is confirmed in additional trials, this will represent a real step forward in finding new, effective treatments for advanced ovarian cancer,” Liu said.

Reference

Liu J, Moore K, Birrer M, et al. Targeting MUC16 with the antibody-drug conjugate (ADC) DMUC5754A in patients with platinum-resistant ovarian cancer: a phase I study of safety and pharmacokinetics. Presented at: American Association for Cancer Research 2013 Annual Meeting; April 9, 2013; Washington, DC. Abstract LB-290.

Genetically Engineered T Cells Show Promising Activity in Pediatric Leukemia A small preliminary study suggests that a unique immunotherapy called “antiCD19 chimeric antigen receptor (CAR) T-cell therapy” can achieve complete remission in children with acute lymphocytic leukemia (ALL) who relapse after bone marrow transplant (BMT).

“Childhood ALL is the most common malignancy in pediatric patients. The majority of children can achieve remission, but this comes with the price of long therapy, toxicity, and cost, with no guarantee of long-term cure. Children who relapse have limited therapeutic options, and new therapies are sorely needed,” stated lead author of the study Daniel W. Lee, MD, assistant clinical investigator in the Pediatric Oncology Branch of the National Cancer Institute in Bethesda, Maryland.

Anti-CD19 CAR T cell therapy is a new way to treat childhood cancer, he continued. This therapy uses the patient’s own immune cells that have been collected and then modified and expanded in the laboratory to attach to the CD19 protein expressed by leukemia cells.

Activation of the T cells for immunity requires 2 signals, Lee explained.

Leukemia cells do not generate the second signal required, and therefore the leukemia is not controlled. “Genetically engineered T cells get around this by being designed specifically to recognize the CD19 antigen. When they are reinfused into the patient, the receptor fires 2 signals and activates the T cells to kill the target tumor tissue,” he added.

At AACR, Lee reported results in the first 4 patients treated with anti-CD19 CAR T-cell therapy. Three patients had ALL and had received BMT, and 1 patient had B-cell lymphoma. All patients received fludarabine and cyclophosphamide prior to receiving the CAR T cells. One ALL patient had a complete

www.TheOncologyPharmacist.com

response (CR), and a second ALL patient had a transient CR, with minimal residual disease remaining. The B-cell lymphoma patient did not respond.

The adverse effects were temporary and not seen in every patient.

“Graft-versus-host disease is a side effect of concern in patients treated with BMT. We saw no evidence of this in the first 3 ALL patients we treated who had undergone previous BMT,” he said.

“Anti-CD 19 CAR T cells represent a new way to attack childhood leukemia. Preliminary evidence suggests that we can induce complete remission in patients refractory to other therapies,” Lee stated.

Reference

The adverse effects were temporary and not seen in every patient, Lee continued.

They included fever and low blood counts and were easily managed in hospital.

Lee DW III, Shah N, Stetler-Stevenson M, et al.

Autologous-collected anti-cd19 chimeric antigen receptor (CAR) T cells for acute lymphocytic leukemia (ALL) and Non-Hodgkin’s lymphoma (NHL) in children who have previously undergone allogeneic stem cell transplantation (HSCT). Presented at: American Association for Cancer Research 2013 Annual Meeting; April 8, 2013; Washington, DC. Abstract LB-138.

Photo from HOPA conference.

Intermittent Vemurafenib May Overcome Resistance Vemurafenib is a relatively new effective option for the treatment of melanoma, but most patients who respond will develop resistance. Studies by researchers at Novartis suggest that an intermittent dosing strategy may be able to overcome the resistance that occurs with standard continuous dosing.

“We were excited about the translational science that led to approval of the BRAF inhibitor vemurafenib, which extends survival in these patients. But most patients relapse with lethal drug-resistant disease,” explained Darrin Stuart, PhD, Novartis Institutes for Biomedical Research in Emeryville, California, who presented results of early animal and human studies.

In a previous study, Stuart and colleagues implanted xenografts of BRAF-expressing tumors in mice and found that the tumors developed resistance to vemurafenib. But possibly more important was the observation that the tumors were dependent on the drug for their proliferation.

When drug treatment was withdrawn, the tumors stopped growing and regressed.

The next step was to determine if the drug dependency of the tumors was exhibited in humans. The investigators collaborated with scientists at the Royal Marsden Hospital

in London, United Kingdom, and evaluated 42 patients with vemurafenib-resistant tumors. Of these, 19 patients had computed tomography scans obtained after drug treatment was stopped. Fourteen of 19 scans showed regression in the rate of tumor growth.

Stuart and colleagues then performed another experiment on mice implanted with BRAF-expressing tumor xenografts and treated them with vemurafenib 4 weeks on and 4 weeks off (intermittent strategy) or continuous vemurafenib. None of the tumors in the animals treated intermittently developed resistance.

This suggests that a drug holiday and intermittent treatment could be beneficial in patients taking vemurafenib and might overcome resistance. Stuart was not at liberty to discuss Novartis’ plans for the future, but stated that intermittent dosing was a strategy that he hopes researchers will pursue.

Reference

Das Thakur M, Fisher R, Salangsang F, et al. Modeling vemurafenib resistance in melanoma reveals a strategy to forestall drug resistance. Presented at: American Association for Cancer Research 2013 Annual Meeting; April 8, 2013; Washington, DC. Abstract LB-144.

May 2013 I VOL 6, NO 2

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Conference News: AACR Genetic Analysis Identifies 4 Subsets of Squamous Cell Carcinoma of the Head and Neck Comprehensive genetic analysis by The Cancer Genome Atlas (TCGA) identified 4 different subtypes of squamous cell carcinoma of the head and neck (SCCHN). The analysis included 279 patients with previously untreated SCCHN. This is the eighth tumor type analysis of TCGA to be presented.

“Our study will likely become a landmark research tool for HNSCC for many years as we gradually unlock the secrets of this massive data set,” said David N. Hayes, MD, MPH, a medical oncologist who is associate professor at the University of North Carolina at Chapel Hill.

SCCHN is the fifth most common cancer worldwide and the sixth most common type in the United States. Fortyfive thousand new cases are diagnosed each year. Smoking is a risk factor, as is the epidemic of human papilloma virus (HPV). Among the 279 patients included in the study, 80% were tobacco related and 13% were HPV positive.

“There is incredible pressure for these tumors to acquire a specific set of losses and gains. If you look across different tumor types, they have assumed a similar set of gains and losses across chromosomes; this may provide patterns that

during the dose-escalation phase had researchers focusing on the patients with BRCA mutations: one, it was reported that the repair of DNA breaks caused by sapacitabine is dependent on the homologous repair pathway, which includes BRCA proteins and is downregulated in their absence; the second was a partial response (PR) observed in a patient with pancreatic cancer who was found to be a BRCA-mutation carrier.

The trial was then limited to patients with BRCA-deficient cancers. Three additional PRs were observed (2 with breast cancer and 1 with ovarian cancer). The PRs have been durable in 3 patients (from 9 to 21 months). These 3 patients are continuing on study.

In total, 6 of the 16 BRCA-mutation carriers benefited from the drug combination (4 with PRs and 2 with stable disease).

Shapiro said that nonresponders were heavily pretreated and too compromised to tolerate a cycle of the combination therapy, and were therefore not evaluable.

“Among the BRCA-proficient group, several patients had prolonged stable disease, but the response was not as dramatic as in the BRCA-deficient group,” he said. “Going forward, the combination therapy has the most chance of efficacy in BRCA-deficient patients.”

Sequential administration of the 2 experimental agents was used in the trial. Concurrent administration of sapacitabine and seliciclib will be studied, as will different dosing schedules.

PARP (poly ADP-ribose polymerase) inhibitors are effective in BRCA-deficient patients. Shapiro said the responders in the trial had not been pretreated with a PARP inhibitor.

“We need to determine if the combination works in patients pretreated with PARP. Finally, we have some drug classes that address inherited cancers,” Shapiro stated.

dylinositide 3-kinase (PIK3CA) mutations 2.

Classical subtype, also seen in squamous cell lung cancer, associated with 2 key mutations: KEAP 1 and NFE2L2 3.

Mesenchymal subtype, mostly mutations of FGR 1 and FGR, and 4.

Basal subtype, highly associated with SOX2 amplifications and overexpression.

Some of these alterations overlap with squamous cell carcinoma of the lung, which is also a tobacco-related cancer.

“We frequently see altered genomes in other tobacco-related cancers. One of the striking findings we observed was a high degree of similarity to other squamous tumors, including lung squamous cell carcinoma. Lessons learned from studying the similarities and differences between tumors, such as copy number alterations, will be an angle to pursue to better understand altered pathways in cancer. The idea that they share properties that go beyond the type of cancer means that this could be studied at a model systems level.”

Additional key observations of this study include: • Other patients as well as those who are HPV positive have infrequent EGFR gene amplification • HPV-positive tumors have a high rate of PIK3CA gene mutations • Patients infected with HPV almost never have p53 alterations • In patients who are HPV negative, druggable mutations include EGFR, FGR, and CNCCC21.

“We have made a lot of observations, but this also makes things more complicated. We are able to recognize patterns, and some of these patterns may turn out to be druggable, or actionable in the future,” Hayes stated.

“This is robust information that gives us data on mutational analysis and copy numbers, expression, promoter methylation, and other aspects of SCCHN. This data set confirms other publications indicating that there is a clear difference between HPV-positive patients who usually have a better prognosis and are easier to treat than HPV-negative patients. HPV-negative patients have many more mutations than HPV-positive patients,” stated Giuseppe Giaccone, MD, Georgetown Lombardi Comprehensive Cancer Center, Washington, DC. Giaccone moderated a press conference at which these data were presented. l

Reference

Reference

CDKN2A, TP53, PIK3CA, NOTCH1, HRAS, and NFE2L2.

Looking at all gene expression subtypes of SCCHN, tumors organize themselves into 4 groups that are reproducible. These subtypes tend to go along

Squamous cell carcinoma of the head and neck is the fifth most common cancer worldwide and the sixth most common type in the United States.

can be leveraged across a set of tumors,” he said. “We need to understand the mutations or individual alterations in the 15 most significant mutated genes in SCCHN.” In the study, significant mutations were found in the following genes:

with differences in mutation patterns and chromosomal alterations, Hayes explained. The 4 subtypes are: 1. Atypical subtype with no amplification of epidermal growth factor receptor (EGFR), HPV positive, and a high rate of phosphati-

Drug Combination Potentially Effective in BRCA-Deficient Solid Tumors Two orally available experimental drugs achieved response in patients with BRCA-deficient solid tumors in a phase 1 study of 38 patients. Responders were patients with BRCA mutations and incurable pancreatic, breast, and ovarian tumors.

“There is definitely a group of responders who appear to benefit from this drug combination. This should be studied in a new, much larger prospective trial,” said lead author Geoffrey Shapiro, MD, PhD, Dana-Farber Cancer Institute and Harvard Medical School in Boston, Massachusetts.

Among the 38 patients, 16 had BRCA-deficient cancers. Patients received treatment with sapacitabine and seliciclib—2 drugs developed by Cyclacel Pharmaceuticals, Inc. Sapacitabine causes single-strand DNA breaks that are converted to double-strand DNA breaks during replication.

The investigators in the phase 1 trial hypothesized that seliciclib would interfere with the repair of damaged DNA and enhance the cytotoxicity of sapacitabine, Shapiro explained.

Patients were treated with sequential administration of both drugs for 10 days, followed by an 11-day rest period.

During the dose-escalation phase of the study, patients without BRCA mutations had stable disease. Two observations

Photo from HOPA conference.

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Shapiro GI, Hilton J, Cleary JM, et al. Responses to sequential sapacitabine and seliciclib in patients with BRCA-deficient solid tumors. Presented at: American Association for Cancer Research 2013 Annual Meeting; April 9, 2013; Washington, DC. Abstract LB-202.

Hayes DN, Grandis J, El-Naggar AK. Comprehensive genomic characterization of squamous cell carcinoma of the head and neck in The Cancer Genome Atlas.

Presented at: American Association for Cancer Research 2013 Annual Meeting; April 7, 2013; Washington, DC. Abstract 1117.

www.TheOncologyPharmacist.com

Faces at the HOPA 9th Annual Conference

A View From the Floor The Hematology/Oncology Pharmacy Association (HOPA) 9th Annual Conference was held in Los Angeles, California, on March 20-23, 2013. The Oncology Pharmacist (TOP) was thereâ&#x20AC;Ś

Mekdese Befikadu Kassa, PharmD, BCOP, of LifeBridge Health in Baltimore, Maryland, attends his first HOPA meeting.

Anthony Jarkowski III, PharmD, BCOP (right), from the University of Rochester, visits the TOP booth with Richard Sweeney, PharmD (left), of the Westchester Medical Center in New York. Jarkowski presented Updates on the Treatment of Skin Cancer at the HOPA conference.

Mirra Vaysman, MS, RPh (left), visits the TOP booth with Lamya Bakass, BCOP, BS (right). Both are from the New York Methodist Hospital in Brooklyn.

First-time HOPA attendee Arpita Shah, PharmD (center), of the Hospital of the University of Pennsylvania visits the TOP booth.

www.TheOncologyPharmacist.com

Anne Marie Valorie-Oberle, PharmD, BCOP (right), from Thomas Jefferson University Hospital in Philadelphia, Pennsylvania, and Kathryn Kong, PharmD (left), of Kaiser Permanente in Torrance, California, visit the TOP booth.

May 2013 I VOL 6, NO 2

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CONTINUING EDUCATION 6th Annual

APRIL 2013 • VOLUME 6 • NUMBER 1

CONSIDERATIONS in

Multiple Myeloma

™

ASK THE EXPERTS: Frontline and Retreatment 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 Chief Operating Officer Pam Rattanonont Ferris Vice President of Finance Andrea Kelly Associate Editorial Director, Projects Division Terri Moore Director, Quality Control Barbara Marino

LETTER

FROM THE

EDITOR-IN-CHIEF

Over the past decade, significant progress has been made in the management of multiple myeloma (MM), 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 first issue, experts from the John Theurer Cancer Center at Hackensack University Medical Center answer questions related to the management of patients with newly diagnosed and relapsed/refractory myeloma in the era of novel agents.

Sincerely, 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

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 Digital Programmer Michael Amundsen

FACULTY David Siegel, MD, PhD Chief, Myeloma Division John Theurer Cancer Center Hackensack University Medical Center Hackensack, NJ

Elizabeth Bilotti, MSN, BSN, APN-C Nurse Practitioner, Multiple Myeloma Division John Theurer Cancer Center Hackensack University Medical Center Hackensack, NJ

Greg Eskinazi, RPh, MAS, BCOP Oncology Research Pharmacist John Theurer Cancer Center Hackensack University Medical Center Hackensack, NJ

Senior Project Manager Andrea Boylston Project Coordinators Deanna Martinez Jackie Luma Business Manager Blanche Marchitto

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.

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MAy 2013 I VOL 6, NO 2

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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 0468-9999-13-007-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

Board for Celgene Corporation and on the Research Advisory Board for Eli Lilly. He does intend to discuss either non–FDAapproved or investigational use for the following products/devices: MLN9708, oprozomib, BT062, CC-223, and BHQ880.

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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.

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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.

David Siegel, MD, PhD, is on the Speaker’s Bureau and Advisory Boards for Celgene Corporation, Millennium: The Takeda Oncology Company, and Onyx Pharmaceuticals. He does intend to discuss either non–FDA-approved or investigational use for the following products/devices: MLN9708, oprozomib, daratumumab, and Arry-520.

Elizabeth Bilotti, MSN, BSN, APN-C, is on the Advisory Board and Speaker’s Bureau for and is a Consultant to Celgene Corporation, Millennium: The Takeda Oncology Company, and Onyx Pharmaceuticals. She does not intend to discuss any non– FDA-approved or investigational use for any products/devices.

Greg Eskinazi, RPh, MAS, BCOP, is on the Pharmacist Advisory

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Recent Advances in the Management of Multiple Myeloma David Siegel, MD, PhD

Chief, Myeloma Division, John Theurer Cancer Center Hackensack University Medical Center, Hackensack, NJ

Introduction The positive impact of novel therapies on newly diagnosed and relapsed/refractory multiple myeloma (MM) has been observed in both transplant-eligible and -ineligible patients. The development of next-generation agents, as well as new dosing schedules and modes of administration, have also contributed to greater efficacy and tolerability for many patients. In this article, David Siegel, MD, PhD, discusses some of the latest advances in myeloma treatment and offers insights on therapy selection and future directions in the management of the disease.

Given the wide array of choices available, is there a standard of care for the frontline treatment of transplant-eligible patients with MM? In myeloma, the main goal of induction therapy is disease cytoreduction.

This is important for improving performance status in newly diagnosed patients, which makes them more viable candidates for autologous stem cell transplantation (ASCT). It is critical during induction to reduce the tumor burden and increase the amount of healthy bone marrow to optimize stem

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cell mobilization. As shown in Table 1a, there are numerous options for treating newly diagnosed transplant-eligible patients.1 Among these choices, I think the most commonly used regimens, at least in larger cancer centers, are lenalidomide/bortezomib/dexamethasone (RVD) and cyclophosphamide/bortezomib/dexamethasone (CyBorD), which have both demonstrated good efficacy and ease of use. In a phase 1/2 study in newly diagnosed patients, treatment with RVD resulted in a partial response (PR) or better rate of 100%, with a 74% very good partial response (VGPR) or better rate in the phase 2 population.2 In a phase 2 study, CyBorD also demonstrated significant activity in newly diagnosed MM, including an overall response (OR) rate of 88% and a VGPR or better rate of 61% after 4 cycles of therapy.3 In the phase 2 EVOLUTION study, CyBorD and RVD were shown to have similar activity4; complete response (CR) was achieved in 22% and 47% of patients treated with 2 different schedules of CyBorD and 24% of patients treated with RVD. The fact that we are now able to offer patients subcutaneous (SQ) bortezomib has decreased the incidence and severity of peripheral neuropathy (PN) with these and other bortezomib-containing regimens. The 2012 approval of SQ bortezomib by the US Food and Drug Administration (FDA) was based on data from a few different studies, including the MMY-3021 trial, which compared the safety and efficacy of SQ versus intravenous (IV) administration in the relapsed myeloma setting.5 Rates of CR and VGPR after 4 cycles, OR after 8 cycles, time to response, duration of response, time to progression, progression-free survival (PFS), and 1-year overall survival (OS) were similar between treatment arms. However, the SQ route demonstrated improved tolerability compared with the IV route, especially in terms of PN.

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Table 1a. NCCN Recommendations: Initial Therapy for Transplant-eligible Patients1 Preferred Regimens

Category

Other Regimens

Category

VD

1

Dexamethasone

2B

PAD

1

DVD

2B

VTD

1

TD

2B

Rd

1

CRd

2A

CyBorD

2A

RVD

2A

Which regimens are being used for newly diagnosed patients who are not eligible for transplant?

CRd indicates carfilzomib/lenalidomide/dexamethasone; CyBorD, cyclophosphamide/bortezomib/dexamethasone; DVD, liposomal doxorubicin/vincristine/dexamethasone; NCCN, National Comprehensive Cancer Network; PAD, bortezomib/doxorubicin/dexamethasone; Rd, lenalidomide plus low-dose dexamethasone; RVD, lenalidomide/bortezomib/dexamethasone; TD, thalidomide plus dexamethasone; VD, bortezomib plus dexamethasone; VTD, bortezomib/thalidomide/dexamethasone.

Table 1b. NCCN Recommendations: Initial Therapy for Transplant-ineligible Patients1 Preferred Regimens

Category

VD

2A

Rd

Other Regimens

Category

Dexamethasone

2B

1

DVD

2B

VMP

1

MP

2A

MPR

1

TD

2B

MPT

1

VAD

2B

DVD indicates liposomal doxorubicin/vincristine/dexamethasone; MP, melphalan plus prednisone; MPR, melphalan/prednisone/lenalidomide; MPT; melphalan/prednisone/thalidomide; NCCN, National Comprehensive Cancer Network; Rd, lenalidomide plus low-dose dexamethasone; TD, thalidomide plus dexamethasone; VAD; vincristine/doxorubicin/dexamethasone; VD, bortezomib plus dexamethasone; VMP; bortezomib/melphalan/prednisone.

There are clinical scenarios in which a 2-drug regimen may be a better option than a 3-drug regimen. For example, in patients who present with significant preexisting PN caused by diabetes or the myeloma itself, clinicians may choose to use lenalidomide plus low-dose dexamethasone (Rd), which has been shown to be active in newly diagnosed MM.6 Conversely, in patients who have significant renal dysfunction, bortezomib plus dexamethasone (VD), which has also demonstrated good clinical activity in the frontline setting,7 may be the preferred option, as physicians may be concerned about adequately dose-adjusting lenalidomide. There is a fear of using lenalidomide in the setting of renal insufficiency, which is based on the false perception that it is going to impact renal function. Physicians do, however, need to carefully follow dose-adjustment recommendations when using lenalidomide in renally impaired patients, because myelosuppression will be impacted by renal function.8 Another 3-drug regimen that is showing impressive results is carfilzomib/ lenalidomide/dexamethasone (CRd), which is the most recent addition to the National Comprehensive Cancer Network (NCCN) recommendations for frontline treatment of transplant-eligible patients.1 This combination was recently evaluated in a multicenter phase 1/2 trial, in which newly diagnosed patients (N=53) received carfilzomib at 20, 27, or 36 mg/m2 on days 1, 2, 8, 9, 15, and 16 of a 28-day cycle for 8 cycles. The 20- and 27-mg/m2 doses were infused over 5 to 10 minutes, whereas the 36-mg/m2 dose was infused over 30 minutes. Patients also received lenalidomide 25 mg on days 1 to 21, and dexamethasone 40 mg weekly for cycles 1 to 4, and 20 mg weekly for cycles 5 to 8.9 Transplant-eligible patients who achieved â&#x2030;ĽPR could proceed to stem cell collection after 4 cycles. All patients received 4 more cycles of CRd, with transplant-eligible patients having the option to proceed with ASCT. Patients who continued therapy beyond 8 cycles received maintenance CRd in 28-day cycles at the doses tolerated at the end of 8 cycles.

Results showed that patients experienced a rapid and good initial response to CRd, and their responses improved as the trial continued. Of the 49 pa-

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tients who completed 4 treatment cycles, 67% achieved at least near-complete response (nCR), with 45% in stringent complete response (sCR), defined as no detectable tumor cells or myeloma protein in the blood or bone marrow. Of the 36 patients who completed 8 or more treatment cycles, 78% achieved nCR with 61% achieving sCR. The investigators also reported PFS rates of 97% at 12 months and 92% at 24 months. This regimen was well tolerated, and PN rates were low. However, I think it is important to remember that this was a relatively small study, and more follow-up with larger cohorts of patients is warranted.

Again, we are fortunate to have numerous combinations to treat this population of patients (Table 1b).1 RVD, although not listed as an NCCN recommendation in the nontransplant setting, is now being widely used, at least here in the United States, where there is less pressure to use melphalan plus prednisone (MP). To date, there are no clinical trial data that clearly show an advantage with MP compared with dexamethasone or other corticosteroids. If you look at results from the large UPFRONT trial

by Niesvizky and colleagues, which compared VD versus bortezomib/thalidomide/dexamethasone (VTD) versus bortezomib/melphalan/prednisone (VMP) as initial therapy in nontransplant patients, you will see that there was no advantage in terms of response or tolerability with VD versus VMP.10 Furthermore, after 22 months of follow-up, median PFS rates were 13.8 months for VD, 14.7 months for VTD, and 17.3 months for VMP; these are not statistically different. One-year OS rates were also similar (87.4%, VD; 86.1%, VTD; 88.9%, VMP).

At our center, we routinely recommend ASCT for patients up to 75 years of age, and in some cases, offer transplant to those between 75 and 80 years. It is important to consider which factors make an individual â&#x20AC;&#x153;transplant-eligible,â&#x20AC;? not just at the time when initial therapeutic decisions are being made, but later in the course of treatment as well. If you have a patient whose disease is refractory to RVD, it may become necessary to consider them for transplant in the secondary setting. Hence, we want to avoid MP whenever possible even in these patients, so we do not compromise stem-cell reserve.

Beyond that, even if a patient is never transplanted, given the improved efficacy seen with novel therapies, he or she may live many years, even decades, after diagnosis. Therefore, it is important to consider the bone marrow injury and risk of secondary malignancies associated with alkylating agents11 and the impact this may have on survival and quality of life.

Which investigational agents are showing the most promise in MM treatment?

I think that MLN9708, which is a next-generation oral proteasome inhibitor, has the potential to be a game-changing drug. This agent is being combined with lenalidomide and dexamethasone in a phase 1/2 trial of newly diagnosed patients.12 After establishing the maximum tolerated dose (MTD) of the drug, 65 patients were evaluated in the study. In the 20 patients who were to undergo ASCT, stem cells were successfully collected. Overall, 52 patients were evaluable for response after a median of 6 cycles of treatment; of these patients, 58% achieved at least a VGPR, 32% achieved a PR, and 23% had a CR. Twenty-one patients (32%) reported neuropathy, which was grade 1 in 20% of patients, grade 2 in 9%, and grade 3 in 3%. Mild rash, fatigue, nausea, vomiting, and diarrhea were reported in 40% of patients. These were well managed with dose reductions and supportive care. Two grade 4 adverse events (AEs) were observed, including end-stage renal disease in 1 patient (resulting from disease progression) and deep vein thromboembolism in 1 patient. In light of the promising results seen with MLN9708, this drug has entered a phase 3 trial, and 2 other trials are planned in newly diagnosed patients and in those with relapsed and refractory disease.

Another second-generation oral proteasome inhibitor that is showing good activity is oprozomib. In a phase 1b study, this agent was administered on days 1 to 5 of a 14-day cycle with a standard 3 + 3 dose-escalation scheme.13 Treatment was initiated at 120 mg/day, with 4 to 6 hours between doses. To date, 13 patients with hematologic malignancies (MM and chron-

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CONSIDERATIONS IN MULTIPLE MYELOMA

Table 2. Common Grade 3/4 Adverse Events in ≥15% of Patients in the Phase 2 MM-002 Trial19 POM + LoDex (%)

POM Alone (%)

Neutropenia

38

47

Anemia

21

22

Thrombocytopenia

19

22

Pneumonia

23

16

Toxicity

LoDex indicates low-dose dexamethasone; POM, pomalidomide.

ic lymphocytic leukemia [CLL]) have been treated. Treatment duration up to 38 weeks has been observed thus far, and MTD has not been reached up to a 210-mg/day dose. Ten patients were evaluable for antitumor activity (9 with MM, 1 with CLL), and PRs were seen in 2 patients with MM and 1 patient with CLL. Researchers also are excited about daratumumab, a humanized anti-CD38 monoclonal antibody with broad-spectrum killing activity, which is showing promise as a single agent in relapsed/refractory MM,14 and Arry-520, a novel kinesin spindle protein inhibitor, which is showing activity alone and in combination with dexamethasone in patients refractory to bortezomib and lenalidomide.15 Can you comment on recent advances in the relapsed/refractory setting?

We now have 2 new agents available for the treatment of relapsed/refractory MM: carfilzomib and pomalidomide. Carfilzomib, a next-generation IV proteasome inhibitor, is currently FDA approved for patients who have received at least 2 prior therapies, including bortezomib and an immunomodulatory drug (IMiD), and who have demonstrated disease progression on or within 60 days of therapy completion.16 This agent represents an important advance in treatment, given its proven efficacy and good safety profile. In the phase 2 PX-171-003-A1 trial, heavily pretreated patients (N=266) received single-agent IV carfilzomib, given over 2 to 10 minutes on days 1, 2, 8, 9, 15, and 16 of each 28-day cycle, for up to 12 cycles. The dose for cycle 1 was 20 mg/m2, which was escalated to 27 mg/m2 for all cycles thereafter provided that patients tolerated the initial dose level of 20 mg/m2.17 Of the evaluable patients, 95% were refractory to their last therapy, and 80% were refractory to both bortezomib and lenalidomide. The OR rate was 23.7%, median duration of response was 7.8 months, and median OS was 15.6 months.

Reported AEs included fatigue (49%), anemia (46%), nausea (45%), and thrombocytopenia (39%). The rate of treatment-related PN was only 12.4%, and this was almost exclusively grade 1 and 2.

Pomalidomide, a next-generation oral immunomodulator, is also approved for patients who have received at least 2 prior therapies, including bortezomib and an IMiD, and who have demonstrated disease progression on or within 60 days of therapy completion.18 This approval was based on data from the multicenter phase 2 MM-002 trial of patients with relapsed/ refractory MM who had previously received lenalidomide and bortezomib and were refractory to their last therapy. The treatment arms were pomalidomide plus low-dose dexamethasone (POM/LoDex) or pomalidomide alone (POM).19 Of the 221 patients evaluated for response, 29.2% achieved a PR or better with POM/LoDex versus 7.4% with POM. The most common grade 3/4 AEs in both arms are shown in Table 2. At a median follow-up of 14.2 months, median PFS was 4.6 months in the POM/LoDex arm and 2.6 months in the POM arm.20 Pomalidomide is also being evaluated in combination with carfilzomib and dexamethasone in a heavily pretreated, lenalidomide-refractory population with prior bortezomib exposure.21 Preliminary results show that this regimen is well tolerated and, among the 30 evaluable patients, the OR rate was 50%, including a VGPR rate of 13% and a PR rate of 37%. A phase 1 trial of pomalidomide, bortezomib, and low-dose dexamethasone in relapsed/refractory MM is also under way.22 This regimen shows good activity,

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with 73% of 15 evaluable patients responding to treatment (VGPR, 27% and PR, 46%). The most common AEs were fatigue (60%), edema (40%), and low platelet counts (40%).

I think that myeloma treatment will continue to evolve with the use of these agents, as well as monoclonal antibodies and other kinds of immunomodulatory manipulators, like the anti-PD1 antibodies that are making an impact on solid tumors. We are definitely going to see immunomanipulation as a breakthrough area in MM in the relatively short-term future. ♦ References

1. National Comprehensive Cancer Network (NCCN). NCCN Clinical Practice Guidelines in Oncology™: Multiple Myeloma. Version 2.2013. http://www.nccn.org. Accessed March 25, 2013.

2. Richardson P, Weller E, Lonial S, et al. Lenalidomide, bortezomib, and dexamethasone combination therapy in patients with newly diagnosed multiple myeloma. Blood. 2010;116: 679-686.

3. Reeder CB, Reece DE, Kukreti V, et al. Cyclophosphamide, bortezomib, and dexamethasone induction for newly diagnosed multiple myeloma: high response rates in a phase II clinical trial. Leukemia. 2009;23:1337-1341.

4. Kumar S, Flinn I, Richardson PG, et al. Randomized, multicenter, phase 2 study (EVOLUTION) of combinations of bortezomib, dexamethasone, cyclophosphamide, and lenalidomide in previously untreated multiple myeloma. Blood. 2012;119:4375-4382.

5. Moreau P, Pylypenko H, Grosicki S, et al. Subcutaneous versus intravenous administration of bortezomib in patients with relapsed multiple myeloma: a randomised, phase 3, noninferiority study. Lancet Oncol. 2011;12:431-440.

6. Rajkumar SV, Jacobus S, Callander NS, et al. Lenalidomide plus high-dose dexamethasone versus lenalidomide plus low-dose dexamethasone as initial therapy for newly diagnosed multiple myeloma: an open-label randomized controlled trial. Lancet Oncol. 2010;11:29-37.

7. Harousseau JL, Attal M, Avet-Loiseau H, et al. Bortezomib plus dexamethasone is superior to vincristine plus doxorubicin plus dexamethasone as induction treatment prior to autologous stem-cell transplantation in newly diagnosed multiple myeloma: results of the IFM 2005-01 phase III trial. J Clin Oncol. 2010;28:4621-4629.

8. Niesvizky R, Naib T, Christos PJ, et al. Lenalidomide-induced myelosuppression is associated with renal dysfunction: adverse events evaluation of treatment-naïve patients undergoing frontline lenalidomide and dexamethasone therapy. Br J Haematol. 2007;138:640-643.

9. 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.

10. Niesvizky R, Flinn IW, Rifkin R, et al. Efficacy and safety of three bortezomib-based combinations in elderly, newly diagnosed multiple myeloma patients: results from all randomized patients in the community-based, phase 3b UPFRONT study. Blood (ASH Annual Meeting Abstracts). 2011;118:Abstract 478.

11. Alkeran [package insert]. Rockville, MD: ApoPharma USA, Inc.; November 2011.

12. Kumar SK, Berdeja JG, Niesvizky R, et al. 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.

13. Savona MR, Berdeja JG, Lee SJ, et al. A phase 1b dose-escalation study of split-dose oprozomib (ONX 0912) in patients with hematologic malignancies. Blood (ASH Annual Meeting Abstracts). 2012;120:Abstract 203.

14. Lokhorst H, Gimsing P, Nahi H, et al. Daratumumab, a CD38 monoclonal antibody in patients with multiple myeloma - preliminary efficacy and pharmacokinetics data from a dose-escalation phase I/II study. Program and abstracts of the 17th Congress of the European Hematology Association; June 14-17, 2012; Amsterdam, the Netherlands. Abstract 1143.

15. Shah JJ, Zonder JA, Cohen A, et al. The novel KSP inhibitor ARRY-520 is active both with and without low-dose dexamethasone in patients with multiple myeloma refractory to bortezomib and lenalidomide: results from a phase 2 study. Blood (ASH Annual Meeting Abstracts). 2012;120:Abstract 449.

16. Kyprolis [package insert]. South San Francisco, CA: Onyx Pharmaceuticals; July 2012.

17. Siegel DS, Martin T, Wang M, et al. A phase 2 study of single-agent carfilzomib (PX-171003-A1) in patients with relapsed and refractory multiple myeloma. Blood. 2012;120: 2817-2825.

18. Pomalyst [package insert]. Summit, NJ: Celgene Corporation; 2013.

19. Richardson PG, Siegel DS, Vij R, et al. Randomized, open label phase 1/2 study of pomalidomide (POM) alone or in combination with low-dose dexamethasone (LoDex) in patients (Pts) with relapsed and refractory multiple myeloma who have received prior treatment that includes lenalidomide (LEN) and bortezomib (BORT): phase 2 results. Blood (ASH Annual Meeting Abstracts). 2011;118:Abstract 634.

20. Jagannath S, Hofmeister CC, Siegel DS, et al. Pomalidomide (POM) with low-dose dexamethasone (LoDex) in patients (Pts) with relapsed and refractory multiple myeloma who have received prior therapy with lenalidomide (LEN) and bortezomib (BORT): updated phase 2 results and age subgroup analysis. Blood (ASH Annual Meeting Abstracts). 2012;120: Abstract 450.

21. Shah JJ, Stadtmauer EA, Abonour R, et al. A multi-center phase I/II trial of carfilzomib and pomalidomide with dexamethasone (Car-Pom-d) in patients with relapsed/refractory multiple myeloma. Blood (ASH Annual Meeting Abstracts). 2012;120:Abstract 74.

22. Richardson PG, Hofmeister CC, Siegel D, et al. MM-005: a phase 1, multicenter, open-label, dose-escalation study to determine the maximum tolerated dose for the combination of pomalidomide, bortezomib, and low-dose dexamethasone in subjects with relapsed or refractory multiple myeloma. Blood (ASH Annual Meeting Abstracts). 2012;120:Abstract 727.

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Nursing Considerations in the Frontline and Relapsed/Refractory Settings Elizabeth Bilotti, MSN, BSN, APN-C

Nurse Practitioner, Multiple Myeloma Division John Theurer Cancer Center Hackensack University Medical Center, Hackensack, NJ

Introduction Patients with multiple myeloma (MM) present with numerous disease- and treatment-related symptoms that require supportive care.

Monitoring for these complications and intervening with appropriate nursing strategies is critical for maintaining the delicate balance of therapeutic efficacy and tolerability. This requires a thorough knowledge of the toxicity profiles of agents currently used to treat the disease, as well as the latest guidelines for dose adjustments and other interventions. In this article, Elizabeth Bilotti, MSN, BSN, APN-C, discusses approaches used at her center for managing common adverse events (AEs) in both the newly diagnosed and relapsed/ refractory settings.

How do you manage common toxicities related to the use of lenalidomide/bortezomib/dexamethasone (RVD)?

Every time a patient comes into the clinic, we conduct an assessment for AEs related to the drugs used in the RVD regimen. Importantly, we compare how patients are currently feeling with how they were feeling at their last appointment and prior to starting treatment. We inform patients of the common toxicities that may develop and encourage them to contact the office immediately if they are unsure how to manage them or feel that they cannot wait until the next follow-up visit.

Toxicities related to dexamethasone used in RVD can be variable and extensive. Some of the subjective symptoms that patients report include insomnia, which may occur for a few days after treatment, as well as a “let-down effect,” which is characterized by an increase in energy for 1 or 2 days, followed by a “drained” feeling.1 We advise patients to be aware of their energy levels throughout the day, and if possible, look for patterns, so that they can modify their schedules around tasks they need to accomplish and when they have the ability to do them.

Treatment with dexamethasone can also increase a patient’s blood glucose levels, which may remain elevated for 24 to 48 hours after each dose.1,2 If a patient is receiving dexamethasone twice weekly as part of a standard RVD regimen, it is not unusual for glucose levels to be compromised 4 or more days each week. When treating a diabetic patient with MM, we notify his or her endocrinologist or primary care physician, so that necessary adjustments in medications can be made. In patients who are not diabetic, we still carefully monitor blood glucose levels throughout each treatment cycle. In addition, we watch for other signs and symptoms of elevated glucose levels, such as increased thirst or urination.

It is also important to evaluate for myopathies or muscle weakness, especially in the quadriceps, hamstrings, gluteal, and upper arm muscles, as these areas can be affected by the long-term use of dexamethasone, especially in elderly patients who are at greater risk for muscle wasting.1 We encourage individuals to exercise these muscles to reduce the risk of injuries due to falls.

The RVD regimen combines dexamethasone with the immunomodulatory drug (IMiD) lenalidomide, which increases the risk of venous thromboembolism (VTE).3 Therefore, it is important for patients to be educated on the potential signs and symptoms of this complication, which usually includes pain in the calf muscles (while walking or at rest), and in some cases, unilateral

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swelling or warmth.3 We tell our patients that anything out of the ordinary should be reported immediately so that we can determine whether further evaluation is necessary.

In patients receiving IMiDs in combination with steroids, it is critical to provide effective VTE prophylaxis.3-7 There are several risk factors, both patient and treatment related, that must be considered when evaluating for this risk in MM. Guidelines on risk assessment and prophylaxis of VTE have been established (Table),4-7 and we follow these recommendations, using aspirin or anticoagulation with low-molecular-weight heparin or warfarin, based on the number of risk factors and the regimen being administered.

One of the common AEs related to the use of lenalidomide is myelosuppression.8,9 When patients become anemic during therapy, they may feel fatigue throughout the day, or it may be evident only when they exert themselves.

For example, individuals may report that they need to stop and catch their breath after climbing a flight of stairs, which they never had to do before.

Interestingly, aside from these types of symptoms, patients often do not know that their blood counts are low until we make a formal assessment.

We also urge patients to immediately report any unusual bleeding or signs of infection, including a fever higher than 101°F (or higher than 100.5°F that occurs twice during a 24-hour period), which can signal infection or febrile neutropenia.8 Other possible signs of infection may include cough and increased frequency of (or burning during) urination. When necessary, the dose or schedule of lenalidomide may need to be adjusted until blood counts return to normal. Growth factor support may also need to be initiated.

Gastrointestinal (GI) toxicities that patients experience while on lenalidomide include constipation, diarrhea, and bloating.9 It is important to gauge how a patient’s condition has changed since he or she started treatment so that proper interventions, including laxatives, antidiarrheals, adequate fluid intake, or changes in the diet, can be initiated. Immediately addressing these toxicities helps to prevent further complications, such as weight loss, dehydration, bowel obstruction, and electrolyte disturbances.

Patients can also develop a low-grade rash from lenalidomide.9 This is more common during the first and second cycles of treatment and usually manifests as itching and redness of the scalp, which can be treated with an over-thecounter antihistamine. If patients report a whole-body rash, we ask that they come into the clinic to be assessed. In some cases, newly diagnosed patients are receiving prophylactic antibiotics, which may also lead to rash. Therefore, it is important to determine which medication is causing the problem so that the appropriate intervention can be chosen.

In patients receiving immunomodulatory drugs in combination with steroids, it is critical to provide effective VTE prophylaxis.

A well-known and challenging AE related to bortezomib use is peripheral neuropathy (PN).10 However, our ability to administer this drug subcutaneously (SQ) has helped to reduce the risk and severity of this toxicity, although some patients still experience it to some degree. Our center has completely switched over to SQ bortezomib, based on results of the phase 3 noninferiority trial by Moreau and colleagues.11 Our approach to monitoring and managing PN has not changed with this new route of administration. Assessing for neuropathy includes posing questions to the patient each time they come in, to determine whether there has been a change in sensation, pain, or function since baseline. When necessary, we withhold or dose-reduce as recommended until we see improvement in symptoms. Fortunately, bortezomib-based PN is often reversible when managed promptly.12

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CONSIDERATIONS IN MULTIPLE MYELOMA

Table. Risk Assessment for VTE Prophylaxis in Patients Treated with Immunomodulatory Drugs4-7 Individual Risk Factors

Treatment-Related Risk Factors

Obesity (BMI ≥30 kg/m )

High-dose dexamethasone (≥480 mg/month or 120 mg/week)

Previous VTE

Doxorubicin

Central venous catheter or pacemaker

Combination chemotherapy

2

Chronic renal disease (CrCl <40 mL/min) Diabetes Medications (erythropoietin, estrogen) Immobility General surgery Trauma (major or lower extremity) Blood-clotting disorders Number of Risk Factors

Prophylaxis

0-1

Aspirin 81-325 mg daily

2+

LMWH (enoxaparin 40 mg SQ daily, or equivalent) Warfarin (INR 2-3)

BMI indicates body mass index; CrCl, creatinine clearance; INR, international normalized ratio; LMWH, low-molecular-weight heparin; SQ, subcutaneously; VTE, venous thromboembolism.

Bortezomib use can increase the risk of herpes zoster reactivation.13 Therefore, for patients being treated with RVD, we always include antiviral prophylaxis with acyclovir or another agent in its class. Similar to lenalidomide, bortezomib can also cause GI toxicities,10 which are managed with the interventions discussed earlier.

What are some of the important nursing considerations related to the use of carfilzomib and pomalidomide in the relapsed/ refractory setting?

When considering the use of carfilzomib for relapsed/refractory MM, the oncology team needs to ascertain whether the patient will be able to travel back and forth to the center for the necessary infusions. Fortunately, there is assistance available through nonprofit groups that help with transportation and lodging expenses for those who live far from the clinic. It is important for patients and their families to be made aware of these resources, to ensure that they have access to necessary treatment. Some of the organizations that provide useful information are Cancer Support Community (www.cancer supportcommunity.org), Chronic Disease Fund (www.cdfund.org), International Myeloma Foundation (www.myeloma.org), and Multiple Myeloma Research Foundation (www.themmrf.org).

When treating patients in the relapsed/refractory setting, myelosuppression is often a concern because patients have received multiple lines of therapy.

Baseline blood counts may be problematic in all cell lines as these patients may be older, are heavily pretreated, and many have been transplanted.

Although carfilzomib and bortezomib are both proteasome inhibitors, their effects on complete blood cell counts are different. Bortezomib causes transient cyclical thrombocytopenia; platelet counts predictably nadir following the last dose of each cycle (day 11), then typically recover prior to the next cycle.10,14 The platelet reduction with carfilzomib is also transient and cyclical, but the nadir occurs on day 8 of treatment.15 This is important to remember, as the most significant drop in platelet count occurs after 2 doses of this drug.

In some instances, a patient with relapsed disease will have bone marrow that is packed with myeloma cells. However, we may see improvement in blood counts if we can get the disease under control. For this reason, we try to forge

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ahead with carfilzomib treatment despite low counts, knowing that we can give blood products and growth factor support to help patients get through to their next cycle of therapy.

Carfilzomib may cause infusion-related reactions, including myalgias, arthralgias, shaking, chills, fever, and shortness of breath.15 These typically occur 6 to 8 hours after initial exposure to the drug or after the dose is escalated for the first time, which is typically on day 1 of cycle 2. When reactions do occur, they are usually transient and dissipate within 24 hours. It is important to recognize, however, that symptoms can develop at any time, not just during the first few cycles. To lower the incidence of these infusion reactions, patients must be premedicated with dexamethasone 4 mg prior to all doses during cycle 1, prior to all doses during the first cycle of dose escalation to 27 mg/m2, and thereafter if infusion reaction symptoms occur during subsequent cycles.15 One of the advantages of pomalidomide is that it is an orally administered agent.16 This can be an attractive option for patients with relapsed or refractory MM, who have already spent a lot of time in the clinic. One of the disadvantages with an oral agent, however, is patient adherence to therapy.

Once individuals leave the clinic, there is no guarantee that they are taking all of their doses as prescribed.

It is important for the nursing staff to maintain regular contact with patients on pomalidomide or other oral medications, to assess how they are doing. The recommendation with pomalidomide is to perform weekly blood counts for the first 8 weeks of treatment, as one of the most common toxicities is neutropenia.16 We like to see patients very frequently during the first 2 cycles of therapy. After that, it really depends on how well they are tolerating the drug.

The resources listed earlier in this article can be used to help patients who are concerned about the high out-of-pocket costs or copayments associated with pomalidomide. In some cases, patients may be eligible to receive treatment at a reduced cost or for free if they have no insurance or are underinsured. It is primarily the responsibility of the nurse, nurse navigator, or social worker to make sure that patients are aware of these and other services. ♦ References

1. Faiman B, Bilotti E, Mangan PA, Rogers K; IMF Nurse Leadership Board. Steroidassociated side effects in patients with multiple myeloma: consensus statement of the IMF Nurse Leadership Board. Clin J Oncol Nurs. 2008;12(suppl 3):53-63.

2. Clore JN, Thurby-Hay L. Glucocorticoid-induced hyperglycemia. Endocr Pract. 2009;15: 469-474.

3. 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.

4. Palumbo A, Rajkumar SV, Dimopoulos MA, et al. Prevention of thalidomide- and lenalidomide-associated thrombosis in myeloma. Leukemia. 2008;22:414-423.

5. 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.

6. Geerts WH, Bergqvist D, Pineo GF, et al. Prevention of venous thromboembolism: American College of Chest Physicians evidence-based clinical practice guidelines (8th edition). Chest. 2008;133(6 suppl):381S-453S. 7. Palumbo A, Cavo M, Bringhen S, et al. Aspirin, warfarin, or enoxaparin prophylaxis in patients with multiple myeloma treated with thalidomide: a phase III, open-label, randomized trial. J Clin Oncol. 2011;29:983-993.

8. Miceli T, Colson K, Gavino M, Lelleby 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.

9. Revlimid [package insert]. Summit, NJ: Celgene Corporation; 2012.

10. Velcade [package insert]. Cambridge, MA: Millennium Pharmaceuticals, Inc.; June 2012.

11. Moreau P, Pylypenko H, Grosicki S, et al. Subcutaneous versus intravenous administration of bortezomib in patients with relapsed multiple myeloma: a randomized, phase 3, non-inferiority study. Lancet Oncol. 2011;12:431-440.

12. Richardson PG, Briemberg H, Jagannath S, et al. Frequency, characteristics, and reversibility of peripheral neuropathy during treatment of advanced multiple myeloma with bortezomib. J Clin Oncol. 2006;24:3113-3120.

13. San Miguel JF, Schlag R, Khuageva NK, et al. Bortezomib plus melphalan and prednisone for initial treatment of multiple myeloma. N Engl J Med. 2008;359:906-917.

14. Lonial S, Walter EK, Richardson PG, et al. Risk factors and kinetics of thrombocytopenia associated with bortezomib for relapsed, refractory multiple myeloma. Blood.

2005;106:3777-3784.

15. Kyprolis [package insert]. South San Francisco, CA: Onyx Pharmaceuticals; July 2012.

16. Pomalyst [package insert]. Summit, NJ: Celgene Corporation; 2013.

May 2013 I VOL 6, NO 2

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CONTINUING EDUCATION

Pharmacologic Considerations in the Era of Novel Therapies for Multiple Myeloma Greg Eskinazi, RPh, MAS, BCOP

Oncology Research Pharmacist John Theurer Cancer Center Hackensack University Medical Center, Hackensack, NJ

Introduction The development and approval of more effective drugs have led to better response rates and prolonged survival in multiple myeloma (MM). When choosing among these novel therapies, it is essential to consider factors such as pharmacologic profiles and dosing requirements and to identify the needs of each patient to promote individualized care. In this article, Greg Eskinazi, RPh, MAS, BCOP, discusses new directions in the treatment of myeloma and answers questions related to the evaluation of new agents in clinical trials.

What are some of the promising investigational agents being evaluated in clinical trials at your center?

We have a very robust clinical research department at the John Theurer Cancer Center, with just under 200 studies available to our patients.

Approximately 70% of these studies have a pharmacy component and many of them include the treatment of MM. We were deeply entrenched in the studies leading to the recent US Food and Drug Administration (FDA) approvals of carfilzomib and pomalidomide, which are indicated for the treatment of relapsed and/or refractory MM.1,2 The approvals have afforded us the opportunity to continue the evaluation of these agents in other settings, including frontline and maintenance, and as early therapy for the management of smoldering myeloma. Our center currently has 6 open trials of carfilzomib that are accruing patients. We are also evaluating several investigational agents that have shown evidence of antimyeloma activity.

MLN9708 is a selective inhibitor of chymotrypsin-like proteolytic (β5) site of the 20S proteasome with IC50 and Ki of 3.4 nM and 0.93 nM, respectively.3 In an upcoming phase 3 trial, patients with relapsed and/ or refractory MM will be randomized to receive lenalidomide (25 mg) on days 1 through 21, dexamethasone (40 mg) on days 1, 8, 15, and 22 every 28 days, and MLN9708 (4 mg orally) on days 1, 8, and 15; or the same dose and schedule of lenalidomide and dexamethasone plus placebo.4 The primary end point of this trial is progression-free survival (PFS), and secondary end points include overall survival (OS), rate of complete and very good partial response, duration of response, time to progression, safety profile, pain response, change in global health status, OS and PFS in the high-risk population, and pharmacokinetic data.

The immunoconjugate BT062 is comprised of the anti-CD138 chimeric monoclonal antibody nBT062 and the cytotoxic agent maytansinoid DM4.5 The proposed mechanism of action of BT062 is mediated by binding to CD138-positive myeloma cells. Once the immunoconjugate is internalized into the target cell, DM4 is released from the targeting molecule, thereby restoring the original toxicity of the drug. Thus, BT062 is considered a tumor-activated prodrug because the conjugation of DM4 to nBT062 keeps the cytotoxic drug inactive until it is released within the CD138-expressing target cell. A phase 1/2a study is under way to determine dose-limiting toxicities (DLTs) and/or the maximum tolerated dose (MTD)/recommended phase 2 dose of BT062 in combination with lenalidomide and dexamethasone in patients with relapsed and/or refractory MM.6 The mammalian target of rapamycin (mTOR) is a serine/threonine kinase related to the lipid kinases of the phosphoinositide 3-kinase family. It

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functions as a sensor of mitogen, energy, and nutrient levels and is a central controller of cell growth.7 In a phase 1/2 study, investigators are assessing the safety and tolerability of the mTOR kinase inhibitor CC-223 when administered orally and will try to define the MTD and the nontolerated dose.

They will also be determining the preliminary pharmacokinetics of CC-223 following both single and multiple oral dosing.8 What are some of the challenges related to the evaluation of novel agents in clinical trials?

Depending on a patient’s condition at the time of diagnosis, the need for immediate disease control must be addressed. Patients with symptomatic disease requiring treatment may present with 1 or more of the following: hypercalcemia, renal insufficiency, anemia, and/or bone lesions (Table).9 Advances in screening procedures (ie, serum protein electrophoresis, urine protein electrophoresis, and serum free light chain assays) and diagnosis and prognostic indicators based on the Durie-Salmon staging system10 and the International Staging System11 enable us to more accurately assess patients to determine the best course of treatment. Being able to offer our patients a wide variety of approved treatments or the opportunity to take part in clinical trials allows us greater leeway in terms of options. There are, however, challenges related to treating patients in clinical trials, as outlined below.

• Screening and enrollment of patients into clinical trials is a very labor intensive process. Patients must meet extremely detailed inclusion and exclusion criteria. Many times, due to advanced age and concomitant disease states, patients will not be eligible for participation.

• Laboratory reports, scans, and test results must be ordered as mandated by the sponsors of the trial. In some cases, these are performed more frequently than some insurance companies deem necessary, and valuable time is spent trying to obtain permissions.

• Adverse events (AEs) and admissions to the emergency department or other outside facility must be documented and reported to the appropriate agencies. Oftentimes, these admissions may be disease related and not based on the clinical treatment. Strict, detailed instructions are typically included in the protocols, including dose interruptions and/or reductions and procedures for infusion-related reactions.

Differentiating treatment-related versus disease-related symptoms is also extremely important, because overlapping toxicities may develop.

• Many agents are still in the development phase and not yet commercially available. Careful attention to AEs related to these medications is imperative. Differentiating treatment-related versus disease-related symptoms is also extremely important, because overlapping toxicities may develop.

• Risk Evaluation and Mitigation Strategies (REMS), often based on the FDA-regulated “Black Box warnings,” involve specialized educational aspects that patients must be aware of prior to consenting to treatment.

For most agents, the REMS address fertility/pregnancy concerns, which fortunately do not affect most of our patient population but still create issues related to drug procurement.

• The newest oral agents in development require strict adherence to be effective. Compliance is a concern because directions are very specific regarding the way that these drugs must be taken. To improve adherence, we encourage patients to keep diaries to help them remember when to take their medications.

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CONSIDERATIONS IN MULTIPLE MYELOMA • Transportation issues need to be addressed because many patients must be available for day-long pharmacokinetic sampling and frequent office visits.

From a pharmacy perspective, we must stay informed of the differences that exist between approved and investigational agents, as well as the doses and schedules that are used outside of standard treatment regimens.

Pharmacies may have multiple studies using the same investigational product at different dosages, routes of administration, and treatment schedules.

Accountability concerns are addressed by separating drugs by study or by investigational versus commercial supply. Single- and double-blind studies may require the pharmacist to handle the final step in the randomization process to determine the patient’s actual treatment.

The educational needs of the pharmacy and nursing staff must also be met. Study-specific educational documents derived from the protocol and investigator’s brochure are prepared for every study with specific instructions for the staff.

How does the multidisciplinary team approach at your center contribute to better patient outcomes?

The John Theurer Cancer Center is comprised of 14 specialized divisions, featuring teams of experts for specific types of cancer. This allows each patient to be evaluated and treated by a specialist in the field. The myeloma division is staffed by oncologists, advanced practice nurses, a research team, and support personnel that focus solely on this disease. The patient will stay with this unit throughout their treatment and will have access to the most comprehensive therapies available, including clinical trials when appropriate. If transplant is an option, appropriate strategies will be followed while patients are prepared for this procedure, at which time they will be transferred to our transplant division.

We provide a mandatory multidisciplinary class that all patients and caregivers must attend prior to transplant.

Our Blood and Marrow Transplant program has performed more than 3000 transplants since its inception. We provide a mandatory multidisciplinary class that all patients and caregivers must attend prior to transplant.

The class is taught by advanced practice nurses, staff nurses, nutritionists, pharmacists, and psychosocial workers, who are all dedicated to the education of transplant patients and their families.

Toxicities must be closely monitored and handled expediently. An evidence-based guidelines tool for symptom management has been developed to promote standardized and appropriate management of several of the commonly observed AEs related to therapy. These guidelines were recently published in an issue of the Clinical Journal of Oncology Nursing.12 Our center has an onsite chemotherapy pharmacy that is open 7 days a week. It is staffed by 13 pharmacists, 4 pharmacy assistants, and 1 research pharmacist (myself). All outpatient treatments are prepared in our facility.

A specialty retail pharmacy is located in the lobby to handle patients’ pre-

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Table. Diagnostic Criteria for Multiple Myeloma9 Clonal bone marrow plasma cells >10% Presence of serum and/or urinary monoclonal protein (except in cases of true nonsecretory myeloma) Evidence of end-organ damage that can be attributed to the underlying plasma cell proliferative disorder (specifically CRAB): • Calcium elevation: serum calcium ≥11.5 mg/dL or • Renal insufficiency: serum creatinine >2 mg/dL • Anemia: hemoglobin >2 g/dL below lower limit of normal or value <10 g/dL • Bone lesions: lytic lesions, severe osteopenia, or pathologic fractures

scription needs. As a specialty pharmacy, we can provide access to many medications that are not available in most standard pharmacies.

We offer consultations with our board-certified nutritional staff, and our center boasts a test kitchen in which weekly demonstrations are held to teach patients better nutritional habits. We also have an on-site meditation room and a resource library that addresses patient needs and provides literature search requests from the staff. ♦ References

1. US Food and Drug Administration announcements. FDA approves Kyprolis® (carfilzomib) for some patients with multiple myeloma. July 20, 2012. http://www.fda.gov/ NewsEvents/Newsroom/PressAnnouncements/ucm312920.htm.

2. US Food and Drug Administration announcements. FDA approves Pomalyst® (pomalidomide) for advanced myeloma. February 8, 2013. http://www.fda.gov/Drugs/Information OnDrugs/ApprovedDrugs/ucm339286.htm.

3. Ocio EM, Mateos MV, San-Miguel JF. Novel agents derived from the currently approved treatments for MM: novel proteasome inhibitors and novel IMIDs. Expert Opin Investig Drugs. 2012;21:1075-1087.

4. ClinicalTrials.gov. A Phase 3, Randomized, Double-Blind, Multicenter Study Comparing Oral MLN9708 Plus Lenalidomide and Dexamethasone Versus Placebo Plus Lenalidomide and Dexamethasone in Adult Patients with Relapsed and/or Refractory Multiple Myeloma. http://clinicaltrials.gov/ct2/show/NCT01564537.

5. Ikeda H, Hideshima T, Fulciniti M, et al. The monoclonal antibody nBT062 conjugated to cytotoxic maytansinoids has selective cytotoxicity against CD138-positive multiple myeloma cells in vitro and in vivo. Clin Cancer Res. 2009;15:4028-4037.

6. ClinicalTrials.gov. A Phase I/IIa Multi-dose Escalation Study of BT062 in Combination With Lenalidomide and Dexamethasone in Subjects with Relapsed or Relapsed/refractory Multiple Myeloma. http://www.clinicaltrials.gov/ct2/show/NCT01638936.

7. Keen H, Ricketts S-A, Bales J, et al. The mTOR kinase inhibitor AZD8055 modulates 18F-FDG uptake in vivo in the human glioma xenograft model U87-MG. Mol Cancer Ther. 2009;8(suppl 1):Abstract A225.

8. ClinicalTrials.gov. A Phase 1/2, Multi-center Open Label, Dose Finding Study to Assess the Safety, Tolerability, Pharmacokinetics and Preliminary Efficacy of the mTOR Kinase Inhibitor CC-223 Administered Orally to Subjects with Advanced Solid Tumors, Non-Hodgkin Lymphoma, or Multiple Myeloma. http://clinicaltrials.gov/show/ NCT01177397.

9. International Myeloma Working Group. Criteria for the classification of monoclonal gammopathies, multiple myeloma and related disorders: a report of the International Myeloma Working Group. Br J Haematol. 2003;121:749-757.

10. Durie BGM, Salmon SE. A clinical staging system for multiple myeloma. Correlation of measured myeloma cell mass with presenting clinical features, response to treatment, and survival. Cancer. 1975;36:842-854.

11. Griepp PR, San Miguel J, Durie BGM, et al. International staging system for multiple myeloma. J Clin Oncol. 2005;23:3412-3420.

12. Weber MS, Eskinazi G. The development of evidence-based supportive therapy guidelines for symptom management. Clin J Oncol Nurs. 2012;16:343-345.

May 2013 I VOL 6, NO 2

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The 2013

T.O.P. Pharmacist Award Winner Jill Drury Awarded the T.O.P. Pharmacist Award

By Wayne Kuznar

she is in the infusion center for a 3-hour infusion,” she said.

A

nostalgia for the way pharmacy used to be motivates Jill Drury, PharmD, BCOP, to build relationships with her patients. For the patient-oriented focus she brings to oncology pharmacy, the Chicago-area pharmacist has been recognized as this year’s winner of the T.O.P. Pharmacist award.

Drury’s philosophy, which she incorporates into her practice, is that pharmacy can play a large role in enhancing a patient’s quality of life through counseling, listening, and being a universal reference point for patients and providers.

Pharmacy was not a profession that tempted Drury until she got a job as a pharmacy technician at a small independent community pharmacy while in high school in Wisconsin. “What I liked most about it was that everyone knew my name,” she said. “My image of a pharmacy is the pharmacy I grew up working in.

Everyone knew the name of the pharmacist behind the counter and he knew all the names of the patients, and it felt like a community.”

She has carried that sense of community forward in her career as an oncology pharmacist, establishing connections with patients at every opportunity, such as in the infusion center. “What better time to talk to someone than when he or

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Blending the Traditional and Nontraditional Her nostalgic view of the pharmacist compliments what she calls the “unique nontraditional” role of the oncology pharmacist, who must assist in medication plans that adhere to evidence-based practices. The blending of the traditional pharmacist role with the nontraditional aspects inherent in being an oncology pharmacist is helpful to devising treatment plans that must be highly individualized, she believes. “I bring the nostalgic part of my profession into my current role,” she said. “I take a lot of what I learned early on in the pharmacy to these new nontraditional roles of how pharmacy is practiced.”

Being involved with the clinical aspects of oncology has enhanced her appreciation for experiences, and the importance of sharing those experiences with her patients. As Drury puts it, “take

out a diagnosis. The famous ‘bucket list’ is what comes to mind for many when they learn they have cancer. Yet, in a number of situations, it’s too late for some to check off travel destinations on that dreamed up list. Instead, Jill’s spent the last few years bringing the bucket to her patients. Jill’s traveled to places around the world that many patients wish they could visit. Jill’s used her savings to bring back photos, culture, videos, authentic recipes, and many stories of adventure and astonishment. In return, she’s been able to see her patients mentally check off a destination with a smile.”

An Immense Curiosity After finishing high school in the Midwest, Drury’s curiosity took her to New York City, where she attended Fordham University and worked in hospital pharmacies and larger chain pharmacies.

“Little by little I tried to bring what I learned as a pharmacy tech or as a pharmacy student into my practice; making

“Little by little I tried to bring what I learned as a pharmacy tech or as a pharmacy student into my practice; making sure my patients knew who I was, making sure I knew who they were, and developing my own sense of pharmacy.” the trips and eat the cake.” Her love of travel and food is well known, and it is not uncommon for her to share stories of her travels.

“Talking to patients about their drug therapies and treatment plans can be overwhelming,” she said. “Sometimes patients don’t want to talk about how they feel. They want to hear something positive.”

Said Rebecca Roche, a colleague of Jill’s, “…Jill has created hundreds of relationships with patients who are experiencing their personal best and worst of times. Jill’s patients are all on journeys living with diagnoses that have made her re-evaluate her life living with-

sure my patients knew who I was, making sure I knew who they were, and developing my own sense of pharmacy,” she said.

Her curiosity serves her well as an oncology pharmacist, she says, a field that encourages creativity in its mixture of science and clinical care. She cherishes her role as a liaison between physicians, nurses, and her patients, a role she refers to as the “center of care” from which a patient’s care plan can be directed. “Oncology is an area of medicine where that model fits in very nicely because you have time and a listening and willing patient in front of you,” she said. “It’s a field of medicine in which creativity and curiosity are encouraged.”

She received her doctorate of pharmacy from Midwestern University in Illinois. Living in Chicago, she appreciates the learning opportunities available with the proximity to large academic centers and national thought leaders.

While working in the outpatient oncology service at Rush University, and later at BioScrip, Drury helped incorporate concepts such as medication therapy management and comprehensive medication brown bag sessions into the oncology practice setting.

Another peer, Joan Linscott, RN, BSN, had this to say about Drury’s efforts, “With over 5000 patients visiting our practice setting, Jill has been very influential in assisting us with compliance measures. As a pharmacist preceptor and professor for a number of pharmacy schools, Jill remains on the cutting edge of therapy by practicing evidence-based medicine.

Pharmacy management has certainly been streamlined in our clinic due to Jill’s ideas and team effort. Her students and patients are a priority and her ability to assist has been beyond rewarding to the health care system.”

Encouraging her coworkers to consider the patient standing in front of them, “brightens the picture and takes away the overwhelming element out of pharmacy,” said Drury. “Hope, courage, and cure are words often used in cancer. Those are big words with a lot of expectations that come from professionals and the patients. The standards are high. The ability to focus and collaborate on thoughts and ideas is essential to achieve those things, like hope.”

Collaboration can take many forms, she said, but the simplest form of collaboration is communication. Talking to her patients and learning their fears and interests as they sit in the infusion chair helps to forms bonds and foster trust. “The foundation of traditional pharmacy is trust, and that’s the nostalgic part of my profession that I bring into my current role,” she said.

Drury would like to thank TEVA Oncology for this 2013 T.O.P. Pharmacist award. l

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SECOND

ANNUAL CONFERENCE

GLOBAL BIOMARKERS Clinical Approaches CONSORTIUM to Targeted Technologies â&#x201E;˘

October 4-6, 2013 â&#x20AC;˘ Seaport Boston Hotel â&#x20AC;˘ Boston, Massachusetts CONFERENCE CO-CHAIRS Professor Rob Coleman, MBBS, MD, FRCP Yorkshire Cancer Research Professor of Medical Oncology Director, Sheffield Cancer Research Centre Associate Director, National Institute for Health Research Cancer Research Network Department of Oncology, Weston Park Hospital Sheffield, United Kingdom

AGENDA* FRIDAY, OCTOBER 4 3:00 pm - 7:00 pm

Registration

5:30 pm - 7:30 pm

Welcome Reception and Exhibits

SATURDAY, OCTOBER 5 7:00 am - 8:00 am

Symposium/Product Theater

8:15 am - 8:30 am

Welcome to the Second Annual Conference of the Global Biomarkers Consortiumâ&#x20AC;&#x201D;Setting the Stage for the Meeting Professor Rob Coleman, MBBS, MD, FRCP

8:15 am - 11:45 am

General Session I â&#x20AC;˘ Personalized Medicine in Oncology: Evolution of Cancer Therapy from Nonspecific Cytotoxic Drugs to Targeted Therapies â&#x20AC;˘ Taking Stock of Molecular Oncology Biomarkers â&#x20AC;˘ Genomics â&#x20AC;˘ Bioinformatics â&#x20AC;˘ Validating Biomarkers for Clinical Use in Solid Tumors - Professor Rob Coleman, MBBS, MD, FRCP â&#x20AC;˘ Validating Biomarkers for Clinical Use in Hematologic Malignancies Jorge E. Cortes, MD â&#x20AC;˘ The Challenges of Biomarker-Based Clinical Trials â&#x20AC;˘ Keynote Lecture: Understanding Cancer at the Molecular Level

12:00 pm - 1:00 pm

Symposium/Product Theater/Exhibits

1:15 pm - 4:30 pm

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

General Session II â&#x20AC;˘ Introduction to Case Studies - Jorge E. Cortes, MD â&#x20AC;˘ Case Studies: Optimal, Value-Based Use of Molecular Biomarkers in Oncology: The Expertâ&#x20AC;&#x2122;s Perspective on How I Treat My Patients, Part I â&#x20AC;˘ Lung Cancer â&#x20AC;˘ Breast Cancer â&#x20AC;˘ Multiple Myeloma â&#x20AC;˘ Prostate Cancer â&#x20AC;˘ Leukemia â&#x20AC;˘ Lymphoma â&#x20AC;˘ Panel Discussion: Management Controversies and Accepted Guidelines for the Personalized Management of Solid Tumors and Hematologic Malignancies â&#x20AC;˘ Keynote Lecture: The Medical-Legal Issues Surrounding the Use of Biomarkers in Oncology

4:30 pm - 6:30 pm

Meet the Experts/Networking/Exhibits

COMMERCIAL SUPPORT ACKNOWLEDGMENT

SUNDAY, OCTOBER 6

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

CONFERENCE OVERVIEW

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

TARGET AUDIENCE

This meeting will be directed toward medical oncologists and hematologists, pathologists, geneticists, advanced practice oncology nurses, research nurses, clinical oncology pharmacists, and genetic counselors involved in the management of patients with solid tumors or hematologic malignancies, and interested in the use of molecular tumor biomarkers to help optimize patient care.

LEARNING OBJECTIVES

Upon completion of this activity, the participant will be able to: â&#x20AC;˘ Assess emerging data and recent advances in the discovery of molecular biomarkers and their impact on the treatment of patients with solid tumors or hematologic malignancies â&#x20AC;˘ Discuss the role of molecular biomarkers in designing personalized therapy for patients with solid tumors or hematologic malignancies â&#x20AC;˘ Outline the practical aspects of integrating molecular biomarkers into everyday clinical practice in the treatment of patients with cancer

DESIGNATION OF CREDIT STATEMENTS SPONSORS

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

PHYSICIAN CREDIT DESIGNATION

7:00 am - 8:00 am

Symposium/Product Theater

8:15 am - 11:45 am

General Session III â&#x20AC;˘ Review of Saturdayâ&#x20AC;&#x2122;s Presentations and Preview of Today - Jorge E. Cortes, MD â&#x20AC;˘ Case Studies: Optimal, Value-Based Use of Molecular Biomarkers in Oncology: The Expertâ&#x20AC;&#x2122;s Perspective on How I Treat My Patients, Part II â&#x20AC;˘ Melanoma â&#x20AC;˘ Colorectal Cancer and Other GI Malignancies â&#x20AC;˘ MDS â&#x20AC;˘ Myeloproliferative Neoplasms â&#x20AC;˘ Keynote Lecture: Promises and Challenges of Personalized Medicine in Improving Cancer Care â&#x20AC;˘ Tumor Board: Challenging Cases in the Use of Biomarkers in Managing Solid Tumors (attendee-contributed cases) â&#x20AC;˘ Tumor Board: Challenging Cases in the Use of Biomarkers in Managing Hematologic Malignancies (attendee-contributed cases)

12:00 pm - 1:00 pm

Symposium/Product Theater/Exhibits

1:15 pm - 3:00 pm

General Session IV â&#x20AC;˘ Keynote Lecture: Making Personalized Medicine a Reality: The Realization of Genomic Medicine â&#x20AC;˘ The Future of Personalized Medicine: Measuring Clinical Outcomes â&#x20AC;˘ Cost-Effective Technologies That Can Drive Therapeutic Decision Making â&#x20AC;˘ Regulatory Perspectives on PMO â&#x20AC;˘ PMO: The Payerâ&#x20AC;&#x2122;s Perspective â&#x20AC;˘ Panel Discussion: Can We Afford PMO? A Value-Based Analysis â&#x20AC;˘ Practical Considerations in Incorporating PMO into Everyday Cinical Management The official publication of â&#x20AC;˘ Reimbursement Challenges

â&#x20AC;˘ Closing Remarks

3:00 pm

Departures

The Medical Learning Institute Inc designates this live activity for a maximum of 12.5 AMA PRA Category 1 Creditsâ&#x201E;˘. 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 12.5 contact hours.

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 knowledge-based activity provides for 12.5 contact hours (1.25 CEUs) of continuing pharmacy education credit.

The Universal Activity Number for this activity is (To be determined).

CONFERENCE REGISTRATION

EARLY BIRD REGISTRATION NOW OPEN! $175.00 until June 30, 2013

www.globalbiomarkersconsortium.com

In partnership with *Agenda is subject to change.

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Implementing the Promise of Prognostic Precision into Personalized Cancer Care TM

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Oncology Pharmacy Safety

Chemotherapy and Pharmacy... Continued from cover excretion or chromosomal damage study in exposed healthcare workers. When studies documenting the risk of hazardous medications are published in major oncology journals every other year or so, they are hardly ever accompanied by a summary of the current recommendations and regulations. The variety of guidelines and regulatory publications available can make full comprehension and application difficult, with information that can be too broad or too narrow.

Chemotherapy drugs constitute the majority of hazardous drugs as defined by the National Institute for Occupational Safety and Health (NIOSH)1 and other organizations. Obviously, these chemotherapy and other drugs provide a therapeutic benefit to patients, but may pose health risks to workers who must handle them on a daily basis. Because most chemotherapy drugs are nonselective in their mechanism of action, their adverse effects have been well recognized in patients. Additionally, similar adverse effects have been observed in healthcare workers who prepare and administer these drugs. The effects can range from acute, such as skin and mucous membrane irritation, headache, and hair loss, to more long-term effects, such as adverse reproductive outcomes (spontaneous abortion, teratogenicity) and genotoxic effects (chromosomal and other genetic damage) to possible cancer.2,3 In fact, the healthcare setting has a large and diverse mixture of chemicals that are genotoxic, teratogenic, reproductive hazards, and carcinogenic.

The original concerns about worker safety appeared in the late 1970s when it was becoming clear that patients were developing secondary cancers after treatment with alkylating agents, antimetabolites, and other drugs in use then. These findings prompted a concern that healthcare workers may be at risk for similar adverse outcomes without the benefit of being treated for a life-threatening disease.

Several seminal publications appeared in the literature and, commencing in the early 1980s, various organizations developed guidance for safe handling of “cytotoxic drugs.” These organizations included the American Society of Hospital Pharmacy (ASHP; now known as the American Society of Health-System Pharmacists), the Oncology Nursing Society (ONS), the Occupational Safety and Health Administration (OSHA) in the United States, and the Society of Hospital Pharmacists of Australia, among others. Over the years, existing guidelines have been updated and revised as new information has become available and new guidelines have been developed by additional organizations (Table 1).2,4-7 In 1990, ASHP added “hazardous drugs” to the cytotoxic classification,8

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Table 1 Current Safe Drug Handling Guidelines in the United States Date

Organization

Title

1999

OSHA

Controlling Occupational Exposure to Hazardous Drugs4

2004a

NIOSH

Preventing Occupational Exposures to Antineoplastic and Other Hazardous Drugs2

2006

ASHP

ASHP Guidelines on Handling Hazardous Drugs5

2008a

USP 797

Revised Chapter <797> Pharmaceutical Compounding—Sterile Preparations6

2011

ONS

Safe Handling of Hazardous Drugs7

Currently undergoing updates and revisions.

Abbreviations: ASHP, American Society of Health-System Pharmacists; NIOSH, National Institute for Occupational Safety and Health; ONS, Oncology Nursing Society; OSHA, Occupational Safety and Health Administration; USP, US Pharmacopeial Convention. a

Table 2 ASHP and NIOSH Criteria for Defining a Hazardous Drug ASHP 19908

NIOSH 20042

Carcinogenicity in animal models, in the patient population, or both, as reported by the International Agency for Research on Cancer

Carcinogenicity

Teratogenicity in animal studies or in treated patients

Teratogenicity or developmental toxicity

Fertility impairment in animal studies or in treated patients

Reproductive toxicity

Evidence of serious organ or other toxicity at low doses in animal models or treated patients

Organ toxicity at low doses

Genotoxicity (ie, mutagenicity and clastogenicity in short-term test systems)

Genotoxicity Structure and toxicity profile of new drugs that mimic existing drugs determined hazardous by the above criteria

Abbreviations: ASHP, American Society of Hospital Pharmacy; NIOSH, National Institute for Occupational Safety and Health. followed by OSHA’s 1995 update to its recommendations that included a sample listing of hazardous drugs. It had become evident that some drugs other than the cytotoxic (antineoplastic) drugs were carcinogenic, teratogenic, and genotoxic, as well as having adverse reproductive effects in laboratory animals and occasionally in patient populations. These characteristics, along with the ability to produce organ toxicity at low doses, became the criteria by which ASHP defined a hazardous drug.

In 2000, based on increased concern about occupational exposure to hazardous drugs sparked by numerous international publications, NIOSH convened a Hazardous Drug Working Group comprising representatives from government and professional practice organizations, academia, pharmacy and nursing organizations, and drug and safety equipment

manufacturers. The primary outcome of this group’s efforts was the publication in 2004 of the NIOSH Alert: Preventing Occupational Exposures to Antineoplastic and Other Hazardous Drugs in Health Care Settings. In this Alert, NIOSH adopted and slightly revised the ASHP criteria for a hazardous drug (Table 2).2,8 While many embrace safe handling and integrate it into their workday, pharmacy personnel have likely encountered a coworker who balks at safe handling. We all have had more than one coworker say “I have worked with chemo for years and I am fine” as well as “I never gowned when I mixed, and here I am.” It is important to explain to such individuals that epidemiologic studies determining the risk of exposure require large study populations to detect significant effects, much like oncologists not relying on

the efficacy results of a treatment regimen evaluated in one patient without a control group and a sufficient study population. Changing the views of resistant personnel is critical to the environmental protection of all staff.

Employee knowledge of management support and assessment of compliance with safe handling guidelines are integral, because a single employee or incident resulting in environmental contamination can function as an indirect source of contamination for the other staff working in the area.

Many studies have examined the excretion of hazardous drugs in the urine of exposed healthcare workers.

One such study, published by Wick and colleagues in the American Journal of Health-System Pharmacy in 2003, uncovered some long-lasting effects of contamination.9 The study was designed to detect reduction of personnel exposure after implementation of a closed-system transfer device (CSTD) and evaluated the urine of nurses, pharmacists, and technicians, including noncompounders. Of the urine samples analyzed prior to implementation of the CSTD, 21% were positive for ifosfamide and 38% were positive for cyclophosphamide. The facility’s compounding diary last documented ifosfamide as being compounded 3 weeks prior to the initiation of urine collection. Ifosfamide and its metabolites are primarily excreted in the urine, and the human half-life is 3 to 10 hours. Though the authors’ focus was on the efficacy of the CSTD, one may conclude that before or at the time ifosfamide was last compounded, an event resulting in environmental contamination with the drug occurred. Unknown to the staff, this source of contamination persisted and functioned as a means of indirect exposure. This reinforces the necessity of complying with safe handling guidelines by all staff members regardless of their personal perspective, because one employee’s actions can affect other employees’ exposure.

Surprisingly, the essentials of safe handling have remained generally the same since the OSHA Technical Manual was published in 1995: proper facilities, engineering controls, personal protective equipment (PPE), and technique, coupled with education, environmental monitoring, and medical surveillance.

With so many published studies documenting contamination of the workplace and exposure of workers, and the availability of new safety products, it is alarming that noncompliance persists in some facilities. Polovich and colleagues have investigated nurses’ use of handling precautions and identified staff characteristics and organizational factors that

www.TheOncologyPharmacist.com

Oncology Pharmacy Safety influence compliance.10,11 An individual’s knowledge and perception of exposure and risk, including proper technique for using PPE, greatly affect that person’s compliance. Organizational factors include management’s perceptions of the value, whether employee compliance is being enforced, and availability of PPE. Friese and colleagues recently reported on factors that contribute to workplace exposure and concluded that “the likelihood of exposure decreased when nurses reported adequate staffing and resources…and when nurses reported that chemotherapy doses were verified by two nurses frequently or very frequently… .”12 Moreover, as workload increases, compliance with safety procedures decreases.

Therefore, if the main barriers today are education of healthcare professionals and lack of compliance because of workload, it should be our goal to educate staff and fight against desensitization to risk in the workplace.

Although all the criteria for a hazardous drug are of concern to health and safety professionals, the possibility of cancer appears to receive the most attention from healthcare workers.

There are more than 20 chemotherapy agents associated with secondary malignancies in patients, and dozens that are carcinogenic in laboratory studies.13 Furthermore, the vast majority of chemotherapy drugs are genotoxic, which can contribute to the primary or subsequent mutations necessary for the process to progress. Focusing on the mechanism of damage caused by hazardous drugs will increase knowledge and potentially change perceptions and increase compliance. When discussing the carcinogenic and genotoxic potential of compounds, it is important to appreciate that current evidence supports a multistage process of carcinogenesis. Simply expressed, cancer does not develop from a single exposure or DNA alteration, but rather results from a series of events that can lead to cellular immortality. Cancer has a long latency period. DNA changes can be caused by an inherited mutation or exposure of a normal cell to radiation, viruses, or carcinogens, which, if not repaired, can lead to irreversible cellular mutations that alter cellular response to the environment and may confer a survival advantage. This

References

Christine Roussel, PharmD, BCOP

Thomas H. Connor, PhD

process can be mediated by carcinogens, other chemicals, or environmental factors that favor the growth of the mutated cells and may occur over decades. Mutated cells undergoing a selective clonal expansion can lead to transformation or conversion, whereby accumulation of genetic changes leads to cell deregulation and increased proliferation.

While less than 5% of chemotherapy drugs have been evaluated for workplace

between increased surface contamination and increased genotoxicity, but continue to evaluate this matter. It is vital that all pharmacists—not just those practicing in oncology—educate pharmacy technicians and other staff about potentially hazardous drugs and work practices that could result in exposure. Pharmacists should lead by example, and have their actions guide others as to how to work with these potentially harmful drugs.

Healthcare workers are exposed to small doses of a broad range of hazardous drugs over decades, with some workers being exposed every workday, year after year. contamination, current and past research provides a solid rationale for existing recommendations about the dangers these drugs pose to healthcare workers and the need to adhere to proper workplace procedures. Surface contamination with carcinogenic drugs has been documented throughout pharmacy and administration areas and in all areas where these drugs are present.14,15 Hazardous drugs and/or their metabolites have been identified and quantified in the urine of exposed healthcare workers, including noncompounding staff.2,16,17 Genotoxic activity in healthcare workers has been documented by various techniques including chromosomal abnormalities, micronuclei, and comet assay studies. Researchers, including pharmacists and environmental toxicologists, have yet to show a direct correlation

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Patients receive concentrated doses of a limited number of agents for a defined period of time. Healthcare workers are exposed to small doses of a broad range of hazardous drugs over decades, with some workers being exposed every workday, year after year.

Pharmacists and other healthcare workers may be exposed to dozens of the more than 100 chemotherapy drugs now in use, besides the other nonchemotherapy drugs that have been identified as hazardous. Given what is known about the potential hazards of these drugs for workers, it is most prudent to be aware of, and to adhere to, existing safe handling guidelines in addition to keeping up-to-date on training and the latest improvements in safety equipment. l

1. National Institute for Occupational Safety and Health. NIOSH list of antineoplastic and other hazardous drugs in healthcare settings 2012. http://www. cdc.gov/niosh/docs/2012-150/. Published June 2012.

Accessed April 22, 2013.

2. National Institute for Occupational Safety and Health. NIOSH Alert. Preventing occupational exposures to antineoplastic and other hazardous drugs in health care settings. www.cdc.gov/niosh/docs/2004-165/.

Published September 2004. Accessed April 22, 2013.

3. Connor TH, McDiarmid MA. Preventing occupational exposures to antineoplastic drugs in health care settings. CA Cancer J Clin. 2006;56(6):354-365.

4. Occupational Safety and Health Administration.

Controlling occupational exposure to hazardous drugs. http://www.osha.gov/dts/osta/otm/otm_vi/otm_vi_2.html.

Published January 20, 1999. Accessed April 22, 2013.

5. American Society of Health-System Pharmacists.

ASHP guidelines on handling hazardous drugs. Am J Health Syst Pharm. 2006;63:1172-1193.

6. US Pharmacopeial Convention (USP) Revised Chapter (797) Pharmaceutical Compounding—Sterile Preparations. http://www.usp.org/store/products-services/ usp-compounding. Accessed April 22, 2013.

7. Polovich M, Bolton DL, Eisenberg S, et al, eds. Safe Handling of Hazardous Drugs. 2nd ed. Pittsburgh, PA: Oncology Nursing Society; 2011.

8. American Society of Hospital Pharmacists. ASHP technical assistance bulletin on handling cytotoxic and hazardous drugs. Am J Hosp Pharm. 1990;47(5):1033-1049.

9. Wick C, Slawson MH, Jorgenson JA, et al. Using a closed-system protective device to reduce personnel exposure to antineoplastic agents. Am J Health Syst Pharm. 2003;60(22):2314-2320.

10. Polovich M, Martin S. Nurses’ use of hazardous drug-handling precautions and awareness of national safety guidelines. Oncol Nurs Forum. 2011;38(6):718-726.

11. Polovich M, Clark PC. Factors influencing oncology nurses’ use of hazardous drug safe-handling precautions.

Oncol Nurs Forum. 2012;39(3):E299-E309.

12. Friese CR, Himes-Ferris L, Frasier MN, et al.

Structures and processes of care in ambulatory oncology settings and nurse-reported exposure to chemotherapy.

BMJ Qual Saf. 2012;21(9):753-759.

13. International Agency for Research on Cancer.

IARC monographs on the evaluation of carcinogenic risks to humans. http://monographs.iarc.fr/ENG/ Classification/index.php. Updated April 10, 2013.

Accessed April 22, 2013.

14. Connor TH, DeBord DG, Pretty JR, et al. Evaluation of antineoplastic drug exposure of health care workers at three university-based US cancer centers. J Occup Environ Med. 2010;52(10):1019-1027.

15. Hon CY, Teschke K, Chua P, et al. Occupational exposure to antineoplastic drugs: identification of job categories potentially exposed throughout the hospital medication system. Saf Health Work. 2011;2(3):273-281.

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

17. Suspiro A, Prista J. Biomarkers of occupational exposure to anticancer agents: a minireview. Toxicol Lett.

2011;207(1):42-52.

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

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

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May 2013 I VOL 6, NO 2

33

Cancer Center Profile

Kimmel Cancer Center... Continued from cover KCC focuses on treating patients with innovative therapies in an environment of collaborative care. KCC’s more than 150 members also focus on oncology research, with programs in basic and clinical science, working to translate scientific discoveries to improved care for patients. Patients have access to more than 120 clinical trials taking place at the cancer center. KCC recently developed a Medical Oncology Phase 1 program to expand the opportunity for patients to receive promising new therapies. The phase 1 clinical trials program encompasses inpatient and outpatient services and studies may involve all oncology disciplines.

The Oncology Pharmacist spoke with Anne Marie Valorie-Oberle, PharmD, BCOP, an advanced practice clinical pharmacist in oncology at KCC, about her position and the evolving role of the oncology pharmacist.

What are your responsibilities at Kimmel?

Anne Marie Valorie-Oberle (AMV-O): My job in the outpatient infusion center consists of providing drug therapy and symptom management recommendations, providing patient education, and being involved in the development of clinical pathways and standards of care.

Most of my days are spent on the frontline with nurses, physicians, and patients, providing education and answering questions.

What approach does your institution take to the treatment of people with cancer?

AMV-O: The KCC truly employs a multidisciplinary approach. We focus on the “comprehensive” aspect of patient care by utilizing many key team players when developing a care plan for each patient. In addition to caring for the patient’s physical needs, team members address other needs, including those related to emotional, financial, and general health issues, through collaboration with physicians, nurse practitioners, pharmacists, magnet nurses, social workers, nutritionists, financial

support through drug replacement and reimbursement specialists—the list goes on. We are heavily engaged in clinical trials and community outreach programs that provide cancer screening and prevention education. We also have an integrative medicine program for patients to help address lifestyle factors as well, including diet and exercise, vitamins, and supplements.

newer therapies can change a terminal diagnosis to more of a chronic condition for several cancers. For example, chronic myelogenous leukemia and multiple myeloma—patients can live for years on these newer therapies before they need to go to transplant.

Myelodsyplastic syndrome is another disease that was previously treated with best supportive care. Now

In the past 5 years, I have transitioned from being an inpatient clinical pharmacist to an outpatient clinical pharmacist, and I think this is a growing trend in the field of oncology.

Anne Marie Valorie-Oberle, PharmD, BCOP

How does this approach translate to improved outcomes for your patients?

AMV-O: I think that each team member from a specific discipline brings a unique expertise to the table when we collaborate on patient management, to meet both the physical and emotional needs of the patient. In the rare case that one team member overlooks something, another team member will pick up on that. I feel this approach leads to a better overall care of the patient; even when the outcome is not ideal for a patient, it can improve the patient’s quality of life during a difficult time.

What are you excited about right now in the field of oncology?

AMV-O: Targeted therapies. Now that genetic abnormalities can be identified in cancer patients, we have new drugs that target those abnormalities for many cancers. These drugs have changed the natural history of the cancer.

Targeted therapies, whether oral or IV, provide more options for patients who have otherwise run out of options.

We are able to help patients that we couldn’t in the past. Some of these

we have hypomethylating agents that allow patients to live for many years.

Most recently, people are excited about T-DM1, an antibody drug conjugate just approved by the FDA for the treatment of HER2-positive breast cancer. This drug appears to improve outcomes compared with trastuzumab—the first HER2-specific targeted therapy.

How has the role of the oncology pharmacist changed in the past 5 years?

AMV-O: In the past 5 years, I have transitioned from being an inpatient clinical pharmacist to an outpatient clinical pharmacist, and I think this is a growing trend in the field of oncology. With new oral chemotherapy agents, the demand is more in the outpatient setting in terms of symptom management and education.

Our role has evolved to become more collaborative in the outpatient setting.

Also, as an oncology pharmacist, I now have a closer focus on being fiscally responsible for both the institution and the patient, making sure patients are treated in the appropriate setting and that they can afford their therapies.

It’s not just the hospital worrying about

money; the patient worries about whether he/she can afford the expensive new targeted therapies.

Oncology pharmacists work with other healthcare practitioners in symptom management clinics. Our teams make sure patients are taking their medications and are being monitored appropriately.

In the future, we may start seeing some cancers managed with oral therapies alone.

What inspired you to become an oncology pharmacist?

AMV-O: When I was in pharmacy school, I asked for a bone marrow transplant rotation. This combined my interest in immunology with cancer therapy.

It turned out to be my favorite rotation.

An oncology pharmacy position opened up, and I decided to take it. I have been an oncology pharmacist for more than 12 years. I cannot imagine myself working in any other specialty. It is rewarding for me and I feel I am where I was meant to be. The one thing about this specialty, you can never complain about being bored. You have to keep up with it, or the field will pass you by.

What advice would you give to people entering the specialty today?

AMV-O: I have students and residents rotate with me. I tell them not to be scared and to put themselves out there.

I emphasize that it is important to take chances and work in practice areas that they aren’t really sure they want.

They may be surprised by what they end up enjoying the most.

What would you be if you weren’t an oncology pharmacist?

AMV-O: If I had all the money in the world and could do anything I wanted to, I would probably like to do event planning, especially the cooking/catering aspect of that. But then, if I did that for a living, I wouldn’t love cooking as much as I do now.

My husband says I approach cooking like a pharmacist—very organized and careful about measurements. So there must be some relationship! l

Take action: get YOUR cancer center profiled!

We are looking to interview oncology pharmacists from cancer centers around the country.

It’s an easy process—a short phone interview and you need to submit some photos.

Contact editorial@greenhillhc.com for information.

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MAy 2013 I VOL 6, NO 2

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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

ancer is an illness associated with substantial cancer.1 More than half are living well beyond 5 years 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 Ha quently, as a disease primarily of older nsen, Associat e Profes PharmD, BCOP adults, cancer will also increase. Secopportunity to assimilate their circumsor, Virgin ia Commond, as the effectiveness of cancer stances. Frequently, a multidisciplinary onwealt iversity â&#x201E;˘ h Unimproves, approach to treatment is necessary, retreatments the number of he past dec ade has see quiring patients to engage with numercured of the disease will inn a drapatients the utiliza matic upsur

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cia ous medical teams comprising and an even larger percentage several lty phcrease, types of Medic armacies are Moder the rap Lea Ann Hansen, for tho eutic mo will be living all se for can different specialties, often in different longer with disease nization Ac dalities, as â&#x20AC;&#x153;athe cer. The BCOP PharmD, t defined part D dru including cost of can a specialty locations. Many patients have beenabout $125 billio receiving multiple of g with plan-n cer carwhile ceed â&#x20AC;&#x153;linesâ&#x20AC;? drug e may rise egotiated n in 2010 00 per mo from etc) over $4 n byand to $2(first-line, prices tha relatively healthy prior to the cancer lio therapy event second-line, time. thethere07 bilend of the fine specia The nth.â&#x20AC;? 2 Other he t exalth plans dec lty tim ade dru e, . gs specialtyserfore are not sophisticated consumers of medical overall demand By that for oncology services is expected to indifferently may dedrugs are .

In gen acc predic ounthealthcare eral, they vices. Consequently, it is incumbent on crease byted 48% for 2 of eve toby 2020, while the supply of oncologists high cost, admini are ry 5 pharm stered by lars spent.

1 acy dol-by only 14% based on current patterns.4or infusion professionals to be able to facilitate patientsâ&#x20AC;&#x2122; transition injection The purpo will increase , require spe se of thi to explai y isdistress cial hand ersittheir , BCO into carePin order to minimize and need for a wide varietyor are used for article underscore the n maxiling, the evolut Theses statistics sen, PharmD Commonwealth Univ to 80%, complex 17% ion cialty ph inia their clinical outcomes.

Lea Ann Han essor, Virgmize from e of dis req rang the s spe eases tha health professionals and ion other support personnel to uire spe armacy men Prof regiof t cial monit anion Associate d the medicat oral can mon assumpt functi term oring. In ser cology, ho Ascom ve in theand .2-4 Challenges existc beyond the initial diagnosis play a on part each and every patient to rent itin enabling nd 50% onwever, the arou agetre atm systemi treatme ts would be an aver andwith ent of can most com cer agen to the agents dis t scenario forperiod as well. dis According to National quality care that addresses all of their needs antican cus cer mon oralceive s the pensed by to ten he predominan treatment invo ce po lved administra- andthat adh eren ase, has been a specialty ally tia disecontinuum ition ch l ma the ben all trad of cy Cancer Institute (NCI), more than 12 throughout the of the illness.

Patients demillion individly en has efi rity pro pharts vider (SP of cancer thesysseve herapy by high pointhigher, ges dueoftothe indicate the P) are the tem targeted fro nous chemot of vie mrue. fine quality of dies care based on are their ability to5: United States aw history unt ent.living with theStu newer patiare of theofpatproven agents tha tion of intraveuals in the apy ient. monitored the t are admi tered ora s for cancer ther el who closely nislly. After adherence rate 5 erence has trained personn in an The Evolu a system vie . Nonadh w of the lite res took place 97% ati edu to c tio Green Hill Healthcare Communications, LLC proc res e 15% n of Spec rature, on outcome When thes Drugs an ital infugroup of e academ ltyciated with worse e or in a hosp d Specia beeniaasso authors pro ic the es and with oncologistâ&#x20AC;&#x2122;s offic of Ph lty stat po on ase ar sed cati cri dise m edu Le of tic the most acy a Ann Ha al descript nsive in a number hos-nsen, er re ors high sion center, exte Mo s, . of Ph visit Th ible drug to be 3 armD, BC ere is a lac a specia sician ily was poss lty : increased phy k of consen ital stays,OP patient and fam comspecialty sus on ion â&#x20AC;˘ High cos s, longer hosp rate drug. The , an increasingly the ever lizat def t pita how , (pr inition incr Food and escriptions recently not define of one or of aeased mor Drug wormi ng, and than $600 cost more seni d the term. involves the use nistration one-third â&#x20AC;˘toDifficult diseaseAd per month Initially, mon situation synonym medicati self-admin) matelyhas the6 App ous with on delive ications and el roxi was virtuaication-relatedâ&#x20AC;&#x201D; Speci biotechn tality. lab ry, such as more oral med teins pro s in the al handlin ology pro rds of all med lly Lea duced by eous therapie Ann Hanse g requiring -thiducts, eithe utan two ion subc rec icat con red om onmed iste strict tem trol n,moPh pro-to binant DN Asct resp noclona ns arer due perature D,l an A zatio BCtib ment. The dire sociate Professo arm techn â&#x20AC;&#x201D; OP odies pro hospitali iquatesa or home environ r, Vir brido admincost of $100 bil- Restricted locati duced wi erenceâ&#x20AC;&#x201D; magin iat Co s, bu on for me acquisition and thismm nonadhth cellular aris noonlon dication pre we sibility for drug alt ents and purp h Unive - ose of this or distribution site ger Thehy y.7 y paration the rsit ting to the pati casuall ann â&#x20AC;&#x201D;tsRestr e. Th lion cep Hansen, con ile istration is shif Ann 20 ava eral ict if Lea 07 gen ed locati he previous ribe ort network, on for me , BCOP to ticle is to desc insPha talrmD dication their social supp lmen e than 20 t in this can erence and the research related tration adminisent time, mor ries examine e Green ceradh car d the able. At the pres g patient dence, risk facroved for se- Hill wi inci rega alth ngrdin are FDA app therap1). In addition, growi impo treatment. TheHe thcarabe e les d.

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mes in ch al outself-admini addition to ronic myelo stered sub id leukemi cutaneous and childho pies for th a theraod acute lym e home en vironment phoblastic leukemia. 5-8 are under that For each of FDA review these disor. ders, prolon When canc ged oral er medicati therapy ha been the ons are ad ministered s standard Lea Ann orally in th of care for Hansen, decade or e home en ronment rat a PharmD, more. It is viher than in BC lik OP ely ative conse the clinic that negof adheren or hospital qu en ce range fro ces of nonadh , the rates m 15% to with other erence at the end will be docu 97%. 2 For oral cancer of the first example, mented in medication year of tre hormonal the future atment wi s apy matur treatment as their rol th adjuvan es. The pu (AHT) for e in t cer, only 79 rpo therse early-stage the result of this art % of patie breast can icle is to dis s of avail nts remain a gap exce able resea cuss ed on therap adherence eding 60 da rch on maxim and suggest y without ys and 85% ceeding 18 izing best practi ical outco without a 0 days. By ces to impro mes. gap exyear 5, on ve clinmained wi ly 27% an thout 60d 29% reand 180-d In another ay gaps, res

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