TON March 2013

March 2013

www.TheOncologyNurse.com

Vol 6, No 2

Register Today

Fourth Annual Navigation and Survivorship Conference November 15-17, 2013

see page 15

Breast Cancer

Cancer Center Profile

The Evolving Role of the Physician Assistant in Oncology

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

By Alice Goodman

By Phoebe Starr

New York-Presbyterian Hospital/ Weill Cornell Medical Center

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 musculoskele-

tal 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 Continued on page 12

Colorectal Cancer The oncology team of physician assistants at New York-Presbyterian Hospital/Weill Cornell Medical Center. Colleen Kalmbach (center in suit) is Director of Physician Assistants and Catherine Brown (far left) is Patient Care Director. Jeremy Heinerich, PA-C, is to the right of Colleen Kalmbach.

T

he movement toward using nonphysician providers is an attractive option in the current healthcare environment. The use of nonphysician providers, including physician assistants (PAs), can expedite timely care, reduce inefficiencies, and improve continuity of care. PAs who specialize in oncology are transforming busy oncology practices at academic centers around the country.

The Oncology Nurse-APN/PA spoke with Jeremy Heinerich, PA-C, Chief PA of Inpatient Oncology at New York-Presbyterian Hospital/ Weill Cornell Medical Center in New York City, about the evolving role of the PA at his institution and other centers.

Continued on page 13

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

Conference News

54th Annual Meeting of the American Society of Hematology

By Alice Goodman

A

wealth of abstracts were presented at the 54th Annual Meeting of the American Society of Hematology (ASH), held in Atlanta, Georgia, on December 8-11, 2012. More than 18,000 hematologists and other healthcare professionals from around the world

gathered to discuss the latest clinical developments in research, therapies, and practice strategies. Attendees had the opportunity to review thousands of selected scientific abstracts.

Following are some of the highlights from the ASH annual meeting.

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 retContinued on page 20

inside Leukemia . . . . . . . . . . . . . . . . . . . . . . . . . .

6

Liposomal Vincristine Allows for Greater Dose Density Without Increased Neurotoxicity Predicting Risk of Significant Side Effects With OnPART. . . . . . . . . . . . . .

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Monitor Adverse Events Early With Regorafenib, Especially After Initiation. . . . . . . . . . . . . . . . . . . . . . . . . . . .

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©2013 Green Hill Healthcare Communications, LLC

22

Home-Based TPN of Little Benefit in Terminally Ill Patients With GI Cancer

Side Effects Management

Continued on page 16

Supportive and Palliative Care. . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

Interview With the Innovators . . . . . . . . . . . . . . . . . . . . .

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Lynch Syndrome: An Interview With the Father of Hereditary Cancer Detection and Prevention, Henry T. Lynch, MD

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eO seri Vie nc es w olo on the gy line Nu a rse t .co m

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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 ™ 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 ma

tic upsurge tio n of specia several ous medical teams comprising and an in even larger percentage lty phcrease, types of Medic arm acies for are Moder rapeutic Lea Annthe Hansen, all different specialties, often in different those for can will be living longer with disease nization Ac mo dalities, as “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 “lines� of g with plan-n cer carwhile ceed $4 drug e may rise egotiated n in 2010 00 per mo lio from etc) over time. n byand to 07 bil prices tha relatively healthy prior to the cancer event second-line, thethereend of the therapy$2(first-line, fine specia The nth.� 2 Other he t exalth plans dec ltyinade. demand drugs dif specialtyserfore are not sophisticated consumerstim ofe,medical overall By that for oncology services is expected to may defer en drugs are tly. In gen accon predic ounthealthcare era hig l, vices. Consequently, it is incumbent crease byted 48% by 2020, while the supply of oncologists h for 2 of eve the cos to y are t, admini 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 patients’ 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 80%, complex ion cialty ph inia their clinical outcomes.

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is in addition comes in al outself-admini chronic my to stered sub eloid leuke cutaneous and childho pies for th mia 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 ge d er medicati oral thera been the py has ons are ad ministered 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 BCOP likely that ative conse the clinic of adheren negor hospital quences of ce range fro , the rates nonadhere m 15% to with other at the end nce will be docu 97%. 2 For ora of the first l ca ncer medic example, mented in year of tre hormonal ations the future atment wi apy matur treatment as their rol th adjuvan es. The pu (AHT) for e in thert cer, only 79 rpose of th early-stage the result % of patie is article is breast can s of avail nts remain to dis a gap exce ab cuss le ed on therap adherence research eding 60 da 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 mained wi cli nly 27% an thout 60d 29% reand 180-d In another ay gaps, res

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Editorial Board EDITOR-IN-CHIEF

Beth Faiman,

PhD(c), MSN, APRNBC, AOCN Cleveland Clinic Taussig Cancer Institute Cleveland, OH

Elizabeth Bilotti, RN, MSN, APRN, BC, OCN

John Theurer Cancer Center Hackensack University Medical Center Hackensack, NJ

Catherine Bishop, DNP, NP, AOCNP

Cassandra J. Hammond, RN,

Dolores “Jeff” Nordquist, RN, MS,

Rita Wickham,

PhD, RN, AOCN

Avid Education Partners, LLC Sharpsburg, MD

CS, FNP

Mayo Clinic Rochester, MN

Northern Michigan University Independent Oncology & Palliative Care Consultant Marquette, MI

Shannon Hazen,

Melinda Oberleitner, RN,

Karla Wilson, RN,

MSN, CRNP

RN, BSN, OCN Novant Health Presbyterian Cancer Center Charlotte, NC

Patricia Irouer Hughes, RN, MSN,

MSN, FNP-C, CPON

DNS, APRN, CNS

City of Hope National Medical Center Duarte, CA

Jayshree Shah, NP

Pharmacy John F. Aforismo,

College of Nursing and Allied Health Professions University of Louisiana Lafayette, LA

Johns Hopkins Kimmel Cancer Center/Sibley Infusion Washington, DC

BSN, OCN

Piedmont Healthcare Rex, GA

John Theurer Cancer Center Hackensack University Medical Center Hackensack, NJ

Deena Damsky Dell, MSN, RN-BC,

Taline Khoukaz,

Gary Shelton,

University of Southern California Norris Cancer Center & Hospital Los Angeles, CA

NYU Clinical Cancer Center New York, NY

Somerset Medical Center Somerville, NJ

Sandra E. Kurtin,

Lori Stover, RN,

Patient Advocate Peg Ford

Arizona Cancer Center Tucson, AZ

Western Pennsylvania Cancer Institute Pittsburgh, PA

Ovarian Cancer Advocacy Alliance San Diego, CA

Ann McNeill,

Joseph D. Tariman,

Social Work Carolyn Messner,

AOCN, LNC

Fox Chase Cancer Center Philadelphia, PA

Wendy DiSalvo,

DNP, APRN, AOCN Genentech New London, NH

Denice Economou,

RN, MN, CNS, AOCN City of Hope National Medical Center Duarte, CA

Constance Engelking, RN,

MS, CNS, OCN

The CHE Consulting Group, Inc. Mt. Kisco, NY

Amy Ford, RN,

BSN, OCN Quintiles Dallas, TX

Sharon S. Gentry, RN, MSN, AOCN

Derrick L. Davis Forsyth Regional Cancer Center Winston-Salem, NC

www.TheOncologyNurse.com

NP, MSN, ACNP-C

RN, MS, AOCN, ANP-C

MSN, RN, NP-C, OCN

John Theurer Cancer Center Hackensack University Medical Center Hackensack, NJ

Kena C. Miller, RN, MSN, FNP

Roswell Park Cancer Institute Buffalo, NY

MSN, NP, ANP-BC, AOCNP

BSN

PhD, APRN, BC

BSc Pharm, RPh, FASCP RJ Health Systems International, LLC Wethersfield, CT

Nutrition Karen Connelly, RD, CSO

Northwestern University Myeloma Program Chicago, IL

DSW, MSW, LCSW-R, BCD

Jacqueline Marie Toia, RN, MS, DNP

Managed Care and Pharmaceutical Management Burt Zweigenhaft,

Northwestern University Myeloma Program Chicago, IL

CancerCare New York, NY

BS

OncoMed Onco360 Great Neck, NY

Patricia Molinelli, MS, RN, APN-C, AOCNS

Somerset Medical Center Somerville, NJ

Ellen A. Neylon, MSN, FNP-BC, CCRP, OCN

Columbia University Medical Center Center for Lymphoid Malignancies New York, NY

Pamela Hallquist Viale, RN, MS,

Isabell Castellano, RN

CS, ANP, AOCN Saratoga, CA

Bristol-Myers Squibb Children’s Hospital Robert Wood Johnson University Hospital New Brunswick, NJ

Connie Visovsky,

Jeanne Westphal, RN

RN, PhD, APRN

University of South Florida College of Nursing Tampa, FL

Meeker County Memorial Hospital Litchfield, MN

March 2013 I VOL 6, NO 2

3

From The Editor PUBLISHING STAFF Senior Vice President, Sales & Marketing Philip Pawelko phil@greenhillhc.com Publisher John W. Hennessy john@greenhillhc.com Director, Client Services Eric Iannaccone eric@greenhillhc.com Editorial Director Kristin Siyahian kristin@greenhillhc.com Managing Editor Kristen Olafson kristen@greenhillhc.com Quality Control Director Barbara Marino Production Manager Stephanie Laudien Business Manager Blanche Marchitto blanche@greenhillhc.com Executive Administrator Jackie Luma Circulation Department circulation@greenhillhc.com Editorial Contact: Telephone: 732.656.7935 Fax: 732.656.7938

1249 South River Road, Suite 202A Cranbury, NJ 08512 The Oncology Nurse-APN/PA®, ISSN 1944-9798 (print); ISSN 1944-9801 (online) is published 11 times a year

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March 2013 I VOL 6, NO 2

W

ith this issue of The Oncology Nurse-APN/ PA (TON), we continue our coverage of the news from the 54th Annual Meeting of the American Society of Hematology (ASH) and the San Antonio Breast Cancer Symposium (SABCS). The news from ASH includes some of the latest research involving treatments for lymphoma, multiBeth Faiman, PhD(c), ple myeloma, and leukemia. Our MSN, APRN-BC, AOCN SABCS coverage tells you about Editor-in-Chief the results of a study suggesting that musculoskeletal toxicity associated with aromatase inhibitor therapy can lead to medication noncompliance in up to one-third of women with breast cancer.

March is national kidney cancer awareness month.

To acknowledge this, Noteworthy Numbers focuses on the statistics of this disease, which is the 6th most common cancer among men and the 8th most common cancer among women in the United States. Our Cancer Center Profile this month is an interview with Jeremy Heinerich, PA-C. Jeremy tells us how physician assistants were incorporated into the oncology department at New York-Presbyterian Hospital/Weill Cornell Medical Center, where he is now Chief PA of Inpatient Oncology.

As always, I encourage you to visit our website, www.

TheOncologyNurse.com. Please answer this month’s Reader Poll about what patients tell you about how well they adhere to their at-home medication regimens and let us know how you help them. Be sure to tell us what topics you want to see covered in TON. We want to hear from you, and we appreciate your feedback. l

Recent FDA News Ado-Trastuzumab Emtansine Approval for Breast Cancer The US Food and Drug Administration (FDA) approved ado-trastuzumab emtansine (Kadcyla for injection; Genentech) for single-agent use for treating patients with HER2-positive metastatic breast cancer who previously received trastuzumab and a taxane, separately or in combination. Approval for ado-trastuzumab emtansine was granted on February 22, 2013.

The FDA approval was granted based on the results of a randomized, multicenter, open-label trial that enrolled 991 patients. Patients in the trial had HER2-positive metastatic breast cancer that had been previously treated with a taxane and trastuzumab-based therapy (patients who received these therapies had disease recurrence during or within 6 months of completing adjuvant therapy). Patients were required to have breast cancer specimens showing HER2 overexpression that was defined as 3+ IHC or FISH ratio ≥2.0.

Patients were randomly assigned on a 1:1 basis to receive ado-trastuzumab emtansine (3.6 mg/kg by intravenous infusion on day 1 every 21 days) or lapatinib (1250 mg/day orally once daily for 21 days) plus capecitabine (1000 mg/m2 orally twice daily for 14 days). The treatment was continued until disease progression, unacceptable toxicity, or patient consent was withdrawn.

Progression-free survival (PFS) and overall survival (OS) were the primary end points. Patients receiving ado-trastuzumab emtansine had a statistically significant improvement in PFS (based on tumor response assessments) compared with patients receiving lapatinib plus capecitabine. The median PFS was 9.6 months for those patients receiving ado-trastuzumab emtansine and 6.4 months for patients receiving lapatinib plus capecitabine. The median OS was 30.9 months for those who received ado-trastuzumab emtansine and 25.1 months for those who received lapatinib plus capecitabine.

Fatigue, nausea, musculoskeletal pain, thrombocytopenia, headache, increased transaminases, and constipation were the most common adverse reactions for those in the ado-trastuzumab emtansine arm (occurring in >25% of patients). Thrombocytopenia, increased transaminases, anemia, hypokalemia, peripheral neuropathy, and fatigue were the most common grade 3 or 4 events (occurring in >2% of patients). There were at least 2 fatal causes of severe drug-induced liver injury and associated hepatic encephalopathy reported during clinical trials with ado-trastuzumab

emtansine. Left ventricular dysfunction, interstitial lung disease, and infusion-associated reactions were other significant adverse events associated with ado-trastuzumab emtansine.

The FDA approved ado-trastuzumab emtansine with a boxed warning in the product label to alert healthcare providers and patients of the risk of hepatotoxicity, reduction in left ventricular ejection fraction, embryo-fetal toxicity and birth defects, and the need for effective contraception prior to starting treatment.

Pomalidomide Accelerated Approval for Multiple Myeloma The FDA granted accelerated approval to pomalidomide (Pomalyst capsules; Celgene Corporation) on February 8, 2013. Pomalidomide was approved to treat patients with multiple myeloma who have received at least 2 prior therapies—including lenalidomide and bortezomib—and who have experienced disease progression within 60 days of completion of their most recent therapy.

The FDA approval was based on the results of the multicenter, randomized, open-label CC-4047-MM-002 clinical trial. This study enrolled 221 patients with relapsed and refractory multiple myeloma who had previously received lenalidomide and bortezomib and who were refractory to their last myeloma therapy. There were 2 treatment arms in the study: pomalidomide alone or pomalidomide plus low-dose dexamethasone.

The efficacy results showed an overall response rate of 7% in patients who received pomalidomide alone; the rate was 29% in patients who received pomalidomide plus low-dose dexamethasone. The median response duration was not evaluable for patients receiving pomalidomide alone and was 7.4 months for patients receiving pomalidomide plus low-dose dexamethasone.

Fatigue and asthenia, neutropenia, anemia, constipation, nausea, diarrhea, dyspnea, upper respiratory tract infections, back pain, and pyrexia were the most common adverse events reported in the clinical trial. The approval includes a boxed warning in the product label to alert healthcare providers and patients that pomalidomide can cause embryo-fetal toxicity and venous thromboembolism. Because of the risk embryo-fetal toxicity, pomalidomide is available only through a restricted risk evaluation and mitigation strategy (REMS) program. l Sources

http://www.fda.gov/Drugs/InformationOnDrugs/ApprovedDrugs/ucm340913.htm. http://www.fda.gov/Drugs/InformationOnDrugs/ApprovedDrugs/ucm339286.htm.

www.TheOncologyNurse.com

Noteworthy Numbers Renal Cancer Although there are several hereditary risk factors related to kidney cancer, there also are lifestyle choices that can increase a person’s risk of the disease. In fact, 3 risk factors (cigarette use, obesity, and hypertension) together are associated with 49% of kidney cancer cases.1 As we continue to encourage healthy lifestyle choices in the fight against kidney cancer, let us examine the following statistics related to this disease.

According to SEER statistics, the overall 5-year relative survival rate for kidney cancer is 70.6%.3 There are several types of kidney cancer. Renal cell carcinoma is the most

common type, comprising almost 85% of kidney cancer diagnoses. Another 10% to 15% of kidney cancer cases are categorized as transitional cell carcinoma. Wilms tumor (the most common kidney can-

cer in children) and renal sarcoma are 2 other types of this disease.4 Sources 1. http://www.clevelandclinicmeded.com/medicalpubs/ diseasemanagement/nephrology/renal-cell-carcinoma/.

2. http://www.cancer.org/cancer/kidneycancer/detailed guide/kidney-cancer-adult-key-statistics.

3. http://seer.cancer.gov/statfacts/html/kidrp.html.

4. http://www.cancer.net/cancer-types/kidney-cancer.

S:7.25”

NOW RECRUITING

Investigators Study of the long-term safety and efficacy of darbepoetin alfa in anemic patients with Non-Small Cell Lung Cancer (NSCLC) receiving chemotherapy

Although kidney cancer death rates have decreased slightly since the mid-1990s, the rate of kidney cancer diagnosis has been rising steadily since the late 1990s.2

Phase 3 study with approximately 3,000 subjects at 500 study sites globally KEY ELIGIBILITY CRITERIA*

PRIMARY ENDPOINT

One in 62 men and women will be diagnosed with kidney cancer during their lifetime.3

• Stage IV NSCLC

• Overall survival

• Receiving 1st-line myelosuppressive

SECONDARY ENDPOINTS

According to the American Cancer Society, approximately 65,150 new cases of kidney cancer will occur in 2013, with 40,430 of them in men and 24,720 in women.2

• ECOG score ≤ 1

chemotherapy • Hemoglobin (Hb) ≤ 11 g/dL

S:9.75”

(darbepoetin alfa:placebo)

End of Investigational Product

End of Treatment Period

Long-term Follow-up

Placebo Q3W

Week 0

Week 1

Disease progression or end of chemotherapy treatment

*Complete inclusion/exclusion criteria and additional study details can be found in the protocol.

ECOG = Eastern Cooperative Oncology Group; Q3W = once every 3 weeks.

Cory Docken/Getty Images

For more information, please email Study-20070782@amgen.com or call 1-866-965-0782.

Products under investigational study have not been approved by the FDA for the use under investigation in this trial.

Between 2005 and 2009, the median age at death for patients with kidney cancer was 71 years.3 www.TheOncologyNurse.com

• Incidence of ≥ 1 red blood cell (RBC) transfusion or Hb ≤ 8.0 g/dL

Darbepoetin alfa 500-mcg Q3W

2:1 Randomization

Among men, kidney cancer is the 6th most common cancer. The disease is the 8th most common cause of cancer for women.4 For people younger than age 45, kidney cancer is very uncommon. The disease most often occurs in people age 55 and older, with an average age of 64 at diagnosis.2

• Progression-free survival

© 2013 Amgen Inc. All rights reserved. Not for Reproduction.

AOCO3X0071_Recruitment782_AdAsize_r3.indd 1

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2/12/13 9:38 AM March 2013 I VOL 6, NO 2 5

LEUKEMIA

Liposomal Vincristine Allows for Greater Dose Density Without Increased Neurotoxicity

By Caroline Helwick

March 2013 I VOL 6, NO 2

90 80 70 60 50 40 30 20 10 0

Dose

Dose Density (mg/week)

1.4 mg/m2/3 wk

0.84

78

Verstappen (VCR)

4 mg/3 wk

1.33

60

Verstappen (VCR)

2 mg/3 wk

0.67

34

2.25 mg/m /wk

4.04

23

Study

VSLI

Haim (VCR)

VSLI

t

6

Figure Higher VSLI Dose Without Increase in PN

t

Increased Delivery of Vincristine to Target Tissue Dose capping is intended to reduce the risk of drug-induced neuropathy, but may also limit clinical efficacy, said Jeffrey A. Silverman, PhD, Vice President of Clinical Pharmacology and Translational Research at Talon Therapeutics, South San Francisco, California.

“In addition to dose capping, standard VCR is limited by a very rapid distribution half-life and large volume of distribution that suggests there is wide and diffuse tissue distribution,” he said.

“VSLI is designed to overcome the dosing and pharmacokinetic limitations of standard VCR. It is intended to take advantage of fenestrated (leaky) vasculature found in bone marrow, lymph nodes, the spleen, and many tumors…to preferentially penetrate, accumulate, and deliver VCR to cancer tissues,” he pointed out.

At ASH, Silverman described plasma pharmacokinetics in rats that received standard VCR or VSLI 2 mg/m2 by slow IV bolus.3 VSLI increased VCR

plasma circulation time and area under the curve, delivered more VCR to tissues that are important in hematologic malignancies, and slowly released VCR in tumors over days, he reported.

Paraesthesia Rate (%)

I

n August 2012, vincristine sulfate LIPOSOME injection (VSLI) (Marqibo) was granted accelerated approval by the US Food and Drug Administration (FDA) for the treatment of adult patients with Philadelphia chromosome-negative (Ph-) acute lymphoblastic leukemia (ALL) in second or greater relapse or whose disease has progressed after 2 or more regimens.1 At the 54th Annual Meeting of the American Society of Hematology (ASH), investigators further described its pharmacokinetics and neurotoxicity profile of the new drug and reported data in pediatric patients.

Standard vincristine sulfate (VCR) is a component of treatment regimens for pediatric and adult hematologic and solid malignancies,2 including ALL, non-Hodgkin lymphoma, Hodgkin lymphoma, Wilms’ tumor, sarcomas, and brain tumors. Dosing of VCR is limited by significant neurotoxicity, which occurs at doses higher than 1.4 mg/m2 and has led to capping of the total dose at 2.0 mg.2 The newly approved vincristine product is a sphingomyelin/cholesterol liposome-encapsulated formulation of VCR.2 Liposomal carriers are capable of increasing the therapeutic index of anticancer drugs by altering the pharmacokinetic behavior of standard agents.

VSLI is administered at 2.25 mg/m2 by IV infusion over 1 hour once every 7 days with no dose cap.1

2

Paraesthesia Rate (%)

Neurotoxicity Profile Marqibo facilitates >2 fold higher dose density without a concomitant Stable, In Spite of High 0 1 2 3 4 5 increase in paraesthesia rate Doses Delivered Dose Density (mg/week) Peripheral neuropathy is the major toxicity associ- Figure used with permission of Jeffrey A. Silverman. ated with the use of VCR, and this limits the individual dose, VCR showed much higher paresthe- of 10 received the VSLI dose that cumulative exposure, and dose density sia rates at much lower dose densities exceeded the 2-mg dose cap for standard VCR. Of 7 patients evaluable for of the drug.

(Figure)4,5: • 78% with a dose density of 0.84 mg/ response, 1 patient achieved a complete “Attempts to increase the dose [of week (1.4 mg/m2 every 3 weeks) remission, 3 had stable disease, 2 had standard VCR] have been met with a • 34% with a dose density of 0.67 mg/ progressive disease, and 1 was too early 100% incidence of peripheral neuropaweek (2 mg every 3 weeks) to assess for response. thy,” Silverman said.

• 60% at a dose density of 1.33 mg/ Most treatment-related adverse events Due to VCR’s dose-dependent antiweek (4 mg every 3 weeks) were grade 1 and 2 and reversible, the tumor activity, it would be beneficial VSLI facilitated more than a 2-fold most common of which were hepatic to be able to increase the dose and dose density without increasing neuropathy, higher dose density without a concomi- transaminase elevations, paresthesias, tant increase in paresthesia rate. neutropenia, and fatigue. No patient he added. discontinued treatment due to neurotoxicity.

“VSLI appears to be safe and tolerable.

Liposomal carriers are capable of increasing The toxicity spectrum appears similar in children and adults,” Shah said. “VSLI the therapeutic index of anticancer drugs may allow for intensification of vincrisby altering the pharmacokinetic behavior of tine therapy in children with cancer.”

“Clearance of total vincristine in our standard agents. study was approximately 100-fold lower in comparison to previously observed values for the administration of standard “One of the advantages of VSLI is no vincristine,” she added.

Investigators dosed VSLI at 2.25 mg/m2 (the FDA-approved dose) with- dose cap, so we can administer more vinAccrual at the adult recommended out a dose cap and evaluated the cristine, and what we saw in this study is dose is ongoing and an expanded phase emergence of neuropathy in 83 adults that higher dosing does not translate into 2 cohort in pediatric patients with ALL with relapsed/refractory ALL and prior greater neurotoxicity. With the conven- is being planned. l VCR exposure; 80% of the subjects tional drug, we see more neurotoxicity had residual neuropathy.2 Peripheral even at much lower doses and lower dose References 1. Marqibo [package insert]. South San Francisco, CA: neuropathy was proactively assessed density,” Silverman said.

Talon Therapeutics, Inc; August 2012. weekly with a detailed evaluation of 16 There were no new or unexpected 2. Deitcher SR, Silverman JA; on behalf of the RALLY signs and symptoms. toxicities observed with VSLI dosed at Trial Investigators. Neurotoxicity profile of vinCRIStine sulfate LIPOSOME injection (VSLI, Marqibo®) The investigators observed that the 2.25 mg/m2, he added. monotherapy in adults with relapsed acute lymphoblasHe acknowledged that the study tic leukemia and universal prior standard vincristine occurrence of peripheral neuropathy exposure. Poster presented at: 54th American Society was consistent with the labeled dose of compared neurotoxicity with VSLI to of Hematology Annual Meeting; December 8-11, 2012; standard VCR, despite the delivery of historical data on VCR. “A head-to- Atlanta, GA. Abstract 3568.

3. Silverman JA, Deitcher SR. Vincristine sulfate lipolarger, normally unachievable individu- head study is ongoing,” he added. some injection (VSLI, Marqibo®) facilitates increased delivery of vincristine sulfate to target cancer tissues. al and cumulative doses of VCR. Presented at: 54th American Society of Hematology Peripheral neuropathy of any grade VSLI in Pediatric Patients Annual Meeting; December 8-11, 2012; Atlanta, GA. occurred in 23% of patients but only 1% “The pediatric experience with VSLI Abstract 2457.

Haim N, Epelbaum R, Ben-Shahar M, et al. Full dose was grade 4 and 22% was grade 3, despite has been limited,” said Nirali N. Shah, 4. vincristine (without 2-mg dose limit) in the treatment a dose density of 4.04 mg/week (2.25 MD, of the National Institutes of Health of lymphomas. Cancer. 1994;73:2515-2519. mg/m2/week). This included peripheral Pediatric Oncology Branch, Bethesda, 5. Verstappen CC, Koeppen S, Heimans JJ, et al.

Dose-related vincristine-induced peripheral neuropamotor neuropathy, pain in the extrem- Maryland. thy with unexpected off-therapy worsening. Neurology. ity, areflexia, decreased vibratory sense, At ASH, Shah presented the results 2005;64:1076-1077.

6. Shah NN, Merchant M, Cole D, et al. Vincristine gait disturbance, hypoesthesia, muscu- of a phase 1 single-institution dose sulfate liposomes injection (VSLI, Marqibo): interim lar weakness, neuralgia, paresthesia, and escalation trial of 10 children and young results from a phase I study in children and adolescents refractory cancer. Presented at: 54th American peripheral sensory neuropathy. adults (2-20 years old) with relapsed or with Society of Hematology Annual Meeting; December In comparison, previous studies of refractory ALL or solid tumors.6 Seven 8-11, 2012; Atlanta, GA. Abstract 1497.

www.TheOncologyNurse.com

ASH Highlights

Abstracts of Interest From the 54th Annual Meeting of the American Society of Hematology Bleed: 8.75”

Trim: 7.875” Live: 6.75”

By Caroline Helwick

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 all-trans 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.

STIVARGA® for Metastatic Colorectal Cancer (mCRC):

The 2-year event-free survival was 97% in the ATRA/ATO arm versus 86.7% in the ATRA/ chemotherapy arm.

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, 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.

Expanding Treatment.

Extending Survival.

• Median overall survival: 6.4 months with STIVARGA vs 5.0 months with placebo; HR, 0.77; 95% CI, 0.64-0.94; P =0.01021

Indication STIVARGA is indicated for the treatment of patients with metastatic colorectal cancer (CRC) who have been previously treated with fluoropyrimidine-, oxaliplatin-, and irinotecan-based chemotherapy, an anti-VEGF therapy, and, if KRAS wild-type, an anti-EGFR therapy.

Important Safety Information WARNING: HEPATOTOXICITY Severe and sometimes fatal hepatotoxicity has been observed in clinical trials. Monitor hepatic function prior to and during treatment. Interrupt and then reduce or discontinue STIVARGA for hepatotoxicity as manifested by elevated liver function tests or hepatocellular necrosis, depending upon severity and persistence.

Reference

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

www.TheOncologyNurse.com

Please see brief summary of full Prescribing Information, including the Boxed Warning, on last pages.

March 2013 I VOL 6, NO 2

7

ASH Highlights Cyclophosphamide Reduces Risk of GVHD After Transplant

B:17

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 S:6.75” 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

Important Safety Information (Continued)

PharmaGraphics

DISK RELEASE SIGNOFF

DATE

CLIENT: Bayer

PG

BLX_REG_Q23666A_JA_D01.indd

JOB#: 23666A

S&H

Hepatotoxicity: Severe drug-induced liver injury with fatal outcome occurred in 0.3% of 1100 STIVARGA®treated patients across all clinical trials. Liver biopsy results, when available, showed hepatocyte necrosis with lymphocyte infiltration. In Study 1, fatal hepatic failure occurred in 1.6% of patients in the STIVARGA arm and 0.4% of patients in the placebo arm; all the patients with hepatic failure had metastatic disease in the liver.

QC

DESC: A-size journal ad

Liver Function Monitoring: Obtain liver function tests (ALT, AST, and bilirubin) before initiation of STIVARGA and monitor at least every 2 weeks during the first 2 months of treatment. Thereafter, monitor monthly or more frequently as clinically indicated. Monitor liver function tests weekly in patients experiencing elevated liver function tests until improvement to less than 3 times the upper limit of normal (ULN) or baseline values. Temporarily hold and then reduce or permanently discontinue STIVARGA, depending on the severity and persistence of hepatotoxicity as manifested by elevated liver function tests or hepatocellular necrosis.

TC AD

FILE NAME: BLX_REG_Q23666A_JA_D01.indd

Hemorrhage: STIVARGA caused an increased incidence of hemorrhage. The overall incidence (grades 1-5) was 21% in STIVARGA-treated patients compared to 8% in placebo-treated patients in Study 1. Fatal hemorrhage occurred in 4 of 500 (0.8%) STIVARGA-treated patients and involved the respiratory, gastrointestinal, or genitourinary tracts. Permanently discontinue STIVARGA in patients with severe or life-threatening hemorrhage and monitor INR levels more frequently in patients receiving warfarin.

CD CW

DATE: 12-18-2012 2:40 PM

AE/AS ED

Dermatological Toxicity: STIVARGA caused an increased incidence of hand-foot skin reaction (HFSR) (also known as palmar-plantar erythrodysesthesia [PPE]) and rash, frequently requiring dose modification. The overall incidence of HFSR (45% vs 7%) and the incidence of grade 3 HFSR (17% vs 0) were increased in STIVARGAtreated patients compared to placebo-treated patients in Study 1. The overall incidence of rash (26% vs 4%) and the incidence of grade 3 rash (6% vs <1%) were higher in STIVARGA-treated patients in Study 1. Temporarily hold and then reduce or permanently discontinue STIVARGA, depending on the severity and persistence of dermatologic toxicity.

PROD

Galley: 2

ROUND: 1

M Y K

12.18.12 133

Cosmos Communications 718.482.1800

C

23822a1

Hypertension: STIVARGA caused an increased incidence of hypertension (30% of STIVARGA-treated patients vs 8% of placebo-treated patients in Study 1). Hypertensive crisis occurred in 0.18% of 1100 STIVARGA-treated patients across all clinical trials. Do not initiate STIVARGA until blood pressure is adequately controlled.

Monitor blood pressure weekly for the first 6 weeks

of treatment and then every cycle, or more frequently, as clinically indicated. Temporarily or permanently withhold STIVARGA for severe or uncontrolled hypertension.

Cardiac Ischemia and Infarction: STIVARGA increased the incidence of myocardial ischemia and infarction (1.2% for STIVARGA-treated patients vs 0.4% of placebotreated patients). Withhold STIVARGA in patients who develop new or acute cardiac ischemia or infarction, and resume only after resolution of acute cardiac ischemic events if the potential benefits outweigh the risks of further cardiac ischemia.

Reversible Posterior Leukoencephalopathy Syndrome (RPLS): RPLS occurred in 1 of 1100 STIVARGA-treated patients across all clinical trials. Confirm the diagnosis of RPLS with MRI and discontinue STIVARGA in patients who develop RPLS. Gastrointestinal Perforation or Fistula: Gastrointestinal perforation or fistula occurred in 0.6% of 1100 patients treated with STIVARGA across clinical trials.

Permanently discontinue STIVARGA in patients who develop gastrointestinal perforation or fistula.

Wound Healing Complications: Treatment with STIVARGA should be stopped at least 2 weeks prior to scheduled surgery. The decision to resume STIVARGA after surgery should be based on clinical judgment of adequate wound healing. STIVARGA should be discontinued in patients with wound dehiscence.

Embryo-Fetal Toxicity: STIVARGA can cause fetal harm when administered to a pregnant woman. Use effective contraception during treatment and up to 2 months after completion of therapy. If this drug is used during pregnancy, or if the patient becomes pregnant while taking this drug, the patient should be apprised of the potential hazard to the fetus.

Nursing Mothers: Because many drugs are excreted in human milk and because of the potential for serious adverse reactions in nursing infants from STIVARGA, a decision should be made whether to discontinue nursing or discontinue the drug, taking into account the importance of the drug to the mother.

Most Frequently Observed Adverse Drug Reactions in Metastatic Colorectal Cancer (mCRC) (≥30%): The most frequently observed adverse drug reactions (≥30%) in STIVARGA-treated patients vs placebo-treated patients in mCRC, respectively, were: asthenia/fatigue (64% vs 46%), decreased appetite and food intake (47% vs 28%), HFSR/PPE (45% vs 7%), diarrhea (43% vs 17%), mucositis (33% vs 5%), weight loss (32% vs 10%), infection (31% vs 17%), hypertension (30% vs 8%), and dysphonia (30% vs 6%).

Please see brief summary of full Prescribing Information, including the Boxed Warning, on last pages.

Reference: 1. STIVARGA Prescribing Information. Wayne, NJ: Bayer HealthCare Pharmaceuticals Inc.; 2012.

1 ej 2

Q1 Q2

8

March 2013 I VOL 6, NO 2

www.TheOncologyNurse.com

T:15.

.75”

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 S:6.75” acute GVHD occurred in 14% for cyclophosphamide and 0% for the convention-

al 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

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.

23% reduction in the risk of death* Overall survival (OS)1 100

STIVARGA (n=505) Placebo (n=255)

75 Survival Probability (%)

7.5”

ASH Highlights

Hazard ratio, 0.77 (95% CI, 0.64-0.94; P =0.0102)

Median: 6.4 months (95% CI, 5.8-7.3) with STIVARGA vs 5.0 months (95% CI, 4.4-5.8) with placebo

50

25

0 0 Patients at Risk STIVARGA + BSC Placebo + BSC

2

4

6

8

10

12

33 9

7 3

Months From Randomization 452 221

352 150

187 75

93 32

14

The CORRECT trial was an international, multicenter, randomized (2:1), doubleblind, placebo-controlled phase 3 trial in 760 patients with previously treated metastatic colorectal cancer. The major efficacy outcome measure was overall survival.1

*Based on hazard ratio.

• There were 275 deaths out of 505 patients with STIVARGA (55%) vs 157 deaths out of 255 patients with placebo (62%)1 T:10.5”

B:11.5”

S:9.75”

• STIVARGA improved OS in the CORRECT study, which included patients with historically collected KRAS status (n=729)1 — Mutated KRAS = 59%; wild-type KRAS = 41%

Indication STIVARGA is indicated for the treatment of patients with metastatic colorectal cancer (CRC) who have been previously treated with fluoropyrimidine-, oxaliplatin-, and irinotecan-based chemotherapy, an anti-VEGF therapy, and, if KRAS wild-type, an anti-EGFR therapy.

Important Safety Information WARNING: HEPATOTOXICITY Severe and sometimes fatal hepatotoxicity has been observed in clinical trials. Monitor hepatic function prior to and during treatment. Interrupt and then reduce or discontinue STIVARGA for hepatotoxicity as manifested by elevated liver function tests or hepatocellular necrosis, depending upon severity and persistence.

www.STIVARGA-US.com

6 West Belt, Wayne, NJ 07470 USA © 2013 Bayer HealthCare Pharmaceuticals Inc., Wayne, NJ STIVARGA is co-promoted in the USA by Bayer HealthCare Pharmaceuticals and Onyx Pharmaceuticals.

Bayer® and the Bayer Cross® are registered trademarks of Bayer.

900-10-002-12 01/13

www.TheOncologyNurse.com

March 2013 I VOL 6, NO 2

9

ASH Highlights Meta-Analysis Examines Adverse Effects of Rituximab Maintenance in Lymphoma Rituximab has improved outcomes of patients with follicular lymphoma and mantle cell lymphoma. Treatment schedules have varied between a single infusion given every 2 or 3 months to 4 weekly infusions every 6 months, all given for a total of 2 years. This

systematic review and meta-analysis analyzed prospective clinical trials of maintenance therapy to determine rates of grade 3 and 4 toxicities.

The study found that maintenance rituximab given every 6 months as 4 weekly infusions for 2 years was asso-

ciated with fewer grade 3 or 4 toxicities compared with a single infusion every 2 months: 10% versus 28% (P = .035). The study was not able to compare the 3-month infusion schedule to other schedules, owing to the limited number of studies.

Stivarga (regorafenib) tablets, oral initial U.S. approval: 2012 BRIEF SUMMARY oF pREScRIBIng InFoRMAtIon conSULt pAcKAgE InSERt FoR FULL pREScRIBIng InFoRMAtIon WarNiNg: HEPatOtOXiCitY Severe and sometimes fatal hepatotoxicity has been observed in clinical trials. Monitor hepatic function prior to and during treatment. interrupt and then reduce or discontinue Stivarga for hepatotoxicity as manifested by elevated liver function tests or hepatocellular necrosis, depending upon severity and persistence [see Dosage and Administration (2.2), Warnings and Precautions (5.1)].

1 iNDiCatiONS aND USagE Stivarga® is indicated for the treatment of patients with metastatic colorectal cancer (CRC) who have been previously treated with fluoropyrimidine-, oxaliplatin- and irinotecan-based chemotherapy, an anti-VEGF therapy, and, if KRAS wild type, an anti-EGFR therapy.

4 None

CONtraiNDiCatiONS

The safety data described below, except where noted, are derived from a randomized (2:1), double-blind, placebo-controlled trial (Study 1) in which 500 patients (median age 61 years; 61% men) with previously treated metastatic colorectal cancer received Stivarga as a single agent at the dose of 160 mg daily for the first 3 weeks of each 4 week treatment cycle and 253 patients (median age 61 years; 60% men) received placebo. The mean duration of therapy was 12 weeks for patients receiving Stivarga and 8 weeks for patients receiving placebo. Due to adverse reactions, 61% of the patients receiving Stivarga required a dose interruption and 38% of the patients had their dose reduced. Drug-related adverse reactions that resulted in treatment discontinuation were reported in 8.2% of Stivarga-treated patients compared to 1.2% of patients who received placebo. Skin toxicity (HFSR/PPE or rash) was the most common cause of permanent drug discontinuation.

The most frequently observed adverse drug reactions (≥30%) in patients receiving Stivarga are asthenia/ fatigue, decreased appetite and food intake, HFSR/PPE, diarrhea, mucositis, weight loss, infection, hypertension and dysphonia.

The most serious adverse drug reactions in patients receiving Stivarga are hepatotoxicity, hemorrhage, and gastrointestinal perforation.

Table 1 compares the incidence of adverse reactions (≥10%) in patients receiving Stivarga and reported more commonly than in patients receiving placebo (Study 1). table 1: Adverse drug reactions (≥10%) reported in patients treated with Stivarga and reported more commonly than in patients receiving placebo

5 WarNiNgS aND PrECaUtiONS 5.1 Hepatotoxicity Severe drug induced liver injury with fatal outcome occurred in 0.3% of 1100 Stivarga-treated patients across all clinical trials. Liver biopsy results, when available, showed hepatocyte necrosis with lymphocyte infiltration. In Study 1, fatal hepatic failure occurred in 1.6% of patients in the regorafenib arm and 0.4% of patients in the placebo arm; all the patients with hepatic failure had metastatic disease in the liver.

Obtain liver function tests (ALT, AST and bilirubin) before initiation of Stivarga and monitor at least every two weeks during the first 2 months of treatment. Thereafter, monitor monthly or more frequently as clinically indicated. Monitor liver function tests weekly in patients experiencing elevated liver function tests until improvement to less than 3 times the ULN or baseline.

Temporarily hold and then reduce or permanently discontinue Stivarga depending on the severity and persistence of hepatotoxicity as manifested by elevated liver function tests or hepatocellular necrosis [see Dosage and Administration (2.2)].

Stivarga (n=500) adverse reactions

5.2 Hemorrhage Stivarga caused an increased incidence of hemorrhage. The overall incidence (Grades 1-5) was 21% in Stivarga-treated patients compared to 8% in placebo-treated patients in Study 1. Fatal hemorrhage occurred in 4 of 500 (0.8%) of Stivarga-treated patients and involved the respiratory, gastrointestinal, or genitourinary tracts.

Permanently discontinue Stivarga in patients with severe or life-threatening hemorrhage. Monitor INR levels more frequently in patients receiving warfarin [see Clinical Pharmacology (12.3)].

5.3 Dermatological toxicity Stivarga caused an increased incidence of hand-foot skin reaction (HFSR) also known as palmar-plantar erythrodysesthesia (PPE) and rash frequently requiring dose modification. The overall incidence of HFSR (45% versus 7%) and the incidence of Grade 3 HFSR (17% versus 0) were increased in Stivarga-treated patients in Study 1. The overall incidence of rash (26% versus 4%) and the incidence of Grade 3 rash (6% versus <1%) were higher in Stivarga-treated patients in Study 1 [see Adverse Reactions (6.1)]. The onset of dermatologic toxicity occurred in the first cycle of treatment in most patients.

Temporarily hold and then reduce or permanently discontinue Stivarga depending on the severity and persistence of dermatologic toxicity [see Dosage and Administration (2.2)]. Institute supportive measures for symptomatic relief.

5.4 Hypertension Stivarga caused an increased incidence of hypertension (30% of Stivarga-treated patients vs. 8% of placebo-treated patients in Study 1) [see Adverse Reactions (6.1)]. Hypertensive crisis occurred in 0.18% of 1100 Stivarga-treated patients across all clinical trials. The onset of hypertension occurred during the first cycle of treatment in most patients. Do not initiate Stivarga until blood pressure is adequately controlled.

Monitor blood pressure weekly for the first 6 weeks of treatment and then every cycle, or more frequently, as clinically indicated. Temporarily or permanently withhold Stivarga for severe or uncontrolled hypertension [see Dosage and Administration (2.2)].

5.5 Cardiac ischemia and infarction Stivarga increased the incidence of myocardial ischemia and infarction (1.2% for Stivarga-treated patients vs.

0.4% of placebo-treated patients) [see Adverse Reactions (6.1)].

Withhold Stivarga in patients who develop new or acute onset cardiac ischemia or infarction. Resume Stivarga only after resolution of acute cardiac ischemic events if the potential benefits outweigh the risks of further cardiac ischemia.

5.6 reversible Posterior Leukoencephalopathy Syndrome (rPLS) RPLS (also known as posterior reversible encephalopathy syndrome) occurred in one of 1100 Stivargatreated patients across all clinical trials. Confirm the diagnosis of RPLS with MRI and discontinue Stivarga in patients who develop RPLS.

March 2013 I VOL 6, NO 2

grade

grade ≥3 %

all %

≥3 %

general disorders and administration site conditions Asthenia/fatigue Pain Fever

64 29 28

15 3 2

46 21 15

9 2 0

Metabolism and nutrition disorders Decreased appetite and food intake

47

5

28

4

Skin and subcutaneous tissue disorders HFSR/PPE Rash

45 26

17 6

7 4

0 <1

gastrointestinal disorders Diarrhea Mucositis

43 33

8 4

17 5

2 0

investigations Weight loss

32

<1

10

0

infections and infestations Infection

31

9

17

6

vascular disorders Hypertension Hemorrhage*

30 21

8 2

8 8

<1 <1

respiratory, thoracic and mediastinal disorders Dysphonia

30

0

6

0

Nervous system disorders Headache

10

<1

7

0

fatal outcomes observed Other clinically important adverse reactions observed more commonly in less than 10% of Stivarga-treated patients and at a higher incidence than in placebo-treated patients included the following: alopecia (7.6% vs. 1.6%), taste disorder (7.6% vs. 2.4%), musculoskeletal stiffness (6.0% vs. 2.0%), dry mouth (4.8% vs.

2.0%), hypothyroidism (4.2% vs. 0.4%), tremor (2.0% vs. 0.0), gastroesophageal reflux (1.4% vs. 0.0), and gastrointestinal fistula (0.8% vs. 0.4%).

Keratoacanthoma/squamous cell carcinoma of the skin occurred in 0.09% of 1100 Stivarga-treated patients across open-label or placebo-controlled clinical trials. *

Laboratory Abnormalities Laboratory abnormalities observed in Study 1 are shown in Table 2. table 2: Laboratory test abnormalities reported in Study 1 Stivarga plus BSC (n=500*) Laboratory Parameter

5.8 Wound Healing Complications No formal studies of the effect of regorafenib on wound healing have been conducted. Since vascular endothelial growth factor receptor (VEGFR) inhibitors such as regorafenib can impair wound healing, treatment with regorafenib should be stopped at least 2 weeks prior to scheduled surgery. The decision to resume regorafenib after surgery should be based on clinical judgment of adequate wound healing.

Regorafenib should be discontinued in patients with wound dehiscence.

5.9 Embryo-Fetal toxicity Stivarga can cause fetal harm when administered to a pregnant woman. Regorafenib was embryolethal and teratogenic in rats and rabbits at exposures lower than human exposures at the recommended dose, with increased incidences of cardiovascular, genitourinary, and skeletal malformations. If this drug is used during pregnancy, or if the patient becomes pregnant while taking this drug, the patient should be apprised of the potential hazard to a fetus [see Use in Specific Populations (8.1)].

6 aDvErSE rEaCtiONS The following serious adverse reactions are discussed elsewhere in the labeling: • Hepatotoxicity [See Warnings and Precautions (5.1)] • Hemorrhage [See Warnings and Precautions (5.2)] • Dermatological Toxicity [See Warnings and Precautions (5.3)] • Hypertension [See Warnings and Precautions (5.4)] • Cardiac Ischemia and Infarction [See Warnings and Precautions (5.5)] • Reversible Posterior Leukoencephalopathy Syndrome (RPLS) [See Warnings and Precautions (5.6)] • Gastrointestinal Perforation or Fistula [See Warnings and Precautions (5.7)]

10

Placebo (n=253)

all %

5.7 gastrointestinal Perforation or Fistula Gastrointestinal perforation or fistula occurred in 0.6% of 1100 patients treated with Stivarga across clinical trials. Permanently discontinue Stivarga in patients who develop gastrointestinal perforation or fistula.

6.1 Clinical trials Experience Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rate observed in practice.

Toxicities in patients receiving treatment in the front-line setting appeared lower than those treated for relapsed disease, but the difference was not statistically significant.

Toxicities were lower when rituximab was given alone compared with

Placebo plus BSC (n=253*)

all %

grade** 3 %

4 %

all %

grade** 3 %

4 %

Blood and lymphatic system disorders Anemia Thrombocytopenia Neutropenia Lymphopenia

79 41 3 54

5 2 1 9

1 <1 0 0

66 17 0 34

3 <1 0 3

0 0 0 0

Metabolism and nutrition disorders Hypocalcemia Hypokalemia Hyponatremia Hypophosphatemia

59 26 30 57

1 4 7 31

<1 0 1 1

18 8 22 11

1 <1 4 4

0 0 0 0

Hepatobiliary disorders Hyperbilirubinemia Increased AST Increased ALT

45 65 45

10 5 5

3 1 1

17 46 30

5 4 3

3 1 <1

renal and urinary disorders Proteinuria

60

<1

0

34

<1

0

investigations Increased INR *** Increased Lipase Increased Amylase

24 46 26

4 9 2

N/A 2 <1

17 19 17

2 3 2

N/A 2 <1

% based on number of patients with post-baseline samples which may be less than 500 (regorafenib) or 253 (placebo) ** Common Terminology Criteria for Adverse Events (CTCAE), v3.0 *** International normalized ratio: No Grade 4 denoted in CTCAE, v3.0 *

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ASH Highlights 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.

Modified Dosing of Pegaspargase Proposed for ALL Induction In the treatment of adults with newly diagnosed acute lymphoblastic leukemia (ALL), a pharmacokinetic-based intravenous dosing of pegaspargase, rationally synchronized with other chemotherapy drugs in a pediatric-inspired 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.

7 DrUg iNtEraCtiONS 7.1 Effect of Strong CYP3a4 inducers on regorafenib Co-administration of a strong CYP3A4 inducer (rifampin) with a single 160 mg dose of Stivarga decreased the mean exposure of regorafenib, increased the mean exposure of the active metabolite M-5, and resulted in no change in the mean exposure of the active metabolite M-2. Avoid concomitant use of strong CYP3A4 inducers (e.g. rifampin, phenytoin, carbamazepine, phenobarbital, and St. John’s Wort) [see Clinical Pharmacology (12.3)].

8.8 Females and Males of reproductive Potential Contraception Use effective contraception during treatment and up to 2 months after completion of therapy.

7.2 Effect of Strong CYP3a4 inhibitors on regorafenib Co-administration of a strong CYP3A4 inhibitor (ketoconazole) with a single 160 mg dose of Stivarga increased the mean exposure of regorafenib and decreased the mean exposure of the active metabolites M-2 and M-5. Avoid concomitant use of strong inhibitors of CYP3A4 activity (e.g. clarithromycin, grapefruit juice, itraconazole, ketoconazole, posaconazole, telithromycin, and voriconazole) [see Clinical Pharmacology (12.3)].

10 OvErDOSagE The highest dose of Stivarga studied clinically is 220 mg per day. The most frequently observed adverse drug reactions at this dose were dermatological events, dysphonia, diarrhea, mucosal inflammation, dry mouth, decreased appetite, hypertension, and fatigue.

There is no specific antidote for Stivarga overdose. In the event of suspected overdose, interrupt Stivarga, institute supportive care, and observe until clinical stabilization.

8 USE iN SPECiFiC POPULatiONS 8.1 Pregnancy Pregnancy Category D [see Warnings and Precautions (5.9)] Risk Summary Based on its mechanism of action, Stivarga can cause fetal harm when administered to a pregnant woman. There are no adequate and well-controlled studies with Stivarga in pregnant women. Regorafenib was embryolethal and teratogenic in rats and rabbits at exposures lower than human exposures at the recommended dose, with increased incidences of cardiovascular, genitourinary, and skeletal malformations.

If this drug is used during pregnancy or if the patient becomes pregnant while taking this drug, the patient should be apprised of the potential hazard to a fetus.

Animal Data In embryo-fetal development studies, a total loss of pregnancy (100% resorption of litter) was observed in rats at doses as low as 1 mg/kg (approximately 6% of the recommended human dose, based on body surface area) and in rabbits at doses as low as 1.6 mg/kg (approximately 25% of the human exposure at the clinically recommended dose measured by AUC).

In a single dose distribution study in pregnant rats, there was increased penetration of regorafenib across the blood-brain barrier in fetuses compared to dams. In a repeat dose study with daily administration of regorafenib to pregnant rats during organogenesis, findings included delayed ossification in fetuses at doses > 0.8 mg/kg (approximately 5% of the recommended human dose based on body surface area) with dose-dependent increases in skeletal malformations including cleft palate and enlarged fontanelle at doses ≥ 1 mg/kg (approximately 10% of the clinical exposure based on AUC). At doses ≥ 1.6 mg/ kg (approximately 11% of the recommended human dose based on body surface area), there were dose-dependent increases in the incidence of cardiovascular malformations, external abnormalities, diaphragmatic hernia, and dilation of the renal pelvis.

In pregnant rabbits administered regorafenib daily during organogenesis, there were findings of ventricular septal defects evident at the lowest tested dose of 0.4 mg/kg (approximately 7% of the AUC in patients at the recommended dose). At doses of ≥ 0.8 mg/kg (approximately 15% of the human exposure at the recommended human dose based on AUC), administration of regorafenib resulted in dosedependent increases in the incidence of additional cardiovascular malformations and skeletal anomalies as well as significant adverse effects on the urinary system including missing kidney/ureter; small, deformed and malpositioned kidney; and hydronephrosis. The proportion of viable fetuses that were male decreased with increasing dose in two rabbit embryo-fetal toxicity studies.

8.3 Nursing Mothers It is unknown whether regorafenib or its metabolites are excreted in human milk. In rats, regorafenib and its metabolites are excreted in milk. Because many drugs are excreted in human milk and because of the potential for serious adverse reactions in nursing infants from Stivarga, a decision should be made whether to discontinue nursing or discontinue the drug, taking into account the importance of the drug to the mother.

8.4 Pediatric Use The safety and efficacy of Stivarga in pediatric patients less than 18 years of age have not been established.

In 28-day repeat dose studies in rats there were dose-dependent findings of dentin alteration and angiectasis. These findings were observed at regorafenib doses as low as 4 mg/kg (approximately 25% of the AUC in humans at the recommended dose). In 13-week repeat dose studies in dogs there were similar findings of dentin alteration at doses as low as 20 mg/kg (approximately 43% of the AUC in humans at the recommended dose). Administration of regorafenib in these animals also led to persistent growth and thickening of the femoral epiphyseal growth plate.

8.5 geriatric Use Of the total number of subjects in clinical studies of Stivarga, 39% were 65 and over, while 8% were 75 and over. No overall differences in safety or efficacy were observed between these patients and younger patients.

8.6 Hepatic impairment No clinically important differences in the mean exposure of regorafenib or the active metabolites M-2 and M-5 were observed in patients with hepatocellular carcinoma and mild (Child-Pugh A) or moderate (Child-Pugh B) hepatic impairment compared to patients with normal hepatic function [see Clinical Pharmacology (12.3)]. No dose adjustment is recommended in patients with mild or moderate hepatic impairment. Closely monitor patients with hepatic impairment for adverse reactions [see Warnings and Precautions (5.1)].

Stivarga is not recommended for use in patients with severe hepatic impairment (Child-Pugh Class C) as it has not been studied in this population.

8.7 renal impairment No clinically relevant differences in the mean exposure of regorafenib and the active metabolites M-2 and M-5 were observed in patients with mild renal impairment (CLcr 60-89 mL/min/1.73m2) compared to patients with normal renal function following regorafenib 160 mg daily for 21 days [see Clinical Pharmacology (12.3)]. No dose adjustment is recommended for patients with mild renal impairment.

Limited pharmacokinetic data are available from patients with moderate renal impairment (CLcr 30-59 mL/min/1.73m2). Stivarga has not been studied in patients with severe renal impairment or end-stage renal disease.

Infertility There are no data on the effect of Stivarga on human fertility. Results from animal studies indicate that regorafenib can impair male and female fertility [see Nonclinical Toxicology (13.1)].

13 NONCLiNiCaL tOXiCOLOgY 13.1 Carcinogenesis, Mutagenesis, impairment of Fertility Studies examining the carcinogenic potential of regorafenib have not been conducted. Regorafenib itself did not demonstrate genotoxicity in in vitro or in vivo assays; however, a major human active metabolite of regorafenib, (M-2), was positive for clastogenicity, causing chromosome aberration in Chinese hamster V79 cells.

Dedicated studies to examine the effects of regorafenib on fertility have not been conducted; however, there were histological findings of tubular atrophy and degeneration in the testes, atrophy in the seminal vesicle, and cellular debris and oligospermia in the epididymides in male rats at doses similar to those in human at the clinical recommended dose based on AUC. In female rats, there were increased findings of necrotic corpora lutea in the ovaries at the same exposures. There were similar findings in dogs of both sexes in repeat dose studies at exposures approximately 83% of the human exposure at the recommended human dose based on AUC. These findings suggest that regorafenib may adversely affect fertility in humans.

13.2 animal toxicology and/or Pharmacology In a chronic 26 week repeat dose study in rats there was a dose-dependent increase in the finding of thickening of the atrioventricular valve. At a dose that resulted in an exposure of approximately 12% of the human exposure at the recommended dose, this finding was present in half of the examined animals.

17 PatiENt COUNSELiNg iNFOrMatiON See FDA-Approved Patient Labeling (Patient Information). inform your patients of the following: • Stivarga may cause severe or life-threatening liver damage. Inform patients that they will need to undergo monitoring for liver damage and to immediately report any signs or symptoms of severe liver damage to their health care provider.

• Stivarga can cause severe bleeding. Advise patients to contact their health care provider for any episode of bleeding.

• Stivarga can cause hand-foot skin reactions or rash elsewhere. Advise patients to contact their health care provider if they experience skin changes associated with redness, pain, blisters, bleeding, or swelling.

• Stivarga can cause or exacerbate existing hypertension. Advise patients they will need to undergo blood pressure monitoring and to contact their health care provider if blood pressure is elevated or if symptoms from hypertension occur including severe headache, lightheadedness, or neurologic symptoms.

• Stivarga increased the risk for myocardial ischemia and infarction. Advise patients to seek immediate emergency help if they experience chest pain, shortness of breath, or feel dizzy or like passing out.

• Contact a healthcare provider immediately if they experience severe pains in their abdomen, persistent swelling of the abdomen, high fever, chills, nausea, vomiting, severe diarrhea (frequent or loose bowel movements), or dehydration.

• Stivarga may complicate wound healing. Advise patients to inform their health care provider if they plan to undergo a surgical procedure or had recent surgery.

• Inform patients that regorafenib can cause fetal harm. Advise women of reproductive potential and men of the need for effective contraception during Stivarga treatment and for up to 2 months after completion of treatment. Instruct women of reproductive potential to immediately contact her health care provider if pregnancy is suspected or confirmed during or within 2 months of completing treatment with Stivarga.

• Advise nursing mothers that it is not known whether regorafenib is present in breast milk and discuss whether to discontinue nursing or to discontinue regorafenib.

• Inform patients to take any missed dose on the same day, as soon as they remember, and that they must not take two doses on the same day to make up for a dose missed on the previous day.

• Inform patients to store medicine in the original container. Do not place medication in daily or weekly pill boxes. Any remaining tablets should be discarded 28 days after opening the bottle. Tightly close bottle after each opening and keep the desiccant in the bottle.

Manufactured in Germany Distributed and marketed by:

Bayer HealthCare Pharmaceuticals Inc., Wayne, NJ 07470 © 2012 Bayer HealthCare Pharmaceuticals Inc. Issued: 09/2012 6708300BS

“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 PEG-ASP at 2-week intervals, the researchers reduced the dose to 2000 IU/m2 at intervals no shorter than 4 weeks.

“Recently, several adult ALL protocols adopted pediatric regimens.”

Dan Douer, MD

They also synchronized the PEG-ASP 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 FDA-approved 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.TheOncologyNurse.com

March 2013 I VOL 6, NO 2

11

ASH HIGHLGHTS 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 injection 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.

12

March 2013 I VOL 6, NO 2

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 decisions,

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 signifi-

cantly 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... Continued from cover 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 retrospective 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.

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 inhibitor-associated 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.

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

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

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

Cancer Center Profile

New York-Presbyterian Hospital... Continued from cover Can you tell me about how PAs were incorporated into oncology departments at your institution?

Jeremy Heinerich (JH): I was hired in 2006 as the first PA to specialize in oncology at New York-Presbyterian/ Weill Cornell inpatient unit. My role was to help organize a busy leukemia service with increasing numbers of patients and a need for more continuity of care.

The interns/residents and attending physicians in the service rotated every 2 weeks, so the new ones who came in were unfamiliar with the patients. My job was to be a focused presence for the oncologic aspects of care. In a relatively short period of time, the benefits of having a PA in the leukemia service were evident, and a second PA was hired.

The patient volume increased, while the length of stay and throughput decreased.

PAs educated interns and residents about issues that included the effects of chemotherapy and early warning signs of problems in oncology inpatients. We also performed procedures that included bone marrow biopsy and lumbar puncture, thus freeing up the attending to focus on other aspects of care.

Over the following years, the number of PAs specializing in oncology has expanded at our center. Currently we have 45 PAs (33 full-time and 12 on a per diem basis) working the night shift, the bone marrow transplant service, the leukemia service, and the lymphoma service. In general, a PA will see from 8 to 10 patients per day. There are additional PAs working on other inpatient as well as outpatient oncology services at Weill Cornell.

We continue to evolve and expand the service to accommodate the growing number of patients, and now we have sick days, vacation days, and maternity leave incorporated into our algorithm to ensure a smooth functioning service.

What exactly is the role of a PA in oncology?

JH: We are an extension of the physician. We see inpatients on the floor.

We do pre-rounding and collect data on patients so we can present that to the attending physician. We update the attending on patient status, we do admissions and discharge, and we can write prescriptions for drugs. We also follow up on the recommendations of the attending physician.

How does having PAs focused on oncology care improve outcomes for patients?

JH: A PA is a consistent presence for the patient. We get to know patients well and also know them from repeated admissions. We develop a bond with the patient and family. We know what needs

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to be done for a particular patient on a specific treatment regimen, and we can schedule appropriate follow-up appointments in a timely way, streamlining the process of care. PAs are readily available on the floor for nurses who need help.

the past 45 years. We are able to fill gaps where there are shortages of physician providers, and help fill a niche market in specialty areas. Hospitals have incorporated PAs into many resident services so that residents would

A PA is a consistent presence for the patient....We develop a bond with the patient and family.

Jeremy Heinerich, PA-C

Is the use of PAs in oncology care a trend in the United States?

JH: Yes, you will see this at many of the academic cancer centers, including Memorial Sloan-Kettering Cancer Center, Fred Hutchinson Cancer Center, H. Lee Moffitt Cancer Center, and others.

be compliant with work hours and could focus on education.

What inspired you to become a PA? JH: I was drawn to the medical profession from a young age, because I wanted to help people. Originally I was planning to go to medical school, but that didn’t happen for a variety of How has the role of the PA evolved reasons. Then I found out about the PA over the years? profession, and it was the best choice I JH: The first class of PAs graduated could have made. It’s a great profession from Duke University in 1968. The PA with a lot of flexibility. I can change my profession has grown exponentially over specialty if I 4:32 wantPM to and get WCMC_2013Conf_horizontalV491212_Layout 1 9/13/12 Page 2 on-the-job

training, and also I can adjust my work schedule based on my personal needs.

What advice would you give to a PA just starting out?

JH: I would say not to take the first job you get offered. Find something that interests you as a potential career path. Also, keep an open mind, and be willing to put in hard work. New PAs who work in oncology should be aware of the Association of Physician Assistants in Oncology (APAO), an organization about 19 years old that has now evolved into a large network.

We have increased membership and visibility for the organization, as well as increased opportunities in oncology.

It is a great networking organization.

I was president in 2007. The website is www.apao.cc. APAO has an annual conference, which is highly attended.

If you weren’t a PA, what would you be doing?

JH: Well, my job is emotionally draining at the same time that it is very rewarding. For diversion and for balance, I seek out entertainment—shows, museums, concerts. I would probably be in the entertainment industry. l

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 March 2013 I VOL 6, NO 2

13

Side Effects Management

Predicting Risk of Significant Side Effects With OnPART

By Alice Goodman

O

nPART can predict 6 common cancer. In the larger study, OnPART side effects of dose-dense doxo- was able to predict the same 6 side rubicin plus cyclophosphamide effects with greater than 92% accuraplus paclitaxel chemotherapy in patients cy in patients receiving dose-dense 5with breast cancer with a high degree fluorouracil and oxaliplatin regimens for of accuracy, according to the results colorectal cancer, and in patients receivof a study presented at the CTRC- ing carboplatin plus paclitaxel-based AACR San Antonio Breast Cancer regimens for lung and ovarian cancer.

Symposium. The 78 patients with breast OnPART utilizes Bayesian networks to cancer were part of a larger study of identify single nucleotide polymorphisms 384COEAsizeCE_fish_71112_House patients that also included patients (SNPs) Ad 7/11/12 11:47 AM Page 1from the DNA of patients’ saliva with colorectal, ovarian, and lung samples that identify whether the patients

FREE

are at risk for the following 6 common side effects of dose-dense chemotherapy: oral mucositis, nausea and vomiting, diarrhea, fatigue, cognitive dysfunction, and peripheral neuropathy. OnPART is a personalized medicine product from Inform Genomics, Inc. “We can now identify patients at risk for 6 common side effects before they ever receive chemotherapy,” said lead author Lee Schwartzberg, MD, senior partner and medical director of the

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

West Clinic in Memphis, Tennessee.

“This allows us to customize our chemotherapy regimens and side-effect-control interventions in a patient-centered care paradigm. These side effects can impair function, create inefficiencies in medical practice, and are costly to patients and payers. We look forward to working with Inform Genomics to help bring this novel product to the market as quickly as possible.”

The rationale for this study was based on the hypothesis that the genetic impact on the risk of side effects depends on “teams” of genes working synergistically, Schwartzberg explained.

The study focused on 78 patients with breast cancer treated with at least 3 cycles of dose-dense doxorubicin plus cyclophosphamide plus paclitaxel chemotherapy. Subjects provided a saliva sample using a DNA Genotek collection tube. SNP expression was determined using microarray technology.

Patients received support care with each chemotherapy cycle. The Patient Care Monitor, a validated patient-reported symptom assessment tool, was used to measure the frequency and severity of the 6 side effects. Those rated ≥4 were considered to be significant. Bayesian methodological programming developed predictive SNP networks for each of the 6 side effects.

Based on the literature, the incidence of moderate-to-severe toxicity for all 6 side effects was higher than expected. Significant fatigue, oral mucositis, and nausea and vomiting were reported in 25% of patients who reported side effects, despite the fact that the patients received recommended antiemetic supportive care prior to treatment. SNPbased Bayesian networks were highly predictive for each side effect of interest.

The accuracy ranged from 92% for predicting nausea and vomiting to 100% for predicting cognitive dysfunction and peripheral neuropathy.

The study showed that, despite current supportive care options, the risk of side effects from common chemotherapy is significant. Previously, no method existed to predict which patients are at risk for these side effects from widely used chemotherapy regimens. The ability to identify prospectively the risk of side effects can lead to modifications in treatment regimens and aggressiveness of care. l Reference

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March 2013 I VOL 6, NO 2

Schwartzberg LS, Sonis ST, Walker MS, et al. Single nucleotide polymorphism (SNP) Bayesian networks (BNs) predict risk of chemotherapy-induced side effects in patients with breast cancer receiving dose dense (DD) doxorubicin/cyclophosphamide plus paclitaxel (AC+T).

Presented at: 2012 CTRC-AACR San Antonio Breast Cancer Symposium; December 4-8, 2012; San Antonio, TX. Poster P1-15-12.

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Side Effects Management

Monitor Adverse Events Early With Regorafenib, Especially After Initiation

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 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 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

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through cycle 6. The rates of fatigue and fatigue and HFSR, and then over time HFSR diminished further in cycles 7 and 8. these side effects decreased in incidence The incidences of hypertension and but also in severity,” he said. rash/desquamation were highest in cycle On average, the dose intensity was 1, at 20% to 25%, “and tapered to low highest in cycle 1 and reached a lower, or no incidence over cycles 2 to 8,” relatively stable dose by cycle 3. said Grothey. The incidence 1of3/14/13 diarrhea AONN_Filler7x10_31413_Layout 11:10 AMBecause Page 1 it works by blocking multiple remained relatively constant from cycles protein kinases, identifying the actions 1 to 6, but was lower in cycles 7 and 8. of regorafenib that contribute to toxicity “The time course suggested an initial and efficacy is difficult, said Grothey. flare up of key side effects, in particular “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

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.

Fourth Annual Navigation and Survivorship Conference Memphis, Tennessee • The Peabody Memphis

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

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Conference News: ASH Continued from cover

Ibrutinib Encouraging in CLL According to expert opinion, ibrutinib is one of the most important treatments to emerge in the past 3 decades. This investigational agent has the promise to change the natural history of chronic lymphocytic leukemia (CLL) and lymphomas, if the results of several phase 2 trials are confirmed in the phase 3 studies currently in progress.

Ibrutinib, an investigational Bruton’s tyrosine kinase (BTK) inhibitor, achieved excellent results in clinical trials of patients with CLL, indolent non-Hodgkin lymphoma, and mantle cell lymphoma (MCL).

“Rarely does a drug come along that helps patients this much. This drug is highly effective and very well tolerated.

We are looking forward to Pharmacyclics bringing this drug forward. The quicker we get this drug across the finish line, the better,” stated John C. Byrd, MD, the D. Warren Brown Chair of Leukemia Research and director of the Division of Hematology at the Ohio State University Comprehensive Cancer Center in Columbus.

Byrd presented the results of a phase 2 trial of 116 patients with CLL/small lymphocytic leukemia (SLL) including elderly treatment-naive, relapsed/refractory, and high-risk relapsed/refractory patients.1 At 26 months, single-agent ibrutinib achieved excellent progression-free survival (PFS) both in elderly treatment-naive individuals (estimated PFS, 96%) and in those with relapsed/ refractory high-risk CLL/SLL (estimated PFS, 75%).

Ibrutinib is also being studied in combination with rituximab in CLL and lymphoma. A separate phase 2 study in 40 patients with high-risk CLL treated with the combination of ibrutinib plus rituximab achieved an overall response rate of 83% and no evidence of disease progression in 38 of 40 patients, who are continuing on therapy.2 “These patients typically have inferior outcomes compared with low- and intermediate-risk patients,” stated Jan Burger, MD, PhD, lead author of this phase 2 trial and associate professor at the University of Texas MD Anderson Cancer Center in Houston. “This study shows profound activity for this combination in high-risk patients with CLL. The overall response rate is favorable compared with standard treatment, and the toxicity compares favorably to other treatment options.”

Interim results of an international phase 2 study of ibrutinib in relapsed/refractory MCL were extremely positive, according to another presentation at the 54th ASH annual meeting by Michael Wang, MD, also of the MD Anderson Cancer Center.3 The phase 2 study enrolled 115 patients (65 bortezomib naive and 50 bortez-

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March 2013 I VOL 6, NO 2

omib exposed) with relapsed/refractory MCL. In these difficult-to-treat patients, ibrutinib achieved an overall response rate of 70% and a complete response rate of 20%, which increased to 50% at 14 months.

by Wyndham Wilson, MD, PhD, of the National Cancer Institute in Bethesda, Maryland, showed that ibrutinib achieved an overall response rate of about 28% in 70 patients with relapsed diffuse large B-cell lymphoma

Ibrutinib, an investigational Bruton’s tyrosine kinase inhibitor, achieved excellent results in clinical trials of patients with chronic lymphocytic leukemia, indolent non-Hodgkin lymphoma, and mantle cell lymphoma.

“With other molecular compounds, response rates in this group of patients are about 30% and progression-free survival is about 6 months. The difference between ibrutinib and other molecular compounds is outrageous,” stated an expert not involved in these studies, Martin Dreyling, MD, of the University of Munich, Germany.

A separate study presented at ASH

(DLBCL).4 However, when patients were stratified according to genetic expression, response rates in activated B-cell (ABC)-like DLBCL were 40% (this group has the worst prognosis) and in germinal center B-cell–like DLBCL were 5.3%.

These results in the ABC subgroup of patients with relapsed DLBCL are considered unprecedented. Wilson and his coin-

vestigators concluded that future clinical trials of ibrutinib in DLBCL should be confined to the ABC subtype.

References

1. Byrd JC, Furman RR, Coutre S, et al. The Bruton’s tyrosine kinase (BTK) inhibitor ibrutinib (PCI-32765) promotes high response rate, durable remissions, and is tolerable in treatment naïve (TN) and relapsed or refractory (RR) chronic lymphocytic leukemia (CLL) or small lymphocytic lymphoma (SLL) patients including patients with high-risk (HR) disease: new and updated results of 116 patients in a phase Ib/II study. Presented at: 54th American Society of Hematology Annual Meeting; December 8-11, 2012; Atlanta, GA. Abstract 189.

2. Burger JA, Keating MJ, Wierda WG, et al. The Btk inhibitor ibrutinib (PCI-32765) in combination with rituximab is well tolerated and displays profound activity in high-risk chronic lymphocytic leukemia (CLL) patients.

Presented at: 54th American Society of Hematology Annual Meeting; December 8-11, 2012; Atlanta, GA. Abstract 187.

3. Wang M, Rule SA, Martin P, et al. Interim results of an international, multicenter, phase 2 study of Bruton’s tyrosine kinase (BTK) inhibitor, ibrutinib (PCI-32765), in relapsed or refractory mantle cell lymphoma (MCL): durable efficacy and tolerability with longer follow-up.

Presented at: 54th American Society of Hematology Annual Meeting; December 8-11, 2012; Atlanta, GA. Abstract 904.

4. Wilson WH, Gerecitano JF, Goy A, et al. The Bruton’s tyrosine kinase (BTK) inhibitor, ibrutinib (PCI32765), has preferential activity in the ABC subtype of relapsed/refractory de novo diffuse large B-cell lymphoma (DLBCL): interim results of a multicenter, open-label, phase 2 study. Presented at: 54th American Society of Hematology Annual Meeting; December 8-11, 2012; Atlanta, GA. Abstract 686.

Daunorubicin-Free Regimen Effective A study presented at the 54th ASH annual meeting minimize their risk of experiencing cardiac damage showed that daunorubicin could be safely omitted from later in life.” an induction regimen without compromising survival in The FRALLE 2000-A study, conducted at 20 centers in children with standard-risk acute lymphocytic leukemia France and 1 center in Belgium, randomized 1128 pediatric (ALL). Daunorubicin is already omitted in this setting patients with standard-risk B-cell ALL to 2 treatment arms: at many cancer centers in the United States and Europe, arm A (n = 560) received standard-dose daunorubicin but until now there has been little evidence to support during induction therapy, and arm B (n = 568) did not. this practice. The French Acute Lymphoblastic Leukemia The induction regimen included vincristine, dexameth(FRALLE) 2000-A study is the first randomized controlled asone, and asparaginase. Patients received doxorubicin trial in the modern era to provide scientific evidence to during delayed intensification (ie, the last treatment phase support daunorubicin-free induction therapy. before maintenance therapy) and standard 24-month The current cure rate for standard-risk ALL in pedi- maintenance therapy from December 2000 through June atric patients is 90%. For many 2010. Five-year event-free survival years, daunorubicin—an anthra(EFS) and overall survival (OS) were cycline that is associated with evaluated during that period.

The current cure myelosuppression and potential Standard-risk ALL of the B-cell linrate for standard-risk long-term cardiac damage—was eage was defined as children between part of the induction protocol.

1 and 10 years of age and white blood acute lymphocytic However, this practice was based cell count <50 g/L. Five-year EFS was leukemia in pediatric on only 3 studies that were more 92.9% in arm A and 93.3% in arm B. than 20 years old.

OS rates were 97.2% for arm A and patients is 90%.

An anthracycline-free induc98.2% for arm B. The amount of minition regimen can achieve the mal residual disease (MRD) was similar same positive outcomes without in both arms: MRD ≥1% was observed putting children at risk for both myelosuppression in 1.8% of arm A and in 1.9% of arm B; MRD ≥0.1% was and cardiac toxicities associated with daunorubicin, seen in 6.5% and 9.3%, respectively. The rates of cumulative said lead author Andre Baruchel, MD, head of the incidence of relapse and site of relapse were also similar in Department of Pediatric Hematology at the Robert both arms.

Debré University Hospital in Paris, France. “These “These results show similar efficacy rates in children data can potentially benefit children with ALL in 2 with standard-risk ALL for induction regimens with and important ways. First, we now have strong evidence without daunorubicin,” Baruchel emphasized. that reducing the amount of chemotherapy initially administered to these children with standard-risk ALL Reference [the majority of ALL patients] does not have a nega- Baruchel A, Petit A, Leblanc T, et al. Daunorubicin or not during the inductreatment of childhood standard-risk B-cell precursor acute lymphoblastic tive effect on their immediate outcome. Perhaps more tion leukemia (SR-BCP-ALL): the randomized Fralle 2000-A protocol. Presented at: importantly, we know and anticipate that removing 54th American Society of Hematology Annual Meeting; December 8-11, 2012; harmful chemotherapy from their treatment can help Atlanta, GA. Abstract 135.

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Conference News: ASH Bendamustine-Rituximab for Lymphoma For many years, rituximab-CHOP (the combination of rituximab plus cyclophosphamide, doxorubicin, vincristine, and prednisone, also known as R-CHOP) has been considered the treatment of choice for indolent lymphoma. Following on the heels of several positive studies, the combination of bendamustine-rituximab is gaining favor in Europe and the United States as a replacement for the more toxic R-CHOP regimen.

Some experts in the United States agreed that bendamustinebased therapy is poised to replace R-CHOP for the treatment of lymphoma, based on promising progressionfree survival data reported last year in the StiL trial.

sive lymphoma. Knauf presented data on 645 patients with indolent lymphoma at the 54th ASH annual meeting.

In terms of second-line therapy, Knauf said that bendamustine is now used more often than CHOP. Of 121 patients treated with second-line therapy, rituximab was used in 102 patients, bendamustine was used in 82 patients, and the combina-

See page 19 for details. www.TheOncologyNurse.com

Reference

Knauf WU, Abenhardt W, Nusch A, et al.

Bendamustine-rituximab (BR) replaces R-CHOP as “standard of care” in the treatment of indolent non-Hodgkin lymphoma in German hematology outpatient centres. Presented at: 54th American Society of Hematology Annual Meeting; December 8-11, 2012; Atlanta, GA. Poster 3666.

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R-CHOP will continue to have a role in select patients, they predicted.

Before

A poster presentation showed that in Germany, R-CHOP accounted for 16% of patients with indolent lymphoma, while bendamustine was included in first-line therapy in 71% of patients, according to lead author Wolfgang Knauf, MD, professor of hematology at Onkologische Gemeinschaftspraxis, Frankfurt, Germany. Rituximab was included as first-line therapy in 94% of patients, and it was combined with bendamustine in 66% of patients.

“R-CHOP is dead. The registry data we present is a description of what is happening in Germany,” Knauf said.

The registry is in the process of recruiting 1000 patients with indolent lymphoma, 1000 with chronic myelogenous leukemia, and 1000 with aggres-

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tion was used in 72 patients. By contrast, R-CHOP was used in 9 patients.

Some experts in the United States agreed that bendamustine-based therapy is poised to replace R-CHOP for the treatment of lymphoma, based on promising progression-free survival data reported last year in the Study Group on Indolent Lymphomas (StiL) trial. However,

3/19/13 9:44 AM

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Conference News: ASH MLN9708 May Revolutionize Treatment of Multiple Myeloma An investigational oral proteasome inhibitor known as MLN9708 had such promising results in phase 1 and 2 trials that it is currently in phase 3 testing. If results are positive, the drug is expected to be approved as soon as 2014.

MLN9708 is an oral drug taken once weekly, and will be an alternative to bortezomib, the first protea-

some inhibitor developed for multiple myeloma. Bortezomib is administered by intravenous infusion or subcutaneous injection. MLN9708 appears to have a more favorable adverse-effect profile than bortezomib; specifically, peripheral neuropathy has been greatly reduced with the oral agent in trials thus far.

GBC2013Asize20813_Layout 1 2/8/13 11:12 AM Page 1

To put this into context, bortezomib given intravenously twice weekly has been associated with peripheral neuropathy in 30% to 40% of patients, compared with rates of about 10% to 15% for MLN9708 in preliminary trials.

Shaji Kumar, MD, of the Mayo Clinic, Rochester, Minnesota, presented results of the phase 1/2 trial at the 54th ASH

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annual meeting after a median of 6 cycles of therapy.

The study had 2 parts. Phase 1 enrolled 15 patients and established 4 mg orally once weekly as the maximum tolerated dose of the investigational agent. Phase 2 included 55 patients with newly diagnosed multiple myeloma. MLN9708 4 mg was given on days 1, 8, and 15, in combination with lenalidomide 25 mg once daily on days 1 to 21 and dexamethasone 40 mg on days 1, 8, 15, and 22.

Twenty patients went on to attempt stem-cell harvesting for transplant. The other 30 remained on therapy at the time of ASH.

MLN9708 had such promising results in phase 1 and 2 trials that it is currently in phase 3 testing. If results are positive, the drug is expected to be approved as soon as 2014.

!

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

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3:00 pm - 7:00 pm

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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

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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

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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

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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

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.

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.

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

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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)

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â&#x20AC;˘ Closing Remarks

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.

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Reference

PMPMERSONALIZED EDICINE IN ONCOLOGY O

www.globalbiomarkersconsortium.com

Minor adverse events were reported in 40% of patients, including fatigue, nausea, and rash. Seven patients discontinued treatment due to adverse events.

The major serious adverse events of grade 3 or higher were gastrointestinal upset and skin rash (about 5% of patients for each adverse event). Two grade 4 events occurred: end-stage renal disease in 1 patient, which was attributed to the disease itself, and deep vein thrombosis in 1 patient.

One patient died from pneumonia.

Mild grade 1 neuropathy occurred in 8.45%, and grade 3 neuropathy developed in only 2.07%.

The overall response rate was 92%; 55% had very good partial response and 23% had complete response.

Longer treatment increased the depth of response. For those patients who finished 12 cycles of therapy, the complete response rate increased to 67%, while 33% had very good partial response.

Kumar SK, Berdeja JG, Niesvizky R, et al. A phase 1/2 study of weekly MLN9708, an investigational oral proteasome inhibitor, in combination with lenalidomide and dexamethasone in patients with previously untreated multiple myeloma (MM). Presented at: 54th American Society of Hematology Annual Meeting; December 8-11, 2012; Atlanta, GA. Abstract 332.

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Conference News: ASH Apixaban Reduced Thromboembolic Events In the randomized, placebo-controlled Apixaban After the Initial Management of Pulmonary Embolism and Deep Vein Thrombosis With FirstLine Therapy–Extended Treatment (AMPLIFY-EXT) trial, oral apixaban taken for another year after a standard course of treatment for venous thromboembolism (VTE) reduced the risk of fatal and nonfatal recurrent VTE without increasing the risk of major bleeding. Extended treatment with oral apixaban was associated with death or recurrent VTE in about 4% of patients who received either 2.5-mg or 5-mg doses of the drug, compared with 12% in the group assigned to placebo.

“Both doses of anticoagulant reduced the risk of recurrent fatal or nonfatal VTE by about 80%, and the rates of major bleeding on apixaban were low and comparable to those in the placebo group.

The number of patients needed to treat [NNT] to prevent 1 episode of recurrent or nonfatal VTE is only 14, while the NNT to cause 1 episode of major or clinically relevant nonmajor bleeding is 200,” stated lead author Giancarlo Agnelli, MD, of the University of Perugia, Italy.

Warfarin is standard treatment for VTE, and after patients discontinue warfarin the risk of recurrent VTE ranges from 6% to 10% in patients without reversible risk factors, he explained.

Apixaban is a new oral Xa inhibitor that is rapidly absorbed, with the kidney

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excreting about 25%. Unlike warfarin, no monitoring is necessary with apixaban.

In the AMPLIFY-EXT trial, patients with deep vein thrombosis or VTE treated for 6 to 12 months with anticoagulant therapy were randomized to receive either apixaban 2.5 mg or 5 mg twice daily versus placebo. Patients were treated for 12 additional months, and safety was assessed at 30 days after treatment initiation.

Recurrence of VTE or all-cause death was 3.8% for the 2.5-mg dose of apixaban, 4.2% for the 5-mg dose, and 11.6% for placebo, for a risk reduction of 65%.

Recurrent VTE or VTE-related deaths

were 1.7%, 1.7%, and 8.8% for the 2.5-mg dose, the 5-mg dose, and placebo, respectively. Myocardial infarction, stroke, or cardiovascular-related deaths were reported in 2.1%, 2.3%, and 10%, respectively.

The rates of major bleeding were 0.2% for the 2.5-mg dose, 0.1% for the 5-mg dose, and 0.5% for placebo. The rates of clinically relevant nonmajor bleeding were 3%, 4.2%, and 2.3%, respectively.

Agnelli said the optimal treatment duration for apixaban has not yet been determined. In the AMPLIFY-EXT trial, patients were treated for 1 year and achieved risk reduction in recur-

rent VTE without an increase in major bleeding, but further study of a longer treatment duration would be needed to establish a benefit.

Going forward, the 2.5-mg dose will be preferred, because the 5-mg dose did not provide further benefit. Apixaban will be reviewed by the US Food and Drug Administration in the future. l Reference

Agnelli G, Buller HR, Cohen A, et al. Two doses of apixaban for the extended treatment of venous thromboembolism. Presented at: 54th American Society of Hematology Annual Meeting; December 8-11, 2012; Atlanta, GA. Abstract LBA-1.

Pharmacokinetics/Pharmacodynamics

Branded Versus Generic Enoxaparin: Biological Activity May Differ

By Caroline Helwick

W

hile branded and generic enoxaparin share many traditional characteristics of low-molecular-weight heparins (LMWHs), they differ in several parameters that are relevant to an antithrombotic effect, according to researchers from Loyola University Medical Center, Maywood, Illinois, who presented their findings at the 54th Annual Meeting of the American Society of Hematology.

“While the traditional characteristics of average molecular weight, anti-FXa, and anti-FIIa potencies were not dissimilar for the generic and branded enoxaparins, other activities of this complex biological drug differed,” Jeanine Walenga, PhD, said.

LMWHs are anticoagulants whose heterogeneity in saccharide chain length and in the composition (sulfate, acetyl), content, and location of functional groups can impact their multiple biological activities. This study was conducted to compare the activity profile of the most widely used LMWH, branded enoxaparin (Lovenox), and the first United States–approved generic enoxaparin (Sandoz US).

Five batches each of branded and generic enoxaparin were studied in parallel. In addition to the anti-factor Xa (FXa) and anti-FIIa potencies, a battery of assays relevant to the antithrombotic activity of LMWHs was employed, covering molecular weight profiling, in vitro activities, and ex vivo pharmacodynamic responses. The concentration response of each batch of branded or generic drug was determined with blood from the same donor. Prefilled syringes containing 40 mg of enoxaparin were purchased through hospital pharmacies.

Similarities and Differences Observed No significant differences were seen in the average molecular weight between branded and generic enoxaparins.

However, both in vitro and in vivo/ex vivo activity differences were found in several parameters known to be relevant to the antithrombotic effect of LMWH, in particular, thrombin generation inhibition and tissue factor pathway inhibitor (TFPI) release, Walenga reported.

The investigations also demonstrated a wider variation in anticoagulant response to generic enoxaparin in

comparison to branded enoxaparin. This variation was due to the response of the individual subject as well as to the batch of the product, she said. Differences appear to be more related to activities associated with the anti-FIIa (higher molecular weight) component of the LMWH. The investigators summarized the main differences between branded and generic enoxaparin: • In vitro investigations Anti-FXa and anti-FIIa potencies were similar; u however, in the thromboelastography, fibrinokinetic, and thrombin generation inhibition assays, the generic compared with the branded enoxaparin showed: n More variation in the individual’s anticoag ulant response n More batch-to-batch variation

n Less predictable concentration-dependent

and linear response n A lower overall anticoagulant effect

• Ex vivo pharmacodynamic investigations u Generic compared with the branded enoxaparin demonstrated: n Less thrombin generation inhibition

n Less TFPI release

n More inhibition of the active form of throm bin-activatable fibrinolysis inhibitor “These findings suggest that simple analytical characterization (average molecular weight, anti-FXa, anti-FIIa) can establish good quality control in manufacturing but may not assume similarity in biological performance between branded and generic enoxaparins,” Walenga said.

Beside the routinely required characterization, the inclusion of additional tests for biological activities and pharmacodynamic profiling of generics in animal models might provide useful information on the bioequivalence of the generic versions, the investigators suggested. l Reference

Walenga JM, Jeske W, Hoppensteadt D, et al. Comparative studies on branded enoxaparin and a US generic version of enoxaparin. Presented at: 54th American Society of Hematology Annual Meeting; December 8-11, 2012; Atlanta, GA. Abstract 2264.

March 2013 I VOL 6, NO 2

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COLORECTAL CANCER

Regorafenib Benefit in Colorectal Cancer... Continued from cover rospective 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-epider-

ASTUTE_DCIS Ad_50712_Layout 1 5/11/12 5:07 PM Page 1

Individualizing Treatment for DCIS of the Breast: New Molecular Approaches LOG ON TODAY TO PARTICIPATE

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TARGET AUDIENCE This initiative will target medical oncologists, hematologists, breast surgeons, radiation oncologists, oncology nurses, advanced practice nurses, nurse practitioners, physician assistants, oncology pharmacists, managed care professionals, and others with clinical research and management interest in treatment of ductal carcinoma in situ (DCIS) and early-stage breast cancer.

STATEMENT OF NEED Ability to detect DCIS has dramatically improved in recent decades, and the current incidence of DCIS is several-fold higher than in the 1970s and 1980s, largely due to increased use of mammography screening.1,2 However, attempts to identify subsets of DCIS women who may be spared radiotherapy and perhaps treated with surgery alone have heretofore been unsuccessful. This inability to predict which patients will develop recurrent DCIS or invasive disease has complicated DCIS management. Many clinicians and other healthcare professionals dealing with patients diagnosed with DCIS are unaware or incompletely knowledgeable about the most recent results from a clinical trial examining the ability of the 12-gene assay, using a prespecified DCIS algorithm, to predict recurrence risk, and the implications these findings may have for management of their patients with DCIS. 1. Kerlikowske K. Epidemiology of ductal carcinoma in situ. J Natl Cancer Inst Monogr. 2010;2010:139-141.

2. Virnig BA, Tuttle TM, Shamliyan T, Kane RL. Ductal carcinoma in situ of the breast: a systematic review of incidence, treatment, and outcomes. J Natl Cancer Inst. 2010;102:170-178.

EDUCATIONAL OBJECTIVES After completion of this activity, participants will be better able to: • Identify approaches currently available or in development to predict recurrence risk in DCIS patients • Explain how the 12-gene expression assay for DCIS was developed and how it compares with the 21-gene assay for early invasive breast cancer • Describe the design and findings of the ECOG 5194 validation study • Apply the 12-gene assay for DCIS into clinical decision-making • Explain relevant information about the 12-gene DCIS assay and DCIS score to patients

Release Date: May 8, 2012 Expiration Date: May 7, 2013

FACULTY Chair: Lawrence J. Solin, MD, FACR, FASTRO

Chairman Department of Radiation Oncology Albert Einstein Medical Center Philadelphia, PA

Michael Jeffers, PhD

Professor and Chief, Breast Surgery Duke University Medical Center Durham, NC

Kathy D. Miller, MD

Associate Professor Department of Medicine IU School of Medicine Indianapolis, IN This activity is supported by an educational grant from Genomic Health, Inc.

Physicians: Creative Educational Concepts, Inc. (CEC) is accredited by the Accreditation Council for Continuing Medical Education (ACCME) to provide continuing medical education for physicians. CEC designates this enduring educational activity for a maximum of 1.0 AMA PRA Category 1 Credits™. Physicians should only claim credit commensurate with the extent of their participation in the activity.

Nurses: CEC is accredited as a provider of continuing nursing education by the American Nurses Credentialing Center’s (ANCC) Commission on Accreditation. CEC provides this activity for 1.0 contact hour. Learners are advised that accredited status does not imply endorsement by the provider or ANCC of any commercial products displayed in conjunction with an activity.

Case Managers: This activity has been approved for 1.0 clock hour through 12/31/12 by the Commission for Case Manager Certification. Case Managers number 790005057.

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“The study overall showed that regardless of biomarker subgroup, regorafenib seems to have benefit.”

E. Shelley Hwang, MD, MPH

ACCREDITATION

20

mal 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.

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Side Effects Management

Peripheral Arterial Disease Seen With Nilotinib

By Audrey Andrews

P

eripheral artery occlusive disease (PAOD) may be an adverse effect of nilotinib treatment in patients with chronic-phase chronic myeloid leukemia (CML), according to a study presented at the 54th Annual Meeting of the American Society of Hematology.1 A significantly higher frequency of PAOD was observed in patients taking nilotinib than in patients taking imatinib, as measured by prospective, sequential ankle-brachial index (ABI) and duplex ultrasonography monitoring, said Philipp le Coutre, MD, of Charité, Universitätsmedizin Berlin in Germany. The occurrence of PAOD was most notable among patients with ≥2 underlying cardiovascular risk factors, and this patient group “should be treated with caution,” le Coutre advised.

A significantly higher frequency of PAOD was observed in patients taking nilotinib than in patients taking imatinib.

Based on a suggestion of risk from previous studies, le Coutre and colleagues assessed 159 patients with CML who received first-line imatinib (n = 53), first-line nilotinib (n = 31), or second-line nilotinib (n = 32), and those who were previously exposed to nilotinib (n = 23) or never treated with nilotinib and currently not receiving imatinib (n = 7).

Patients received nilotinib 300 mg or 400 mg twice daily for 6 months or longer. Laboratory parameters were measured as early as 4 weeks in some patients. A pathologic ABI, defined as <0.9, occurred in 31 of 129 patients with available ABI data (24%), and was found to occur more frequently among those treated with nilotinib, le Coutre reported.

At baseline, patients who received first-line imatinib tended to have a significantly longer duration of CML than those who received nilotinib (P <.0001) and a significantly longer first-line treatment duration—a median duration of 97.5 months versus 29 months with nilotinib (P <.0001). The higher risk for PAOD was observed with nilotinib, despite much shorter treatment exposure, he pointed out.

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“At present, we are recommending baseline and follow-up ABI and lab chemistries before nilotinib is given, and in patients with 2 or more cardiovascular risk factors, nilotinib should be given with caution.”

Philipp le Coutre, MD

Risk of PAOD in Subgroups Risk Factors Associated PAOD was diagnosed in 6.3% of With Nilotinib patients on first-line imatinib, compared Increases in cholesterol and low-denwith 26% on first-line nilotinib (P = sity lipoprotein were observed with .0297), 35.7% on second-line nilotinib nilotinib over imatinib, but there were (P = .0029), 16.6% of those previously no significant differences in high-denexposed to nilotinib, and 12.5% who sity lipoprotein, triglycerides, glucose, or hemoglobin A1C levels among the never received nilotinib.

The rate of PAOD in patients treatment cohorts.

Total cholesterol was 164 mg/dL receiving imatinib has been reported to be essentially the same as the upper among the first-line imatinib cohort, limit observed historically in the but was 209 mg/dL with first-line non-CML population: 6.7%.2 “There nilotinib (P <.0001), 222 mg/dL with is no decrease in PAOD frequency in second-line nilotinib (P <.0001), and imatinib-treated patients, when com- 193 mg/dL after any nilotinib expopared to historical non-CML cohorts. sure (P <.034). Low-density lipoproWe believe our findings are therefore tein values were 95 mg/dL, 135 mg/ not due to a reduction in PAOD dL (P <.0003), 139 mg/dL (P <.0001), with imatinib, but that it’s a nilo- and 117 mg/dL (P <.03), respectively. tinib issue,” le Coutre suggested. Five “Although nilotinib may cause PAOD-related events occurred,31413 all in3/14/13 hyperglycemia and AONN_Filler7x5_31413_AONN_Filler 10:58 AM Page 1 dyslipidemia, the patients who received nilotinib. exact mechanism leading to PAOD is

unclear. We think that atherosclerotic disease caused by dyslipidemia should take longer to develop, and we may be seeing the effect of nilotinib accelerating these metabolic problems,” le Coutre said.

These risk factors may have contributed to the development of PAOD, the investigators maintained. In a subgroup analysis of 17 patients with severe PAOD that was newly diagnosed while they were on treatment, 94% had received nilotinib and only 1 patient (6%) had received imatinib. Of these patients, 53% had 1 or 2 underlying risk factors (tobacco, hypertension, diabetes, and dyslipidemia) and 47% had 3 or 4 risk factors.

“At present, we are recommending baseline and follow-up ABI and lab chemistries before nilotinib is given, and in patients with 2 or more cardiovascular risk factors, nilotinib should be given with caution,” he concluded. l References

1. Schwartz M, Kim T, Mirault T, et al. Elevated risk of peripheral artery occlusive disease (PAOD) in nilotinib treated chronic phase chronic myeloid leukemia (CML) patients assessed by ankle-brachial-index (ABI) and duplex ultrasonography. Presented at: 54th American Society of Hematology Annual Meeting; December 8-11, 2012; Atlanta, GA. Abstract 914.

2. Lamina C, Meisinger C, Heid IM, et al. Association of ankle-brachial index and plaques in the carotid and femoral arteries with cardiovascular events and total mortality in a population-based study with 13 years of follow-up. Eur Heart J. 2006;27(21):2580-2587.

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Side Effects Management

Evidence Lacking for Eliminating Prophylactic Platelet Transfusions

By Audrey Andrews

T

o prevent bleeding related to stem cell transplant or intense induction and conditioning regimens, prophylactic platelet infusion remains the standard of care, according to a study that compared outcomes for patients who received prophylaxis versus those who did not.

The noninferiority TOPPS (Trial of Prophylactic Platelets) trial results were presented at the 54th Annual Meeting of the American Society of Hematology (ASH) by Simon

“This multicenter study has not shown that a no-prophylaxis platelet transfusion policy is noninferior to prophylaxis.”

Simon Stanworth, MRCP, FRCPath, DPhil

Stanworth, MRCP, FRCPath, DPhil, from John Radcliffe Hospital, Oxford University Hospitals NHS Trust, in the United Kingdom.

Investigators questioned whether a policy of no prophylaxis with platelet transfusions in adults with hematologic malignancies was not worse than

Supportive and Palliative Care

Home-Based TPN of Little Benefit in Terminally Ill Patients With GI Cancer

By Caroline Helwick

Table Outcomes of TPN in Terminally Ill Cancer Patients Receiving Home TPN Variable

Total

GI Cancer Other Malignancy

TPN duration (median), days

38

39

45

Survival (TPN to death), days

70

55

77

Resumed eating, %

16

12

22

Changed to enteral support, %

3

3.5

3

Received Rx while on TPN, %

50

47

56

Readmitted, %

74

68

84

Positive blood cultures, %

21

17

28

Liver toxicity, %

6

3

6

Electrolyte imbalance, %

15

14

15

Abbreviations: GI, gastrointestinal; TPN, total parenteral nutrition.

T

otal parenteral nutrition (TPN) continues to be inappropriately used at the end of life in cancer patients, according to a review of home-based TPN reported by researchers from Moffitt Cancer Center in Tampa, Florida, at the 2013 Gastrointestinal Cancers Symposium.

“Our study of home TPN did not show a great outcome.

In fact, the results were pretty dismal,” said Margaret Cass-Garcia, RN, MSN, CNSC. “The patients often are readmitted with the same symptoms they had when we started them on TPN.” TPN is increasingly used in terminally ill cancer patients with cachexia or bowel dysfunction, but the American College of Physicians discourages this practice. In addition to providing little benefit to the dying patient, the practice is costly: $15,000 to $18,000 a month for home TPN, according to the investigator.

The purpose of this retrospective study was to determine the validity of TPN in patients who were terminally ill from advanced gastrointestinal (GI) cancer, and to compare this group with patients with other malignancies.

The study focused on 89 patients treated at Moffitt Cancer

22

March 2013 I VOL 6, NO 2

Center who were receiving TPN in their own home between 2007 and 2012. All had stage IV cancer with a nonfunctional GI tract (two-thirds had bowel dysfunction) or failure to thrive (surgical patients were excluded), and were ineligible for surgery.

Forty-four percent had palliative gastrostomy tubes.

Outcomes, Complications Although they received TPN for the same duration, patients with GI cancer lived for a shorter time than did patients with other malignancies.

Very few patients resumed eating, and these had primarily been started on TPN because of failure to thrive,

not bowel obstruction.

TPN-related complications were common, with 74% of patients requiring readmission and many admitted several times. While some readmissions were related to the chemotherapy that half the patients continued to receive, most admissions were in some way due to TPN-related conditions, in particular, lack of symptom resolution, she said.

Overall, 17 patients had restored bowel function, and only 1 patient was still alive at the time of the analysis.

“We recognize that there are subjective reasons for giving TPN to terminally ill cancer patients, and they include compassionate, ethical, religious, and emotional reasons,” Cass-Garcia acknowledged, “but essentially, your body has told you it doesn’t want to eat. TPN may be prolonging life or prolonging death, and there is a grey area. This is a hard conversation with the family.” l Reference

Cass-Garcia M, Hodul PJ, Almhanna K. Use of total parenteral nutrition (TPN) in terminally ill gastrointestinal (GI) cancer patients (pts) compared to other malignancies (OM): a single-institution experience. Presented at: 2013 Gastrointestinal Cancers Symposium; January 24-26, 2013; San Francisco, CA. Abstract 309.

(ie, noninferior to) a prophylactic policy of platelet infusion at <10 x 109/L, as judged by World Health Organization grade 2, 3, or 4 bleeding, up to 30 days from randomization.

The study included 600 patients with hematologic malignancies and severe thrombocytopenia.

To protect against bleeding, the current practice is to give platelets prophylactically to patients when their platelet counts drop below 10,000/µL. The findings indicated that hemostatic outcomes were comparable for the 2 approaches, and a new recommendation cannot be made at this time, Stanworth said. “This multicenter study has not shown that a no-prophylaxis platelet transfusion policy is noninferior to prophylaxis.”

No Differences in Bleeding There were no significant differences between the study arms in period of thrombocytopenia, number of days in the hospital, or number of serious adverse events. Overall, grade 2 to 4 bleeding was seen in 43% of the prophylaxis group and in 50% of the no-prophylaxis group. Most bleeding was grade 2.

“Serious bleeding complications were rare,” Stanworth noted. “The proportion of patients with grade 2 to 4 bleeding was reduced by 7% with prophylactic platelets.”

Significant differences were, however, seen in a couple of end points.

Without prophylaxis, patients experienced significantly more days on which bleeding occurred (1.7 days vs 1.2 days; P = .004) and had a shorter time to the first occurrence of bleeding (P = .02). Time to recovery from thrombocytopenia was also no different, he reported.

Grade 3 and 4 bleeds were observed in 1 of 298 (0.3%) patients who had prophylaxis and in 6 of 300 (2%) who lacked prophylaxis. While this amounted to a 6-fold increased risk, the difference was not statistically significant (P = .13). One intracranial bleed occurred in the group without prophylaxis.

In a predefined subgroup analysis, patients were divided into those with autologous stem cell transplant versus “other” approaches. The benefit of prophylaxis appeared to be most striking in the “other” group, Stanworth said. Interestingly, this included more patients with acute myeloid leukemia.

In the autologous transplant group, which mainly comprised lymphoma and myeloma patients, bleeding occurred in 45% without prophylaxis and in 47% with prophylaxis. In the “other” group, grade 2 to 4 bleeding occurred in 38% with prophylaxis and 58% without prophylaxis.

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Side Effects Management “The role of prophylactic transfusions in autograft patients is less clear,” Stanworth said.

He also noted that the rates of bleeding in the study, overall, were high, even when patients received platelet infusions, and suggested that other approaches to the problem should be explored. He added that factors other than those addressed by prophylactic platelet transfusions are important in assessing bleeding risk in this population.

Can Unnecessary Transfusions Be Eliminated?

While the results were considered a validation of the current standard of care, some experts at ASH commented on the fact that many patients receive prophylactic platelet transfusions unnecessarily.

Writing in the ASH Daily News, Andrew Leavitt, MD, of the University of California San Francisco, observed that “with half of the no-prophylaxis group experiencing no significant bleeding, it is clear that we transfuse many patients unnecessarily,” yet this practice is actually increasing. Although there were no significant differences in outcomes, patients in the prophylaxis group received 61% more transfusions.

Nationwide, approximately 1.5 million transfusions were administered in 1999, and a decade later more than 2 million platelet transfusions were recorded by the US National Blood Collection and Utilization Survey Report, he said. “It is estimated that about two-thirds of the platelet transfusions are for prophylac-

Some experts at ASH commented on the fact that many patients receive prophylactic platelet transfusions unnecessarily.

spent more than $1.3 billion on prophylactic platelet transfusions in 2008, yet we lack good evidence that prophylactic platelet transfusions provide clinical benefit.” l Reference

tic use, while approximately one-third cult to determine, an average total cost are administered to treat bleeding.” of $1000 per platelet transfusion is a “While product acquisition and infu- reasonable estimate,” Leavitt added. sion costs vary regionally and are diffi- “The US health care system, therefore, VBCC0112_VBMAsize_Layout 1 2/9/12 4:21 PM Page 2

Stanworth SJ, Estcourt L, Powter G, et al. The effect of a no-prophylactic versus prophylactic platelet transfusion strategy on bleeding in patients with hematological malignancies and severe thrombocytopenia (TOPPS trial). A randomized controlled, non-inferiority trial. Presented at: 54th American Society of Hematology Annual Meeting; December 8-11, 2012; Atlanta, GA. Abstract 1.

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

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

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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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Conference News: AVBCC

Introducing the Third Annual Conference of the Association for Value-Based Cancer Care

By Burt Zweigenhaft, BS Chief Executive Officer and Chairman, OncoMed Onco360; Co-chair of the AVBCC Conference

Burt Zweigenhaft, BS

A

s we know, the American healthcare system is going through exorbitant changes, changes that will affect all providers and all stakeholders in the cancer care ecosystem. The goal of the Association for Value-Based Cancer Care (AVBCC) is to bring together all the cancer care stakeholders in one unified meeting to discuss the many issues facing us today. One of the main objectives of the AVBCC Annual Conference is to be able to map out and help guide our members and attendees through the various changes in the US healthcare system.

Changes in Reimbursement and Purchasing We are at an inflection point in cancer drug distribution and management.

We are seeing the typical wholesalerto-physician channel control change rapidly. Managed market payers are stepping up and exerting more control over what happens in oncologist offices. The landscape is changing in terms of reimbursement and their contracting capabilities as Managed Market Payers are responding as we experiment and move into an accountable care organization (ACO) world.

It is very important that the AVBCC Annual Conference convenes an agenda and forum to guide and mentor people through the changes, and to be able to inflect strong opinions and to encourage people to participate in helping flush out important changes in the chain to ensure that we can impact change in a very positive way.

It is no longer the traditional wholesaler-to-physician group purchasing organization (GPO) model in this business today. This is rapidly changing as managed market payers’ control and oversight of cancer care are taking hold and influencing the outcomes of decisions, pathways, formulas, reimbursement, and prior authorization.

It is very important that your staff gets to meet and see all of the stakeholders and decision makers in this chain of rapidly changing events that impact cancer care today. Without that, you and your organization are not going to be prepared for the market changes, and the impact on your brand could be tremendous.

Then again, if you attend the meeting and you observe and understand the changes, enter into the discussion and debate, and lastly, you have the foresight to plan for the changes: hence you will be more successful in the long run.

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In addition to Web-only exclusives, news coverage, journal articles, contests, and polling questions, you’ll have the opportunity to earn Continuing Education credits at NO CHARGE by participating in a number of activities offered!

Meeting Key Opinion Leaders Who are these key opinion leaders specifically? For the most part, they are the medical directors of the big insurance plans, the ones who are leading the change in cancer care, whether in Medicare, Medicaid, or in commercial plans. We have certain leaders that you may recognize, because you have read

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March 2013 I VOL 6, NO 2

An All-Inclusive Agenda We have an all-inclusive agenda. It allows us in the mornings, over the couple of days that we meet, to have all the “big-ticket” topics discussed by some of the greatest thought leaders— the people who are driving change in the oncology space today—whether it is regulatory, reimbursement, coverage, policy, benefits, healthcare systems, hospital systems, or the large community practices that are changing the way we operate in cancer care.

This allows all of the stakeholders, main issues, and agendas to be discussed in an open forum. We have panels, channel experts, and key opinion leaders. This is important; you never see such a mix in this business.

Our afternoon tracks allow you to have breakouts, depending on whether it is reimbursement, genetics, product launch, pathways, or care management that is important to you. These are all separate tracks that allow you and your staff to move around with flexibility in the afternoon, and to make sure that you all cover the wide array of topics that we have available to enjoy and learn from.

We all know how important networking is. I know that we are in an e-mail and health information exchange market. But meeting key opinion leaders and exchanging in open dialogue, and being able to sit with them at lunch, at breakfast, or between sessions and hear what their thoughts are, is very important.

This is the only conference where the key people in the channel are at the meeting, and they are available for you to meet and to have personal time with them. There is no better way to get ahead and to stay ahead in cancer care than to be at the AVBCC Annual Conference in its third year, in Hollywood, Florida.

This is your chance to see some of the greatest key opinion leaders, the people who are truly driving change in cancer care today.

3/15/13 2:21 PM

www.TheOncologyNurse.com

Conference News: AVBCC about them frequently in many pubThis is the only meeting I am aware lications, including the Association’s of that affords this type of inclusive publication—Value-Based Cancer venue, where everyone in the space Care. We have coding experts. We can get to meet those important leaders have advocacy experts. We have pol- who are driving change in cancer care. icy experts. This is why the AVBCC One of the most important things Annual Conference is a very inclusive that we know is changing is the dismeeting, because we bring all the tribution model as we are moving stakeholders together. from the typical manufacturer to the When we put together the agenda, wholesaler through GPO to communiour goal was to make sure that we ty-based or system-based oncologists. had the right people, the right health plans, the right health systems, andAVBCC2013Asize13013_AVBCC 2/4/13 2:10 PM Page 1 the right leaders. We did not want to see ourselves with another small, myopic view of this industry. We knew that the only way to effect change in a positive way is to get everyone and every voice in the room together to share information. That is the overall goal of the AVBCC Annual Conference—inclusiveness.

The system is changing and manufacturers are now finding that they are no longer totally dependent on the wholesale channel or on GPOs to make and control the influential buying decisions to drive their products to market. Today it is being heavily influenced by the managed care channels and by payers’ coverage and reimbursement decisions.

In this meeting, in addition to hav-

ing all the managed market payers represented, we also have the new stakeholders in the distribution channel. We have specialty pharmacies, we have oncology pharmacies, and we have hospital systems and others that are now taking hold of a new distribution model in cancer care.

As this business is changing, what we have done at the AVBCC is to Continued on page 26

THIRD ANNUAL

Association for Value-Based Cancer Care Conference Influencing the Patient-Impact Factor

This activity is jointly sponsored by the Florida Society of Clinical Oncology, Medical Learning Institute Inc, Association for Value-Based Cancer Care, Inc., Center of Excellence Media, LLC, and Core Principle Solutions, LLC.

May 2-5, 2013 • Westin Diplomat • Hollywood, Florida There is no better way to get ahead and to stay ahead in cancer care than to be at the AVBCC conference in its third year. This is your chance to see some of the greatest key opinion leaders, the people who are truly driving change in cancer care today.

I have always believed that it is very important to meet face to face with the key people who are driving change in the business. One of the goals of our association is to make sure that we have a cast that includes everyone who is leading that change. We have people from Aetna, and people from the University of Pittsburgh Medical Center. We have people from hospital systems, such as the “Roswells” and the “Dana-Farbers” of the world.

We have employer groups and coalitions, such as Caterpillar, Delta, the National Business Group on Health, UnitedHealthcare, and many others.

The goal of the AVBCC Annual Conference is to bring them all together to make sure that we all have access to each other and that we can share ideas in an open forum and help chart the future of cancer care in America. This is why you want to be with us at this meeting, and this is why you need to have your staff attend the conference.

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AGENDA* THURSDAY, MAY 2, 2013 8:00 am - 5:00 pm

Registration

FRIDAY, MAY 3, 2013

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

Gary M. Owens, MD President Gary Owens Associates

Burt Zweigenhaft, BS President and CEO OncoMed

PROGRAM OVERVIEW

Following on the success of our Second Annual Conference, AVBCC will be coming to Hollywood, Florida, on May 2-5, 2013. We continue to be guided by the expertise of leaders in these fields providing attendees with a thorough understanding of the evolution of the value equation as it relates to cancer therapies. Our goal is to be able to assist them in implementing, improving, and sustaining their organizations and institutions, while improving access for patients and ultimately quality patient care.

7:00 am - 8:00 am

Simultaneous Symposia/Product Theaters

8:15 am - 9:15 am

Session 1: Welcome, Introductions, and Opening Remarks Conference Co-Chairs - Craig K. Deligdish, MD; Gary M. Owens, MD; Burt Zweigenhaft, BS

9:15 am - 10:15 am

Keynote Address

10:15 am - 10:30 am

Break

10:30 am - 11:45 am

Session 2: Trends in Treatment Decision-Making: Pathways and Stakeholder Collaborations Marcus Neubauer, MD; Michael Kolodziej, MD

12:00 pm - 1:00 pm

Exclusive Lunch Symposium/Product Theater

1:15 pm - 2:00 pm

Session 3: Cost of Cure: When, How, and How Much?

John Fox, MD; John Hennessy

2:00 pm - 2:45 pm

Session 4: Where Is Oncology Care Headed in the Future?

Jayson Slotnick, JD, MPH (Moderator); Barbara L. McAneny, MD

Upon completion of this activity, the participant will be able to: • Discuss the current trends and challenges facing all stakeholders in optimizing value in cancer care delivery.

• Define the barriers associated with cost, quality, and access as they relate to healthcare reform and what solutions are currently being considered.

• Compare and contrast the different approaches/tools providers and payers are utilizing to manage and deliver care collaboratively.

• Examine the current trends in personalized care and companion diagnostics.

• Analyze the patient issues around cost, quality, and access to care.

2:45 pm - 3:30 pm

Session 5: What Will the Cancer Delivery System Look Like in 2015?

Ted Okon; John D. Sprandio, MD

TARGET AUDIENCE

LEARNING OBJECTIVES

3:30 pm - 3:45 pm

Break

3:45 pm - 4:30 pm

Session 6: Employers and Oncology Care F. Randy Vogenberg, PhD, RPh (Moderator); Bridget Eber, PharmD; Patricia Goldsmith; Darin Hinderman

4:30 pm - 5:15 pm

Session 7: Advanced Care Directives: Palliative Care, Hospice, Ethics J. Russell Hoverman, MD, PhD; Thomas Smith, MD, FACP, FASCO

5:15 pm - 5:45 pm

Summary/Wrap-Up of Day 1

This conference is intended for medical oncologists, practice managers/administrators, and managed care professionals. Stakeholders in a position to impact cancer patient care, such as advanced practice nurses, pharmacists, and medical directors, are also invited to join this exciting forum.

6:00 pm - 8:00 pm

Cocktail Reception in the Exhibit Hall

DESIGNATION OF CREDIT STATEMENTS

8:15 am - 8:30 am

Opening Remarks

8:30 am - 9:15 am

Session 8: The Role of Government in the Future of Oncology Care Jayson Slotnick, JD, MPH

9:15 am - 10:00 am

Session 9: Medicaid: A Healthcare Delivery System Review Matthew Brow

10:00 am - 10:15 am

Break

10:15 am - 11:00 am

Session 10: Payer, Government, and Industry Insights: Balancing Cost and Quality Kip Piper

11:00 am - 11:45 am

Session 11: National Coalition for Cancer Survivorship: Medication Nonadherence Issues Pat McKercher; Lillie Shockney, RN, BS, MAS

SPONSORS

This activity is jointly sponsored by the Florida Society of Clinical Oncology, Medical Learning Institute Inc, Association for Value-Based Cancer Care, Inc., Center of Excellence Media, LLC, and Core Principle Solutions, LLC.

COMMERCIAL SUPPORT ACKNOWLEDGMENT

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

SATURDAY, MAY 4, 2013 7:00 am - 8:00 am

PHYSICIAN CREDIT DESIGNATION

The Medical Learning Institute Inc designates this live activity for a maximum of 17.25 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

Simultaneous Symposia/Product Theaters

12:00 pm - 1:00 pm

Exclusive Lunch Symposium/Product Theater

1:15 pm - 3:00 pm

Session 12: Meet the Experts Networking Roundtable Session

3:00 pm - 3:45 pm

Session 13: Personalized Medicine, Companion Diagnostics, Molecular Profiling, Genome Sequencing—The Impact on Cost, Treatment, and the Value Proposition Mark S. Boguski, MD, PhD; Gary Palmer, MD, JD, MBA, MPH

3:45 pm - 4:15 pm

Summary/Wrap-Up of Day 2

4:30 pm - 6:30 pm

Cocktail Reception in the Exhibit Hall

Medical Learning Institute Inc. Provider approved by the California Board of Registered Nursing, Provider Number 15106, for 17.25 contact hours.

SUNDAY, MAY 5, 2013

REGISTERED PHARMACY DESIGNATION

8:15 am - 8:30 am

Opening Remarks

8:30 am - 9:15 am

Session 14: Cancer Rehabilitation: The Next Frontier in Survivorship Care Julie Silver, MD

9:15 am - 10:00 am

Session 15: Current and Future Considerations for the Oncology Practice Manager Dawn Holcombe, MBA, FACMPE, ACHE; Leonard Natelson

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 17.25 contact hours (1.725 CEUs) of continuing pharmacy education credit. The Universal Activity Number for this activity is (To be determined).

CONFERENCE $375.00 until March 15, 2013 REGISTRATION $425.00 after March 15, 2013 REGISTER TODAY AT

www.regonline.com/avbcc2013

7:00 am - 8:00 am

Simultaneous Symposia/Product Theaters

10:00 am - 10:15 am

Break

10:15 am - 11:00 am

Session 16: Access to Drugs—Shortages, Biosimilars Douglas Burgoyne, PharmD; James T. Kenney, Jr., RPh, MBA

11:00 am - 11:45 am

Session 17: Perspectives from Oncology Group Practices—Successes, Issues, and Challenges Thomas Marsland, MD; David Eagle, MD

11:45 am - 12:00 pm

Summary and Conclusion of Conference

*Agenda is subject to change.

AVBCCAsize20413

March 2013 I VOL 6, NO 2

25

Conference News: AVBCC

Introducing the Third Annual Conference... Continued from page 25 make sure that we have at this Third weighed to come up with the value-based Annual Conference all of the people who purchasing proposition. are effecting change, so that they can discuss that change and what it means The â&#x20AC;&#x153;New Worldâ&#x20AC;? of Healthcare to the healthcare markets. One of the Part of the mission of the AVBCC is to major challenges that most manufacturers come up with a formula for value-based have to address in the cancer marketplace purchasing that will include not only today will be now dealing in a compara- clinical elements but economic eletive world of clinical and cost-effective- ments of overall cost as well. Part of Bendamustine Asize_030413_TON0210 3/13/13 4:34 PM Page 2 ness, where evidence is increasingly being our agenda is to make sure that the

Association can put forth a framework for â&#x20AC;&#x153;value-based purchasingâ&#x20AC;? and the corresponding proper process and formula for evaluating effectiveness so appropriate contracting for cancer drug therapies is in the marketplace.

The timing of the Third AVBCC Annual Conference could not be better.

We are coming right off of a national election. We did not know whether

Th

eO seri Vie nc es w olo on the gy line Nu a rse t .co m

Faculty Perspectives

â&#x201E;˘

A 4-part series The publishers of The Oncology Nurse-APN/PA, The Oncology Pharmacist, and Personalized Medicine in Oncology are proud to present Faculty Perspectives: The History of Bendamustine series.

Upcoming topics include: â&#x20AC;˘ â&#x20AC;˘ â&#x20AC;˘ â&#x20AC;˘

Characterization of bendamustine Registration studies - efficacy Registration studies - safety Ongoing clinical investigations

Faculty Perspectives

Part 1 of a 4-Part Serie s

DECEMBER

A Retrospectiv

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CONTRIBUT

ING FACULTY

Julie M. Vos e, MD, MBA

University of Nebraska Medical Cen ter

Colleen Ros s, RN, MSN, MHA, OC

PMP M O

P University of Nebraska Medical Cen ter

ERSONALIZED EDICINE

ONCOLOGY

IN

Supported

through fund ing by

www.TheOncologyNurse.com March 2013 I VOL 6, NO 2

â&#x201E;˘

Community-Based Versus Hospital-Based Care Also at this yearâ&#x20AC;&#x2122;s AVBCC conference, we are going to explore one of the biggest changes in cancer careâ&#x20AC;&#x201D; the move from community oncology to hospital-based cancer care.

We have representatives from the Community Oncology Alliance, the Association of Community Cancer Centers, the National Comprehensive Cancer Network, the American Society of Clinical Oncology, and others, who are going to be discussing these changes.

We have seen a tremendous consolidation in the purchase of hematology and oncology practices by hospital systems as they are getting ready for ACO opportunities. This is going to have a dramatic impact on our marketplace.

We are going to explore this critical change in depth in some of the sessions.

Anyone who is involved in this oncology space must know what is going on, and must be able to predict the new models of distribution and service, given the consolidation and the changes in cancer care as we go forward.

Susanne Liew er, PharmD, BCO

N University of Nebraska Medical Cen ter

TO VIEW THE SERIES ONLINE PLEASE LOG ON TO:

26

2012 â&#x20AC;˘ VO LUME 4 â&#x20AC;˘ NUMBER 1

ObamaCare was going to last. Now we know that health information exchanges, state exchanges, and the novel products of the â&#x20AC;&#x153;new worldâ&#x20AC;? of healthcare are going to take effect and are here to stay, and change is permanent.

Obviously, we are moving from a utilization-focused model to a quality model of healthcare. These changes are going to be dramatic. These issues are part of the agenda of change that we are going to be discussing this year at the AVBCC Annual Conference in the various segments and forums.

Personalized Medicine Personalized medicine is probably going to be launched through cancer care.

Why? Because cancer is so expensive, and all of the molecular tests that can really make a difference in clinical utility and drive change are going to be the companion diagnostics to cancer care. Thus, given the effect on comparative effectiveness research and the value-based approach of cancer care purchasing, the economics around personalized medicine make economic sense to embrace beyond the quality drivers.

This is a hugely important topic, and it is part of our agenda at the Third Annual Conference of AVBCC, where we have experts who will be speaking on the impact of personalized medicine, companion diagnostics, and molecular pathways as we move forward in improving patient care in America. l

www.TheOncologyNurse.com

ENTER OUR iPad GIVEAWAY Visit us at booth #530 during the 38th Annual ONS Congress, April 25 - 28 in Washington, DC for your chance to WIN!*

*Drawing will be held at noon on Saturday, April 27. To win, you must be present at the conference.

Interview With the Innovators The following interview originally appeared in the December issue of Personalized Medicine in Oncology.™

PMPMO O

ERSONALIZED EDICINE IN NCOLOGY TM

Implementing the Promise of Prognostic Precision into Personalized Cancer Care TM

Lynch Syndrome: An Interview With the Father of Hereditary PMPM O Cancer Detection and Prevention, Henry T. Lynch, MD

L

ynch syndrome is a hereditary disorder caused by a mutation in a mismatch repair gene in which affected individuals have an increased risk of developing colorectal cancer, endometrial cancer, and various other types of aggressive cancers. The syndrome is named after its discoverer, Henry T. Lynch, MD, director of Creighton University’s Hereditary Cancer Center. It’s estimated that about 3 of every 100 colon cancers are caused by Lynch syndrome, making it the most common inherited cause for colon cancer.

Hereditary cancers were not actively researched until the second half of the last century. There is documentation that physicians acknowledged family cancer clusters during the 1800s; how-

O

Today, based on worldwide estimates, it is projected that over 600,000 individuals have the defective gene; however, less than 5% of them have been diagnosed.

ever, it wasn’t until the late 1950s and early 1960s that statistics were used in cancer research to establish the existence of hereditary cancers.

Dr Lynch was a pioneer in the study of cancer and genetics in the 1960s, when cancer incidence was largely attributed to environmental causes.

His use of statistics to prove genet-

Dr Lynch has identified patterns of genetic inheritance through generations of extended families.

Dr Lynch (5th from left) has worked since the 1960s in the fields of oncology and genetics.

28

March 2013 I VOL 6, NO 2

ic links to certain cancer types was unique from other researchers at that time. His early cancer research significantly influenced how physicians and researchers treat and study hereditary cancers today. Dr Lynch demonstrated Mendelian inheritance patterns for a previously unrecognized form of colon cancer (hereditary nonpolyposis colorectal cancer, now known as Lynch syndrome), and for the hereditary breast-ovarian cancer syndrome, which he subsequently helped link to the BRCA1 and BRCA2 genes.

In addition, he provided some of the first findings of hereditary malignant melanoma and prostate and pancreatic cancers. The purpose of his work has been to enable physicians to more quickly and accurately identify highrisk patients, leading to earlier and more effective surveillance, management, and treatment.

Today, based on worldwide estimates, it is projected that over 600,000 individuals have the defective gene; however, less than 5% of them have been diagnosed. Part of Dr Lynch’s vision is a network to serve those with Lynch syndrome that includes genetic testing, a registry, treatment centers, and ongoing surveillance for early prevention. To this end, he helped establish Lynch Syndrome International, a nonprofit organization founded in 2009 to raise public awareness and support for individuals afflicted with the syndrome. It was our great pleasure to interview Dr Lynch about his contributions to the field of oncology, particularly in genetics.

Thank you for speaking with us, Dr Lynch. We’d like you to describe the process that led to the discovery of Lynch syndrome.

Dr Lynch: I developed an interest in genetics early in my medical training, particularly as it related to cancer. Many individuals with an extensive family his-

ERSONALIZED EDICINE IN NCOLOGY

TM

Implementing the Promise of Prognostic Precision into Personalized Cancer Care TM

tory of colon cancer were diagnosed with familial adenomatous polyposis (FAP), a hereditary colon cancer that produces hundreds to thousands of polyps.

However, some patients diagnosed with FAP did not have symptoms characteristic of the syndrome; the typical numerous polyps were not present in the first family I studied. I suspected another hereditary cancer might exist.

Does the research of Lynch syndrome have implications for other research models/strategies?

Dr Lynch: Yes, our research has extremely important implications for preventive as well as other clinical translational research models/strategies.

Is there a research strategy specific to Lynch syndrome?

Dr Lynch: The research strategy for the Lynch syndrome revolves around issues related to its diagnosis and ultimate management strategies. Its clinical importance relates to the fact that it is by far the most common hereditary colorectal cancer syndrome and extracolonic cancer syndrome problem. These often result in extremely important clinical/ preventive cancer syndrome issues.

Does Lynch syndrome resemble other disease states in terms of disease process, patient selectivity, or progression? In other words, is there any analog for gaining an understanding of it?

Dr Lynch: Lynch syndrome, in fact, has strong similarities to disease processes relevant to patient selectivity and cancer progression. There are multiple clinical analogs revolving around the need for a comprehensive family history and ultimately genetic testing, when appropriate, in the search for cancer-causing mutations and design of preventive opportunities.

What has been the greatest significance of the discovery and management of Lynch syndrome on cancer and/or personalized medicine research?

Dr Lynch: The most significant issue, by far, in terms of its diagnosis and management pertains to the need for its personalized medical research contributing to a reduction in morbidity and mortality when compliance is adhered to. www.TheOncologyNurse.com

Interview With the Innovators How has the discovery and clinical usage of diagnosis of Lynch syndrome changed morbidity and mortality outcomes of the various cancers it concerns?

Dr Lynch: Discovery and clinical usage of diagnosis of Lynch syndrome has definitely changed morbidity and mortality outcomes. We have profound evidence of this in the study of countless families throughout the United States, South America, and Europe, where we have been highly privileged to have been involved clinically and genetically with physicians in multiple specialties; medical genetics, surgery – particularly surgical oncology and colorectal surgery – gastroenterology, and gynecologic oncology.

understand the science behind Lynch syndrome, or just its impact on outcomes?

Dr Lynch: Our pathology colleagues, among other specialists, have been working very hard at attempts to understand the pathogenesis, pathophysiology, and clinical sequelae of Lynch syndrome in terms that can be most useful to practicing oncologists. Understanding the science of the Lynch syndrome has been emerging, particularly at the molecular genetics level, but we have a long way to go in order to have its impact more fully explained on clinical outcomes.

Dr Lynch has been an invited speaker worldwide. Here he is pictured at a speaking engagement in Saudi Arabia.

How aware of and responsive to Lynch syndrome are practicing oncologists?

Dr Lynch: Well, it’s more fitting to ask if the patients are aware, and their response. We find that our patients have been partially responsive to the preventive implications of Lynch syndrome and the advice given by their family doctors as well as practicing oncologists.

However, this only happens when the patients are adequately educated and have constant encouragement.

Which factors tend to limit, and which increase, awareness and management of Lynch syndrome?

Dr Lynch: As part of our goals at the Hereditary Cancer Center, we strive to promote awareness and preventive management. Compliance is hopefully magnified through our genetic counselor and physician interventions.

Awareness and management is based on many years of our intensive research, with attempts to come up with what is best for a particular patient.

Factors that limit increased awareness and management of Lynch syndrome revolve around physician interest and willingness to learn about the syndrome and provide its diagnostic and preventive implications to highrisk patients in their practices. Other factors that limit increased awareness and management revolve around limited interest on the part of the patient and willingness of insurance companies to help cover the cost, which can be very high in the case of the sine qua non for diagnosis, namely the search for the cancer-causing germline mutation.

How would you describe awareness and management of the syndrome at Creighton?

Dr Lynch: This has been done admirably well, in my opinion, in our academic setting. The preventive measures we use, particularly colonoscopy, with initiation at age 25 and repeated every

www.TheOncologyNurse.com

Dr Lynch attends genetic testing for a large, extended family of more than 70 people for a known mutation.

other year to age 40 and then annually thereafter, have been successful.

Implications for prophylactic hysterectomy and bilateral salpingo-oophorectomy, in collaboration with colleagues at the MD Anderson Cancer Center, in Houston, Texas, have been successful.

Does any particular stakeholder group – practicing oncologists at the academic centers or community centers, payers, patients, etc – stand out as more, or less, cognizant of Lynch syndrome and its management? Put differently, where do healthcare disparities for Lynch syndrome tend to occur regarding patient risk stratification, diagnosis, treatment, patient management/follow-up, and payer coverage/reimbursement?

Dr Lynch: The stakeholder groups, including practicing oncologists and academic centers, have worked very hard to get insurance companies’ support for its costly management.

Healthcare disparities for Lynch syndrome enter the picture and may be a particular hazard for ethnic and racial factors, particularly those involving African Americans and patients of Latino background. These issues must be resolved.

Are medical directors and pharmacy directors at health plans sufficiently informed about Lynch syndrome to provide proper coverage of its care?

Dr Lynch: Our experience indicates that medical and pharmacy directors have, for the most part, not been sufficiently informed about Lynch syndrome to the extent that they can reasonably provide proper coverage of its diagnosis and management.

While Lynch syndrome increases risk for some cancers, it does not for others. What accounts for the absence of risk for developing certain cancers?

Dr Lynch: Lynch syndrome increases the risk for multiple primary cancers, particularly cancer of the colorectum, endometrium, ovary, among other extracolonic cancers. So far as we can determine, its risk for so-called environmental cancers, inclusive of head and neck and lung cancer, has not been an exceptionable problem. However, we have no knowledge at this time about the absence of risk for developing certain cancers.

How would you briefly describe the pathogenesis, pathophysiology, and clinical sequelae of Lynch syndrome in terms relevant to practicing oncologists? Do clinicians

Where is Lynch syndrome trending in terms of clinician recognition, diagnosis, and management? How has this progressed over the past 5 years?

Dr Lynch: The Lynch syndrome has been increasing significantly in its clinical recognition, diagnosis, and management, and it has progressed favorably over the past 5 years in diagnosis. This is in contrast to my initial discovery of the Lynch syndrome in 1962, when I was a second-year medical resident at the University of Nebraska College of Medicine. Clearly, there was no editorial concern about what I was attempting to publish. Attention to the syndrome throughout the world and the lack of believability of my work was truly profound. Over the years interest gradually increased, but at a slow pace. It began to emerge relevant to mounting evidence supporting the existence of Lynch syndrome. However, it wasn’t until the early 1990s when linkage analysis and other technology emerged in support of the diagnosis of Lynch syndrome. Substantial evidence emerged rapidly following the discovery of germline mutations giving evidence for its existence.

Thank you so much for your time today, and our best to you in your continued pursuit of making a difference in the lives of those with Lynch syndrome. l Henry T. Lynch, MD, is Professor of Medicine at the Creighton University School of Medicine and Director of the Creighton Cancer Center. His research involves clinical as well as laboratory investigations into a variety of hereditary cancer-prone disorders. Dr Lynch was an Assistant Professor at the University of Texas MD Anderson Hospital and Tumor Institute in Houston prior to joining the Creighton University School of Medicine faculty in 1967. In 1984, he established Creighton University’s Hereditary Cancer Prevention Clinic, an interdisciplinary clinic that provides information and services related to hereditary cancers.

March 2013 I VOL 6, NO 2

29

Breast Cancer

Venlafaxine Lowers Endoxifen Levels, May Affect Tamoxifen Effectiveness

By Caroline Helwick

T

he antidepressant venlafaxine is often prescribed to patients with breast cancer who are taking tamoxifen, to help reduce the side effect of hot flashes. But according to research presented at the 2012 CTRC-AACR San Antonio Breast Cancer Symposium, venlafaxine may reduce the effectiveness of the drug.

The findings came from a multicenter prospective pharmacologic study that analyzed paired blood samples from 30 women taking venlafaxine for at least 4 weeks for the treatment of hot flashes. Blood was taken before starting venlafaxine and 8 to 16 weeks afterward. Genotyping was conducted for alleles associated with no, reduced, and ultrarapid metabolism. The aim was to examine whether venlafaxine altered the pharmacokinetics of tamoxifen and to determine the distribution of CYP2D6 genotypes in this population.

Women with tamoxifeninduced vasomotor symptoms requiring ameliorative treatment with venlafaxine were predominantly CYP2D6 extensive and ultrarapid metabolizers.

CYP2D6 is the rate-limiting enzyme responsible for the metabolic activation of tamoxifen to endoxifen.

Among women taking tamoxifen, those who are extensive metabolizers of CYP2D6 have higher endoxifen concentrations, have more vasomotor symptoms, and are more likely to discontinue treatment, compared with poor metabolizers. â&#x20AC;&#x153;The data regarding CYP2D6 genotype and cancer recurrence [have] been mixed,â&#x20AC;? said lead investigator Matthew Goetz, MD, of the Mayo Clinic in Rochester, Minnesota. â&#x20AC;&#x153;Venlafaxine is a weak CYP2D6 inhibitor not known to alter tamoxifen pharmacokinetics and is commonly recommended for tamoxifen-induced hot flashes.â&#x20AC;?

Women with tamoxifen-induced vasomotor symptoms requiring ameliorative treatment with venlafaxine were predominantly CYP2D6 extensive and ultrarapid metabolizers.

Venlafaxine significantly decreased

30

March 2013 I VOL 6, NO 2

endoxifen concentrations. Across all genetic subgroups, levels were

depressed by a median of about 1.6 ng/mL over time (P = .04). Limited

evidence suggests that at least 6 ng/mL is needed for the prevention of breast

(continued) Table 1. Adverse Reactions in the Randomized Trial XTANDI N = 800 Grade 1-4 Grade 3-4 (%) (%)

XTANDIÂŽ (enzalutamide) capsules for oral use Initial U.S. Approval: 2012 BRIEF SUMMARY OF PRESCRIBING INFORMATION The following is a brief summary: please see the package insert for full prescribing information.

------------------------------ INDICATIONS AND USAGE ----------------------------XTANDI is indicated for the treatment of patients with metastatic castrationresistant prostate cancer who have previously received docetaxel.

--------------------------------- CONTRAINDICATIONS ------------------------------Pregnancy XTANDI can cause fetal harm when administered to a pregnant woman based on its mechanism of action. XTANDI is not indicated for use in women. XTANDI is contraindicated in women who are or may become pregnant. If this drug is used during pregnancy, or if the patient becomes pregnant while taking this drug, apprise the patient of the potential hazard to the fetus and the potential risk for pregnancy loss >VHH 8VH LQ 6SHFLÂżF 3RSXODWLRQV@.

-------------------------- WARNINGS AND PRECAUTIONS ------------------------Seizure In the randomized clinical trial, 7 of 800 (0.9%) patients treated with XTANDI 160 mg once daily experienced a seizure. No seizures occurred in patients treated with placebo. Seizures occurred from 31 to 603 days after initiation of XTANDI. Patients experiencing seizure were permanently discontinued from therapy and all seizures resolved. There is no clinical trial experience re-administering XTANDI to patients who experienced seizures.

The safety of XTANDI in patients with predisposing factors for seizure is not known because these patients were excluded from the trial. These exclusion criteria included a history of seizure, underlying brain injury with loss of consciousness, transient ischemic attack within the past 12 months, cerebral vascular accident, brain metastases, brain arteriovenous malformation or the use of concomitant medications that may lower the seizure threshold.

Because of the risk of seizure associated with XTANDI use, patients should be advised of the risk of engaging in any activity where sudden loss of consciousness could cause serious harm to themselves or others.

--------------------------------- ADVERSE REACTIONS ------------------------------Clinical Trial Experience Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared WR UDWHV LQ WKH FOLQLFDO WULDOV RI DQRWKHU GUXJ DQG PD\ QRW UHĂ&#x20AC;HFW WKH UDWHV REVHUYHG in practice.

In the randomized clinical trial in patients with metastatic castration-resistant prostate cancer who had previously received docetaxel, patients received XTANDI 160 mg orally once daily (N = 800) or placebo (N = 399). The median duration of treatment was 8.3 months with XTANDI and 3.0 months with placebo.

All patients continued androgen deprivation therapy. Patients were allowed, but not required, to take glucocorticoids. During the trial, 48% of patients on the XTANDI arm and 46% of patients on the placebo arm received glucocorticoids.

All adverse events and laboratory abnormalities were graded using NCI CTCAE version 4.

7KH PRVW FRPPRQ DGYHUVH GUXJ UHDFWLRQV Â&#x2022; UHSRUWHG LQ SDWLHQWV UHFHLYLQJ XTANDI in the randomized clinical trial were asthenia/fatigue, back pain, GLDUUKHD DUWKUDOJLD KRW Ă&#x20AC;XVK SHULSKHUDO HGHPD PXVFXORVNHOHWDO SDLQ KHDGDFKH upper respiratory infection, muscular weakness, dizziness, insomnia, lower respiratory infection, spinal cord compression and cauda equina syndrome, hematuria, paresthesia, anxiety, and hypertension. Grade 3 and higher adverse UHDFWLRQV ZHUH UHSRUWHG DPRQJ RI ;7$1', WUHDWHG SDWLHQWV DQG RI placebo-treated patients. Discontinuations due to adverse events were reported for 16% of XTANDI-treated patients and 18% of placebo-treated patients. The most common adverse reaction leading to treatment discontinuation was seizure, which occurred in 0.9% of the XTANDI-treated patients compared to none (0%) of the placebo-treated patients. Table 1 shows adverse reactions reported in the UDQGRPL]HG FOLQLFDO WULDO WKDW RFFXUUHG DW D Â&#x2022; DEVROXWH LQFUHDVH LQ IUHTXHQF\ LQ the XTANDI arm compared to the placebo arm.

Table 1. Adverse Reactions in the Randomized Trial XTANDI Placebo N = 800 N = 399 Grade 1-4 Grade 3-4 Grade 1-4 Grade 3-4 (%) (%) (%) (%) General Disorders

9.0 44.4 9.3 Asthenic Conditionsa Peripheral Edema

1.0 13.3 0.8 Musculoskeletal And Connective Tissue Disorders Back Pain 26.4

24.3 4.0 Arthralgia

17.3 1.8 Musculoskeletal Pain

1.3

0.3 Muscular Weakness 9.8

6.8 1.8 Musculoskeletal 2.6 0.3 0.3 0.0 Stiffness

B20211_1a_StopGap_Brief_PI_pg1.indd 11.30.2013 133LS

Placebo N = 399 Grade 1-4 Grade 3-4 (%) (%)

Gastrointestinal Disorders Diarrhea 21.8 1.1

0.3 Vascular Disorders Hot Flush 20.3 0.0 10.3 0.0 Hypertension 6.4 2.1 2.8 1.3 Nervous System Disorders Headache 12.1 0.9

0.0

Dizzinessb Spinal Cord 7.4 6.6

3.8 Compression and Cauda Equina Syndrome Paresthesia 6.6 0.0

0.0 4.3 0.3 1.8 0.0 Mental Impairment Disordersc Hypoesthesia 4.0 0.3 1.8 0.0 Infections And Infestations 10.9 0.0

0.3 Upper Respiratory Tract Infectiond Lower Respiratory

2.4 4.8 1.3 Tract And Lung e Infection Psychiatric Disorders Insomnia 8.8 0.0 6.0

Anxiety

0.3 4.0 0.0 Renal And Urinary Disorders Hematuria 6.9 1.8

1.0 Pollakiuria 4.8 0.0

0.0 Injury, Poisoning And Procedural Complications Fall 4.6 0.3 1.3 0.0 Non-pathologic 4.0 1.4 0.8 0.3 Fractures Skin And Subcutaneous Tissue Disorders Pruritus 3.8 0.0 1.3 0.0 Dry Skin

0.0 1.3 0.0 Respiratory Disorders Epistaxis 3.3 0.1 1.3 0.3 a Includes asthenia and fatigue. b Includes dizziness and vertigo. c Includes amnesia, memory impairment, cognitive disorder, and disturbance in attention. d Includes nasopharyngitis, upper respiratory tract infection, sinusitis, rhinitis, pharyngitis, and laryngitis. e Includes pneumonia, lower respiratory tract infection, bronchitis, and lung infection.

Laboratory Abnormalities ,Q WKH UDQGRPL]HG FOLQLFDO WULDO *UDGH QHXWURSHQLD RFFXUUHG LQ RI patients on XTANDI (1% Grade 3-4) and in 6% of patients on placebo (no Grade 3-4). The incidence of Grade 1-4 thrombocytopenia was similar in both DUPV RI SDWLHQWV RQ ;7$1', DQG RQ SODFHER H[SHULHQFHG *UDGH thrombocytopenia. Grade 1-4 elevations in ALT occurred in 10% of patients on ;7$1', *UDGH DQG RI SDWLHQWV RQ SODFHER *UDGH

Grade 1-4 elevations in bilirubin occurred in 3% of patients on XTANDI and 2% of patients on placebo.

Infections In the randomized clinical trial, 1.0% of patients treated with XTANDI compared to 0.3% of patients on placebo died from infections or sepsis. Infection-related serious adverse events were reported in approximately 6% of the patients on both treatment arms.

Falls and Fall-related Injuries In the randomized clinical trial, falls or injuries related to falls occurred in 4.6% of patients treated with XTANDI compared to 1.3% of patients on placebo. Falls were not associated with loss of consciousness or seizure. Fall-related injuries were more severe in patients treated with XTANDI and included non-pathologic fractures, joint injuries, and hematomas.

Hallucinations In the randomized clinical trial, 1.6% of patients treated with XTANDI were reported to have Grade 1 or 2 hallucinations compared to 0.3% of patients on placebo. Of the patients with hallucinations, the majority were on opioidcontaining medications at the time of the event. Hallucinations were visual, WDFWLOH RU XQGHÂżQHG

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Breast Cancer cancer events; in the present study, 3 women with low CYP2D6 activity had levels drop below that.

Goetz acknowledged that the optimal endoxifen concentration needed for benefit is still unknown, as is the effect of venlafaxine on breast cancer outcomes. â&#x20AC;&#x153;The bottom line is that there is a decrease [in concentration]. Itâ&#x20AC;&#x2122;s small

but itâ&#x20AC;&#x2122;s statistically significant. The question really is, â&#x20AC;&#x2DC;Are there subgroups of patients in which this is important?â&#x20AC;&#x2122;â&#x20AC;?

He concluded that â&#x20AC;&#x153;given prior data linking low endoxifen concentrations with recurrence, venlafaxine should be used with caution in tamoxifen-treated patients.â&#x20AC;?

Session moderator Hiltrud Brauch,

----------------------------------DRUG INTERACTIONS ------------------------------Drugs that Inhibit or Induce CYP2C8 &R DGPLQLVWUDWLRQ RI D VWURQJ &<3 & LQKLELWRU JHPÂżEUR]LO LQFUHDVHG the composite area under the plasma concentration-time curve (AUC) of enzalutamide plus N-desmethyl enzalutamide in healthy volunteers.

Co-administration of XTANDI with strong CYP2C8 inhibitors should be avoided if possible. If co-administration of XTANDI with a strong CYP2C8 inhibitor cannot be avoided, reduce the dose of XTANDI >VHH 'RVDJH DQG $GPLQLVWUDWLRQ

DQG &OLQLFDO 3KDUPDFRORJ\ @ The effects of CYP2C8 inducers on the pharmacokinetics of enzalutamide have not been evaluated LQ YLYR. Co-administration of XTANDI with strong or moderate CYP2C8 inducers (e.g., rifampin) may alter the plasma exposure of XTANDI and should be avoided if possible. Selection of a concomitant medication with no or minimal CYP2C8 induction potential is recommended >VHH &OLQLFDO 3KDUPDFRORJ\@ Drugs that Inhibit or Induce CYP3A4 Co-administration of a strong CYP3A4 inhibitor (itraconazole) increased the composite AUC of enzalutamide plus N-desmethyl enzalutamide by 1.3 fold in healthy volunteers >VHH &OLQLFDO 3KDUPDFRORJ\ @ The effects of CYP3A4 inducers on the pharmacokinetics of enzalutamide have not been evaluated LQ YLYR. Co-administration of XTANDI with strong CYP3A4 inducers (e.g., carbamazepine, phenobarbital, phenytoin, rifabutin, rifampin, rifapentine) may decrease the plasma exposure of XTANDI and should be avoided if possible. Selection of a concomitant medication with no or minimal CYP3A4 induction potential is recommended. Moderate CYP3A4 inducers (e.g., ERVHQWDQ HIDYLUHQ] HWUDYLULQH PRGDÂżQLO QDIFLOOLQ DQG 6W -RKQÂśV :RUW PD\ DOVR reduce the plasma exposure of XTANDI and should be avoided if possible >VHH &OLQLFDO 3KDUPDFRORJ\ @.

Effect of XTANDI on Drug Metabolizing Enzymes Enzalutamide is a strong CYP3A4 inducer and a moderate CYP2C9 and CYP2C19 inducer in humans. At steady state, XTANDI reduced the plasma exposure to midazolam (CYP3A4 substrate), warfarin (CYP2C9 substrate), and omeprazole (CYP2C19 substrate). Concomitant use of XTANDI with narrow therapeutic index drugs that are metabolized by CYP3A4 (e.g., alfentanil, cyclosporine, dihydroergotamine, ergotamine, fentanyl, pimozide, quinidine, sirolimus and tacrolimus), CYP2C9 (e.g., phenytoin, warfarin) and CYP2C19 (e.g., S-mephenytoin) should be avoided, as enzalutamide may decrease their exposure. If co-administration with warfarin cannot be avoided, conduct additional INR monitoring >VHH &OLQLFDO 3KDUPDFRORJ\ @.

-------------------------- USE IN SPECIFIC POPULATIONS -----------------------Pregnancy- Pregnancy Category X >VHH &RQWUDLQGLFDWLRQV@ XTANDI can cause fetal harm when administered to a pregnant woman based on its mechanism of action. While there are no human or animal data on the use of XTANDI in pregnancy and XTANDI is not indicated for use in women, it is important to know that maternal use of an androgen receptor inhibitor could affect development of the fetus. XTANDI is contraindicated in women who are or may become pregnant while receiving the drug. If this drug is used during pregnancy, or if the patient becomes pregnant while taking this drug, apprise the patient of the potential hazard to the fetus and the potential risk for pregnancy loss. Advise females of reproductive potential to avoid becoming pregnant during treatment with XTANDI. Nursing Mothers XTANDI is not indicated for use in women. It is not known if enzalutamide is excreted in human milk. Because many drugs are excreted in human milk, and because of the potential for serious adverse reactions in nursing infants from XTANDI, a decision should be made to either discontinue nursing, or discontinue the drug taking into account the importance of the drug to the mother.

Pediatric Use Safety and effectiveness of XTANDI in pediatric patients have not been established.

Geriatric Use Of 800 patients who received XTANDI in the randomized clinical trial, 71 percent ZHUH DQG RYHU ZKLOH SHUFHQW ZHUH DQG RYHU 1R RYHUDOO GLIIHUHQFHV in safety or effectiveness were observed between these patients and younger SDWLHQWV 2WKHU UHSRUWHG FOLQLFDO H[SHULHQFH KDV QRW LGHQWLÂżHG GLIIHUHQFHV LQ responses between the elderly and younger patients, but greater sensitivity of some older individuals cannot be ruled out.

Patients with Renal Impairment A dedicated renal impairment trial for XTANDI has not been conducted. Based on the population pharmacokinetic analysis using data from clinical trials in patients with metastatic castration-resistant prostate cancer and healthy YROXQWHHUV QR VLJQLÂżFDQW GLIIHUHQFH LQ HQ]DOXWDPLGH FOHDUDQFH ZDV REVHUYHG LQ SDWLHQWV ZLWK SUH H[LVWLQJ PLOG WR PRGHUDWH UHQDO LPSDLUPHQW P/ PLQ Â&#x201D; FUHDWLQLQH FOHDUDQFH >&U&/@ Â&#x201D; P/ PLQ FRPSDUHG WR SDWLHQWV DQG YROXQWHHUV ZLWK EDVHOLQH QRUPDO UHQDO IXQFWLRQ &U&/ Â&#x2022; P/ PLQ 1R LQLWLDO GRVDJH adjustment is necessary for patients with mild to moderate renal impairment.

Severe renal impairment (CrCL < 30 mL/min) and end-stage renal disease have not been assessed >VHH &OLQLFDO 3KDUPDFRORJ\@.

Patients with Hepatic Impairment A dedicated hepatic impairment trial compared the composite systemic exposure of enzalutamide plus N-desmethyl enzalutamide in volunteers with baseline mild or moderate hepatic impairment (Child-Pugh Class A and B, respectively) versus healthy controls with normal hepatic function. The composite AUC of enzalutamide plus N-desmethyl enzalutamide was similar in volunteers with mild or moderate baseline hepatic impairment compared to volunteers with normal hepatic function. No initial dosage adjustment is necessary for patients with baseline mild or moderate hepatic impairment. Baseline severe hepatic impairment (Child-Pugh Class C) has not been assessed >VHH &OLQLFDO 3KDUPDFRORJ\@

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B20211_1a_StopGap_Brief_PI_pg2.indd 11.30.2013 133LS

PhD, of the Margarete Fischer-Bosch Institute of Clinical Pharmacology in Stuttgart, Germany, led a 2009 study showing that variations in CYP2D6 metabolism have an effect on disease-free and event-free survival in patients taking tamoxifen. â&#x20AC;&#x153;Poor metabolizers do not benefit from tamoxifen as well as extensive metabolizers,â&#x20AC;? she said.

â&#x20AC;&#x153;The long and the short of it is that this matters to women.â&#x20AC;? l Reference Goetz MP, Suman V, Henry NL, et al. Venlafaxine inhibits the CYP2D6 mediated metabolic activation of tamoxifen: results of a prospective multicenter study: (NCT00667121). Presented at: 2012 CTRC-AACR San Antonio Breast Cancer Symposium; December 4-8, 2012; San Antonio, TX. Abstract PD10-08.

-------------------------------------- OVERDOSAGE -------------------------------------In the event of an overdose, stop treatment with XTANDI and initiate general VXSSRUWLYH PHDVXUHV WDNLQJ LQWR FRQVLGHUDWLRQ WKH KDOI OLIH RI GD\V ,Q D GRVH escalation study, no seizures were reported at < 240 mg daily, whereas 3 seizures were reported, 1 each at 360 mg, 480 mg, and 600 mg daily. Patients may be at increased risk of seizures following an overdose.

Carcinogenesis, Mutagenesis, Impairment of Fertility Long-term animal studies have not been conducted to evaluate the carcinogenic potential of enzalutamide.

Enzalutamide did not induce mutations in the bacterial reverse mutation (Ames) assay and was not genotoxic in either the LQ YLWUR mouse lymphoma thymidine kinase (Tk) gene mutation assay or the LQ YLYR mouse micronucleus assay. %DVHG RQ QRQFOLQLFDO ÂżQGLQJV LQ UHSHDW GRVH WR[LFRORJ\ VWXGLHV ZKLFK ZHUH consistent with the pharmacological activity of enzalutamide, male fertility may be impaired by treatment with XTANDI. In a 26-week study in rats, atrophy RI WKH SURVWDWH DQG VHPLQDO YHVLFOHV ZDV REVHUYHG DW Â&#x2022; PJ NJ GD\ HTXDO to the human exposure based on AUC). In 4- and 13-week studies in dogs, hypospermatogenesis and atrophy of the prostate and epididymides were observed DW Â&#x2022; PJ NJ GD\ WLPHV WKH KXPDQ H[SRVXUH EDVHG RQ $8&

PATIENT COUNSELING INFORMATION See FDA-approved patient labeling (PATIENT INFORMATION). Â&#x2021; ,QVWUXFW SDWLHQWV WR WDNH WKHLU GRVH DW WKH VDPH WLPH HDFK GD\ RQFH GDLO\

XTANDI can be taken with or without food. Each capsule should be swallowed whole. Do not chew, dissolve, or open the capsules. Â&#x2021; ,QIRUP SDWLHQWV UHFHLYLQJ D *Q5+ DQDORJ WKDW WKH\ QHHG WR PDLQWDLQ WKLV treatment during the course of treatment with XTANDI. Â&#x2021; ,QIRUP SDWLHQWV WKDW ;7$1', KDV EHHQ DVVRFLDWHG ZLWK DQ LQFUHDVHG risk of seizure. Discuss conditions that may predispose to seizures and medications that may lower the seizure threshold. Advise patients of the risk of engaging in any activity where sudden loss of consciousness could cause serious harm to themselves or others. Â&#x2021; ,QIRUP SDWLHQWV WKDW ;7$1', PD\ FDXVH GL]]LQHVV PHQWDO LPSDLUPHQW paresthesia, hypoesthesia, and falls. Â&#x2021; ,QIRUP SDWLHQWV WKDW WKH\ VKRXOG QRW LQWHUUXSW PRGLI\ WKH GRVH RU VWRS ;7$1', ZLWKRXW ÂżUVW FRQVXOWLQJ WKHLU SK\VLFLDQ ,QIRUP SDWLHQWV WKDW if they miss a dose, then they should take it as soon as they remember.

If they forget to take the dose for the whole day, then they should take their normal dose the next day. They should not take more than their prescribed dose per day. Â&#x2021; $SSULVH SDWLHQWV RI WKH FRPPRQ VLGH HIIHFWV DVVRFLDWHG ZLWK ;7$1', DVWKHQLD IDWLJXH EDFN SDLQ GLDUUKHD DUWKUDOJLD KRW Ă&#x20AC;XVK SHULSKHUDO edema, musculoskeletal pain, headache, upper respiratory infection, muscular weakness, dizziness, insomnia, lower respiratory infection, spinal cord compression and cauda equina syndrome, hematuria, paresthesia, anxiety, and hypertension. Direct the patient to a complete list of adverse drug reactions in PATIENT INFORMATION. Â&#x2021; ,QIRUP SDWLHQWV WKDW ;7$1', PD\ EH KDUPIXO WR D GHYHORSLQJ IHWXV Patients should also be informed that they should use a condom if having sex with a pregnant woman. A condom and another effective method of birth control should be used if the patient is having sex with a woman of child-bearing potential. These measures are required during and for three months after treatment with XTANDI.

Manufactured by: Catalent Pharma Solutions, LLC, St. Petersburg, FL 33716 Manufactured for and Distributed by: Astellas Pharma US, Inc., Northbrook, IL 60062 Marketed by: Astellas Pharma US, Inc., Northbrook, IL 60062 0HGLYDWLRQ ,QF 6DQ )UDQFLVFR &$ Issued: August 2012 $ (1= %56 Rx Only Š 2012 Astellas Pharma US, Inc. XTANDIŽ is a registered trademark of Astellas Pharma Inc.

ONCOLOGY

March 2013 I VOL 6, NO 2

31

For the treatment of patients with metastatic castration-resistant prostate cancer (mCRPC) who have previously received docetaxel

18.4 MONTHS MEDIAN OVERALL SURVIVALL VS 13.6 MONTHS WITH PLACEBO

AND...

• 37% reduction in risk of death vs placebo

(P < 0.0001; HR = 0.63 [95% CI, 0.53, 0.75])1

• XTANDI can be taken with or without food1 • Patients were allowed, but not required, to take glucocorticoids1

—

In the clinical trial, 48% of patients in the XTANDI arm and 46% of patients in the placebo arm received glucocorticoids1

• Oral, once-daily dosing1 • The rate of grade 3 and higher adverse reactions with XTANDI was 47% vs placebo at 53%1

• Seven patients (0.9%) out of 800 treated

with XTANDI 160 mg once daily experienced a seizure. No seizures occurred in patients treated with placebo1

AFFIRM: A phase 3, global, placebo-controlled, randomized study of patients with mCRPC who previously received docetaxel1

XTANDI (enzalutamide) capsules is indicated for the treatment of patients with metastatic castration-resistant prostate cancer (mCRPC) who have previously received docetaxel.

Important Safety Information Contraindications XTANDI can cause fetal harm when administered to a pregnant woman based on its mechanism of action. XTANDI is not indicated for use in women. XTANDI is contraindicated in women who are or may become pregnant.

Warnings and Precautions In the randomized clinical trial, seizure occurred in 0.9% of patients on XTANDI. No patients on the placebo arm experienced seizure. Patients experiencing a seizure were permanently discontinued from therapy. All seizures resolved.

Patients with a history of seizure, taking medications known to decrease the seizure threshold, or with other risk factors for seizure were excluded from the clinical trial. Because of the risk of seizure associated with XTANDI use, patients should be advised of the risk of engaging in any activity where sudden loss of consciousness could cause serious harm to themselves or others.

Adverse Reactions The most common adverse drug reactions (≥ 5%) reported in patients receiving XTANDI in the randomized clinical trial were asthenia/fatigue, back pain, diarrhea, arthralgia, hot flush, peripheral edema, musculoskeletal pain, headache, upper respiratory infection, muscular weakness, dizziness, insomnia, lower respiratory

NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines®) include enzalutamide (XTANDI) with a category 1 recommendation for use following docetaxel in patients with mCRPC.2 infection, spinal cord compression and cauda equina syndrome, hematuria, paresthesia, anxiety, and hypertension.

Drug Interactions XTANDI is a strong CYP3A4 inducer and a moderate CYP2C9 and CYP2C19 inducer in humans. Administration of strong CYP2C8 inhibitors can increase the plasma exposure to XTANDI. Co-administration of XTANDI with strong CYP2C8 inhibitors should be avoided if possible. If co-administration of XTANDI cannot be avoided, reduce the dose of XTANDI. Co-administration of XTANDI with strong or moderate CYP3A4 and CYP2C8 inducers can alter the plasma exposure of XTANDI and should be avoided if possible. Avoid CYP3A4, CYP2C9 and CYP2C19 substrates with a narrow therapeutic index, as XTANDI may decrease the plasma exposures of these drugs.

If XTANDI is co-administered with warfarin (CYP2C9 substrate), conduct additional INR monitoring.

Please see adjacent pages for brief summary of Full Prescribing Information.

L Learn earn m more ore a att X XtandiHCP.com tandiHCP.com References: 1. XTANDI [prescribing information]. Northbrook, IL: Astellas Pharma US, Inc; 2012.

2. Referenced with permission from The NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines®) for Prostate Cancer V.1.2013. © National Comprehensive Cancer Network, Inc 2012. All rights reserved. Accessed December 20, 2012. To view the most recent and complete version of the guidelines, go online to www.nccn.org. NATIONAL COMPREHENSIVE CANCER NETWORK®, NCCN®, NCCN GUIDELINES®, and all other NCCN Content are trademarks owned by the National Comprehensive Cancer Network, Inc. © 2013 Astellas Pharma US, Inc. All rights reserved. Printed in USA. 013A-076-7020 1/13 XTANDI, Astellas, and the flying star logo are trademarks of Astellas Pharma Inc.