TOP October 2013 by The Oncology Pharmacist

OCTOBER 2013

www.TheOncologyPharmacist.com

VOL 6, NO 4

COMPLIMENTARY CE Considerations in Multiple Myeloma—Ask the Experts: The Role of Transplantation

see page 22

ONCOLOGY PHARMACY SAFETY

CANCER CENTER PROFILE

Memorial Sloan-Kettering Cancer Center

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

Chemotherapy: Every Step You Take, Every Move You Make…

Oncology Pharmacists on the Front Lines By Alice Goodman

Christine Roussel, PharmD, BCOP Clinical Pharmacy Manager, Doylestown Hospital Pharmacy Thomas H. Connor, PhD Research Biologist, National Institute for Occupational Safety and Health

I The oncology pharmacy team at Memorial Sloan-Kettering Cancer Center. Richard Tizon, PharmD, BCOP, is in the second row, third from left.

emorial Sloan-Kettering Cancer Center (MSKCC) is 1 of 41 National Cancer Institute–designated comprehensive cancer centers. Founded in 1884 as the New York Cancer Hospital, the hospital had its name changed in 1916 to the General Memorial Hospital for the Treatment of Cancer and Allied Diseases. The facility moved to its current location in New York City in 1936. The Sloan-Kettering Institute, established in 1945, incorporated with Memorial Hospital in 1960 to better apply laboratory advances to the care and treatment of patients. Today, MSKCC has 469 inpatient beds and provides state-of-theart outpatient services, offering comprehensive care using the latest technology via a multidisciplinary approach. MSKCC is also a fertile ground for clinical trials that advance the standard of care nationwide. Richard Tizon, PharmD, BCOP, clinical pharmacy manager, talked to The Oncology Pharmacist about his work at MSKCC and the role that oncology pharmacists play in multidisciplinary care.

n the May 2013 issue of The Oncology Pharmacist, Roussel and Connor described some of the hazards associated with working with antineoplastic drugs in the pharmacy and discussed some of the published recommendations for their safe handling.1 The present article describes sources of workplace contamination with hazardous drugs and how healthcare workers may be exposed

Raising Awareness of Cancer Anorexia-Cachexia Syndrome in Patients With Lung Cancer By Alice Goodman

ancer anorexia-cachexia syndrome (CACS) is underrecognized and underreported in patients with advanced lung cancer receiving routine clinical care, according

s October is Breast Cancer Awareness Month, this month’s column focuses on several studies in the literature about breast cancer that explore such topics as survival among people who carry the BRCA1 mutation, potential mark-

Breast Cancer BREAST CANCER IN THE NEWS

By Alice Goodman

ers for response to endocrine therapy, overdiagnosis and overtreatment of women with ductal carcinoma in situ (DCIS), and mistaken perceptions among women about their personal risk of developing breast cancer.

to a retrospective, single-institution study presented at the 2013 Annual Meeting of the Multinational Association of Supportive Care in Cancer (MASCC). Continued on page 20

INSIDE NOTEWORTHY NUMBERS . . . . . . . . .

Breast Cancer in the News

Continued on page 8

SIDE EFFECTS MANAGEMENT

Continued on page 31

NEWS BRIEFS

to hazardous drugs during the course of their duties. Measurement of surface contamination is currently the only indication of the amount of environmental contamination in areas where hazardous drugs are prepared, administered to patients, or otherwise handled (such as receiving areas, in transit throughout the facil-

Predictors of Survival Benefit From Endocrine Therapy. . . . . . . . . . 14 DCIS Overdiagnosed and Overtreated in the United States. . 14 1 in 5 Women Do Not Believe Their Breast Cancer Risk Assessment. . 15

Similar Survival in Early BRCA1Positive and -Negative Breast Cancer. . . . . . . . . . . . . . . . . . . . . DRUG ECONOMICS . . . . . . . . . . . . . .

15 20

Off-Label Drug Use Accounts for 18% of Spending DRUG SHORTAGES. . . . . . . . . . . . . . .

Surveys Confirm Drug Shortages Are a Persistent Problem

Coming soon

GRANIX™ is a new option in short-acting G-CSF therapy

Teva’s filgrastim, the same compound as GRANIX, is now available in 39 countries*1

Approved through the rigorous US BLA† process

*As of August 2013.

Brought to you by Teva—a top-10 global pharmaceutical company‡2 » 1 out of every 6 prescriptions filled daily in the US is a Teva product » Teva offers supportive care, hematologic and oncolytic malignancy products; with a substantial portfolio of more than 50 oncology products in the US » Teva uses state-of-the-art manufacturing facilities and the most advanced testing equipment to produce quality biologics ‡

Excluding supportive care.

Indication » GRANIX is a leukocyte growth factor indicated for reduction in the duration of severe neutropenia in patients with nonmyeloid malignancies receiving myelosuppressive anticancer drugs associated with a clinically significant incidence of febrile neutropenia.

Important Safety Information » Splenic rupture: Splenic rupture, including fatal cases, can occur following the administration of human granulocyte colony-stimulating factors (hG-CSFs). Discontinue GRANIX and evaluate for an enlarged spleen or splenic rupture in patients who report upper abdominal or shoulder pain after receiving GRANIX. » Acute respiratory distress syndrome (ARDS): ARDS can occur in patients receiving hG-CSFs. Evaluate patients who develop fever and lung infiltrates or respiratory distress after receiving GRANIX, for ARDS. Discontinue GRANIX in patients with ARDS. » Allergic reactions: Serious allergic reactions, including anaphylaxis, can occur in patients receiving hG-CSFs. Reactions can occur on initial exposure. Permanently discontinue GRANIX in patients with serious allergic reactions. Do not administer GRANIX to patients with a history of serious allergic reactions to filgrastim or pegfilgrastim. » Use in patients with sickle cell disease: Severe and sometimes fatal sickle cell crises can occur in patients with sickle cell disease receiving hG-CSFs. Consider the potential risks and benefits prior to the administration of GRANIX in patients with sickle cell disease. Discontinue GRANIX in patients undergoing a sickle cell crisis. » Potential for tumor growth stimulatory effects on malignant cells: The granulocyte colony-stimulating factor (G-CSF) receptor, through which GRANIX acts, has been found on tumor cell lines. The possibility that GRANIX acts as a growth factor for any tumor type, including myeloid malignancies and myelodysplasia, diseases for which GRANIX is not approved, cannot be excluded. » Most common treatment-emergent adverse reaction: The most common treatment-emergent adverse reaction that occurred in patients treated with GRANIX at the recommended dose with an incidence of at least 1% or greater and two times more frequent than in the placebo group was bone pain. Please see adjacent brief summary of full Prescribing Information. References: 1. Data on file. Teva Pharmaceuticals: Filgrastim MA Approvals Worldwide. May 2013. 2. EvaluatePharma®, March 2013. †

Biologics License Application.

NOTEWORTHY NUMBERS

Breast Cancer Throughout the year, many organizations promote breast cancer awareness. Especially during October, Breast Cancer Awareness Month, healthcare professionals, public service groups, and government agencies work diligently to provide education and information about the prevention, screening, diagnosis, and treatment of breast cancer. Here are a few statistics to illustrate these efforts.

The American Institute for Cancer Research estimates that 38% of all breast cancer cases in the United States could be prevented

with simple changes to everyday diet and exercise.1 If followed, these 5 rec-

BRIEF SUMMARY OF PRESCRIBING INFORMATION FOR GRANIX™ (tbo-filgrastim) Injection, for subcutaneous use SEE PACKAGE INSERT FOR FULL PRESCRIBING INFORMATION 1 INDICATIONS AND USAGE GRANIX is indicated to reduce the duration of severe neutropenia in patients with non-myeloid malignancies receiving myelosuppressive anti-cancer drugs associated with a clinically significant incidence of febrile neutropenia. 4 CONTRAINDICATIONS None. 5 WARNINGS AND PRECAUTIONS 5.1 Splenic Rupture Splenic rupture, including fatal cases, can occur following administration of human granulocyte colony-stimulating factors. In patients who report upper abdominal or shoulder pain after receiving GRANIX, discontinue GRANIX and evaluate for an enlarged spleen or splenic rupture. 5.2 Acute Respiratory Distress Syndrome (ARDS) Acute respiratory distress syndrome (ARDS) can occur in patients receiving human granulocyte colony-stimulating factors. Evaluate patients who develop fever and lung infiltrates or respiratory distress after receiving GRANIX, for ARDS. Discontinue GRANIX in patients with ARDS. 5.3 Allergic Reactions Serious allergic reactions including anaphylaxis can occur in patients receiving human granulocyte colony-stimulating factors. Reactions can occur on initial exposure. The administration of antihistamines‚ steroids‚ bronchodilators‚ and/or epinephrine may reduce the severity of the reactions. Permanently discontinue GRANIX in patients with serious allergic reactions. Do not administer GRANIX to patients with a history of serious allergic reactions to filgrastim or pegfilgrastim. 5.4 Use in Patients with Sickle Cell Disease Severe and sometimes fatal sickle cell crises can occur in patients with sickle cell disease receiving human granulocyte colony-stimulating factors. Consider the potential risks and benefits prior to the administration of human granulocyte colony-stimulating factors in patients with sickle cell disease. Discontinue GRANIX in patients undergoing a sickle cell crisis. 5.5 Potential for Tumor Growth Stimulatory Effects on Malignant Cells The granulocyte colony-stimulating factor (G-CSF) receptor through which GRANIX acts has been found on tumor cell lines. The possibility that GRANIX acts as a growth factor for any tumor type, including myeloid malignancies and myelodysplasia, diseases for which GRANIX is not approved, cannot be excluded. 6 ADVERSE REACTIONS The following potential serious adverse reactions are discussed in greater detail in other sections of the labeling: • Splenic Rupture [see Warnings and Precautions (5.1)] • Acute Respiratory Distress Syndrome [see Warnings and Precautions (5.2)] • Serious Allergic Reactions [see Warnings and Precautions (5.3)] • Use in Patients with Sickle Cell Disease [see Warnings and Precautions (5.4)] • Potential for Tumor Growth Stimulatory Effects on Malignant Cells [see Warnings and Precautions (5.5)] The most common treatment-emergent adverse reaction that occurred at an incidence of at least 1% or greater in patients treated with GRANIX at the recommended dose and was numerically two times more frequent than in the placebo group was bone pain. 6.1 Clinical Trials Experience Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in clinical practice. GRANIX clinical trials safety data are based upon the results of three randomized clinical trials in patients receiving myeloablative chemotherapy for breast cancer (N=348), lung cancer (N=240) and non-Hodgkin’s lymphoma (N=92). In the breast cancer study, 99% of patients were female, the median age was 50 years, and 86% of patients were Caucasian. In the lung cancer study, 80% of patients were male, the median age was 58 years, and 95% of patients were Caucasian. In the non-Hodgkin’s lymphoma study, 52% of patients were male, the median age was 55 years, and 88% of patients were Caucasian. In all three studies a placebo (Cycle 1 of the breast cancer study only) or a nonUS-approved filgrastim product were used as controls. Both GRANIX and the non-US-approved filgrastim product were administered at 5 mcg/kg subcutaneously once daily beginning one day after chemotherapy for at least five days and continued to a maximum of 14 days or until an ANC of ≥10,000 x 106/L after nadir was reached. Bone pain was the most frequent treatment-emergent adverse reaction that occurred in at least 1% or greater in patients treated with GRANIX at the

www.TheOncologyPharmacist.com

ommendations from the Centers for Disease Control and Prevention can help lower the risk of breast cancer2:

recommended dose and was numerically two times more frequent than in the placebo group. The overall incidence of bone pain in Cycle 1 of treatment was 3.4% (3.4% GRANIX, 1.4% placebo, 7.5% non-US-approved filgrastim product). Leukocytosis In clinical studies, leukocytosis (WBC counts > 100,000 x 106/L) was observed in less than 1% patients with non-myeloid malignancies receiving GRANIX. No complications attributable to leukocytosis were reported in clinical studies. 6.2 Immunogenicity As with all therapeutic proteins, there is a potential for immunogenicity. The incidence of antibody development in patients receiving GRANIX has not been adequately determined. 7 DRUG INTERACTIONS No formal drug interaction studies between GRANIX and other drugs have been performed. Drugs which may potentiate the release of neutrophils‚ such as lithium‚ should be used with caution. Increased hematopoietic activity of the bone marrow in response to growth factor therapy has been associated with transient positive bone imaging changes. This should be considered when interpreting bone-imaging results. 8 USE IN SPECIFIC POPULATIONS 8.1 Pregnancy Pregnancy Category C There are no adequate and well-controlled studies of GRANIX in pregnant women. In an embryofetal developmental study, treatment of pregnant rabbits with tbo-filgrastim resulted in adverse embryofetal findings, including increased spontaneous abortion and fetal malformations at a maternally toxic dose. GRANIX should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus. In the embryofetal developmental study, pregnant rabbits were administered subcutaneous doses of tbo-filgrastim during the period of organogenesis at 1, 10 and 100 mcg/kg/day. Increased abortions were evident in rabbits treated with tbo-filgrastim at 100 mcg/kg/day. This dose was maternally toxic as demonstrated by reduced body weight. Other embryofetal findings at this dose level consisted of post-implantation loss‚ decrease in mean live litter size and fetal weight, and fetal malformations such as malformed hindlimbs and cleft palate. The dose of 100 mcg/kg/day corresponds to a systemic exposure (AUC0-24) of approximately 50-90 times the exposures observed in patients treated with the clinical tbo-filgrastim dose of 5 mcg/kg/day. 8.3 Nursing Mothers It is not known whether tbo-filgrastim is secreted in human milk. Because many drugs are excreted in human milk, caution should be exercised when GRANIX is administered to a nursing woman. Other recombinant G-CSF products are poorly secreted in breast milk and G-CSF is not orally absorbed by neonates. 8.4 Pediatric Use The safety and effectiveness of GRANIX in pediatric patients have not been established. 8.5 Geriatric Use Among 677 cancer patients enrolled in clinical trials of GRANIX, a total of 111 patients were 65 years of age and older. No overall differences in safety or effectiveness were observed between patients age 65 and older and younger patients. 8.6 Renal Impairment The safety and efficacy of GRANIX have not been studied in patients with moderate or severe renal impairment. No dose adjustment is recommended for patients with mild renal impairment. 8.7 Hepatic Impairment The safety and efficacy of GRANIX have not been studied in patients with hepatic impairment. 10 OVERDOSAGE No case of overdose has been reported.

©2013 Cephalon, Inc., a wholly owned subsidiary of Teva Pharmaceutical Industries Ltd. All rights reserved. GRANIX is a trademark of Teva Pharmaceutical Industries Ltd. Manufactured by: Sicor Biotech UAB Vilnius, Lithuania U.S. License No. 1803 Distributed by: Teva Pharmaceuticals USA, Inc. North Wales, PA 19454 Product of Israel FIL-40045 July 2013 This brief summary is based on TBO-003 GRANIX full Prescribing Information.

• Get screened for breast cancer regularly • Control your weight and increase your physical activity • Know your family history of breast cancer • Find out the risks and benefits of hormone replacement therapy • Limit the amount of alcohol you drink In recent years, mammography screening has generated some controversy, but mammograms have been shown to lower the risk of dying of breast cancer by 35% in women over the age of 50.3 For non-Hispanic white, African American, and Hispanic women in the United States, breast cancer incidence rates differ geographically. Incidence ranges from 110.8 cases per 100,000 women in Arkansas to 140.4 cases per 100,000 in California and the District of Columbia for nonHispanic white women. Rates for African American women range from 73.2 in New Mexico to 131.0 in Delaware; and for Hispanic women, incidence ranges from 34.1 in Mississippi to 133.3 in Delaware.4 According to the American Society of Plastic Surgeons, 5,612,649 reconstructive procedures were preformed in 2012; of those, 91,655 were breast cancer reconstructive surgeries.5 Sources 1. www.aicr.org/learn-more-about-cancer/breast-cancer/? gclid=CISakI6YzLkCFWxyQgodd08AaA#facts. 2. www.cdc.gov/cancer/breast/basic_info/prevention.htm. 3. www.breastcancer.org. 4. www.cancer.org/acs/groups/content/@epidemiologysur veilance/documents/document/acspc-030975.pdf. 5. www.plasticsurgery.org/Documents/news-resources/sta tistics/2012-Plastic-Surgery-Statistics/ReconstructiveSurgery-Procedure-Trends-2012.pdf.

OCTOBER 2013 I VOL 6, NO 4

EDITORIAL BOARD EDITOR-IN-CHIEF

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

Anjana Elefante, PharmD, BSc, BSc Pharm, RPh

Dwight Kloth, PharmD, FCCP, BCOP

Timothy G. Tyler, PharmD, FCSHP

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

Jim Koeller, MS

John M. Valgus, PharmD, BCOP

Christopher Fausel, PharmD

Christopher J. Lowe, PharmD

Roswell Park Cancer Institute Buffalo, NY

Fox Chase Cancer Center Philadelphia, PA

Desert Regional Medical Center Palm Springs, CA

ASSOCIATE EDITOR-IN-CHIEF

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

John F. Aforismo, BSc Pharm, RPh, FASCP

University of Texas at Austin San Antonio, TX

Cleveland Clinic Taussig Cancer Institute Cleveland, OH

Indiana University Simon Cancer Center Indianapolis, IN

Indiana University Hospital Indianapolis, IN

David Baribeault, RPh, BCOP

Rebecca S. Finley, PharmD, MS

Emily Mackler, PharmD, BCOP

Betty M. Chan, PharmD, BCOP

David C. Gammon, BSPh

Laura Boehnke Michaud, PharmD, BCOP, FASHP

RJ Health Systems International, LLC Wethersfield, CT

Boston Medical Center Boston, MA

USC/Norris Cancer Hospital Los Angeles, CA

Jefferson School of Pharmacy Philadelphia, PA

OncologyPharmacist.net Warwick, RI

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

The University of Texas MD Anderson Cancer Center Houston, TX

University of North Carolina Hospitals and Clinics Chapel Hill, NC

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

Burt Zweigenhaft, BS

OncoMed Onco360 Great Neck, NY

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

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

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

OCTOBER 2013 I VOL 6, NO 4

Lew Iacovelli, BS, PharmD, BCOP, CPP

Moses H. Cone Health System Greensboro, NC

LeAnn Best Norris, PharmD, BCPS, BCOP South Carolina College of Pharmacy Columbia, SC

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

www.TheOncologyPharmacist.com

2ND ANNUAL

nc seri Vie olo es w gy on the Ph lin ar e a m t ac ist .co

ONQUERING THE C ANCER ARE C C

CONTINUUM

™

A 6-part series The publishers of The Oncology Nurse-APN/PA, The Oncology Pharmacist, and Personalized Medicine in Oncology are proud to present our 2nd annual Conquering the Cancer Care Continuum series. Upcoming topics include:

NEXT ISSUE

• Palliation • Pain management • Hospice care • Treatment planning • Survivorship care • Biosimilars in supportive care

FIRST ISSUE IN THE 2013 SERIES

CONQUERING THE CANCER CARE CONTINUUM CONQUERING THE A C N C E R I C O N T C ARE IN SECOND ANNUAL

SECON

D ISSUE ™ IN THE 2013 SE RIES SE C O N D ANN UAL

Changing the Image of Palliative Care Lillie D. Shockney, RN, BS, MAS

vention and relief of suffering by means of early identiam enthusiastic about this 6-part series titled Confication and impeccable assessment and treatment of quering the Cancer Care Continuum. Each edition of pain and other problems, physical, psychosocial, and CCCC will address an important topic in oncology ES RI spiritual.” (http://www.who.int/cancer/ management and offer expert stake2013 SE E TH IN ISSUE Topics will palliative/en/). IRD commentaries. THholder For too long, however, the image of include: palliative care, pain manageNU AL AN O ND ™ palliative care has been tied exclusively SE Ccare, ment, hospice comprehensive to end-of-life care and focused solely on treatment planning, survivorship care, pain control. and the role of biosimilars in supportLillie D. Sho ckney, RN , BS, MA The articles that follow provide a ive care. In this issue, we address palS n part 2 of clear understanding of the intent of liative care. our Conqu series, the ering the Ca palliative care today, with the primary Palliation in cancer care is a topic focus is on ncer Care ma Continuum pai goal ending its identification that commonly makes people (medical well tic improvements n managem ent.ofDe inabilitysolely as surgic in ph spite drato overco provideddie for wh theile dying. providers as well as patients) uncom- we still hav al procedures des armaceasuticancer me it effe cal agecare nts, as igned ctivel in gre ea p con monly res Instead, palliative be pon asso- at pain. Family y, fearing they wil fortable. I recently had the opportunity cessful on beh long way to go to be to hel ™tro l pain, care should l memb d tha suc Lillie D.alf Shockney, RN, of our patien nesscare I was recent theirforlov ciated with quality-of-life alled t their greatest fea ers, too, comto speak with members of our palliative ts. BS, MAS ly r is wa one in gre tch ute at pain wit having to witcare team at Johns Hopkins and learned ern s of an old, black- ing a few min- cancer patients and survivors, no mat- ease hout a wa and-white the suffer movie. A y to ing we cow . stter what their clinical outcome. that the word “palliative” comes from the word “palliare,” fea Fam boy r by a gunslin these ily had been shot patients may not tell you about the sidewitnes will be the final im members , and as Your tor att cancer which means to disguise or cloak. Centuries ago, this ger word s before the ages they em pted to rem the town docir ove m hisAlthough effects treatment they are experiencing or about their Many organiza loved one dies. was used for the drapes that covered afro casket. theofbul che let tions have oped me the woun st, another discomfort cow asu develdue we continue to drape coffins—most memorably withma the ded tice guidel rement tools an e to their cancer diagnosis or its treatment. n a bottle boy gav to drink d pracines for whisk many cases they may simply assume that the discomflag—the drape is no longer referred to this and term.a knife to In of ey he the lpi hisby ng pu teeth. I’m bite betwe rpo providers sure back fort enwith the disease.” However, with the imeffective se of age pain The World Health Organizationwamodified s how peoits origin the “comes ly ass day this ple coped itsit treatm ociated with can manprovements in medicine and the power of science, inal definition of palliative care as quo follows: “Palliative wit r to nu cer and ent. The h pain – mb them lifol pro harthe d toquality anymore. Docall not wait for your patients vide you with a lowing articles care is an approach that improves life and doesn’t somethhave bite onof. Th ing to ma wealth of asking him to is is far fro back BS, MAS Today him teinitiate he symptoms; be proac-tion associated m rised their to a discussion all pat problems as- . I wro ckney, RN, of patients and their families facing the ide said t sank and guidel with the inforhow surpabout ien hear Lillie D. Sho ts wh andal. se talMy that o ent of hospithrough enviro est thatat the time you are planafter tive er initiate soon and thisrequ discussion sociatedyou withthe life-threatening thenm prethat thoughines. They also pro tools a to even did next edition illness, ent He an , and inp me. wh all to ati ater be ent un ondeth tion he to bring s. This sure that tful care be taken mote Lillirma or resp e D. Sho a clinic visrateitd all for meitto of the info wastor t is my privilege cer Care Continuum serie ons, their doc all to ckney, I reite it with journey , by pho Can opti RN, cancer pat of us address wit enaskne. ed to com talk are about the long BS,ther n me weasu Conquering the ses specifically on hospice Hopee-pai MAS me �� Green Hill Healthcare Communications, told ple te a had endLLC focu ured toge experien ients the pain the h our read. of wheth rement toolhad thaand issue, which cin important to t prohis 30. er vidwife he es som to be vitally to relieve g and impleme y are nosis at age gree. Pat they are presen diag e be ial exp will nt ways init is one I believe tly res it. i iher here ien e in pain, and Pain steals n clinph of her time, psy s addressed on sio ripti what to cir ts have trosinc of aw to ysi s desc ay ubl wh cal ch way his fully, concept it soc er e, at on olo s, en d cle (a hap ial gic durance Base however, intlimited deand bett alertnes tually pain was and can ma al well-being, n and erpreting ely ill. e or adopted as newterminally ill cancer I absent for bad in the py faccal and con a ditio ke quali grav y sad facshe som an cause the morning ver e) ifwas supporting our r families. ent that theirthe doctord adequate treatme patients. Accur ty of life viry evidno but t so bad thei ate assess ment ne doctor. Fur took a pain pillwas ent for ing an nowght that I thou patients and before himcom years ago gett He self thatthehecan ed to be prioritie effective pain ma ment himbeing viewed by thermore, is thitold ssetod see e . I recall several tr s Bill s di s cer na for his o inf ed s the ger any s fie orm all of us wa ld. one dur ation cult a man nam and someti tolylinger afte I fee working diffi actual rnet and e-mail from it So ir vis dit? next l confident you remes it is no ing thefoun in via the Inte metimnesregarding thisprovok t. will find Certainl had found me ing that his young it is, what he is ing and con f conversatio stat that taining val these articles tho will assaist cer patien y one of the greate brie can st canMary. And wrote to me ught st fearsfor uable ts is the you in exp metastatic brea fear of pai step webut ressed is not a drug oncan ll(He as develo reassessing your information that herby ing wife, Mary, had gressed to her liver, n plac and ice. now pin cur suffering called hosp future ren g more effe pro and the cer that had ctive ways t patients as n. She was eipatients hav special program before eie quality and now brai Lilliesleeping rd this term fectively lungs, bone, of life by to help your had not hea n to explain some ofmanaged. Q hospital and D. Shockney, RN having pai I bega , BS, MAS currently in the awake, confused at n ef©ther , he .)3As 201 Greenefits was hospice care RN, of alth more than she ben Hill He “had still Shockney, my key D. but lie, car the ht, Lillie “Lil weig l t and said, e Communi I ons untifou MAS times, losing chemotherapy he , LLC got very upse , 6 and 8 years old. cati rth issue of BS, g doctor been receivin e 2 sons the Co she hav that nq that We te uer die. wro Continuum cann theotCancer alone.” I then told him k with wifeing yesterday.” He for the last ser thiad s n care of her would wor dresse raise them Care staff and meet himies nin e and cansnot sitIua who had take Treat g Thro ice to com tio ir mTh said omeand ment hosp ugs.hHethe asked him Planlosing then. Followiabo next step go n n for the Ca would die but that 4 years had ng utare ds who al of the team these childre a while ncer Ca room to talk re tin rap paon 2 er for art andy frien preC outco is optimal him tore morning in her onthe uu me t would ling key ng ily members icl imm. e, ogis s. fam es col plac rol tify to medical e he iden hasized the im pro t taki of ns were empere vidhim help e insightraise these boys. I Th clinic that usually ad discussiothe are – adof that al s som now said ph int type gis him e or row armacolo e co o doct in a as brie ks ly a me would help f. The lowhenever thes was tvery ugh nsiderations tha mber all the duccal to bee Tho ng ing “goi etc. n gett of , he abs of was rney t have his en but can ance plilong mutoltidiscport king, so he thet on nary but this time no , power of atto realized thattthis er wor tea toriiwill no e, i im wen lon ctiv wo then ger remain ce dire ng llabo ed, he husbandrki treatments were to izz.” 5 want so. Patients ly overwhelm rativelyvan t find the hosp renThe she died just to know abo der recin but I can’co he was obvious put my wife on soon. Though ut the pros ndati drug Hercept ommeabou t how treatm d the of treatmen onseff--abou did have to happen very and cons hing entmepla anyt write, “I foun t t, tell risk nn you s?” ing s met Can an d benefits, their quali drug Hospizz. are liver, and lungoptions. Gone thebrai n, s, day what is for ty of life wi or fective this drug ll be while oncology spe they should be, when treatment ons, LLC on as well as aft cialists me n Hill Healthcare Communicati rely passed er treatmen – either on completed © 2013 Gree on t is .

the g n i r e u q n Co ancer ICare C M

UUM

Introduc tion to O ncology Pain Ma nagem ent

CONTIN

FOURTH

ISSUE IN THE 201 3 SERIES S E CPa ntsA Otie ND to t or NNUAL pp al Su itic Cr g in re: Provid Hospice Ca s and Familie

Conquering t Cancer Carehe CONTI

NUUM

™

Personaliz ed Treatm ent Plann ing

paper or ele And there is a new wr ctronically prescription kle in the inin – treatment ins plann by the pharm tructions to be filled – what wil l this treatm ing process acologist or ent cost? W These ind pharmacist. patients ha ividuals, ex ill ve to pay ou perts in dru t of pocke manageme their treatm t for g nt, i ent? Is the cost of tre mization, are nteraction, and opt ment worth at atiintegral to the clinic the oncology care team. al outcome to be achiev You will s ed? No pa soo tients want learn why. n read an leave their Lillie D. Sh d to ockney, family in RN, deep debt, although we And speaki BS, MAS an d ha ng of the tea that the pat era of person ve entered an excitin m, it is cri tically impo g ient, and cer alized medic rtant tain family cases, be con of these ne ine, the cos compared members in w drugs is t sidered me with treatm incredibly some mbers of the ning team. ents we ha high to in the We should ve been acc past. Even not be doing treatment plan we must be nust prior treatm omed been daunti things to a doing thing ent regim patient; ng from a s with a pat patients, of ens have cost perspe ient. Thou Everyone course, are ctive. gh the wa not expert many have s on oncol the right tre nts to make sure tha desperatel ogy care, t the patien atment at y tried to sort by tur the right tim t gets become ex way. Now ning to the perts off a e and in the clinicians Internet an for themselv must realize d trying to right treatment’s es what tre determine that treatm sake is ne atment wo ent for ver wise an uld be bes Thoughtfu t for their d not the l decision mi s ssion. about treatm and patients ent are a , oncologist must, s, pharmaco logists, pa © 2013 Gr lliative een Hill He althcare Co mmunicatio ns, LLC

TOPKsizeCCC_081513

TO VIEW THE SERIES ONLINE PLEASE LOG ON TO:

TheOncologyPharmacist.com

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

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

Patrick Medina, PharmD, BCOP Editor-in-Chief

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

n this month’s issue of The Oncology Pharmacist (TOP), we present the second in a series of articles about oncology pharmacy safety and issues related to hazardous materials in the workplace. Christine Roussel, PharmD, BCOP, and Thomas H. Connor, PhD, discuss the sources of workplace contamination and how healthcare workers may be exposed to hazardous drugs during the course of their duties. Roussel and Connor point out that “Although other routes (inhalation, oral, needlesticks) may be factors in uptake of these drugs, the dermal route appears to be the most common.” They emphasize that “while appropriate facility design and proper equipment are critical, so is a strong employee training program with continuing education” to promote compliance and safety. October is Breast Cancer Awareness Month. The September 30, 2013, presidential proclamation acknowledging this points out that “This disease touches every

corner of the United States—in 2013 alone, more than 230,000 women and over 2,000 men will be diagnosed with breast cancer, and tens of thousands will die from it.” In this issue of TOP, we bring you some of the latest research news as well as present some basic statistics about the disease in Noteworthy Numbers. Be sure to read the article about the continuing problem of drug shortages. Presentations at the 2013 American Society of Clinical Oncology Annual Meeting confirm that this is a persistent problem that affects how healthcare professionals practice medicine and how patients with cancer receive care. One especially worrisome aspect is how the drug shortages have interfered with patient participation in clinical trials. Please visit our website, www.TheOncologyPharmacist. com, and tell us what topics you want to see covered in TOP. We appreciate your feedback—positive and negative—about what you see in print and on the website. l

READER POLL Are you involved in recommending patients for clinical trials? o Yes o No

Director, Production & Manufacturing Alaina Pede Director, Creative & Design Robyn Jacobs Creative & Design Assistant Lora LaRocca Director, Digital Media Anthony Romano Web Content Managers David Maldonado Anthony Travean Digital Programmer Michael Amundsen Senior Project Manager Andrea Boylston Project Coordinators Deanna Martinez Jackie Luma Executive Administrator Rachael Baranoski Office Coordinator Robert Sorensen

1249 South River Road - Ste 202A Cranbury, NJ 08512 phone: 732-656-7935 fax: 732-656-7938

OCTOBER 2013 I VOL 6, NO 4

©iStockphoto.com/Slobodan Vasic

Go to www.TheOncologyPharmacist.com to answer the question and add your comments.

The Oncology Pharmacist®, ISSN 1944-9607 (print); ISSN 1944-9593 (online) is published 4 times a year by Green Hill Healthcare Communications, LLC, 1249 South River Road, Suite 202A, Cranbury, NJ 08512. Telephone: 732.656.7935. Fax: 732.656.7938. Copyright ©2013 by Green Hill Healthcare Communications, LLC. All rights reserved. The Oncology Pharmacist® logo is a registered trademark of Green Hill Healthcare Communications, LLC. No part of this publication may be reproduced or transmitted in any form or by any means now or hereafter known, electronic or mechanical, including photocopy, recording, or any informational storage and retrieval system, without written permission from the Publisher. Printed in the United States of America. EDITORIAL CORRESPONDENCE should be addressed to EDITORIAL DIRECTOR, The Oncology Pharmacist®, 1249 South River Road, Suite 202A, Cranbury, NJ 08512. E-mail: editorial@greenhillhc.com. YEARLY SUBSCRIPTION RATES: United States and possessions: individuals, $105.00; institutions, $135.00; single issues, $17.00. Orders will be billed at individual rate until proof of status is confirmed. Prices are subject to change without notice. Correspondence regarding permission to reprint all or part of any article published in this journal should be addressed to REPRINT PERMISSIONS DEPARTMENT, Green Hill Healthcare Communications, LLC, 1249 South River Road, Suite 202A, Cranbury, NJ 08512. The ideas and opinions expressed in The Oncology Pharmacist® do not necessarily reflect those of the Editorial Board, the Editorial Director, or the Publisher. Publication of an advertisement or other product mention in The Oncology Pharmacist® should not be construed as an endorsement of the product or the manufacturer’s claims. Readers are encouraged to contact the manufacturer with questions about the features or limitations of the products mentioned. Neither the Editorial Board nor the Publisher assumes any responsibility for any injury and/or damage to persons or property arising out of or related to any use of the material contained in this periodical. The reader is advised to check the appropriate medical literature and the product information currently provided by the manufacturer of each drug to be administered to verify the dosage, the method and duration of administration, or contraindications. It is the responsibility of the treating physician or other healthcare professional, relying on independent experience and knowledge of the patient, to determine drug dosages and the best treatment for the patient. Every effort has been made to check generic and trade names, and to verify dosages. The ultimate responsibility, however, lies with the prescribing physician. Please convey any errors to the Editorial Director.

www.TheOncologyPharmacist.com

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

“Managing patients with myeloma means staying current.” Ira Klein, MD, MBA, FACP Senior Medical Director Clinical Consulting, Strategy & Analysis National Accounts Aetna Hartford, CT

Value-BasedCare IN Myeloma

™

RESOURCE CENTER FOR PAYERS, PROVIDERS, AND THE ENTIRE CANCER CARE TEAM

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.

ONCOLOGY PHARMACY SAFETY

Chemotherapy: Every Step You Take… Continued from cover ity, and waste storage areas) (Table 1). Although limited associations have been demonstrated between surface contamination and actual worker exposure,2 surface contamination is the most commonly used metric for evaluation of the workplace for hazardous drugs (Table 22-12). Workplace contamination with hazardous drugs in the United States and other countries has remained fairly constant over the past decade or more, indicating that worker exposure probably has not changed considerably over that time, despite efforts to reduce or eliminate environmental contamination. The introduction of Class II biological safety cabinets (BSCs) for the preparation of hazardous drugs in the 1980s substantially reduced the potential for worker exposure,13 but BSCs did not prove to be as efficient at reducing contamination as first believed.4 The recent use of isolators has not been widespread in the United States, nor have they proven to offer more protection to workers than do BSCs, as contamination from the inside surfaces of the isolator may be transferred to the outside of syringes and infusion bags.14 Use of robotic systems to prepare hazardous drugs may reduce environmental contamination and worker exposure to these drugs; however, their high cost makes them prohibitive for all but large cancer centers.15 The addition of closed-system drug transfer devices (CSTDs) for the preparation and administration of hazardous drugs has been shown to reduce surface contamination and possibly worker exposure, but they do not totally eliminate it.5,6,10,11 Recent research has shown that even when all of these controls are used in healthcare settings, the potential for exposure to antineoplastic and other hazardous drugs cannot be completely eliminated.2,10,11,16-22 Despite improvements in engineering controls and other attempts to reduce environmental contamination, hazardous drugs are still being released into the work environment and subsequently workers are being exposed to them. Therefore, for the foreseeable future, as the number of patients requiring treatment with hazardous drugs increases,23,24 contamination of the workplace with hazardous drugs and/or worker exposure to hazardous drugs will be an issue that does not have an immediate solution. Surface Contamination and Wipe Sampling for Hazardous Drugs Wipe sampling for surface contamination has been used in many industrial settings to measure materials such as pesticides, lead, asbestos, etc. Sampling for hazardous drugs usually involves a

OCTOBER 2013 I VOL 6, NO 4

Table 1 Common Locations in the Pharmacy Where Antineoplastic Drugs Have Been Detected Locations where high levels of contamination are seen: Working surface of BSC Surfaces inside the compounding isolator Leading edge (airfoil) of BSC Floor in front of BSC Locations where lower levels of contamination are seen: Floor in pharmacy Countertops Storage bins and trays Storage shelves Inside and outside pass-through windows Waste containers Keyboards Door handles Shoes of pharmacy employees Employee telephones Abbreviation: BSC, biological safety cabinet.

battery of a small number of drugs for which sampling and analytic methods have been developed (Table 3). Methodology allows measurement as low as picogram amounts, but most values are reported as ng/cm2. The method for surface sampling typically follows this approach: an appropriate solvent is applied to a specified area; the surface is wiped with a swab; then the swab is extracted with a solvent and analyzed using either gas chromatography-tandem mass spectrometry or liquid chromatography-tandem mass spectrometry (GC-MS/MS or LC-MS/MS).25 Values typically seen in pharmacies range from

shipped to the laboratory for analysis. It is important for individual institutions to test their own workplace for hazardous drug contamination, rather than make assumptions about their facilities and staff. Pharmacy and other healthcare provider management may worry about the employee perception of these results or the risk incurred by searching for such data. It is not uncommon to question the point of testing, or the greater worry about what the action plan will be if contamination is detected and whether this opens up an institution to litigation. While standard assays and established acceptable levels

Measurement of surface contamination is currently the only indication of the amount of environmental contamination in areas where hazardous drugs are prepared, administered to patients, or otherwise handled. <1 ng/cm2 to a few hundred ng/cm2 (Table 2 provides specific contamination levels detected in studies from the US). Although there are no standards for surface contamination with hazardous drugs, and an action level has not been validated, <1 ng/cm2 is a value to aim for in the pharmacy.26 Table 3 also lists laboratories that provide analysis of hazardous drug wipe samples and the drugs that they can analyze. Some provide kits for sampling that can be

of workplace contamination have yet to be formally established, the latest revision of USP Chapter 797 (2008) includes a recommendation that surface sampling for hazardous drugs be tested for at baseline and every 6 months or more frequently for larger-volume facilities.26 It is recommended that surface sampling be conducted in a targeted manner, such as the surfaces of the BSC, floor beneath the BSC, counters adjacent to primary engineering con-

trols, counters where final compounded hazardous drug products are placed, and patient administration areas. Evaluation of facility controls should include the type of engineering control in use and to what extent the device is vented to the outside, where exhausting 100% of the filtered air is most appropriate based on volume and the extent of contamination.27 All employees’ techniques and knowledge should be evaluated, and retraining should be conducted as appropriate. Poor technique by one individual can lead to an area of concentrated drug on a surface that can, in turn, lead to worker uptake weeks after that drug was originally mishandled. Workflow processes including waste disposal could also be a contributor to contamination. Each institution should consider a self-evaluation of its workflow. Following simple recommendations, such as discarding all waste including syringes into a sealable plastic bag within the BSC while compounding, can dramatically reduce contamination. Once the contaminated waste is contained, it can then be removed from the engineering control and put into chemotherapy disposal bins. Otherwise, if the waste is open (ie, used syringes) during the transfer process, small droplets can contaminate the gown of the compounder, the floor, and the lid of the chemotherapy disposal container.28 Drug Vial Contamination The reporting of external contamination on drug vials is an important reminder that safe handling of hazardous drugs by healthcare workers begins with receiving. Studies in the United States,7 France,29 Germany,30 Switzerland,31 and Japan32 all show the high frequency of external vial contamination, with more than one study reporting contamination on 100% of samples. Favier and colleagues detected 2.4 µg of hazardous drug on the external surface of a single vial and 1.5 µg of hazardous drug on the plastic overwrap of a 25-vial package.29 Connor and colleagues measured 12 µg (cisplatin), 69 µg (cyclophosphamide), and 630 µg (5-fluorouracil) on vials in a multicenter study.7 Fleury-Souverain and colleagues detected traces of cytotoxic drugs different from the active ingredient in the vial on 35% of vials analyzed,31 and Schierl and colleagues reported cross-contamination on 54% of the vials tested.30 Connor, FleurySouverain, Schierl, and their respective colleagues all noted a reduction in contamination on the external surface of vials coated in plastic shrink-wrap.7,30,31 These studies highlight the importance of wearing gloves during handling of vials when performing Continued on page 11

www.TheOncologyPharmacist.com

ONCOLOGY PHARMACY SAFETY Table 2

US Studies of Surface and Drug Vial Contamination With Hazardous Drugs

Authors

Study Description

Drugs Evaluated

Summary

McDevitt et al, 19933

Evaluated incidence and extent of contamination for both surfaces and air at 1 hospital’s outpatient cancer center

Surface Samples 18% pharmacy surfaces + for CP 14% nursing surfaces + for CP

Connor et al, 19994

Evaluated surface contamination in 6 cancer treatment centers

CP, IF, 5-FU

Connor et al, 20025

Evaluated surface conCP, IF, 5-FU tamination prior to and every 4 weeks after the implementation of a CSTD in a highvolume outpatient cancer center. CSTD used for compounding CP and IF. Standard compounding technique used for 5-FU as a control group

Air Samples 3/73 air samples + for CP 75% of pharmacy + for CP, IF, or 5-FU 65% of administration area + for CP, IF, or 5-FU

Max Contamination Values (ng/cm2 for surface; ng/L for urine) Comment CP surface = 35 ng/cm2

CP air = 0.407 µg/m3 CP = 65.66 ng/cm2 IF = 459.0 ng/cm2 5-FU = 208.59 ng/cm2

Almost 100% of samples had detectable surface contaminated with CP, IF, and/ or 5-FU

Levels of contamination were higher in pharmacy samples. Site with the highest compounding volume had considerably more contamination than other sites The pharmacy underwent construction in which the BSCs and other equipment were replaced, yet after 2 months of construction and cleaning, some areas of the floor were still positive for 5-FU and IF. CP spill was still detected 6 months later on the floor

There was a decline in the level of contamination for CP and IF over the 24-week periods of CSTD use, with a few spikes in contamination throughout the study Compounding with 5-FU did not include the use of a CSTD, and the level of 5-FU contamination increased during the study period There was a CP spill at the beginning of the study, and the elevated CP contamination from the spill was still detected 6 months later

Wick et al, 20036

Connor et al, 20057

Surface sampling and employee urine analysis performed preimplementation and 6 months postimplementation of CSTD in hospital pharmacy

CP, IF

Data from 3 studies: CP, IF, 5-FU, Cis Examined contamination of chemotherapy drug vials and evaluated a new vial-cleaning technique in a multicenter study

Baseline 17/17 surfaces + for CP 11/17 surfaces + for IF 6/8 employee urine + for CP 2/8 employee urine + for IF 6 Months Post-CSTD Implementation 7/21 surfaces + for CP 15/21 surfaces + for IF 0/8 employee urine + for CP 0/8 employee urine + for IF 5-FU Vials 7% (4/54 vials) + for 5-FU 5-FU mean = 209,280 ng/vial 5-FU max = 630,560 ng/vial CP Vials 89% (48/54 vials) + for CP CP median = 1468 ng/vial CP max = 69,819 ng/vial IF Vials (n=36) Variability between lots 100% (6/6) + for IF in one lot # IF mean = 1660 ng/vials 2 lots had no IF detected 3 lots had a mix of + and –

Max Values Pre-CSTD Surface CP >100 ng/cm2 IF >100 ng/cm2 Employee Urine CP >100 ng/L IF >100 ng/L

IF was last mixed more than 3 weeks prior to the baseline urine analysis, of which 25% of staff were positive for IF uptake

Post-CSTD CP = 80 ng/cm2 IF >100 ng/cm2 Max Contamination on Vials 5-FU = 630,560 ng/vial CP = 69,819 ng/vial IF = 1705 ng/vial Cis = 256 ng/vial

Vial contamination was widespread, with large variability between lots for certain medications. This study includes a summary table of European studies of vial contamination

Cis Vials (n=368) “Almost all vials” + for Cis 1st Cleaning Technique CP median = 32 ng/vial CP max = 245 ng/vial Table 2 continued on page 10

www.TheOncologyPharmacist.com

OCTOBER 2013 I VOL 6, NO 4

ONCOLOGY PHARMACY SAFETY Table 2 continued from page 9

Table 2

US Studies of Surface and Drug Vial Contamination With Hazardous Drugs (continued )

Authors

Study Description

Drugs Evaluated

Summary

Max Contamination Values (ng/cm2 for surface; ng/L for urine) Comment

2nd Cleaning Method CP median = 7 ng/vial CP max = 79 ng/vial

Connor et al, 20057 (continued)

2nd Cleaning Method Plus Plastic Wrap on Vial CP median = 4 ng/vial CP max = 146 ng/vial Harrison et al, 20068

CP, 5-FU Evaluated surface contamination in 3 pharmacies for CP and 5-FU to compare 3 methods for compounding HDs: standard HD techniques while within a BSC for both CP and 5-FU; the addition of a CSTD to compounding within a BSC for CP only; use of a CSTD while compounding on a counter for 5-FU (not within a BSC)

8% (28/342) surfaces + for 5-FU throughout all phases of the study and all sites

CP = 35.72 ng/cm2 5-FU = 18.8 ng/cm2

Authors concluded that due to the high incidence of CP surface contamination (95%) compared with the overall incidence of 5-FU surface contamination (8%), it is difficult to assess whether compounding 5-FU on a counter using a CSTD yields comparable incidence and magnitude of surface contamination compared with compounding CP in a BSC with or without the use of a CSTD

Surface Max CP = 0.037 ng/cm2 IF = 0.737 ng/cm2

CSTD reduced the incidence of surface contamination and percentage of employees with CP detected in their urine. However, despite these reductions, a noncompounding employee had both IF and CP detected in their urine

Incidence of surface samples positive for 5-FU was significantly less during the control phase in which CSTDs were used, despite that 5-FU was compounded on a counter and not in a BSC 95% (324/342) surface samples + for CP Both incidence of contaminated surfaces and level of contamination were decreased during the phase where CSTDs were used

Authors note that compounding outside of a BSC was limited to immediate-use sterile products when a proper facility was not available Nyman et al, 20079

Evaluation of new cancer CP, IF facility that has exclusively used a CSTD for 6 months, plus data for 6 months of CSTD at old facility. Surface sampling of pharmacy, nursing, and patient areas; urine sampling of employees including pharmacists, technicians, and nurses

Connor et al, 20102

Sessink et al, 201010

Surface sampling and employee urine analysis from 7 pharmacies and 10 nursing/patient areas at 3 university-based hospitals

CP, IF, paclitaxel, 5-FU, cytarabine

Surface contamination evaluated in 22 US hospital pharmacies pre- and post-CSTD implementation

CP, IF, 5-FU

Prior to Implementation 71% (5/7) employee urine + CP 6 Months Post-CSTD at Old Facility 33% (7/21 surfaces) + for CP 71% (15/21 surfaces) + for IF 6 Months After Opening New Facility, CSTD Used Exclusively 21% (7/34 surfaces) + for CP 12% (4/34 surfaces) + for IF 9% (1/11) employee urine + CP 9% (1/11) employee urine + IF (+ employee was not involved in compounding) IF detected on floor in patient room 60% (86/143 surfaces) + for HD 32% surfaces + for >1 HD 40% surfaces + for CP 3/68 employee urine + for HD

Surface Max CP = 143 ng/cm2 5-FU = 910 ng/cm2 Max not provided for other HDs

HD refers to all hazardous drugs tested for

Employee Urine CP = 0.079 ng/L Paclitaxel = 0.01 ng/L

Surface Samples Pre-CSTD Implementation 78% + for CP 54% + for IF 33% + for 5-FU

Surface Max CP = 158.0 ng/cm2 IF = 14.19 ng/cm2 5-FU = 228.7 ng/cm2

CSTD reduced incidence and magnitude of surface contamination of the 3 drugs tested

Surface Sampling Post-CSTD 68% + for CP 45% + for IF 20% + for 5-FU Reduction in quantity of contamination detected

OCTOBER 2013 I VOL 6, NO 4

www.TheOncologyPharmacist.com

ONCOLOGY PHARMACY SAFETY Table 2

US Studies of Surface and Drug Vial Contamination With Hazardous Drugs (continued ) Max Contamination Values (ng/cm2 for surface; ng/L for urine) Comment

Authors

Study Description

Drugs Evaluated

Summary

Sessink et al, 201311

Evaluated surface contamination in pre- and post-CSTD implementation in 30 hospitals

Pre-CSTD Implementation 83% for all surfaces Median CP = 0.22 ng/cm2

Compared 2 brands of CSTDs for effects on surface contamination at a hospital cancer center. CSTD #1 in place prior to study. Facility decontaminated after staff had adjustment period to CSTD #2, and new baseline created

CP, 5-FU

Clark and Sessink, 201312

CP max = 44.17 ng/cm2

Post-CSTD Implementation 80% for all surfaces Median CP = 0.03 ng/cm2 CSTD #1 (in place prior to study) 7/12 samples + for CP (max of 1.33 ng/ cm2) No 5-FU detected

CSTDs significantly reduced the concentration of surface contamination, but use of CSTDs showed little to no change in the incidence of contaminated surfaces

CP = 1.33 ng/cm2 5-FU = 0.40 ng/cm2

Start CSTD #2 Then Decontamination With NaOH 7/12 samples + for CP (CP max = 0.09 ng/cm2) 1/12 samples + 5-FU (5-FU max = 0.040 ng/cm2) CSTD #2 (1-year post) No CP detected No 5-FU detected

Abbreviations: BSC, biological safety cabinet; Cis, cisplatin; CP, cyclophosphamide; CSTD, closed-system transfer device; 5-FU, 5-fluorouracil; HD, hazardous drug; IF, ifosfamide; max, maximum; –, negative; +, positive.

Chemotherapy: Every Step You Take… Continued from page 8 noncompounding activities such as unloading shipping containers and managing stock. Vials become contaminated during manufacturing from lack of cleaning, incomplete cleaning, improper vial washing, contamination by broken vials during transportation, or contact with contaminated surfaces or employees’ hands.7 Globally, manufacturers must improve their procedures to provide the healthcare industry with products free from external contamination. If the external surfaces of drug vials are contaminated, the result is a continuous source of contamination, and it can be assumed that hazardous drug contamination can be spread to pharmacy surfaces, storage shelves, and bins, as well as employees’ hands. In light of external drug vial contamination, healthcare workers should consider the process of cleaning compounding supplies prior to entry into a cleanroom. USP Chapter 797 recommends sterile 70% isopropyl alcohol (IPA) delivered from a spray bottle or other suitable delivery method to compounding supplies prior to entering the buffering room; then transferred to a clean and properly sanitized metal cart.26 However, the vials themselves should not be sprayed directly with alcohol, as this may produce an aerosol of the drug that could lead to inhalation, and excess contaminated disinfecting solution could then drip off the vials, thus transferring contamination

www.TheOncologyPharmacist.com

Christine Roussel, PharmD, BCOP

Thomas H. Connor, PhD

to other surfaces. The best practice is to spray the wipe materials and then use them to wipe the vials. The contaminated wipes should then be disposed of as hazardous waste. Alcohol solubilizes hazardous drugs and is not known to decontaminate drugs through chemical degradation like bleach does. The use of alcohol to sanitize areas where chemotherapy is compounded has been shown to spread contamination.28 Therefore, even cleaning procedures for these vials must be thoroughly evaluated to minimize the inadvertent spread of contamination.

a direct relationship with worker uptake of hazardous drugs, it is important to think about how workplace contamination leads to systemic exposure. Dermal absorption is a principal route of chemical exposure for nonvolatile chemicals, often exceeding respiratory exposure.33 Nonvolatile antineoplastic drugs can persist for several weeks on work surfaces, functioning as sources of worker contamination for long periods of time.5,6 In addition to a chemical’s local effects on the skin, including contact dermatitis and irritation, skin exposure to chemicals can function as a pathway to the bloodstream for hazardous chemicals to enter the body. The skin has 2 basic layers, the epidermis and the dermis, providing protection against chemical absorption.33

Skin Absorption of Hazardous Drugs Although the magnitude of surface contamination has yet to be proven to have

Chemicals can diffuse passively across the stratum corneum, reaching the blood vessels in the dermis where significant dermal exposure can produce detectable blood levels. The rate and magnitude of skin absorption can be affected by many occupational factors. Organic solvents such as alcohol, as found in hand sanitizer, can “defat” the skin, damaging the external layer and allowing increased chemical absorption. Wearing gloves for extended periods of time can increase the water content of the stratum corneum, both from perspiration and trapping normal skin water evaporation, thus increasing absorption of hydrophilic chemicals. Frequent hand washing with strong detergents throughout the workday can also lead to skin damage in healthcare settings. Increased moisture, skin irritation, damage from exposure to harsh chemicals, small cuts, or skin tears alter the physical barrier function of the skin and allow for increased chemical permeability. If chemical penetration did occur through a glove, due to prolonged contact of the chemical on the external surface or from a tear in the glove, the glove would function as an occlusive dressing, increasing chemical absorption through increasing temperature, friction, and contact between the glove and skin. Dermal uptake has been postulated to be the major route of exposure to antineoplastic drugs in workplace settings.34-37 Inhalation appears to be the second Continued on page 12

OCTOBER 2013 I VOL 6, NO 4

ONCOLOGY PHARMACY SAFETY

Chemotherapy: Every Step You Take… Continued from page 11 most common route, with oral (handto-mouth) and accidental injection with sharps less common. Although a few antineoplastic drugs have been shown to have the ability to produce vapors, most antineoplastic drugs have very low vapor pressures.38,39 Numerous studies from the United States and countries around the world have documented surface contamination with antineoplastic drugs in areas where they are used.40 Uptake of Hazardous Drugs As stated previously, it is difficult to directly relate worker exposure to surface contamination with hazardous drugs. However, Connor and colleagues were able to detect cyclophosphamide in the urine of 2 pharmacists working in an area that had high levels of surface contamination with this drug.2 Both pharmacy and nursing personnel have been shown to have measurable amounts of antineoplastic drugs in their urine as a result of working where the drugs are handled. As with wipe samples, analysis is available for determining a battery of drugs in the urine of healthcare workers. Interestingly, in some studies, specific antineoplastic drugs have been measured in the urine of workers not directly involved with their preparation, suggesting indirect or incidental exposure from contact with contaminated surfaces. Uptake of these drugs by pharmacists and nurses has been well documented in more than 50 studies in the world literature.40 Analysis of the urine for hazardous drugs is usually done strictly on a research basis, as there are no standards for the amount of drugs in the urine and what the consequences might be concerning workers’ health. However, it does indicate that the workplace environment is contaminated with the drugs or that the worker may not have good technique, indicating the need for better engineering controls and cleaning procedures of the pharmacy and/or retraining of the worker. Although findings of hazardous drugs can be alarming to the worker, the OSHA Technical Manual states, “Results of biologic monitoring which have been voluntarily conducted by an employer should not be used as a basis for citations. In fact OSHA promotes the use of biologic monitoring of employees as a useful means of minimizing exposure and for evaluating effectiveness of control measures.”33 Summary Surface contamination with hazardous drugs, in particular, antineoplastic drugs, is usually present in pharmacies and all areas where the drugs are handled. Most work surfaces and drug vials have been demonstrated to be contaminated with antineoplastic drugs in numerous stud-

OCTOBER 2013 I VOL 6, NO 4

Table 3 Laboratories That Test for Hazardous Drugs and Some Commonly Tested Drugs Laboratory

Drugs

Exposure Control B.V. www.exposurecontrol.nl

Cyclophosphamide, ifosfamide, 5-fluorouracil, methotrexate, etoposide, mitomycin C, platinum-containing compounds

RJ Lee Group www.rjlg.com

Cyclophosphamide, ifosfamide, 5-fluorouracil, methotrexate, cisplatin, carboplatin, oxaliplatin

ChemoGlo, LLC www.chemoglo.com

Cyclophosphamide, ifosfamide, 5-fluorouracil, paclitaxel, docetaxel

BVNA www.us.bureauveritas.com/ labs/ChemoAlert

Cyclophosphamide, ifosfamide, 5-fluorouracil, paclitaxel, methotrexate, doxorubicin, daunorubicin, idarubicin, cisplatin, carboplatin, cytarabine, imatinib, capecitabine

ies from the United States and internationally. Although other routes (inhalation, oral, needlesticks) may be factors in uptake of these drugs, the dermal route appears to be the most common. Uptake has been well documented by the presence of some antineoplastic drugs in the urine of healthcare workers. A prospective gap analysis of the work environment and compounding process, including surface analysis for hazardous drugs, is a good starting point. While appropriate facility

While appropriate facility design and proper equipment are critical, so is a strong employee training program with continuing education.

design and proper equipment are critical, so is a strong employee training program with continuing education. Components of employee education should include a hazard communication document, with didactic and demonstrative components and spill kit training. Access to proper personal protective equipment and a “safety culture” can promote employee compliance.41 l Disclaimers The findings and conclusions of this presentation have not been formally disseminated by NIOSH and should not be construed to represent any agency determination or policy. Mention of company names or products does not constitute endorsement by the National Institute for Occupational Safety and Health.

References

1. Roussel C, Connor TH. Chemotherapy and pharmacy: a toxic mix? Oncol Pharmacist. 2013;6:32-33. 2. Connor TH, DeBord G, Pretty JR, et al. Evaluation of antineoplastic drug exposure of health care workers at three university-based US cancer centers. J Occup Environ Med. 2010;52:1019-1027. 3. McDevitt JJ, Lees PS, McDiarmid MA. Exposure of hospital pharmacists and nurses to antineoplastic agents. J Occup Med. 1993;35:57-60. 4. Connor TH, Anderson RW, Sessink PJ, et al. Surface contamination with antineoplastic agents in six cancer treatment centers in the United States and Canada. Am J Health Syst Pharm. 1999;56:1427-1432. 5. Connor TH, Anderson RW, Sessink PJ, et al. Effectiveness of a closed-system device in containing surface contamination with cyclophosphamide and ifosfamide in an i.v. admixture area. Am J Health Syst Pharm. 2002;59:68-72. 6. Wick C, Slawson MH, Jorgenson JA, et al. Using a closed-system protective device to reduce personnel exposure to antineoplastic agents. Am J Health Syst Pharm. 2003;60:2314-2320. 7. Connor TH, Sessink PJ, Harrison BR, et al. Surface contamination of chemotherapy drug vials and evaluation of new vial-cleaning techniques: results of three studies. Am J Health Syst Pharm. 2005;62:475-484. 8. Harrison BR, Peters BG, Bing MR. Comparison of surface contamination with cyclophosphamide and fluorouracil using a closed-system drug transfer device versus standard preparation techniques. Am J Health Syst Pharm. 2006;63:1736-1744. 9. Nyman H, Jorgenson J, Slawson MH. Workplace contamination with antineoplastic agents in a new cancer hospital using a closed-system drug transfer device. Hosp Pharm. 2007;42:219-225. 10. Sessink PJ, Connor TH, Jorgenson JA, et al. Reduction in surface contamination with antineoplastic drugs in 22 hospital pharmacies in the US following implementation of a closed-system drug transfer device. J Oncol Pharm Pract. 2010;17:39-48. 11. Sessink PJM, Trahan J, Coyne JW. Reduction in surface contamination with cyclophosphamide in 30 US hospital pharmacies following implementation of a closed-system drug transfer device. Hosp Pharm. 2013;48:204-212. 12. Clark BA, Sessink PJM. Use of a closed system drug-transfer device eliminates surface contamination with antineoplastic agents. J Oncol Pharm Pract. 2013;19:99-104. 13. Anderson RW, Puckett WH, Dana WJ, et al. Risk of handling antineoplastic agents. Am J Hosp Pharm. 1982;39:1881-1887. 14. Vyas N, Yainnakis D, Turner A, et al. Occupational exposure to anti-cancer drugs: a review of effects of new technology [published online ahead of print August 22, 2013]. J Oncol Pharm Pract. doi: 10.1177/1078155213498630. 15. Seger AC, Churchill WW, Keohane CA, et al. Impact of robotic antineoplastic preparation on safety, workflow, and costs. J Oncol Pract. 2012;8:344-349. 16. Schierl R, Bohlandt A, Nowak D. Guidance values for surface monitoring of antineoplastic drugs in German pharmacies. Ann Occup Hyg. 2009;53:1-9. 17. Siderov J, Kirsa S, McLauchlan R. Reducing workplace cytotoxic surface contamination using a closed-system drug transfer device. J Oncol Pharm Pract. 2010;16:19-25. 18. Yoshida J, Koda S, Nishida S, et al. Association between occupational exposure levels of antineoplastic drugs and work environment in five hospitals in Japan. J Oncol Pharm Pract. 2010;17:29-38. 19. Davis J, McLauchlan R, Connor TH. Exposure to

hazardous drugs in healthcare: an issue that will not go away. J Oncol Pharm Pract. 2011;17:9-13. 20. Turci R, Minola C, Sottani C, et al. Occupational exposure to antineoplastic drugs in seven Italian hospitals: the effect of quality assurance and adherence to guidelines. J Oncol Pharm Pract. 2011;17:320-332. 21. Chu WC, Hon C-Y, Danyluk Q, et al. Pilot assessment of the antineoplastic drug contamination levels in British Columbia hospitals pre- and post-cleaning. J Oncol Pharm Pract. 2012;18:46-51. 22. Kopp B, Schierl R, Nowak D. Evaluation of working practices and surface contamination with antineoplastic drugs in outpatient oncology health care settings. Int Arch Occup Environ Health. 2013;86:47-55. 23. Howlader N, Noone AM, Krapcho M, et al, eds. SEER Cancer Statistics Review, 1975-2010, National Cancer Institute. Bethesda, MD, http://seer.cancer. gov/csr/1975_2010/, based on November 2012 SEER data submission, posted to the SEER website, April 2013. 24. World Health Organization. WHO cancer control programme. http://www.who.int/cancer/en/. Accessed September 10, 2013. 25. Turci R, Sottani C, Spagnoli G, et al. Biological and environmental monitoring of hospital personnel exposed to antineoplastic agents: a review of analytical methods. J Chromatog B. 2003;789:169-209. 26. US Pharmacopeial Convention. USP revised chapter (797) pharmaceutical compounding—sterile preparations. http://www.pbm.va.gov/linksother resources/docs/USP797PharmaceuticalCompounding SterileCompounding.pdf. Accessed September 10, 2013. 27. Centers for Disease Control and Prevention. NIOSH Publications and Products. Preventing occupational exposure to antineoplastic and other hazardous drugs in health care settings. http://www.cdc.gov/ niosh/docs/2004-165/. Accessed September 10, 2013. 28. Sessink PJ, Anzion RB, Van den Broek PH, et al. Detection of contamination with antineoplastic agents in a hospital pharmacy department. Pharm Weekbl Sci. 1992;14:16-22. 29. Favier B, Gilles L, Ardiet C, et al. External contamination of vials containing cytotoxic agents supplied by pharmaceutical manufacturers. J Oncol Pharm Pract. 2003;9:15-20. 30. Schierl R, Herwig A, Pfaller A, et al. Surface contamination of antineoplastic drug vials: comparison of unprotected and protected vials. Am J Health Syst Pharm. 2010;67:428-429. 31. Fleury-Souverain S, Nussbaumer S, Mattiuzzo M, et al. Determination of the external contamination and cross-contamination by cytotoxic drugs on the surfaces of vials available on the Swiss market [published online ahead of print May 14, 2013]. J Oncol Pharm Pract. doi: 10.1177/1078155213482683. 32. Naito T, Osawa T, Suzuki N, et al. Comparison of contamination levels on the exterior surfaces of vials containing platinum anticancer drugs in Japan. Biol Pharm Bull. 2012;35:2043-2049. 33. US Department of Labor, Occupational Safety & Health Administration. OSHA Technical Manual; Section II: Chapter 2, Occupational Skin Exposure. https://www.osha.gov/dts/osta/otm/otm_ii/otm_ii_2. Updated June 24, 2008. Accessed September 10, 2013. 34. Kromhout H, Hoek F, Uitterhoeve R, et al. Postulating a dermal pathway for exposure to antineoplastic drugs among hospital workers. Applying a conceptual model to the results of three workplace surveys. Ann Occup Hyg. 2000;44:551-560. 35. Fransman W, Vermeulen R, Kromhout H. Occupational dermal exposure to cyclophosphamide in Dutch hospitals: a pilot study. Ann Occup Hyg. 2004;48:237-244. 36. Fransman W, Vermeulen R, Kromhout H. Dermal exposure to cyclophosphamide in hospitals during preparation, nursing and cleaning activities. Int Arch Occup Environ Health. 2005;78:403-412. 37. Fransman W, Huizer D, Tuerk J. Inhalation and dermal exposure to eight antineoplastic drugs in an industrial laundry facility. Int Arch Occup Environ Health. 2007;80:396-403. 38. Connor TH, Shults M, Fraser MP. Determination of the vaporization of solutions of mutagenic antineoplastic agents at 23 and 37 degrees C using a desiccator technique. Mutat Res. 2000;470:85-92. 39. Kiffmeyer TK, Kube C, Opiolka S, et al. Vapor pressures, evaporation behavior and airborne concentrations of hazardous drugs: implications for occupational safety. Pharm J. 2002;268:331-337. 40. Centers for Disease Control and Prevention, National Institute for Occupational Safety and Health. Occupation exposure to antineoplastic agents. http://www.cdc.gov/niosh/topics/antineoplas tic/. Updated April 13, 2012. Accessed September 10, 2013. 41. Polovich M, Clark PC. Factors influencing oncology nurses’ use of hazardous drug safe-handling precautions. Oncol Nurs Forum. 2012;39:E299-E309.

www.TheOncologyPharmacist.com

BD PhaSeal™ Closed System Transfer Device Raising the Bar in Hazardous Drug Protection

The First and Only FDA cleared CSTD indicated to reduce exposure to hazardous drugs BD PhaSeal™ Closed System Transfer Device is the first and only CSTD cleared under the FDA’s newly created product code, ONB: Closed Antineoplastic and Hazardous Drug Reconstitution and Transfer System. New FDA code clarifies misconceptions in the marketplace*

• Establishes a specific product code for CSTD’s indicated to reduce exposure to hazardous drugs

• Requires data to prove a system is closed for use with hazardous drugs

• Requires data to demonstrate reduction in healthcare worker exposure Learn more at www.bd.com/phaseal

Visit us online at www.bd.com/phaseal

MSS0284 (1/13)

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

NEWS BRIEFS Continued from cover

Predictors of Survival Benefit From Endocrine Therapy Two related studies identified potential predictors of survival benefit from endocrine therapy in women with breast cancer. Both studies were published in a recent issue of the Journal of Clinical Oncology. The first study found that the presence of vasomotor symptoms (eg, hot flashes) and other specific adverse events (AEs) associated with endocrine therapy, especially during the first year of treatment, predicted improved disease-free survival (DFS) and overall survival (OS).1 The second study showed that women on treatment with endocrine therapy who had a reduction of more than 20% in mammographic density from baseline to the first follow-up mammogram had a 50% reduced risk of breast cancer–specific death.2 In an accompanying editorial, the authors point out that a woman may be more willing to tolerate the considerable

AEs of endocrine therapy if this means she will gain a survival advantage.3 Adverse Events, Vasomotor Symptoms A retrospective analysis of the international, randomized, phase 3 TEAM (Tamoxifen Exemestane Adjuvant Multinational) trial looked at the association between survival outcomes and specific AEs.1 The study included 9325 women with postmenopausal estrogen receptor (ER)positive and/or progesterone receptor (PR)-positive breast cancer eligible for endocrine therapy. Participants were randomized to exemestane 25 mg once daily for 5 years or tamoxifen 20 mg once daily for 2.5 to 3 years, followed sequentially by exemestane 25 mg once daily for 2.5 to 3 years. The specific AEs associated with endocrine therapy and which deplete

or block circulating estrogens included vasomotor symptoms (hot flashes and night sweats), musculoskeletal events, and vulvovaginal symptoms (dryness/ itching, discharge, painful sexual intercourse, and lack of libido).

The findings from this analysis may provide a potential biomarker of treatment efficacy. Both DFS and OS were improved in patients with specific AEs versus those with nonspecific or no AEs. The incidences of distant metastases, relapse, and death were all reduced in patients with specific AEs. Outcomes were not related to treatment assignment.

DCIS Overdiagnosed and Overtreated in the United States The increased use of screening leads to detection of more The working group called for a change in cancer tercancers that are potentially clinically insignificant, includ- minology based on companion diagnostics and avoiding ing DCIS and Barrett esophagus, according to a recent the use of the word cancer for lesions that are unlikely to report published in the Journal of the American Medical be lethal if left untreated. They stated that premalignant Association. conditions such as DCIS or high-grade prostatic intraepThe detection and removal of these specific precancerous ithelial neoplasia should not be designated as cancer by lesions have not led to a lower incidence of invasive cancer, name. They also recommended that molecular diagnostics stated the authors. that can identify indolent and low-risk lesions be adoptThe authors noted that the word cancer carries associations ed and validated. The working group emphasized the of “an inexorably lethal process,” but lesions like DCIS and necessity for a new taxonomy and classification system for Barrett esophagus often represent indolent diseases that will indolent lesions of epithelial origin (IDLE). not cause harm during a patient’s lifeThe creation of observational time if left untreated. Naming them patient registries for IDLE would cancers can lead to unnecessary anxibe useful to trace the course of ety, incorrect expectations of risk, and these lesions over time. The data unnecessary treatment. from such registries would provide In March 2012, the In March 2012, the National a link between disease dynamics National Cancer Cancer Institute (NCI) convened a (growth rate over time) and dismeeting to evaluate the overdiagnosis ease diagnostics that could support Institute convened a of tumors that would not cause harm the use of less invasive intervenmeeting to evaluate the if left untreated. Overdiagnosis, the tions for these lesions. panel noted, necessarily often leads The strategies called for by the overdiagnosis of tumors to overtreatment if not recognized. working group include reducing that would not cause Overdiagnosis of indolent cancer is frequency of screening for IDLE common and is a consequence of lesions, focusing screening on harm if left untreated. screening programs, they state. high-risk populations, raising the A working group was formed to threshold for recall and biopsy, develop a strategy related to the and testing the safety and efficacy current approach to cancer screening of risk-based screening approachand prevention. The panel noted that an ideal screening es to help select appropriate patients for cancer screenintervention should focus on detection of diseases that are ing. The goal is to detect potentially lethal lesions while ultimately harmful and more likely to be cured if detected avoiding detection of inconsequential disease. early. Going forward, avoiding overtreatment will require The authors stated that physicians and patients better screening programs that incorporate improved char- should engage in open discussion about these complex acterization of the biology of the disease detected and use issues. disease dynamics (ie, how the disease will behave over time) as well as molecular diagnostics that can determine Reference Esserman LJ, Thompson IM Jr, Reid B. Overdiagnosis and overtreatment in cancer: an opportunity for improvement. JAMA. 2013;310(8):797-798. whether a cancer is aggressive or indolent.

OCTOBER 2013 I VOL 6, NO 4

The findings from this analysis may provide a potential biomarker of treatment efficacy. The authors stated that prospective studies are warranted “to advance the personalization of treatment strategies for patients with breast cancer.” Reduction in Mammographic Density According to results of a retrospective population-based case-control study in Sweden, patients taking tamoxifen who experienced a reduction in breast density of more than 20% from their baseline mammogram to their first follow-up mammogram had improved survival versus women with stable mammographic density on tamoxifen treatment.2 Study participants were 974 postmenopausal patients with breast cancer with both a baseline and follow-up mammogram. Of these women, 474 received tamoxifen and 500 did not. The authors measured mammographic density as a percentage change from baseline. After a 15-year follow-up, 121 patients (12.4%) had died of breast cancer. Among women who had received tamoxifen, 35% of the breast cancer– associated deaths occurred in women who had had a reduction in mammographic density of 20% or more, compared with a 48% reduction in women who did not die from breast cancer. Women treated with tamoxifen who had a 20% or more reduction in mammographic density had a 50% reduced risk of death compared with women who had stable mammographic density from baseline mammogram to first follow-up mammogram. Although the relationship between density change on mammogram and survival was not statistically significant, it trended toward improved survival for those with reduced breast density. The authors suggested that change in breast density from baseline to first follow-up mammogram in patients treated with tamoxifen could be a biomarker for response. If change in mammographic density on treatment is validated as an early marker for response to endocrine therapy, it could be a cost-effective tool for routine clinical use, the authors said. References

1. Fontein DB, Seynaeve C, Hadji P, et al. Specific adverse events predict survival benefit in patients treated with tamoxifen or aromatase inhibitors: an international tamoxifen exemestane adjuvant multinational trial analysis. J Clin Oncol. 2013;31(18):2257-2264. 2. Li J, Humphreys K, Eriksson L, et al. Mammographic density reduction is a prognostic marker of response to adjuvant tamoxifen therapy in postmenopausal patients with breast cancer. J Clin Oncol. 2013;31(18):22492256. 3. Henry NL, Stearns V. Treatment-emergent effects may predict benefit from endocrine therapy. J Clin Oncol. 2013;31(18):2233-2235.

www.TheOncologyPharmacist.com

NEWS BRIEFS 1 in 5 Women Do Not Believe Their Breast Cancer Risk Assessment A recent study reported that nearly 20% of women who participated in a risk-assessment study did not believe the breast cancer risk they were assigned. Most of the women who distrusted their numbers stated that they felt that the risk-assessment tool did not fully incorporate their family history of cancer or their personal health habits. If women don’t believe their actual risk of developing breast cancer, then they cannot make informed medical decisions, stated senior author of the study Angela Fagerlin, PhD. This goes both ways—if they believe their risk is not high when it is, they might not seek chemoprevention strategies that could significantly reduce their risk; if, on the other hand, they have been assigned a low risk and they believe their risk assessment should be higher, they may seek out medically inappropriate treatments that can cause longterm problems, she explained. The findings, which are part of a larger study that provides information about medications that can reduce risk of breast cancer, were published in Patient Education and Counseling. The study included 690 women at above-average risk of developing breast cancer. They completed a web-based decision aid that included questions about age, ethnicity, personal history of breast cancer, and the number of first-degree relatives with breast cancer. Based on their answers, they were assigned a 5-year risk of developing breast cancer and were given information on prevention strategies. They then were asked to recall their 5-year risk of developing breast cancer, and those who gave an incorrect answer were asked why they forgot or disagreed with the number. Among participants, 22% who incorrectly reported their risk said that they disagreed with the numbers. The most common reason for disagreement was that their family history made them either more or less likely to devel-

The study results suggest that a proportion of women who are given a risk assessment for developing cancer will not seek the most appropriate medical care. op breast cancer. Other participants believed that having no family history of breast cancer should place them in the low-risk category. One-third of

women said their “gut instinct” told them that their risk numbers were either too high or too low. Lead author of the study, Laura D.

Scherer, PhD, said that fear could account for some of this distrust. Many women assumed certain factors would affect their risk, but these factors did not place them at increased risk. Both Scherer and Fagerlin found the study results of concern, since they suggest that a proportion of women who are given a risk assessment for developing cancer will not seek the most appropriate medical care. Reference

Scherer LD, Ubel PA, McClure J, et al. Belief in numbers: when and why women disbelieve tailored breast cancer risk specifics. Patient Educ Couns. 2013;92(2):253-259.

Similar Survival in Early BRCA1-Positive and -Negative Breast Cancer According to a study recently published in the Journal of Clinical Oncology, patients with early-onset BRCA1positive breast cancer have a survival rate similar to that of patients with early-onset BRCA1-negative breast cancer. Among BRCA1 mutation carriers, positive nodal status was a significant predictor of poorer survival, while oophorectomy strongly predicted improved survival. The study enrolled 3345 women aged 50 years or younger with stage I-III invasive breast cancer diagnosed between 1996 and 2006. Only patients with a first primary cancer were included. Of the 3345 enrollees, 233 (7%) carried a BRCA1 mutation. Mutation carriers were diagnosed at an earlier age than noncarriers (42 years vs 44 years, respectively; P <.001) and were significantly less likely to be estrogen receptor (ER)-positive, progesterone receptor (PR)positive, and HER2-positive (P <.001 for all 3 comparisons) but significantly more likely to have triple-negative disease (69% vs 13%, respectively; P <.001) and more likely to have undergone oophorectomy (50% vs 14%, respectively), with most having the procedure following their diagnosis of breast cancer. At a mean follow-up of 7.4 years, the 10-year survival rate was 80.9% for mutation carriers and 82.2% for noncarriers. Among the 485 women with triple-negative breast cancer, overall survival was not inferior among carriers versus noncarriers. Among BRCA1 mutation carriers, lymph node status was highly predictive of survival, with positive nodal status associated with significantly lower 10-year

survival (P <.001). Overall, as well as in carriers, survival was similar in women with tumors 0.1 to 1.0 cm and 1.1 to 2 cm. The 10-year survival rate among carriers with small (<2 cm) breast tumors was 89.9% for node-negative patients and 68.6% for node-positive patients. Among carriers with breast tumors ≤1 cm, 27.5% were node positive, and their 10-year survival rate was 81.1%. Of the 233 BRCA1-positive patients, 101 (43.6%) were deemed high risk (node positive or tumors >5 cm), and their survival was 68.2% at 10 years. Oophorectomy had a positive effect on prognosis among carriers, and to a smaller extent, in noncarriers. “Oophorectomy in BRCA1 carriers is beneficial for reducing death after breast cancer. The reduction in death is largely for those occurring as a result of breast cancer, but a number of avoidable deaths will be from secondary primary ovarian cancers,” wrote the authors. “If these observations are replicated in other populations, oophorectomy should be considered a standard of care for women with breast cancer and a BRCA1 mutation,” they said. Chemotherapy improved survival among carriers compared with no chemotherapy, even though the tumors of those treated with chemotherapy tended to be larger, node positive, and ER negative. l Reference

Huzarski T, Byrski T, Gronwald J, et al. Ten-year survival in patients with BRCA1negative and BRCA1-positive breast cancer. J Clin Oncol. 2013;31(26):31913196.

TAKE ACTION: GET YOUR CANCER CENTER PROFILED! We are looking to interview oncology pharmacists from cancer centers around the country. It’s an easy process—a short phone interview and you need to submit some photos.

Contact editorial@greenhillhc.com for information.

www.TheOncologyPharmacist.com

OCTOBER 2013 I VOL 6, NO 4

LUNG CANCER MPDL3280A in Advanced NSCLC

MPDL3280A) was directly correlated with response, with the best response seen in those with the highest expres-

sion of PD-L1 on immunohistochemistry (IHC 3). Those with IHC 3 also had less progressive disease. Although based on

very small numbers of patients, ORR was 46% in patients with PD-L1 IHC 2 and IHC 3, and 86% in those with IHC 3.

By Alice Goodman

or the first time, a therapy for non-small cell lung cancer (NSCLC) has achieved more responses in smokers than nonsmokers. The antibody MPDL3280A also achieved good responses in the squamous and adenoma histologic types of NSCLC. These phase 1 study results in patients with metastatic NSCLC were so encouraging that experts suggested bypassing phase 2 and going directly to phase 3 studies. Genentech’s development program for the monoclonal antibody includes ongoing recruitment for phase 2 and 3 trials in NSCLC. “We are at the beginning of a new era. After 30 years of research in immunotherapy for lung cancer, we have one that works, and it works in smokers,” said lead author Jean-Charles Soria, MD, Institut Gustave Roussy, Paris, France, at the European Cancer Congress (ESMO/ECCO/ESTRO), held September 27-October 1, 2013, in Amsterdam, the Netherlands. “In this study, smokers responded much better than nonsmokers. This is great news for lung cancer patients—the majority are current or former smokers. The data are preliminary, but the trends are extremely promising,” Soria added. The study results were based on 85 patients (53 evaluable for efficacy) who received treatment with an intravenous infusion of MPDL3280A every 3 weeks for a median duration of 106 days (range, 1-450 days). Median duration of therapy was 48 weeks. Of the 85 patients with NSCLC, 55% were heavily pretreated with 3 or more previous therapies and the majority were smokers or ex-smokers (81%); 19% never smoked. MPDL3280A was considered safe. Most adverse events were mild. No dose-limiting toxicities were identified in this trial, nor was any grade 3 to 5 pneumonitis or diarrhea reported. Grade 3 and 4 adverse events were reported in 34%, but these were not necessarily treatment related, as some were cancer related (ie, dyspnea, fatigue). Objective response rate (ORR) was 24% in the overall population and 23% in patients with NSCLC; 17% of responders were stable over 24 weeks. The 24-week progression-free survival rate was 44% in squamous cell NSCLC and 46% in nonsquamous cell NSCLC. PD-L1 expression (the target of

For appropriate patients receiving highly emetogenic chemotherapy,

Prevention of CINV With Triple Therapya Starts on Cycle 1, Day 1 EMEND® (fosaprepitant dimeglumine) for Injection, in combination with other antiemetic agents, is indicated in adults for prevention of acute and delayed nausea and vomiting associated with initial and repeat courses of highly emetogenic cancer chemotherapy, including high-dose cisplatin. EMEND for Injection has not been studied for treatment of established nausea and vomiting. Chronic continuous administration of EMEND for Injection is not recommended.

Selected Important Safety Information

• EMEND for Injection is contraindicated in patients who are hypersensitive to EMEND for Injection, aprepitant, polysorbate 80, or any other components of the product. Known hypersensitivity reactions include flushing, erythema, dyspnea, and anaphylactic reactions. • Aprepitant, when administered orally, is a moderate cytochrome P450 isoenzyme 3A4 (CYP3A4) inhibitor. Because fosaprepitant is rapidly converted to aprepitant, neither drug should be used concurrently with pimozide or cisapride. Inhibition of CYP3A4 by aprepitant could result in elevated plasma concentrations of these drugs, potentially causing serious or life-threatening reactions. • EMEND for Injection should be used with caution in patients receiving concomitant medications, including chemotherapy agents, that are primarily metabolized through CYP3A4. Inhibition of CYP3A4 by EMEND for Injection could result in elevated plasma concentrations of these concomitant medications. Conversely, when EMEND for Injection is used concomitantly with another CYP3A4 inhibitor, aprepitant plasma concentrations could be elevated. When EMEND for Injection is used concomitantly with medications that induce CYP3A4 activity, aprepitant plasma concentrations could be reduced, and this may result in decreased efficacy of aprepitant.

Selected Important Safety Information (continued)

• Chemotherapy agents that are known to be metabolized by CYP3A4 include docetaxel, paclitaxel, etoposide, irinotecan, ifosfamide, imatinib, vinorelbine, vinblastine, and vincristine. In clinical studies, EMEND® (aprepitant) was administered commonly with etoposide, vinorelbine, or paclitaxel. The doses of these agents were not adjusted to account for potential drug interactions. In separate pharmacokinetic studies, EMEND did not influence the pharmacokinetics of docetaxel or vinorelbine. • Because a small number of patients in clinical studies received the CYP3A4 substrates vinblastine, vincristine, or ifosfamide, particular caution and careful monitoring are advised in patients receiving these agents or other chemotherapy agents metabolized primarily by CYP3A4 that were not studied. • There have been isolated reports of immediate hypersensitivity reactions including flushing, erythema, dyspnea, and anaphylaxis during infusion of fosaprepitant. These hypersensitivity reactions have generally responded to discontinuation of the infusion and administration of appropriate therapy. It is not recommended to reinitiate the infusion in patients who have experienced these symptoms during first-time use. • Coadministration of EMEND® (fosaprepitant dimeglumine) for Injection with warfarin (a CYP2C9 substrate) may result in a clinically significant decrease in international normalized ratio (INR) of prothrombin time. In patients on chronic warfarin therapy, the INR should be closely monitored in the 2-week period, particularly at 7 to 10 days, following initiation of EMEND for Injection with each chemotherapy cycle. Triple Therapy=EMEND for Injection, a 5-HT 3 antagonist, and a corticosteroid. CINV=chemotherapy-induced nausea and vomiting.

emendforinjection.com

Please see the adjacent Brief Summary of the Prescribing Information.

EMENUS-5180_M08_JournalAd.indd 1-2

OCTOBER 2013 I VOL 6, NO 4

www.TheOncologyPharmacist.com

LUNG CANCER Responses were sustained over time in all patients except one, Soria said. Smoking status was a predictor of

response; former/current smokers had an ORR of 26% (n = 43) compared with 10% in never-smokers (n = 10).

Reference

Soria JC, Cruz C, Bahleda R, et al. Clinical activity, safety and biomarkers of PD-L1 blockade in non-small cell lung cancer (NSCLC): additional

analyses from a clinical study of the engineered antibody MPDL3280A (anti-PDL1). Presented at: 2013 European Cancer Congress; September 27-October 1, 2013; Amsterdam, the Netherlands. Abstract 3408.

Major oncology professional society guidelines recommend first-line use of a regimen including EMEND® (fosaprepitant dimeglumine) for Injection, a 5-HT3 antagonist, and a corticosteroid1–3,b

Receive your complimentary copy of guidelines for antiemetic treatment.

Scan this QR code or visit emendforinjection.com. Selected Important Safety Information (continued)

• The efficacy of hormonal contraceptives may be reduced during coadministration with and for 28 days after the last dose of EMEND for Injection. Alternative or backup methods of contraception should be used during treatment with and for 1 month after the last dose of EMEND for Injection. • Chronic continuous use of EMEND for Injection for prevention of nausea and vomiting is not recommended because it has not been studied and because the drug interaction profile may change during chronic continuous use. • In clinical trials of EMEND® (aprepitant) in patients receiving highly emetogenic chemotherapy, the most common adverse events reported at a frequency greater than with standard therapy, and at an incidence of 1% or greater were hiccups (4.6% EMEND vs 2.9% standard therapy), asthenia/fatigue (2.9% vs 1.6%), increased ALT (2.8% vs 1.5%), increased AST (1.1% vs 0.9%), constipation (2.2% vs 2.0%), dyspepsia (1.5% vs 0.7%), diarrhea (1.1% vs 0.9%), headache (2.2% vs 1.8%), and anorexia (2.0% vs 0.5%). • In a clinical trial evaluating safety of the 1-day regimen of EMEND for Injection 150 mg compared with the 3-day regimen of EMEND, the safety profile was generally similar to that seen in prior highly emetogenic chemotherapy studies with aprepitant. However, infusion-site reactions occurred at a higher incidence in patients who received fosaprepitant (3.0%) than in those who received aprepitant (0.5%). Those infusionsite reactions included infusion-site erythema, infusionsite pruritus, infusion-site pain, infusion-site induration, and infusion-site thrombophlebitis.

Selected Important Safety Information (continued)

• In clinical trials, EMEND for Injection increased the AUC of dexamethasone, a CYP3A4 substrate, by approximately 2-fold; therefore, the oral dose of dexamethasone administered in the regimen with EMEND for Injection should be reduced by approximately 50% to achieve exposures of dexamethasone similar to those obtained without EMEND for Injection. EMEND® (aprepitant) increased the AUC of methylprednisolone by 1.34-fold and 2.5-fold on Days 1 and 3, respectively. The intravenous dose of methylprednisolone should be reduced by approximately 25% and the oral dose by 50% when coadministered with EMEND for Injection 115 mg. b

Based on the Category 2A level of evidence and consensus. Category 2A is based upon lower-level evidence, there is uniform National Comprehensive Cancer Network ® consensus that the intervention is appropriate.2

References: 1. Basch E, Prestrud AA, Hesketh PJ, et al. Antiemetics: American Society of Clinical Oncology clinical practice guideline update. J Clin Oncol. 2011;29(31):4189–4198. 2. NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines ®) Version 1.2013. Antiemesis. www.nccn.org/professionals/physician_ gls/pdf/antiemesis.pdf. Published December 6, 2012. Accessed July 15, 2013. 3. Irwin MM, Lee J, Rodgers C, et al. Putting Evidence Into Practice: Improving Oncology Patient Outcomes. Chemotherapy-Induced Nausea and Vomiting Resource. Pittsburgh, PA: Oncology Nursing Society; 2012.

8/20/13 1:36 PM

www.TheOncologyPharmacist.com

OCTOBER 2013 I VOL 6, NO 4

LUNG CANCER QOL Improved With Crizotinib Versus Chemotherapy

n the ongoing phase 3 PROFILE 1007 study of patients with previously treated anaplastic lympho-

ma kinase (ALK)-positive non-small cell lung cancer, crizotinib improved quality of life (QOL) and key lung

cancer symptoms compared with chemotherapy (investigator’s choice: pemetrexed or docetaxel). Crizotinib

INDICATIONS AND USAGE EMEND for Injection is a substance P/neurokinin 1 (NK1) receptor antagonist indicated in adults for use in combination with other antiemetic agents for the prevention of acute and delayed nausea and vomiting associated with initial and repeat courses of highly emetogenic cancer chemotherapy (HEC) including high-dose cisplatin. Limitations of Use: EMEND for Injection has not been studied for the treatment of established nausea and vomiting Chronic continuous administration is not recommended [see Warnings and Precautions]. CONTRAINDICATIONS Hypersensitivity: EMEND for Injection is contraindicated in patients who are hypersensitive to EMEND for Injection, aprepitant, polysorbate 80, or any other components of the product. Known hypersensitivity reactions include flushing, erythema, dyspnea, and anaphylactic reactions [see Adverse Reactions]. Concomitant Use With Pimozide or Cisapride: Aprepitant, when administered orally, is a moderate cytochrome P450 isoenzyme 3A4 (CYP3A4) inhibitor following the 3-day antiemetic dosing regimen for CINV. Since fosaprepitant is rapidly converted to aprepitant, do not use fosaprepitant concurrently with pimozide or cisapride. Inhibition of CYP3A4 by aprepitant could result in elevated plasma concentrations of these drugs, potentially causing serious or life-threatening reactions [see Drug Interactions]. WARNINGS AND PRECAUTIONS CYP3A4 Interactions: Fosaprepitant is rapidly converted to aprepitant, which is a moderate inhibitor of CYP3A4 when administered as a 3-day antiemetic dosing regimen for CINV. Fosaprepitant should be used with caution in patients receiving concomitant medications that are primarily metabolized through CYP3A4. Inhibition of CYP3A4 by aprepitant or fosaprepitant could result in elevated plasma concentrations of these concomitant medications. When fosaprepitant is used concomitantly with another CYP3A4 inhibitor, aprepitant plasma concentrations could be elevated. When aprepitant is used concomitantly with medications that induce CYP3A4 activity, aprepitant plasma concentrations could be reduced, and this may result in decreased efficacy of aprepitant [see Drug Interactions]. Chemotherapy agents that are known to be metabolized by CYP3A4 include docetaxel, paclitaxel, etoposide, irinotecan, ifosfamide, imatinib, vinorelbine, vinblastine, and vincristine. In clinical studies, the oral aprepitant regimen was administered commonly with etoposide, vinorelbine, or paclitaxel. The doses of these agents were not adjusted to account for potential drug interactions. In separate pharmacokinetic studies, no clinically significant change in docetaxel or vinorelbine pharmacokinetics was observed when the oral aprepitant regimen was coadministered. Due to the small number of patients in clinical studies who received the CYP3A4 substrates vinblastine, vincristine, or ifosfamide, particular caution and careful monitoring are advised in patients receiving these agents or other chemotherapy agents metabolized primarily by CYP3A4 that were not studied [see Drug Interactions]. Brief Summary of the Prescribing Information for

Hypersensitivity Reactions: Isolated reports of immediate hypersensitivity reactions including flushing, erythema, dyspnea, and anaphylaxis have occurred during infusion of fosaprepitant. These hypersensitivity reactions have generally responded to discontinuation of the infusion and administration of appropriate therapy. Reinitiation of the infusion is not recommended in patients who experience these symptoms during first-time use. Coadministration With Warfarin (a CYP2C9 substrate): Coadministration of fosaprepitant or aprepitant with warfarin may result in a clinically significant decrease in international normalized ratio (INR) of prothrombin time. In patients on chronic warfarin therapy, the INR should be closely monitored in the 2-week period, particularly at 7 to 10 days, following initiation of fosaprepitant with each chemotherapy cycle [see Drug Interactions]. Coadministration With Hormonal Contraceptives: Upon coadministration with fosaprepitant or aprepitant, the efficacy of hormonal contraceptives may be reduced during and for 28 days following the last dose of either fosaprepitant or aprepitant. Alternative or backup methods of contraception should be used during treatment with and for 1 month following the last dose of fosaprepitant or aprepitant [see Drug Interactions]. Chronic Continuous Use: Chronic continuous use of EMEND for Injection for prevention of nausea and vomiting is not recommended because it has not been studied and because the drug interaction profile may change during chronic continuous use. ADVERSE REACTIONS Clinical Trials Experience: Because clinical trials are conducted under widely varying conditions, adversereaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in clinical practice. Since EMEND for Injection is converted to aprepitant, those adverse reactions associated with aprepitant might also be expected to occur with EMEND for Injection. The overall safety of fosaprepitant was evaluated in approximately 1,100 individuals and the overall safety of aprepitant was evaluated in approximately 6,500 individuals. Oral Aprepitant: Highly Emetogenic Chemotherapy (HEC): In 2 well-controlled clinical trials in patients receiving highly emetogenic cancer chemotherapy, 544 patients were treated with aprepitant during Cycle 1 of chemotherapy and 413 of these patients continued into the multiple-cycle extension for up to 6 cycles of chemotherapy. Oral aprepitant was given in combination with ondansetron and dexamethasone. In Cycle 1, adverse reactions were reported in approximately 17% of patients treated with the aprepitant regimen compared with approximately 13% of patients treated with standard therapy. Treatment was discontinued due to adverse reactions in 0.6% of patients treated with the aprepitant regimen compared with 0.4% of patients treated with standard therapy. The most common adverse reactions reported in patients treated with the aprepitant regimen (n=544) with an incidence of ≥1% and greater than with standard therapy (n=550), respectively, are listed below: Respiratory system: hiccups 4.6 vs 2.9 Body as a whole/Site unspecified: asthenia/fatigue 2.9 vs 1.6 Investigations: increased ALT 2.8 vs 1.5, increased AST 1.1 vs 0.9 Digestive system: constipation 2.2 vs 2.0, dyspepsia 1.5 vs 0.7, diarrhea 1.1 vs 0.9 Nervous system: headache 2.2 vs 1.8 Metabolism and nutrition: anorexia 2.0 vs 0.5 A listing of adverse reactions in the aprepitant regimen (incidence <1%) that occurred at a greater incidence than with standard therapy are presented in the Less Common Adverse Reactions subsection below. In an additional active-controlled clinical study in 1,169 patients receiving aprepitant and HEC, the adverseexperience profile was generally similar to that seen in the other HEC studies with aprepitant. Less Common Adverse Reactions: Adverse reactions reported in either HEC or moderately emetogenic chemotherapy (MEC) studies in patients treated with the aprepitant regimen with an incidence of <1% and greater than with standard therapy are listed below. Infection and infestations: candidiasis, staphylococcal infection Blood and lymphatic system disorders: anemia, febrile neutropenia Metabolism and nutrition disorders: weight gain, polydipsia Psychiatric disorders: disorientation, euphoria, anxiety Nervous system disorders: dizziness, dream abnormality, cognitive disorder, lethargy, somnolence Eye disorders: conjunctivitis Ear and labyrinth disorders: tinnitus Cardiac disorders: bradycardia, cardiovascular disorder, palpitations

OCTOBER 2013 I VOL 6, NO 4

EMENUS-5180_M08_JournalAd.indd 3-4

was associated with a significantly higher improvement rate in global QOL compared with chemotherapy

EMEND® (fosaprepitant dimeglumine) for Injection Vascular disorders: hot flush, flushing Respiratory, thoracic, and mediastinal disorders: pharyngitis, sneezing, cough, postnasal drip, throat irritation Gastrointestinal disorders: nausea, acid reflux, dysgeusia, epigastric discomfort, obstipation, gastroesophageal reflux disease, perforating duodenal ulcer, vomiting, abdominal pain, dry mouth, abdominal distension, hard feces, neutropenic colitis, flatulence, stomatitis Skin and subcutaneous tissue disorders: rash, acne, photosensitivity, hyperhidrosis, oily skin, pruritus, skin lesion Musculoskeletal and connective tissue disorders: muscle cramp, myalgia, muscular weakness Renal and urinary disorders: polyuria, dysuria, pollakiuria General disorders and administration site conditions: edema, chest discomfort, malaise, thirst, chills, gait disturbance Investigations: increased alkaline phosphatase, hyperglycemia, microscopic hematuria, hyponatremia, decreased weight, decreased neutrophil count In another chemotherapy-induced nausea and vomiting (CINV) study, Stevens-Johnson syndrome was reported as a serious adverse reaction in a patient receiving aprepitant with cancer chemotherapy. The adverse-experience profiles in the multiple-cycle extensions of HEC studies for up to 6 cycles of chemotherapy were similar to that observed in Cycle 1. Fosaprepitant: In an active-controlled clinical study in patients receiving HEC, safety was evaluated for 1,143 patients receiving the 1-day regimen of EMEND for Injection 150 mg compared with 1,169 patients receiving the 3-day regimen of EMEND. The safety profile was generally similar to that seen in prior HEC studies with aprepitant. However, infusion-site reactions occurred at a higher incidence in patients in the fosaprepitant group (3.0%) compared with those in the aprepitant group (0.5%). The reported infusion-site reactions included infusion-site erythema, infusion-site pruritus, infusion-site pain, infusion-site induration, and infusion-site thrombophlebitis. The following additional adverse reactions occurred with fosaprepitant 150 mg and were not reported with the oral aprepitant regimen in the corresponding section above: General disorders and administration site conditions: infusion-site erythema, infusion-site pruritus, infusion-site induration, infusion-site pain Investigations: increased blood pressure Skin and subcutaneous tissue disorders: erythema Vascular disorders: thrombophlebitis (predominantly infusion-site thrombophlebitis) Other Studies: Angioedema and urticaria were reported as serious adverse reactions in a patient receiving aprepitant in a non-CINV/non-PONV study. Postmarketing Experience: The following adverse reactions have been identified during postapproval use of fosaprepitant and aprepitant. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to the drug. Skin and subcutaneous tissue disorders: pruritus, rash, urticaria, rarely Stevens-Johnson syndrome/toxic epidermal necrolysis Immune system disorders: hypersensitivity reactions including anaphylactic reactions DRUG INTERACTIONS Drug interactions following administration of fosaprepitant are likely to occur with drugs that interact with oral aprepitant. Aprepitant is a substrate, a moderate inhibitor, and an inducer of CYP3A4 when administered as a 3-day antiemetic dosing regimen for CINV. Aprepitant is also an inducer of CYP2C9. Fosaprepitant 150 mg, given as a single dose, is a weak inhibitor of CYP3A4 and does not induce CYP3A4. Fosaprepitant and aprepitant are unlikely to interact with drugs that are substrates for the P-glycoprotein transporter. The following information was derived from data with oral aprepitant, 2 studies conducted with fosaprepitant and oral midazolam, and 1 study conducted with fosaprepitant and dexamethasone. Effect of Fosaprepitant/Aprepitant on the Pharmacokinetics of Other Agents: CYP3A4 substrates: Aprepitant, as a moderate inhibitor of CYP3A4, and fosaprepitant 150 mg, as a weak inhibitor of CYP3A4, can increase plasma concentrations of concomitantly coadministered oral medications that are metabolized through CYP3A4 [see Contraindications]. 5-HT3 antagonists: In clinical drug interaction studies, aprepitant did not have clinically important effects on the pharmacokinetics of ondansetron, granisetron, or hydrodolasetron (the active metabolite of dolasetron). Corticosteroids: Dexamethasone: Fosaprepitant 150 mg administered as a single intravenous dose on Day 1 increased the AUC0–24hr of dexamethasone, administered as a single 8-mg oral dose on Days 1, 2, and 3, by approximately 2-fold on Days 1 and 2. The oral dexamethasone dose on Days 1 and 2 should be reduced by approximately 50% when coadministered with fosaprepitant 150 mg I.V. on Day 1. An oral aprepitant regimen of 125 mg on Day 1 and 80 mg/day on Days 2 through 5, coadministered with 20-mg oral dexamethasone on Day 1 and 8-mg oral dexamethasone on Days 2 through 5, increased the AUC of dexamethasone by 2.2-fold on Days 1 and 5. The oral dexamethasone doses should be reduced by approximately 50% when coadministered with a regimen of fosaprepitant 115 mg followed by aprepitant. Methylprednisolone: An oral aprepitant regimen of 125 mg on Day 1 and 80 mg/day on Days 2 and 3 increased the AUC of methylprednisolone by 1.34-fold on Day 1 and by 2.5-fold on Day 3, when methylprednisolone was coadministered intravenously as 125 mg on Day 1 and orally as 40 mg on Days 2 and 3. The intravenous methylprednisolone dose should be reduced by approximately 25% and the oral methylprednisolone dose should be reduced by approximately 50% when coadministered with a regimen of fosaprepitant 115 mg followed by aprepitant. Chemotherapeutic agents: Docetaxel: In a pharmacokinetic study, oral aprepitant (CINV regimen) did not influence the pharmacokinetics of docetaxel [see Warnings and Precautions]. Vinorelbine: In a pharmacokinetic study, oral aprepitant (CINV regimen) did not influence the pharmacokinetics of vinorelbine to a clinically significant degree [see Warnings and Precautions]. Oral contraceptives: When oral aprepitant, ondansetron, and dexamethasone were coadministered with an oral contraceptive containing ethinyl estradiol and norethindrone, the trough concentrations of both ethinyl estradiol and norethindrone were reduced by as much as 64% for 3 weeks posttreatment. The coadministration of fosaprepitant or aprepitant may reduce the efficacy of hormonal contraceptives (these can include birth control pills, skin patches, implants, and certain IUDs) during and for 28 days after administration of the last dose of fosaprepitant or aprepitant. Alternative or backup methods of contraception should be used during treatment with and for 1 month following the last dose of fosaprepitant or aprepitant. Midazolam: Interactions between aprepitant or fosaprepitant and coadministered midazolam are listed below (increase is indicated as ↑, decrease as ↓, no change as ↔): Fosaprepitant 150 mg on Day 1, oral midazolam 2 mg on Days 1 and 4: AUC ↑ 1.8-fold on Day 1 and AUC ↔ on Day 4 Fosaprepitant 100 mg on Day 1, oral midazolam 2 mg: oral midazolam AUC ↑ 1.6-fold Oral aprepitant 125 mg on Day 1 and 80 mg on Days 2 to 5, oral midazolam 2 mg SD on Days 1 and 5: oral midazolam AUC ↑ 2.3-fold on Day 1 and ↑ 3.3-fold on Day 5 Oral aprepitant 125 mg on Day 1 and 80 mg on Days 2 and 3, intravenous midazolam 2 mg prior to 3-day

www.TheOncologyPharmacist.com

LUNG CANCER in all domains, said Vera Hirsh, MD, McGill University, Montreal, Canada. “These improvements in QOL are particularly important for this palliative group of patients. Our findings

support the improvement in PFS [progression-free survival] seen in the trial with crizotinib,” she said. The QOL study randomized 172 patients to receive crizotinib and 171

to standard-of-care chemotherapy with either pemetrexed or docetaxel. Patient-reported outcomes were assessed at baseline, on day 1 of each cycle, and at the end of treatment

EMEND® (fosaprepitant dimeglumine) for Injection regimen of aprepitant and on Days 4, 8, and 15: intravenous midazolam AUC ↑ 25% on Day 4, AUC ↓ 19% on Day 8, and AUC ↓ 4% on Day 15 Oral aprepitant 125 mg, intravenous midazolam 2 mg given 1 hour after aprepitant: intravenous midazolam AUC ↑ 1.5-fold A difference of less than 2-fold increase of midazolam AUC was not considered clinically important. The potential effects of increased plasma concentrations of midazolam or other benzodiazepines metabolized via CYP3A4 (alprazolam, triazolam) should be considered when coadministering these agents with fosaprepitant or aprepitant. CYP2C9 substrates (Warfarin, Tolbutamide): Warfarin: A single 125-mg dose of oral aprepitant was administered on Day 1 and 80 mg/day on Days 2 and 3 to healthy subjects who were stabilized on chronic warfarin therapy. Although there was no effect of oral aprepitant on the plasma AUC of R(+) or S(–) warfarin determined on Day 3, there was a 34% decrease in S(–) warfarin trough concentration accompanied by a 14% decrease in the prothrombin time (reported as INR) 5 days after completion of dosing with oral aprepitant. In patients on chronic warfarin therapy, the prothrombin time (INR) should be closely monitored in the 2-week period, particularly at 7 to 10 days, following initiation of fosaprepitant with each chemotherapy cycle. Tolbutamide: Oral aprepitant, when given as 125 mg on Day 1 and 80 mg/day on Days 2 and 3, decreased the AUC of tolbutamide by 23% on Day 4, 28% on Day 8, and 15% on Day 15, when a single dose of tolbutamide 500 mg was administered orally prior to the administration of the 3-day regimen of oral aprepitant and on Days 4, 8, and 15. Effect of Other Agents on the Pharmacokinetics of Aprepitant: Aprepitant is a substrate for CYP3A4; therefore, coadministration of fosaprepitant or aprepitant with drugs that inhibit CYP3A4 activity may result in increased plasma concentrations of aprepitant. Consequently, concomitant administration of fosaprepitant or aprepitant with strong CYP3A4 inhibitors (eg, ketoconazole, itraconazole, nefazodone, troleandomycin, clarithromycin, ritonavir, nelfinavir) should be approached with caution. Because moderate CYP3A4 inhibitors (eg, diltiazem) result in a 2-fold increase in plasma concentrations of aprepitant, concomitant administration should also be approached with caution. Aprepitant is a substrate for CYP3A4; therefore, coadministration of fosaprepitant or aprepitant with drugs that strongly induce CYP3A4 activity (eg, rifampin, carbamazepine, phenytoin) may result in reduced plasma concentrations and decreased efficacy. Ketoconazole: When a single 125-mg dose of oral aprepitant was administered on Day 5 of a 10-day regimen of 400 mg/day of ketoconazole, a strong CYP3A4 inhibitor, the AUC of aprepitant increased approximately 5-fold and the mean terminal half-life of aprepitant increased approximately 3-fold. Concomitant administration of fosaprepitant or aprepitant with strong CYP3A4 inhibitors should be approached cautiously. Rifampin: When a single 375-mg dose of oral aprepitant was administered on Day 9 of a 14-day regimen of 600 mg/day of rifampin, a strong CYP3A4 inducer, the AUC of aprepitant decreased approximately 11-fold and the mean terminal half-life decreased approximately 3-fold. Coadministration of fosaprepitant or aprepitant with drugs that induce CYP3A4 activity may result in reduced plasma concentrations and decreased efficacy. Additional Interactions: Diltiazem: In a study in 10 patients with mild to moderate hypertension, intravenous infusion of 100 mg of fosaprepitant with diltiazem 120 mg 3 times daily resulted in a 1.5-fold increase of aprepitant AUC and a 1.4-fold increase in diltiazem AUC. It also resulted in a small but clinically meaningful further maximum decrease in diastolic blood pressure (mean [SD] of 24.3 [±10.2] mmHg with fosaprepitant vs 15.6 [±4.1] mmHg without fosaprepitant) and resulted in a small further maximum decrease in systolic blood pressure (mean [SD] of 29.5 [±7.9] mmHg with fosaprepitant vs 23.8 [±4.8] mmHg without fosaprepitant), which may be clinically meaningful, but did not result in a clinically meaningful further change in heart rate or PR interval beyond those changes induced by diltiazem alone. In the same study, administration of aprepitant once daily as a tablet formulation comparable to 230 mg of the capsule formulation, with diltiazem 120 mg 3 times daily for 5 days, resulted in a 2-fold increase of aprepitant AUC and a simultaneous 1.7-fold increase of diltiazem AUC. These pharmacokinetic effects did not result in clinically meaningful changes in ECG, heart rate, or blood pressure beyond those changes induced by diltiazem alone. Paroxetine: Coadministration of once-daily doses of aprepitant as a tablet formulation comparable to 85 mg or 170 mg of the capsule formulation, with paroxetine 20 mg once daily, resulted in a decrease in AUC by approximately 25% and Cmax by approximately 20% of both aprepitant and paroxetine. USE IN SPECIFIC POPULATIONS Pregnancy: Teratogenic effects: Pregnancy Category B: In the reproduction studies conducted with fosaprepitant and aprepitant, the highest systemic exposures to aprepitant were obtained following oral administration of aprepitant. Reproduction studies performed in rats at oral doses of aprepitant of up to 1000 mg/kg twice daily (plasma AUC0–24hr of 31.3 mcg•hr/mL, about 1.6 times the human exposure at the recommended dose) and in rabbits at oral doses of up to 25 mg/kg/day (plasma AUC0–24hr of 26.9 mcg•hr/mL, about 1.4 times the human exposure at the recommended dose) revealed no evidence of impaired fertility or harm to the fetus due to aprepitant. There are, however, no adequate and well-controlled studies in pregnant women. Because animal reproduction studies are not always predictive of human response, this drug should be used during pregnancy only if clearly needed. Nursing Mothers: Aprepitant is excreted in the milk of rats. It is not known whether this drug is excreted in human milk. Because many drugs are excreted in human milk and because of the potential for possible serious adverse reactions in nursing infants from aprepitant and because of the potential for tumorigenicity shown for aprepitant in rodent carcinogenicity studies, a decision should be made whether to discontinue nursing or to discontinue the drug, taking into account the importance of the drug to the mother. Pediatric Use: Safety and effectiveness of EMEND for Injection in pediatric patients have not been established. Geriatric Use: In 2 well-controlled CINV clinical studies, of the total number of patients (N=544) treated with oral aprepitant, 31% were 65 and over, while 5% were 75 and over. No overall differences in safety or effectiveness were observed between these subjects and younger subjects. Greater sensitivity of some older individuals cannot be ruled out. Dosage adjustment in the elderly is not necessary. Patients With Severe Hepatic Impairment: There are no clinical or pharmacokinetic data in patients with severe hepatic impairment (Child-Pugh score >9). Therefore, caution should be exercised when fosaprepitant or aprepitant is administered in these patients. OVERDOSAGE There is no specific information on the treatment of overdosage with fosaprepitant or aprepitant. In the event of overdose, fosaprepitant and/or oral aprepitant should be discontinued and general supportive treatment and monitoring should be provided. Because of the antiemetic activity of aprepitant, drug-induced emesis may not be effective. Aprepitant cannot be removed by hemodialysis. Thirteen patients in the randomized controlled trial of EMEND for Injection received both fosaprepitant 150 mg and at least one dose of oral aprepitant, 125 mg or 80 mg. Three patients reported adverse reactions that were similar to those experienced by the total study population. NONCLINICAL TOXICOLOGY Carcinogenesis, Mutagenesis, Impairment of Fertility: Carcinogenicity studies were conducted in Sprague-Dawley rats and in CD-1 mice for 2 years. In the rat carcinogenicity studies, animals were treated with oral doses ranging from 0.05 to 1000 mg/kg twice daily. The highest dose produced a systemic exposure to aprepitant (plasma AUC0–24hr) of 0.7 to 1.6 times the human exposure (AUC0–24hr=19.6 mcg•hr/mL) at the recommended dose of 125 mg/day. Treatment with aprepitant at doses of 5 to 1000 mg/kg twice daily caused an increase in the incidences of thyroid follicular cell adenomas and carcinomas in male rats. In female rats, it

www.TheOncologyPharmacist.com

produced hepatocellular adenomas at 5 to 1000 mg/kg twice daily and hepatocellular carcinomas and thyroid follicular cell adenomas at 125 to 1000 mg/kg twice daily. In the mouse carcinogenicity studies, the animals were treated with oral doses ranging from 2.5 to 2000 mg/kg/day. The highest dose produced a systemic exposure of about 2.8 to 3.6 times the human exposure at the recommended dose. Treatment with aprepitant produced skin fibrosarcomas at 125 and 500 mg/kg/day doses in male mice. Carcinogenicity studies were not conducted with fosaprepitant. Aprepitant and fosaprepitant were not genotoxic in the Ames test, the human lymphoblastoid cell (TK6) mutagenesis test, the rat hepatocyte DNA strand break test, the Chinese hamster ovary (CHO) cell chromosome aberration test and the mouse micronucleus test. Fosaprepitant, when administered intravenously, is rapidly converted to aprepitant. In the fertility studies conducted with fosaprepitant and aprepitant, the highest systemic exposures to aprepitant were obtained following oral administration of aprepitant. Oral aprepitant did not affect the fertility or general reproductive performance of male or female rats at doses up to the maximum feasible dose of 1000 mg/kg twice daily (providing exposure in male rats lower than the exposure at the recommended human dose and exposure in female rats at about 1.6 times the human exposure). PATIENT COUNSELING INFORMATION [See FDA-Approved Patient Labeling]: Physicians should instruct their patients to read the patient package insert before starting therapy with EMEND for Injection and to reread it each time the prescription is renewed. Patients should follow the physician’s instructions for the regimen of EMEND for Injection. Allergic reactions, which may be sudden and/or serious, and may include hives, rash, itching, redness of the face/skin, and may cause difficulty in breathing or swallowing, have been reported. Physicians should instruct their patients to stop using EMEND and call their doctor right away if they experience an allergic reaction. In addition, severe skin reactions may occur rarely. Patients who develop an infusion-site reaction such as erythema, edema, pain, or thrombophlebitis should be instructed on how to care for the local reaction and when to seek further evaluation. EMEND for Injection may interact with some drugs, including chemotherapy; therefore, patients should be advised to report to their doctor the use of any other prescription or nonprescription medication or herbal products. Patients on chronic warfarin therapy should be instructed to have their clotting status closely monitored in the 2-week period, particularly at 7 to 10 days, following initiation of fosaprepitant with each chemotherapy cycle. Administration of EMEND for Injection may reduce the efficacy of hormonal contraceptives. Patients should be advised to use alternative or backup methods of contraception during treatment with and for 1 month following the last dose of fosaprepitant or aprepitant.

using the European Organisation for Research and Treatment of Cancer Quaity of Life Questionnaire Core 30 (EORTC QLQ-C30) and lung cancer module QLQ-LC13. Scores on these instruments ranged from 0 to 100, with higher scores reflecting higher symptom severity or better functioning/QOL, depending on the instrument and question. A 10-point or greater change from baseline was deemed clinically meaningful for either improvement or worsening. As of March 30, 2012, 162 patients in the crizotinib arm and 151 in the chemotherapy arm completed at least 1 question at baseline, and this population was analyzed for QOL. Baseline scores were well balanced between the 2 arms and were relatively low. Crizotinib achieved significantly greater improvement in global QOL versus chemotherapy (42.6% vs 20.7%, respectively; P <.001). Crizotinib also significantly improved physical functioning (27.2% vs 11.9%; P <.001), role functioning (30.9% vs 14.6%; P <.001), and emotional functioning (37.0% vs 24.0%; P <.05).

For more detailed information, please read the Prescribing Information. Rx only

“These improvements in QOL are particularly important for this palliative group of patients.”

Vera Hirsh, MD

Lung cancer symptoms were significantly improved in the crizotinib arm versus chemotherapy (P <.001 for all comparisons): fatigue (46.3% vs 20.5%, respectively), pain (43.8% vs 20.5%), cough (55.3% vs 33.3%), dyspnea (39.1% vs 17.3%), chest pain (40.0% vs 22.3%), and pain in arm or shoulder (33.5% vs 19.5%). Domains significantly worsened on crizotinib (P <.001 for both comparisons) were constipation (44.4% vs 22.5%) and diarrhea (41.4% vs 19.2%). “Deterioration was slowed in a significantly greater proportion of patients in the crizotinib arm versus chemotherapy,” Hirsh reported. The study was supported by Pfizer Inc. l —AG Reference

Blackhall F, Hirsh V, Kim DW, et al. Impact of crizotinib on patient-reported symptoms and global quality of life (QoL) compared with chemotherapy in a phase III study of advanced alk-positive non-small cell lung cancer (NSCLC). Presented at: 2013 European Cancer Congress; September 27-October 1, 2013; Amsterdam, the Netherlands. Abstract 3400.

8/20/13 1:36 PM

OCTOBER 2013 I VOL 6, NO 4

SIDE EFFECTS MANAGEMENT

Raising Awareness of Cancer Anorexia-Cachexia... Continued from cover The study found that 62% of patients with stage IV metastatic non-small cell lung cancer (mNSCLC) met at least 1 of 4 defining criteria for CACS. The investigators from Duke Clinical Research Institute and Duke Cancer Institute, Durham, North Carolina, said that the underreporting of CACS “demonstrates a substantial opportunity for clinical and patient education as to the presence and impact of the condition, especially as new therapies become available.” CACS, a multifactorial condition leading to muscle wasting, affects up to 80% of patients with advanced malignancies, said the investigators. The presence of CACS impairs quality of life and compromises response to chemotherapy. Patients with CACS have more frequent and severe toxicity and require more dose reductions and treatment delays than those without the syndrome, thus interfering with the beneficial effect of anticancer therapy. Reasons for the underrecognition and undertreatment of CACS include lack

of a standardized definition, lack of effective treatments, and poor education about CACS and its impact. As new treatment options become available, it is important to look at how CACS is identified and addressed in the current clinical landscape. To look at the prevalence of CACS in patients with mNSCLC, the Duke investigators gathered data from an electronic patient-reported outcomes (ePRO) database combined with other electronic data systems and paper case notes available at Duke. CACS was identified according to the following 4 criteria: 1. Weight loss ≥5% or weight loss >2% with a body mass index (BMI) <20 kg/m2 within 3 to 6 months of diagnosis. 2. CACS-related International Classification of Diseases, Ninth Revision (ICD-9) codes assigned by healthcare providers. 3. A score of ≥7 on patient-reported questions related to weight loss or lack of appetite.

4. A prescription for drugs that treat CACS (eg, megesterol acetate, dronabinol). Of the 495 patients identified with mNSCLC between May 2007 and April 2012, 307 (62%) met at least 1 of the 4 criteria for CACS. For example, among patients with weight loss data available at 3 and 6 months (n = 215), 51% met the criteria. Healthcare providers assigned the ICD-9 code for CACS to 22% of patients. Among patients completing the ePRO survey (n = 202) during the course of treatment, 32% met the predefined threshold for severe loss of weight or appetite. Finally, 5% of patients (n = 26) received either megesterol acetate or dronabinol. Of the 109 patients who fulfilled weight loss criteria for CACS, less than 50% were captured by ePRO, ICD-9 code, or medication adherence. The prevalence of CACS was 42% and 17% in patients with weight loss ≥5% at 3 months and 6 months, respectively. Weight loss criteria of ≥2% with a BMI ≤20 kg/m2 were met by 1% of patients at

3 months and 2% at 6 months. The study’s senior author, Amy Abernethy, MD, commented on the importance of the findings: “In the setting of advanced cancer, anorexiacachexia syndrome is woefully underrecognized. Over half of the patients with available weight data could have met the criteria for CACS by weight loss criteria alone. In this single setting, over 60% met at least 1 criterion. If we aren’t identifying people burdened by this syndrome, then we cannot initiate approaches to help them. Simple maneuvers like education will help patients and families know what to expect. And, we anticipate that our treatment toolbox will soon be filled with new efficacious medications. We need to learn how to identify the red flags of CACS so that we can be ready to treat people who suffer from the syndrome.” l Reference

Benner A, Hirsch B, Abernethy A. Cancer anorexia-cachexia syndrome (CACS) is under-recognized among patients with metastatic non-small cell lung cancer (mNSCLC). Support Care Cancer. 2013;21(suppl 1):S33. Abstract 0808.

DRUG ECONOMICS

Off-Label Drug Use Accounts for 18% of Spending Mean Number of Unapproved Claims Averaged 11 per Patient By Caroline Helwick

n examination of the Surveillance, Epidemiology and End Results (SEER)-Medicare database from 1998 through 2008 revealed that a significant number of patients with cancer received unapproved drugs—anticancer agents that are neither approved by the US Food and Drug Administration (FDA) nor endorsed by the compendia of the National Comprehensive Cancer Network (NCCN)—and that off-label drug use accounted for 18% of drug costs. “We found a lot of off-label use,” said Dawn Hershman, MD, of Columbia University Medical Center, New York, at the 2013 American Society of Clinical Oncology Annual Meeting. The extent of off-label use is a policy concern because the clinical benefits of such use to patients may not outweigh costs or adverse health outcomes, she said. The study identified 42,634 patients with metastatic breast, ovarian, uterine, lung, colon, and prostate cancer, or multiple myeloma. It documented the proportion of drug claims in a given year that were FDA approved, NCCN compendia approved, or unapproved. FDA drug approvals and their dates

OCTOBER 2013 I VOL 6, NO 4

Table Appropriateness of Drug Use and Related Costs (n = 42,634)1 Approval Status

Cost in Millions ($)

Percentage of Costs (%)

FDA-approved drug

531.8

Compendia-supported drug

144.7

Unapproved

149.5

Abbreviation: FDA, US Food and Drug Administration.

were identified; if the drug claim was within 1 year prior to FDA approval, it was categorized as compendia supported. If it followed the approval date, it was categorized as FDA approved. The researchers also determined which of the drugs were ever approved. The Medicare reimbursement rate was determined, calculated for the most common regimen and dosing, and was not adjusted for inflation. The investigators considered all anticancer agents used for the 7 common tumor types and found the following number of unapproved drugs (ie, neither FDA approved nor compendia endorsed): 33 in prostate cancer, 28 in ovarian cancer, 20 in breast cancer, 18 in multiple myeloma, 13 in uterine cancer, and 8 each in colon

and lung cancer, Hershman reported. The percentage of patients receiving only an approved drug was 55%, meaning that 45% of patients received a drug that was neither FDA approved nor compendia supported. There was strong variability by tumor type, with patients with multiple myeloma the most likely to receive an unapproved drug (~80%) and patients with colon cancer the least likely (~10%). The pattern was consistent across the 10-year time period. Then the investigators evaluated which of the unapproved drugs were compendia approved and found that 70% were endorsed and 30% were not. The mean number of unapproved claims averaged 11 per patient overall,

while the mean number of unapproved drugs averaged 1.5 per patient. “The bulk of unapproved drugs are, however, compendia approved, and this is reassuring because we think the compendia are appropriate,” Hershman acknowledged. About half the compendia-supported drugs were eventually approved by the FDA for that indication, but those that did not become FDA approved were not deleted from the compendia, she added. Cost of Off-Label Use: $150 Million A breakdown of the cost according to appropriate use revealed that nearly $150 million in reimbursements was paid for drugs that were neither FDA approved nor compendia supported (Table).1 Most of the cost for off-label drug use was for the treatment of patients with multiple myeloma and prostate cancer. “Of $850 million spent on drugs in this cohort, $150 million was for drugs only supported by compendia and $150 million was for unapproved indications,” she concluded, adding that drug costs have increased substantially in the past 5 years and therefore the costs today may be much greater.

www.TheOncologyPharmacist.com

DRUG ECONOMICS

Off-Label Drug Use Accounts for 18% of Spending Hershman cited data from another recent study that detailed which patent-protected chemotherapy agents were the most likely to be used inappropriately.2 Conti and colleagues showed that off-label use (neither FDA approved nor NCCN endorsed) was greatest for rituximab and gemcitabine (~40%) and bevacizumab (~25%). The least inappropriate use was for trastuzumab, for which essentially no inappropriate use was documented, and for pemetrexed (<10%). The estimated national spending on these common, patent-protected drugs amounted to $12 billion, of which $2.5 billion was for off-label and NCCN-unsupported use, the Conti study reported. While acknowledging limitations to her group’s study that pertain to the use of billing codes, estimates of cost, and other factors, Hershman commented, “We didn’t think we would find any unapproved use of drugs. We thought regulations were in place to stop that.” l References

1. Hershman DL, Neugut AI, Buono D, et al. Off-label and compendia use of chemotherapy in patients with metastatic cancer. J Clin Oncol. 2013;31(suppl):Abstract 6509. Presented at: 2013 American Society of Clinical Oncology Annual Meeting; May 31-June 4, 2013; Chicago, IL. 2. Conti RM, Bernstein AC, Villaflor VM, et al. Prevalence of off-label use and spending in 2010 among patent-protected chemotherapies in a population-based cohort of medical oncologists. J Clin Oncol. 2013;31(9):1134-1139.

The Good, the Bad, and the Ugly Monika K. Krzyzanowska, MD, MPH, of the Princess Margaret Cancer Centre, Toronto, Canada, discussed the study by Hershman and colleagues and noted that some off-label use is not completely “inappropriate” but may exist in terms of a different administration schedule, or a different context for the same disease. In some cases, of course, the drug is used in the treatment of a disease for which it has not been well studied. Bevacizumab is a good example of this, she said. According to Krzyzanowska, this matters because there can be “bad” consequences, such as a negative impact on trial accrual and undue financial costs, or “ugly” consequences, such as harm to the patient. Of course, she noted, some consequences are “good,” such as drug access for patients with rare diseases and the promotion of innovation. She said the study by Hershman and colleagues confirms previous research showing that off-label prescribing is common in oncology and varies by disease, though a substantial proportion of off-label use is supported by NCCN compendia. Several questions remain to be answered: • Is compendium-compliant use of drugs appropriate? • What is the impact of off-label prescribing on patients (ie, benefit and toxicity)? • What is the motivation for off-label prescribing? • How can the cost of off-label therapy be best estimated? • What is the incidence of off-label use in oral chemotherapy? • How would molecular profiling affect off-label prescribing? Clearly, Krzyzanowska said, oncologists are not “choosing wisely” in all circumstances. She concluded that greater scrutiny of off-label use is needed, “especially for diseases or drugs with a high prevalence of this, for expensive drugs, and for situations where the benefit is likely small and the risk of toxicity substantial.” Reference Krzyzanowska MK. The good, the bad, and the ugly of off-label prescribing in oncology. Presented at: 2013 American Society of Clinical Oncology Annual Meeting; May 31-June 4, 2013; Chicago, IL.

VISIT OUR RECENTLY ENHANCED USER-FRIENDLY WEB SITE www.TheOncologyPharmacist.com

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!

Web Ad_TOP_v2.indd 1

www.TheOncologyPharmacist.com

8/13/13 1:16 PM

OCTOBER 2013 I VOL 6, NO 4

CONTINUING EDUCATION 6th Annual

OCTOBER 2013 • VOLUME 6 • NUMBER 4

CONSIDERATIONS in

Multiple Myeloma

™

ASK THE EXPERTS: The Role of Transplantation PUBLISHING STAFF Group Director, Sales & Marketing John W. Hennessy john@greenhillhc.com Editorial Director Susan A. Berry susan@coexm.com Senior Copy Editor BJ Hansen Copy Editors Dana Delibovi Rosemary Hansen Grants/Project Associate Susan Yeager The Lynx Group President/CEO Brian Tyburski Chief Operating Officer Pam Rattananont Ferris Vice President of Finance Andrea Kelly Director, Human Resources Blanche Marchitto Associate Editorial Director, Projects Division Terri Moore Director, Quality Control Barbara Marino

LETTER

FROM THE

EDITOR-IN-CHIEF

Over the past decade, significant progress has been made in the management of multiple myeloma, including new standards of care and the development and approval of several novel, effective agents. Despite this progress, more work needs to be done and numerous questions remain regarding the application and interpretation of recent clinical advances. In this 6th annual “Considerations in Multiple Myeloma” newsletter series, we continue to explore unresolved issues related to the management of the disease and new directions in treatment. To ensure an interprofessional perspective, our faculty is comprised of physicians, nurses, and pharmacists from leading cancer institutions, who provide their insight, knowledge, and clinical experience related to the topic at hand. In this fourth issue, experts from Abramson Cancer Center answer questions related to the use of transplantation in patients with MM. Sincerely, Sagar Lonial, MD Professor Vice Chair of Clinical Affairs Department of Hematology and Medical Oncology Winship Cancer Institute Emory University School of Medicine Atlanta, GA

Quality Control Assistant Theresa Salerno

FACULTY

Edward A. Stadtmauer, MD Professor of Medicine Chief, Hematologic Malignancies Abramson Cancer Center University of Pennsylvania Philadelphia, PA

Patricia A. Mangan, MSN, CRNP Coordinator Bone Marrow and Stem Cell Transplant Program Abramson Cancer Center University of Pennsylvania Philadelphia, PA

Alex Ganetsky, PharmD, BCOP Hematology/Oncology Clinical Pharmacy Specialist Abramson Cancer Center University of Pennsylvania Philadelphia, PA

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

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

Executive Administrator Rachael Baranoski Office Coordinator Robert Sorensen

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

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

OCTOBER 2013 I VOL 6, NO 4

www.TheOncologyPharmacist.com

CONSIDERATIONS IN MULTIPLE MYELOMA Sponsors This activity is jointly sponsored by Medical Learning Institute Inc and Center of Excellence Media, LLC. Commercial Support Acknowledgment This activity is supported by educational grants from Onyx Pharmaceuticals and Millennium: The Takeda Oncology Company. Target Audience The activity was developed for physicians, nurses, and pharmacists involved in the treatment of patients with multiple myeloma (MM). Purpose Statement The purpose of this activity is to enhance competence of physicians, nurses, and pharmacists concerning the treatment of MM. Physician Credit Designation The Medical Learning Institute Inc designates this enduring material for a maximum of 1.0 AMA PRA Category 1 Credits™. Physicians should claim only the credit commensurate with the extent of their participation in the activity. This activity has been planned and implemented in accordance with the Essential Areas and policies of the Accreditation Council for Continuing Medical Education through the joint sponsorship of the Medical Learning Institute Inc and Center of Excellence Media, LLC. The Medical Learning Institute Inc is accredited by the Accreditation Council for Continuing Medical Education to provide continuing medical education for physicians. Registered Nurse Designation Medical Learning Institute Inc Provider approved by the California Board of Registered Nursing, Provider Number 15106, for 1.0 contact hour. Registered Pharmacy Designation The Medical Learning Institute Inc is accredited by the Accreditation Council for Pharmacy Education as a provider of continuing pharmacy education. Completion of this application-based activity provides for 1.0 contact hour (0.1 CEU) of continuing pharmacy education credit. The Universal Activity Number for this activity is 0468-9999-13-022-H01-P. Learning Objectives Upon completion of this activity, the participant will be able to: • Discuss existing and emerging therapeutic options for patients with newly diagnosed or relapsed/refractory MM and how to tailor therapy for individual patients • Describe the pharmacokinetics and pharmacodynamics of novel

agents when integrating these agents into treatment regimens for MM • Evaluate adverse event management strategies for patients with MM receiving novel therapies and multidrug regimens Disclosures Before the activity, all faculty and anyone who is in a position to have control over the content of this activity and their spouse/life partner will disclose the existence of any financial interest and/or relationship(s) they might have with any commercial interest producing healthcare goods/services to be discussed during their presentation(s): honoraria, expenses, grants, consulting roles, speakers’ bureau membership, stock ownership, or other special relationships. Presenters will inform participants of any off-label discussions. All identified conflicts of interest are thoroughly vetted by Medical Learning Institute Inc for fair balance, scientific objectivity of studies mentioned in the materials or used as the basis for content, and appropriateness of patient care recommendations. The associates of Medical Learning Institute Inc, the accredited provider for this activity, and Center of Excellence Media, LLC, do not have any financial relationships or relationships to products or devices with any commercial interest related to the content of this CME/CPE/CE activity for any amount during the past 12 months. Planners’ and Managers’ Disclosures Dana Delibovi, Medical Writer, has nothing to disclose. She does not intend to discuss non-FDA-approved or investigational use for any products/devices. William J. Wong, MD, MLI Reviewer, has nothing to disclose. Shannon Woerner, RN, MSN, MLI Reviewer, has nothing to disclose. Shelly Chun, PharmD, MLI Reviewer, has nothing to disclose. Faculty Disclosures Sagar Lonial, MD, is on the advisory board for and is a Consultant to Bristol-Myers Squibb, Celgene Corporation, Millennium: the Takeda Oncology Company, Novartis, Onyx Pharmaceuticals, and sanofi-aventis. He does not intend to discuss any non–FDA-approved or investigational use for any products/devices. Edward A. Stadtmauer, MD, is a consultant to Celgene Corporation, Millennium: the Takeda Oncology Company, and Onyx Pharmaceuticals. He does not intend to discuss non-FDA-approved or investigational use for any products/devices. Patricia A. Mangan, MSN, CRNP, is on the advisory board for sanofi-aventis and the speaker’s bureau for Celgene Corporation, Millennium: The Takeda Oncology Company, and Onyx Pharma-

ceuticals. She does not intend to discuss any non-FDA-approved or investigational use for any products/devices. Alex Ganetsky, PharmD, BCOP, is on the advisory board for Cephalon. He does intend to discuss either non-FDA-approved or investigational use for the following product/device: cyclophosphamide. Disclaimer The information provided in this CME/CPE/CE activity is for continuing education purposes only and is not meant to substitute for the independent medical judgment of a healthcare provider relative to diagnostic and treatment options of a specific patient’s medical condition. Recommendations for the use of particular therapeutic agents are based on the best available scientific evidence and current clinical guidelines. No bias toward or promotion for any agent discussed in this program should be inferred. Instructions for Credit There is no fee for this activity. To receive credit after reading this CME/CPE/CE activity in its entirety, participants must complete the pretest, posttest, and evaluation. The pretest, posttest, and evaluation can be completed online at www.mlicme.org/P13008D.html. Upon completion of the evaluation and scoring 70% or better on the posttest, you will immediately receive your certificate online. If you do not achieve a score of 70% or better on the posttest, you will be asked to take it again. Please retain a copy of the certificate for your records. For questions regarding the accreditation of this activity, please contact Medical Learning Institute Inc at 609-333-1693 or cgusack@mlicme.org. For pharmacists, Medical Learning Institute Inc will report your participation in this educational activity to the NABP only if you provide your NABP e-Profile number and date of birth. For more information regarding this process or to get your NABP e-Profile number, go to www.mycpemonitor.net. Estimated time to complete activity: 1.0 hour Date of initial release: October 15, 2013 Valid for CME/CPE/CE credit through: October 15, 2014 SCAN HERE to Download the PDF or Apply for Credit. To use 2D barcodes, download the ScanLife app: • Text “scan” to 43588 • Go to www.getscanlife.com on your smartphone’s Web browser, and select “Download” • Visit the app store for your smartphone

The Role of Transplantation in Improving Patient Outcomes in Multiple Myeloma Edward A. Stadtmauer, MD

Professor of Medicine, Chief, Hematologic Malignancies Abramson Cancer Center, University of Pennsylvania Philadelphia, PA

Introduction With the advent of upfront transplantation, survival rates among patients with multiple myeloma (MM) have improved dramatically. Ongoing debate continues, however, on the utility of early transplantation, given the increasing efficacy of multidrug induction regimens that include such novel, molecularly targeted agents as bortezomib and lenalidomide. In this article, Edward A. Stadtmauer, MD, shares his insights and experience regarding the clinical pathway from induction, to high-dose melphalan therapy and transplantation, to posttransplant maintenance in transplant-eligible patients with MM.

Should all transplant-eligible patients receive early high-dose therapy and autologous stem cell transplantation (HDT/ASCT), or can transplantation be delayed in some cases? This is a very interesting and important question—particularly here in the United States. Most centers in the rest of the world that have the capability

www.TheOncologyPharmacist.com

for transplantation have concluded that induction therapy to achieve remission, followed by consolidation with 1 or 2 cycles of high-dose melphalan and ASCT, followed by some form of maintenance therapy, are the steps that lead to the best outcomes among transplant-eligible patients.1 In the United States, however, some debate exists regarding the timing of HDT/ASCT. According to some experts, in the era of very effective initial treatment with novel agents, it may be possible to delay transplantation until first relapse with no untoward effect on patient survival.2,3 Recent data showing high response rates and similar survival for early versus delayed transplant provide support for this view (Figure).3 In clinical practice, prudent individualization of care dictates that not all transplant-eligible patients with MM should receive upfront HDT/ASCT as part of initial treatment. Nevertheless, all potentially transplant-eligible individuals should be evaluated for the procedure. Although not every patient needs to consult with a transplant specialist, the oncology team should inform every patient that HDT/ASCT is one of many options that may fit into his or her treatment plan. Let’s not be too quick to minimize the positive impact of the new chemotherapies for myeloma on patient outcomes. A major miracle has occurred over the last decade with the increased likelihood of deep durable remissions for patients with MM.4 A decade ago, we were pleased if half of our patients responded to initial therapy and, with good supportive care, survived for an additional 2 or 3 years. We now expect that more than 90% of our patients will respond to therapy and will survive for many years or even for decades. Contributing to this improvement is the use of such agents as thalidomide,

OCTOBER 2013 I VOL 6, NO 4

CONTINUING EDUCATION

Patients (%)

Figure. Comparable OS with early vs delayed transplantation in patients treated with novel agent-based initial therapy.3 100 90 80 70 60 50 40 30 20 10 0

Table. Significant Improvement in PFS/TTP with Lenalidomide Maintenance vs Placebo Following HDT/ASCT17,18 Number of patients

Parameter

Lenalidomide

Placebo

McCarthy et al17

460

TTP

<.001

Attal et al18

614

PFS

<.001

Study 82.0% 72.7% 73.4%

67.8%

86.0%

Early ASCT Delayed ASCT

63.6%

Median duration (months)

P value

HDT/ASCT indicates high-dose therapy/autologous stem cell transplantation; PFS, progression-free survival; TTP, time to progression. 4-year OS

OS from diagnosis, TD initial treatment

OS from diagnosis, RD initial treatment

All between-group (early vs delayed ASCT) differences nonsigniﬁcant; P≥.3. ASCT indicates autologous stem cell transplantation, OS, overall survival; RD, lenalidomide plus dexamethasone; TD, thalidomide plus dexamethasone.

lenalidomide, and bortezomib, and, more recently, pomalidomide and carfilzomib. We cannot ignore, however, the fact that widespread use of HDT/ASCT even before these agents were widely available had generated improved survival across the MM population. Well-designed clinical trials have demonstrated that compared with nontransplant approaches, the incorporation of 1 or 2 cycles of high-dose melphalan and ASCT into first-line therapy is associated with both prolonged remission and improved overall survival (OS).5-7 Thus, although the results are very promising for initial multidrug therapy that includes novel agents,8,9 evidence continues to support the use of early transplantation. For example, an Italian study randomized patients to 1 of 2 treatment arms: (1) induction followed by either 1 or 2 doses of high-dose melphalan and ASCT or (2) induction followed by treatment with lenalidomide, melphalan, and a corticosteroid with no ASCT. Then, patients were once again randomly assigned to maintenance therapy with lenalidomide or observation. A substantial prolongation of time to relapse was reported among patients who received HDT/ASCT, despite the use of lenalidomide both in induction and maintenance.10,11 More clinical evidence is warranted to determine the conditions under which HDT/ASCT might be delayed. Currently, clinical trials in France and the United States are comparing early versus late transplantation; within the next 5 years, we hope to have data available that can help with this decision-making.12 Currently, however, upfront transplantation remains the standard of care for eligible patients with MM,13 which generally means an individual who is 70 years of age or younger has adequate organ function and good performance status, and is responding well to initial therapy. Are the high initial response rates seen with novel agents translating into improved outcomes following transplantation? Definitely. Data show that a complete response (CR) or very good partial response (VGPR) following induction with novel agents trends toward prolonged survival following HDT/ASCT.14 With some of the current induction regimens, at least two-thirds of patients achieve VGPR and one-third to onehalf of patients achieve CR,8,9,15 which is predictive of a favorable outcome following HDT/ASCT. VGPR has been defined by the Intergroupe Francophone du Myélome (IFM) and the International Myeloma Working Group as a 90% decrease in serum monoclonal component level or, in the subset of patients with BenceJones MM, a urine monoclonal component lower than 100 mg/24 hours.16 In clinical practice, however, our definition of response is multifactorial, including the serum monoclonal component level but also taking into account symptomatic response. When treatment is initiated in a patient, we want to rapidly reduce or reverse the symptoms that led to a diagnosis of active MM— that is, painful bone lesions, renal dysfunction, low blood counts, fatigue, and infections. Our goal is to protect patients from permanent organ dysfunction, prevent fractures, and offer a substantial improvement in quality of life. Fortunately, current initial treatments allow us to achieve these goals in the

great majority of patients. An ancillary benefit is that patients feel well and are fit to proceed to stem cell harvest and transplantation. Data show that effective induction resulting in deep remission prior to HDT/ASCT is clearly a good strategy. This does not translate, however, into an obligation to do everything possible to pound the patient into remission prior to harvesting his or her stem cells. Philosophically, we need moderation, and we need to know our patients. If a patient shows a modest response to therapy but is experiencing organ dysfunction or serious treatment-related adverse events, we cannot be overzealous about moving on to transplantation. If patients are feeling well and their symptoms have improved to a certain degree, but they have only a 50% reduction in measurable disease, we do not have to keep driving them into a deeper remission before we proceed to transplantation. Such patients may have disease that is somewhat resistant to the proteasome inhibitors, immunomodulators, and/or corticosteroids used for induction. It is likely that the best treatment for these individuals will be highdose melphalan, an alkylating agent, and ASCT. We do not delay treatment in such patients. In fact, a useful approach is to intensify the stem cell mobilization technique with chemotherapy using cyclophosphamide alone or multichemotherapy regimens (such as combinations of doxorubicin, etoposide, and cisplatin) in order to attempt to get these patients into a deeper remission while collecting their stem cells, in preparation for HDT/ASCT. What is the role played by the use of novel agents as consolidation and maintenance therapy following HDT/ASCT? Even though we now have excellent regimens for induction therapy and evidence-based protocols for HDT/ASCT, the vast majority of patients with MM will nonetheless eventually experience disease progression. This suggests that despite all that we do up front, residual disease still remains a key issue. A major recent finding is that we can improve duration of remission and survival by providing continuous therapy (also called posttransplant maintenance therapy) with regimens that are based on molecularly targeted agents. Data from clinical trials reveal that following HDT/ASCT, a maintenance course of lenalidomide, at a dose range of 5 to 15 mg daily for 1 year or more improves patient outcomes compared with placebo.17,18 The use of lenalidomide maintenance in the posttransplant population was associated with significant improvement in the primary end points of progression-free survival (PFS) or time to progression (TTP) (Table).17,18 OS was also significantly improved in one trial among patients who received lenalidomide maintenance.17 In this study, at a median follow-up of 34 months, 35 patients (15%) who received lenalidomide maintenance had died, compared with 53 patients (23%) in the placebo group (P=.03).17 These studies were designed to continue lenalidomide treatment to either intolerable toxicity or disease progression, and thus provide robust evidence that lenalidomide is generally well tolerated and effective as maintenance therapy. In one of the trials,17 TTP was improved to the extent that the study was unblinded at a median follow-up of 18 months, and patients receiving placebo who did not experience progressive disease were allowed to cross over to lenalidomide. Despite the crossover, however, patients who initially received lenalidomide maintenance benefited more in terms of PFS and OS than did those who received placebo.17 Continuous treatment with lenalidomide is associated with certain toxicities—in particular, cytopenias, gastrointestinal effects, and fatigue.17,18 More worrisome is the finding of an increased incidence of second primary malignancies (SPMs)—predominantly hematologic—among patients who receive lenalidomide maintenance. In the Cancer and Leukemia Group B 100104 and IFM

Continued on page 29 24

OCTOBER 2013 I VOL 6, NO 4

www.TheOncologyPharmacist.com

CONSIDERATIONS IN MULTIPLE MYELOMA

Patient-Centered Nursing Care in the Transplant Setting Patricia A. Mangan, MSN, CRNP

Coordinator, Bone Marrow and Stem Cell Transplant Program Abramson Cancer Center, University of Pennsylvania Philadelphia, PA

Introduction In the setting of high-dose therapy/autologous stem cell transplantation (HDT/ASCT) for multiple myeloma (MM), nurses encourage patients through the process while providing supportive care for myelotoxicity and other adverse events associated with treatment. In this article, Patricia Mangan, MSN, CRNP, describes the advantages and disadvantages of early versus delayed HDT/ASCT. Ms. Mangan also advocates for multidisciplinary psychosocial support for the patient undergoing ASCT, utilizing a team that encompasses clinicians—social workers, nurses, and nurse navigators—as well as patient support groups. Finally, she offers her perspectives on older transplant recipients—a special population that must be selected judiciously and treated with extreme caution.

What are some of the advantages and disadvantages of early versus delayed transplantation in patients with MM? The main advantage of early transplantation is a robust evidence base. When we incorporate transplantation into initial therapy when myeloma disease is active, it offers patients very good outcomes and improves the likelihood of survival.1-3 Another advantage of early transplantation is that it facilitates easier collection of stem cells. With a delayed transplant, we are prolonging the time that patients receive drugs that can hinder the harvest of peripheral stem cells. One of these drugs is lenalidomide, which in some studies has been associated with a decline in peripheral stem cell collection when used for an extended period of time.4-7 Delaying transplant also increases the likelihood that a patient may be treated with melphalan, an alkylating agent that is generally contraindicated pre-ASCT because it interferes with stem cell harvest. Granted, we can sometimes solve this problem by collectTable 1. Evidence-Based Transplant Recommendations9 • Patients: Active, symptomatic myeloma eligible for transplantation - Sufficient liver, renal, pulmonary, cardiac function to tolerate high-dose therapy (melphalan)

ing stem cells early and cryopreserving them for transplantation later on. This is an option that appeals to many patients, because it provides them with a kind of “transplant insurance.” Moreover, even if the stored cells are not used for ASCT, they can be administered later in the course of therapy to manage cytopenias associated with the use of myelosuppressive agents. Conversely, if we do not perform early stem cell collection in a patient or if too many cells are lost during a very long period of preservation, we may face the difficult task of late stem cell harvest. Early rather than late transplantation also makes sense for patients who are on the older end of the eligibility range. Someone who is 68 years of age at the time of MM diagnosis may have organ function and performance status sufficient to allow HDT/ASCT. Two years later, however, at the time of relapse, this same patient may no longer be eligible for transplantation. Thus, delaying transplant deprives such patients of a treatment that may improve survival.

Early rather than late transplantation also makes sense for patients who are on the older end of the eligibility range. Of course, some disadvantages to early transplantation exist as well. The HDT/ASCT process requires hospitalization and exposes patients to significant treatment-related toxicities—especially risk for infection and organ dysfunction from HDT.2 The patient’s family, employment, and quality of life (QoL) all can be adversely affected, too. It takes approximately 3 months for individuals to recover from a transplant. Patients undergoing transplantation are not usually acutely ill for 3 months, but they can experience a considerable amount of fatigue. At 1 year posttransplant, patients are generally functioning well again,8 but recovery during that year is a gradual process. When we weigh the advantages and disadvantages, the balance favors early transplantation in those individuals with good organ function up to the age of 70 years; this has become the standard of care. At our center, we follow current evidence-based recommendations (Table 1)9 and offer early transplantation to eligible patients; we believe this provides the best outcome in terms of QoL and prolonged disease remission. What strategies do you use to guide your transplant-eligible patients through the process? Do you utilize a multidisciplinary approach to patient education and counseling? The overarching goal of patient education in the MM population must be

• Induction: Antimyeloma therapy that does not contain melphalan • Collection: Stem cell harvest sufficient for 2 transplants • HDT/ASCT - Patients who have ≥ partial response to induction—HDT/ASCT upfront (Category 1* evidence) or perform allogeneic transplant in clinical trial or continue antimyeloma therapy until best response - Patients who do not respond to induction—HDT/ASCT upfront (Category 1 evidence) • Posttransplant - Response or stable disease—Maintenance therapy or second tandem transplant or observation - Progression—Salvage, including additional transplantation if patient remains a candidate *Category 1 = the most robust clinical evidence from randomized trials. HDT/ASCT indicates high-dose therapy/autologous stem cell transplantation.

www.TheOncologyPharmacist.com

Table 2. Patient Concerns in Anticipation of HDT/ASCT10-12 • Fear of being overwhelmed physically, emotionally, psychologically10 • Concern over missing work, losing productivity, job security10 • Inability to cover out-of-pocket costs of HDT/ASCT; concerns exacerbated by lack of open discussion of cost10 • Expectation of unmanageable, dangerous symptoms or adverse events during the process10* • Worries about family relationships and support11 • Sense of isolation11 *May be a mythical belief or exaggerated fear, since nursing practice for infection control is very consistent, and 72% of nurses surveyed report having institution-wide policies for transplantation nursing care.12 HDT/ASCT indicates high-dose therapy/autologous stem cell transplantation.

OCTOBER 2013 I VOL 6, NO 4

CONTINUING EDUCATION

Figure. Stem cell reinfusion with reduced-intensity melphalan (MEL100) conditioning vs standard therapy with melphalan plus prednisone (MP) in older patients (55 to 74 years; n=142).14

Median overall survival (months)

56 MP (standard Tx) MEL100 17.7

Median event-free survival (months)

Treatment groups: MEL100 = 2 to 3 courses of vincristine, doxorubicin, and dexamethasone, followed by stem cell harvest, melphalan dosed at 100 mg/m2, stem cell reinfusion, and 2 additional cycles of melphalan 100 mg/m2 at 2-month intervals post–stem cell reinfusion; MP = melphalan (6 mg/m2) and prednisone (60 mg/m2) administered for six 7-day courses at 4-week intervals.

to alleviate fears about transplantation. Many patients, regardless of their willingness to undergo HDT/ASCT, have a preconceived, negative notion of transplantation. They are burdened by worries, concerns, and sometimes myths about the experience (Table 2).10-12 For a few individuals, anxiety may be so great that they elect to postpone or avoid transplantation despite their oncologist’s recommendation. If we determine that early transplant is appropriate, we invite the patient to our center to meet with the transplant team, which includes a physician, a nurse, and a social worker or nurse navigator. If possible, we have patients and families speak with other patients who have undergone transplant. We utilize our waiting room as one of the best opportunities for patients to talk very casually. Myeloma support groups have sprung up across the country, and they provide new patients with a valuable opportunity to meet others who have undergone HDT/ASCT. Creating patient-to-patient rapport need not always be formal.

HDT/ASCT is often successful in this older population, but careful selection of patients and diligent monitoring throughout the process is critical for success. The International Myeloma Foundation and the Multiple Myeloma Research Foundation provide excellent online and printed materials. That being said, we tend to caution patients that online information may not always be accurate and can lead them astray. The multidisciplinary team, including the support group, is a much better source of information. In our role as nurse educators, we need to remember that the patient is not the only person who needs support. Caregivers benefit from help as well. Getting to know the family and friends involved in a patient’s care enables nurses to ascertain the needs of each individual. Many patients rely on loved ones to help them navigate through the HDT/ASCT process—from traveling to the transplant center to sharing ideas and feelings. Finally, nurses can encourage patients a great deal by always keeping the focus on the overarching goal of extending survival while maintaining QoL. Focusing on this goal helps to alleviate a lot of the stress involved in trans-

OCTOBER 2013 I VOL 6, NO 4

plant decision-making, because you retain the perspective that the purpose of transplantation is a longer, more productive life. What are some of the special considerations in older patients undergoing transplantation? Today, patients with MM who are between 60 and 70 years of age and in otherwise good health are usually candidates for transplantation. HDT/ ASCT is often successful in this older population, but careful selection of patients and diligent monitoring throughout the process is critical for success. In selecting patients, a person’s overall performance status is very important.13 We need to ask: How frail is the patient? Can he or she perform the activities of daily life independently? Does he or she require considerable assistance moving around the house or yard? The answers to these questions can help to determine a patient’s ability to tolerate HDT/ASCT. The next step in patient selection is assessment of comorbidities and organ function. Patients 60 years of age or older are at increased risk for chronic diseases, such as type 2 diabetes, cardiovascular disease, and chronic obstructive pulmonary disease. These conditions reduce organ function and can advance a patient’s physiologic age beyond their chronological age. Once we decide to proceed to transplantation in an older patient, we may have to stratify risk and, if warranted, use a slightly lower dose of melphalan for conditioning. The dose is still high and effective, but it is scaled back a bit to get these older patients through the procedure more easily. One study has demonstrated the efficacy of a reduced-intensity, high-dose conditioning regimen of melphalan dosed at 100 mg/m2 in elderly patients (instead of the usual dose of 200 mg/m2), followed by stem cell reinfusion (Figure).14 As with any transplant candidate, older patients require individualized care. Although all patients with MM share the common goal of prolonged survival with good QoL, each one is unique and has his or her own path to that goal. As nurses, it is our job to help each patient walk that path. ♦ References

1. Kumar SK, Rajkumar SV, Dispenzieri A, et al. Improved survival in multiple myeloma and the impact of novel therapies. Blood. 2008;111:2516-2520. 2. Attal M, Harousseau J-L, Stoppa A-M, et al; Intergroupe Français du Myélome. A prospective, randomized trial of autologous bone marrow transplantation and chemotherapy in multiple myeloma. N Engl J Med. 1996;335:91-97. 3. Fermand J-P, Katsahian S, Divine M, et al. High-dose therapy and autologous blood stem-cell transplantation compared with conventional treatment in myeloma patients aged 55 to 65 years: long-term results of a randomized control trial from the Group Myelome-Autogreffe. J Clin Oncol. 2005;23:9227-9233. 4. Nazha A, Cook R, Vogl DT, et al. Stem cell collection in patients with multiple myeloma: impact of induction therapy and mobilization regimen. Bone Marrow Transplant. 2011; 46:59-63. 5. Cavallo F, Bringhen S, Milone G, et al. Stem cell mobilization in patients with newly diagnosed multiple myeloma after lenalidomide induction therapy. Leukemia. 2011;25:1627-1631. 6. Kumar S, Dispenzieri A, Lacy MQ, et al. Impact of lenalidomide therapy on stem cell mobilization and engraftment post-peripheral blood stem cell transplantation in patients with newly diagnosed myeloma. Leukemia. 2007;21:2035-2042. 7. Bhutani D, Zonder J, Valent J, et al. Evaluating the effects of lenalidomide induction therapy on peripheral stem cells collection in patients undergoing autologous stem cell transplant for multiple myeloma. Support Care Cancer. 2013;21:2437-2442. 8. Grulke N, Albani C, Bailer H. Quality of life in patients before and after haematopoietic stem cell transplantation measured with the European Organization for Research and Treatment of Cancer (EORTC) Quality of Life Core Questionnaire QLQ-C30. Bone Marrow Transplant. 2012;47:473-482. 9. National Comprehensive Cancer Network (NCCN). NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines®): Multiple Myeloma, Version 2.2013. http://www.nccn. org. Accessed June 2, 2013. 10. Sheldon LK, Kazmi M, Klein C, Berry DL. Concerns of stem cell transplant patients during routine ambulatory assessment. Patient Prefer Adherence. 2013;7:15-20. 11. Stephens M. The lived experience post-autologous haematopoietic stem cell transplant (HSCT): a phenomenological study. Eur J Oncol Nurs. 2005;9:204-215. 12. Bevans M, Tierney DK, Bruch C, et al. Hematopoietic stem cell transplantation nursing: a practice variation study. Oncol Nurs Forum. 2009;36:E317-E325. 13. Palumbo A, Bringhen S, Ludwig H, et al. Personalized therapy in multiple myeloma according to patient age and vulnerability: a report of the European Myeloma Network (EMN). Blood. 2011;118:4519-4529. 14. Palumbo A, Triolo S, Argentino C, et al. Dose-intensive melphalan with stem cell support (MEL100) is superior to standard treatment in elderly myeloma patients. Blood. 1999;94:1248-1253.

www.TheOncologyPharmacist.com

CONSIDERATIONS IN MULTIPLE MYELOMA

Pharmacologic Considerations in the Transplant Setting for Myeloma Alex Ganetsky, PharmD, BCOP

Hematology/Oncology Clinical Pharmacy Specialist Abramson Cancer Center, University of Pennsylvania Philadelphia, PA

Introduction Over the past 2 decades, research has delineated the molecular biology of multiple myeloma (MM). These discoveries have given clinicians the ability to stratify risk in the disease and have also led to the development of more effective antimyeloma agents. Frontline regimens that include these novel targeted therapies produce high rates of response prior to high-dose therapy/autologous stem cell transplantation (HDT/ASCT). Induction therapy plus HDT/ASCT consistently yields favorable outcomes. In this article, Alex Ganetsky, PharmD, BCOP, describes the current paradigm for risk stratification and treatment selection in MM.

What is the role of risk stratification in the selection of induction therapy for transplant-eligible patients? Risk stratification is a relatively new approach that derives from a more thorough knowledge of myeloma biology. Historically, we had a limited understanding of the pathophysiology of the disease and didn’t realize just how heterogeneous it was. As a result, most patients were treated very similarly. In the past 10 to 15 years, however, there have been significant advances in our understanding of the molecular biology of MM, with a corresponding advent of new molecularly targeted drugs and combination regimens.1 We are now moving toward the goal of stratifying initial therapy based on the risk associated with different molecular characteristics of myeloma cells. Cytogenetics—which can identify chromosomal abnormalities predictive of risk—is critically important in patient stratification.2,3 Currently, cytogenetic testing is conducted via conventional karyotyping and fluorescence in situ hybridization (FISH) testing. This testing identifies standard and high levels of risk on the basis of specific mutations. According to current, evidence-based guidelines and consensus, patients with MM have a worse prognosis when their myeloma cells display the following abnormalities: deletion of chromosome 13 [del(13q)], deletion at the locus of the tumor suppressor gene p53 [del(17p13)], the chromosomal translocations t(4;14) and t(14;16), and an amplification at chromosome 1q21.4 FISHdetected del(17p), t(4;14), and t(14;16) have been associated with a particularly high level of risk,3-6 although there is some evidence that t(14;16) may not confer as high a risk as the other 2 abnormalities.6 While data have suggested that translocation t(11;14) may have a positive prognostic impact,7 evidence for this is not yet sufficient. Clinicians must err on the side of caution whenever a cytogenetic abnormality is detected in a patient with MM. Some experts assert that any cytogenetic abnormality may indicate higher-risk disease.5 In assessing risk, we also evaluate tumor burden and extramedullary disease, as high tumor burden and the finding of malignant plasma cells in soft tissue/visceral organ sites both confer a poorer prognosis.5,6,8 Whether a clinician relies on Durie-Salmon or International Staging System criteria to stage a patient, both methods link a greater tumor burden to a higher stage.4 We also look at a patient’s age, renal and other organ function, and overall health status in rounding out our risk assessment. Once we stratify a patient’s risk, we can use this information to select induction therapy. This is far from an exact science, but risk assessment does give us a good deal of guidance. For a transplant-eligible patient with standard-risk myeloma—most impor-

www.TheOncologyPharmacist.com

tantly, with normal cytogenetic findings—we may select an effective but not exceedingly aggressive therapy. We might consider patient preferences for an oral regimen or their concerns regarding adverse events (AEs). Oftentimes, in this patient type, we will use 4 cycles of lenalidomide and low-dose dexamethasone (Rd) before proceeding to HDT/ASCT. There is good clinical evidence for this regimen from a randomized trial, which showed that four 28-day cycles of Rd (oral lenalidomide 25 mg/day on days 1-21 plus low-dose dexamethasone 40 mg on days 1, 8, 15, and 22) produced better 1-year survival with lower toxicity than a regimen of the same length and lenalidomide dose but incorporating high-dose dexamethasone (40 mg on days 1-4, 9-12, and 17-20), referred to as the RD regimen.9 Overall, 1-year survival was 96% with Rd, compared with 87% with RD (P=.0002). After 4 cycles of treatment, the incidence of grade 3 or higher AEs was 35% with Rd and 52% with RD (P<.001). For a clinician who prefers to use a bortezomib-based regimen, acceptable induction therapy for the patient at standard risk is cyclophosphamide, bortezomib, and dexamethasone (CyBorD). Historically, this regimen included twice-weekly intravenous (IV) bortezomib, but a clinical trial has shown that CyBorD using only once-weekly bortezomib also had good efficacy with manageable toxicity. Among patients whose CyBorD included once-weekly IV bortezomib (1.5 mg/m2 on days 1, 8, 15, and 22), overall response rates (ORRs) and rates of very good partial response or better (≥VGPR) to induction were comparable to those seen with CyBorD that included twice-weekly IV bortezomib (1.3 mg/m2 on days 1, 4, 8, and 11): ORR 93% versus 88% and ≥VGPR 60% versus 61%, respectively. In addition, grade 3 or higher AEs were lower in the once-weekly bortezomib cohort than in the twice-weekly cohort (37% vs 48%, respectively).10 In a patient with intermediate-risk disease (ie, with some cytogenetic abnormalities but negative for del[17p13] or t[4;14]), CyBorD and Rd remain good choices. At this time, although we have markers that enable us to stratify patients into risk groups, we do not have the ability to make certain treatment recommendations for each group—with the possible exception of 2 high-risk groups: patients who exhibit t(4;14) and those who exhibit del(17p13).6 Bortezomib-based therapy is appropriate in these patients, because data suggest that this agent improves outcomes in patients with t(4;14). Studies have shown that the addition of bortezomib to induction therapy enhances survival in patients with t(4;14).11,12 Recent evidence also suggests that lenalidomide has some ability to mitigate the effect of t(4;14) but with less favorable effect than bortezomib.13 Thus, bortezomib is an especially prudent choice for the t(4;14) population. Results have been somewhat mixed, however, regarding the ability of bortezomib to overcome the adverse effect of del(17p13). For example, data from a 2010 trial suggested that outcomes in patients with this high-risk feature could not be improved with 4 cycles of bortezomib-based therapy prior to HDT/ASCT (with no maintenance).12 However, recent data from the HOVON-65 trial reported that patients with del(17p13) attained significantly higher rates of progression-free survival (PFS) and overall survival (OS) when bortezomib was included in their pretransplant induction and posttransplant maintenance regimens (Figure).14 Lenalidomide, on the other hand, has not been shown to improve poor prognosis associated with del(17p13).15 However, as an effective antimyeloma agent, it can be part of a multidrug combination for high-risk patients. Aggressive 3-drug regimens that contain bortezomib are appropriate as induction for high-risk patients. One of these regimens—lenalidomide, bortezomib, and dexamethasone (RVD)—has shown very good results in newly diagnosed patients.16 In a phase 1/2 trial, RVD produced a 97% rate of 18month OS, with promising survival rates reported in the small number of patients with FISH-detected del(17p) and t(4;14).16 There may be no gain in adding a fourth drug to the regimen, as shown by a recent trial in which cyclophosphamide added to RVD provided no advan-

OCTOBER 2013 I VOL 6, NO 4

CONTINUING EDUCATION

Figure. 3-year overall survival in 37 patients with del(17p13) treated with and without bortezomib in the HOVON-65 trial.14

Plerixafor + G-CSF

Placebo + G-CSF

P Value

Patients achieving collection of ≥6 × 106 CD34+ cells/kg in ≤2 days

71.6%

34.4%

<.001

Median number of apheresis days required to collect ≥6 × 106 CD34+ cells/kg

1 day

4 days

<.001

Injection site reaction

20.4%

3.3%

Diarrhea

18.4%

5.3%

Nausea

16.3%

7.3%

Bone pain

9.5%

7.9%

Fatigue

8.2%

3.3%

69%*

Patients (%)

70 60 50 40

Incidence of most common adverse events:

30 17%

Treatment without bortezomib

Bortezomib-based treatment

*P=.028. Treatment without bortezomib: 3 cycles of induction with vincristine 0.4 mg IV on days 1-4; doxorubicin 9 mg/m2 IV on days 1-4; and dexamethasone 40 mg PO on days 1-4, 9-12, and 17-20/HDT/ ASCT/2 years of thalidomide maintenance (50 mg/day PO). Bortezomib-based treatment: Bortezomib 1.3 mg/m2 IV on days 1, 4, 8, and 11; doxorubicin 9 mg/m2 IV on days 1-4; and dexamethasone 40 mg PO on days 1-4, 9-12, and 17-20/HDT/ASCT/2 years of bortezomib maintenance (1.3 mg/m2 IV once every 2 weeks). HDT/ASCT indicates high-dose therapy/autologous stem cell transplantation; IV, intravenously; PO, orally.

tage in response or 1-year PFS compared with RVD or CyBorD in transplant-eligible patients; all patients received bortezomib maintenance therapy.17 A caveat here is that individuals in this study were predominantly classified as standard risk; data are not sufficient to predict the utility of a 4-drug regimen in high-risk MM. What strategies can be used to optimize stem-cell mobilization prior to transplant? There are 3 key strategies for stem cell mobilization. The first and historical strategy is to use growth factor support with filgrastim. The second is combination therapy with growth factor and chemotherapy. The third is combination therapy with growth factor plus the chemokine receptor CXCR4 antagonist plerixafor. There are advantages and disadvantages to each approach. First, if you mobilize with growth factor alone, you can do this in the outpatient setting. Toxicity is low; the most common AE associated with filgrastim is bone pain,18 which is relatively manageable. Also, the timing for apheresis is more predictable with this method. The disadvantages of mobilizing with growth factor alone are that stem cell yields are lower than with the other 2 methods, more apheresis sessions are required, and there is no antitumor effect. The second type of mobilization strategy—growth factor plus chemotherapy—produces a higher stem cell collection yield than does growth factor alone.19 This technique also provides cytoreduction of the malignancy via the chemotherapy drug. For MM, the most common chemotherapeutic agent to use for mobilization is cyclophosphamide. One of the disadvantages of this second strategy is that there is actually quite a bit of variability in peak CD34+ cell counts, which renders timing of apheresis sessions unpredictable. Another issue is that adding chemotherapy increases toxicity. Nevertheless, a recent retrospective study reported that the combination of chemotherapy plus a growth factor produced higher CD34+ cell yields and required fewer days of apheresis than did the use of a growth factor alone.20 Although rates of febrile neutropenia were higher with the chemotherapy–growth factor combination than with growth factor alone (17% vs 2%; P<.05), rates of other AEs were comparable between groups. Cost for chemotherapy plus growth factor mobilization was significantly higher than for growth factor alone, predominantly because of hospital admissions in the former group; febrile neutropenia often requires immediate hospitalization for a few days for IV antibiotics. The final mobilization strategy—growth factor plus plerixafor—has been shown to improve stem cell collection.21 In a phase 3 trial, the combination of these agents significantly increased the likelihood that patients with MM would achieve adequate stem cell harvest in 2 days or less of apheresis com-

Table. Stem-Cell Mobilization with Plerixafor + G-CSF vs Placebo + G-CSF: Efficacy and Tolerability21

OCTOBER 2013 I VOL 6, NO 4

G-CSF indicates granulocyte colony-stimulating factor; NR, not reported.

pared with growth factor alone (Table).21 Plerixafor is very well tolerated; the most common AEs are gastrointestinal complaints, fatigue, and subcutaneous injection site reaction (Table). The disadvantages of plerixafor are timing of administration (it must be given 11 hours prior to initiation of apheresis)22 and cost. There have actually been a few studies to address these 2 disadvantages. A recent study suggested that the drug can be given 17 hours prior to apheresis with no untoward effect, which would improve the convenience factor.22 Costs of plerixafor can be contained by using it selectively, with a risk-adapted approach, in which preemptive plerixafor is given to patients with low CD34+ cell counts on day 4 of apheresis.23 At our center, we use multiple approaches, based on the patients’ needs. Patients with active myeloma who can benefit from additional cytoreductive therapy are good candidates for mobilization with growth factor plus chemotherapy. Patients in ≥VGPR who appear to have good cellularity in bone marrow may be candidates for mobilization with growth factor alone. In patients suspected to be poor mobilizers (ie, heavily pretreated, with poor cellularity on a bone marrow exam, or with low peripheral CD34+ cell counts), we like to administer filgrastim plus plerixafor. The next step in mobilization may be to combine all 3 strategies: growth factor, chemotherapy, and plerixafor. This approach has been studied in a small trial and was found safe in poor mobilizers.24 ♦ References

1. Lombardi L, Poretti G, Mattioli M, et al. Molecular characterization of human multiple myeloma cell lines by integrative genomics: insights into the biology of the disease. Genes Chromosom Cancer. 2007;46:226-238. 2. Stewart AK, Fonseca R. Prognostic and therapeutic significance of myeloma genetics and gene expression profiling. J Clin Oncol. 2005;23:6339-6344. 3. Kumar SK, Mikhael JR, Buadi FK, et al. Management of newly diagnosed symptomatic multiple myeloma: updated Mayo Stratification of Myeloma and Risk-Adapted Therapy (mSMART) consensus guidelines. Mayo Clin Proc. 2009;84:1095-1110. 4. National Comprehensive Cancer Network (NCCN). NCCN Clinical Practice Guidelines in Oncology: Multiple Myeloma. Version 2.2013. http://www.nccn.org. Accessed June 2, 2013. 5. Munshi NC, Anderson KC, Bergsagel L, et al; on behalf of the International Myeloma Workshop Consensus Panel 2. Consensus recommendations for risk stratification in multiple myeloma: report of the International Myeloma Workshop Consensus Panel 2. Blood. 2011;117: 4696-4700. 6. Chng W-J, Dispenzieri A, Chim CS, et al; on behalf of the International Myeloma Working Group. IMWG consensus on risk stratification in multiple myeloma [published online ahead of print August 26, 2013]. Leukemia. doi:10.1038/leu.2013.247. 7. Fonseca R, Barlogie B, Bataille R, et al. Genetics and cytogenetics of multiple myeloma: a workshop report. Cancer Res. 2004;64:1546-1558. 8. Usmani SZ, Heuck C, Mitchell A, et al. Extramedullary disease portends poor prognosis in multiple myeloma and is over-represented in high-risk disease even in the era of novel agents. Haematologica. 2012;97:1761-1767. 9. Rajkumar SV, Jacobus S, Callander NS, et al. Lenalidomide plus high-dose dexamethasone versus lenalidomide plus low-dose dexamethasone as initial therapy for newly diagnosed multiple myeloma: an open-label randomised controlled trial. Lancet Oncol. 2010;11:29-37. 10. Reeder CB, Reece DE, Kukreti V, et al. Once- versus twice-weekly bortezomib induction therapy with CyBorD in newly diagnosed multiple myeloma. Blood. 2010;115:3416-3417. 11. Cavo M, Tacchetti P, Patriarca F, et al; for the GIMEMA Italian Myeloma Network.

www.TheOncologyPharmacist.com

CONSIDERATIONS IN MULTIPLE MYELOMA

Bortezomib with thalidomide plus dexamethasone compared with thalidomide plus dexamethasone as induction therapy before, and consolidation therapy after, double autologous stem-cell transplantation in newly diagnosed multiple myeloma: a randomised phase 3 study. Lancet. 2010;376:2075-2085. 12. Avet-Loiseau H, Leleu X, Roussel M, et al. Bortezomib plus dexamethasone induction improves outcome of patients with t(4;14) myeloma but not outcome of patients with del(17p). J Clin Oncol. 2010;28:4630-4634. 13. Kalff A, Spencer A. The t(4;14) translocation and FGFR3 overexpression in multiple myeloma: prognostic implications and current clinical strategies. Blood Cancer J. 2012;2:e89. 14. Neben K, Lokhorst HM, Jauch A, et al. Administration of bortezomib before and after autologous stem cell transplantation improves outcome in multiple myeloma patients with deletion 17p. Blood. 2012;119:940-948. 15. Reece D, Song KW, Fu T, et al. Influence of cytogenetics in patients with relapsed or refractory multiple myeloma treated with lenalidomide plus dexamethasone: adverse effect of deletion 17p13. Blood. 2009;114:522-525. 16. Richardson PG, Weller E, Lonial S, et al. Lenalidomide, bortezomib, and dexamethasone combination therapy in patients with newly diagnosed multiple myeloma. Blood. 2010;116:679-686. 17. Kumar S, Flinn I, Richardson PG, et al. Randomized, multicenter, phase 2 study (EVOLUTION) of combinations of bortezomib, dexamethasone, cyclophosphamide, and lenalidomide in previously untreated multiple myeloma. Blood. 2012;119:4375-4382.

18. Pulsipher MA, Chitphakdithai P, Miller JP, et al. Adverse events among 2408 unrelated donors of peripheral blood stem cells: results of a prospective trial from the National Marrow Donor Program. Blood. 2009;113:3604-3611. 19. Pusic I, Jiang SY, Landua S, et al. Impact of mobilization and remobilization strategies on achieving sufficient stem cell yields for autologous transplantation. Biol Blood Marrow Transplant. 2008;14:1045-1056. 20. Sung AD, Grima DT, Bernard LM, et al. Outcomes and costs of autologous stem cell mobilization with chemotherapy plus G-CSF vs G-CSF alone [published online ahead of print June 10, 2013]. Bone Marrow Transplant. doi:10.1038/bmt.2013.80. 21. DiPersio JF, Stadtmauer EA, Nademanee A, et al. Plerixafor and G-CSF versus placebo and G-CSF to mobilize hematopoietic stem cells for autologous stem cell transplantation in patients with multiple myeloma. Blood. 2009;113:5720-5726. 22. Harvey RD, Kaufman JL, Johnson HR, et al. Temporal changes in plerixafor administration and hematopoietic stem cell mobilization efficacy: results of a prospective clinical trial in multiple myeloma. Biol Blood Marrow Transplant. 2013;19:1393-1395. 23. Chen AI, Bains T, Murray S, et al. Clinical experience with a simple algorithm for plerixafor utilization in autologous stem cell mobilization. Bone Marrow Transplant. 2012;47:1526-1529. 24. Attolico I, Pavone V, Ostuni A, et al. Plerixafor added to chemotherapy plus G-CSF is safe and allows adequate PBSC collected in predicted poor mobilizer patients with multiple myeloma or lymphoma. Biol Blood Marrow Transplant. 2012;18:241-249.

The Role of Transplantation in Improving Patient Outcomes in Multiple Myeloma Continued from page 24 2005-02 studies, approximately 8% of patients who received lenalidomide maintenance developed SPMs, compared with 3% to 4% of those who received placebo. Fortunately, many types of SPMs are treatable. Furthermore, development of an SPM does not appear to erode the significant survival benefit derived from continuing or utilizing lenalidomide maintenance.17,18 Based on the strength of this evidence, lenalidomide is emerging as a standard of care for posttransplant maintenance therapy in patients with MM. Thalidomide maintenance, although effective, is limited by the development of neurotoxicity and fatigue.19 In a recent study in which our center participated, only about 15% of the patients who were assigned to thalidomide were able to continue taking the agent for 1 year.20 Bortezomib also has demonstrated efficacy as maintenance therapy following HDT/ASCT, with particular utility in patients with the high-risk cytogenetic abnormality deletion 17p (del 17p).21,22 Bortezomib is usually dosed once every 2 weeks as maintenance therapy; in the HOVON-65 trial, the agent was administered for approximately 2 years.21 The appropriate duration of this maintenance program has not been as well studied as the program for lenalidomide; however, 1 year of bortezomib maintenance is a reasonable estimate for treatment duration. The use of bortezomib with thalidomide plus a corticosteroid as induction prior to HDT/ASCT and as consolidation/maintenance following remission both in transplant-eligible and -ineligible patients improved outcomes compared with thalidomide plus dexamethasone or bortezomib plus prednisone.15,23 These results further suggest that bortezomib in combination with an immunomodulator may be useful as maintenance therapy following HDT/ASCT. ♦ References

1. Cavo M, Rajkumar SV, Palumbo A, et al; International Myeloma Working Group. International Myeloma Working Group consensus approach to the treatment of multiple myeloma patients who are candidates for autologous stem cell transplantation. Blood. 2011;117:6063-6073. 2. Dunavin NC, Wei L, Elder P, et al. Early versus delayed autologous stem cell transplantation in patients receiving novel therapies for multiple myeloma. Leuk Lymphoma. 2013;54:1658-1664. 3. Kumar S, Lacy MQ, Dispenzieri A, et al. Early versus delayed autologous transplantation following IMiD-based induction therapy in patients with newly diagnosed multiple myeloma. Cancer. 2012;118:1585-1592. 4. Kumar SK, Rajkumar SV, Dispenzieri A, et al. Improved survival in multiple myeloma and the impact of novel therapies. Blood. 2008;111:2516-2520. 5. Attal M, Harousseau J-L, Stoppa A-M, et al; Intergroupe Français du Myélome. A prospective, randomized trial of autologous bone marrow transplantation and chemotherapy in multiple myeloma. N Engl J Med. 1996;335:91-97. 6. Fermand J-P, Katsahian S, Divine M, et al. High-dose therapy and autologous blood stem-cell transplantation compared with conventional treatment in myeloma patients aged 55 to 65 years: long-term results of a randomized control trial from the Group Myelome-Autogreffe. J Clin Oncol. 2005;23:9227-9233. 7. Child JA, Morgan GJ, Davies FE, et al; Medical Research Council Adult Leukaemia Working Party. High-dose chemotherapy with hematopoietic stem-cell rescue for multiple myeloma. N Engl J Med. 2003;348:1875-1883. 8. Richardson PG, Weller E, Lonial S, et al. Lenalidomide, bortezomib, and dexamethasone combina-

tion therapy in patients with newly diagnosed multiple myeloma. Blood. 2010;116:679-686. 9. Jakubowiak AJ, Dytfeld D, Griffith KA, et al. Treatment outcome with the combination of carfilzomib, lenalidomide, and low-dose dexamethasone (CRd) for newly diagnosed multiple myeloma (NDMM) after extended follow-up. J Clin Oncol (ASCO Annual Meeting Abstracts). 2013;31(suppl):Abstract 8543. 10. Palumbo A, Cavallo F, Hardan I, et al. Melphalan/prednisone/lenalidomide (MPR) versus high-dose melphalan and autologous transplantation (MEL200) in newly diagnosed multiple myeloma (MM) patients <65 years: results of a randomized phase III study. Blood (ASH Annual Meeting Abstracts). 2011;118:Abstract 3069. 11. Boccadoro M, Cavallo F, Gay FM, et al. Melphalan/prednisone/lenalidomide (MPR) versus high-dose melphalan and autologous transplantation (MEL200) plus lenalidomide maintenance or no maintenance in newly diagnosed multiple myeloma (MM) patients. J Clin Oncol. 2013;31(suppl);Abstact 8509. 12. US National Institutes of Health. ClinicalTrials.gov. Study comparing conventional dose combination RVD to high-dose treatment with ASCT in the initial myeloma up to 65 years (IFM/DCFI2009) [NCT01191060]. http://clinicaltrials.gov/show/NCT01191060. Accessed September 27, 2013. 13. National Comprehensive Cancer Network (NCCN). NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines®): Multiple Myeloma. Version 2.2013. http://www.nccn.org. Accessed June 2, 2013. 14. Harousseau J-L, Attal M, Avet-Loiseau H, et al. Bortezomib plus dexamethasone is superior to vincristine plus doxorubicin plus dexamethasone as induction treatment prior to autologous stem-cell transplantation in newly diagnosed multiple myeloma: results of the IFM 2005-01 phase III trial. J Clin Oncol. 2010;28:4621-4629. 15. Cavo M, Tacchetti P, Patriarca F, et al; for the GIMEMA Italian Myeloma Network. Bortezomib with thalidomide plus dexamethasone compared with thalidomide plus dexamethasone as induction therapy before, and consolidation therapy after, double autologous stem-cell transplantation in newly diagnosed multiple myeloma: a randomised phase 3 study. Lancet. 2010;376:2075-2085. 16. Harousseau J-L, Avet-Loiseau H, Attal M, et al. Achievement of at least a very good partial response is a simple and robust prognostic factor in patients with multiple myeloma treated with high-dose therapy: long-term analysis of the IFM 99-02 and 99-04 trials. J Clin Oncol. 2009; 27:5720-5726. 17. McCarthy PL, Owzar K, Hofmeister CC, et al. Lenalidomide after stem-cell transplantation for multiple myeloma. N Engl J Med. 2012;366:1770-1781. 18. Attal M, Lauwers-Cances V, Marit G, et al; IFM Investigators. Lenalidomide maintenance after stem-cell transplantation for multiple myeloma. N Engl J Med. 2012;366:1782-1791. 19. Attal M, Harousseau J-L, Leyvraz S, et al; Inter-Groupe Francophone du Myélome (IFM). Maintenance therapy with thalidomide improves survival in patients with multiple myeloma. Blood. 2006;108:3289-3294. 20. Krishnan A, Pasquini MC, Logan B, et al. Autologous haemopoietic stem-cell transplantation followed by allogeneic or autologous haemopoietic stem-cell transplantation in patients with multiple myeloma (BMT CTN 0102): a phase 3 biological assignment trial. Lancet Oncol. 2011;12:1195-1203. 21. Sonneveld P, Schmidt-Wolf IG, van der Holt B, et al. Bortezomib induction and maintenance treatment in patients with newly diagnosed multiple myeloma: results of the randomized phase III HOVON-65/GMMG-HD4 trial. J Clin Oncol. 2012;30:2946-2955. 22. Neben K, Lokhorst HM, Jauch A, et al. Administration of bortezomib before and after autologous stem cell transplantation improves outcome in multiple myeloma patients with deletion 17p. Blood. 2012;119:940-948. 23. Mateos MV, Oriol A, Martínez-López J, Gutiérrez N. Maintenance therapy with bortezomib plus thalidomide or bortezomib plus prednisone in elderly multiple myeloma patients included in the GEM2005MAS65 trial. Blood. 2012;120:2581-2588.

COE106-4 www.TheOncologyPharmacist.com

OCTOBER 2013 I VOL 6, NO 4

DRUG SHORTAGES

Surveys Confirm Drug Shortages Are a Persistent Problem By Caroline Helwick

ecent surveys of oncolKeerthi Gogineni, MD, ogists and hematoloof the Abramson Cancer gists show that drug Center in Philadelphia, at shortages persist, that practithe 2013 Annual Meeting tioners are adapting in ways of the American Society that often raise the cost of of Clinical Oncology cancer care, and that most (ASCO).1 Shortages have also have no guidance to aid in interfered with patient decision making in the face of participation in clinical these shortages. Richard L. trials, slowing the pace A survey of 250 physiSchilsky, MD of research progress, she cians, by investigators at the added. University of Pennsylvania, “We were surprised by the large Philadelphia, showed that 83% encountered shortages of curative and palliative number of oncologists who had to chemotherapy agents between March make changes in how they care for and September of 2012. Many reported patients due to drug shortages,” she that shortages affected the quality and said at a press briefing at ASCO. cost of patient care, as they were forced “Unfortunately, cancer drug shortages to substitute more expensive drugs for are likely to persist, but doctors are adapting to this new reality as best they cheaper generics. “Drug shortages are affecting the treat- can. We need more uniform guidance ment of curable malignancies. We don’t to ensure that the modifications in know the extent to which adaptations treatment are being made in the most forced by these shortages led to adverse educated and ethical way.” Gogineni and colleagues distributclinical outcomes for patients,” said

HAVE YOU EVER WANTED TO WRITE AN ARTICLE FOR TOP ?

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

Contact editorial@greenhillhc.com for information. 30

OCTOBER 2013 I VOL 6, NO 4

ed the survey to 454 oncologists and hematologists in the United States randomly selected from the ASCO membership; 250 responded and 214 surveys were analyzed. About two-thirds practiced in community-based private settings while one-third practiced in academic settings. The data reflect drug shortage experiences from March 2012 to March 2013. Shortages were most commonly reported for leucovorin, liposomal doxorubicin, 5-fluorouracil (5-FU), bleomycin, and cytarabine. More Than 80% of Patients Had Treatment Altered The respondents were asked about the impact of drug shortages over the previous 6 months. In response, 94% reported that their patients’ treatment had been affected and for 83% they were unable to provide standard chemotherapy. About 13% said that shortages had prevented enrollment in clinical trials or had suspended participation in them. The physicians adapted to shortages in various ways, including changing the treatment regimen (78%), substituting drugs partway through therapy (77%), delaying treatment (43%), “rationing” treatment to certain patients (37%), omitting doses (29%), reducing doses (20%), and referring patients to other practices (17%). Most providers (70%) indicated that they lacked institutional guidelines or committees to advise them in these difficult treatment decisions; academic physicians had more help. Clinical trial participation was affected in some way 11% of the time. Costly Substitutions Nearly 60% of physicians substituted more expensive agents when cheaper generics were not available. This included levoleucovorin for leucovorin, capecitabine for 5-FU, and nab-paclitaxel for paclitaxel. “This is adding to healthcare costs,” Gogineni emphasized. Levoleucovorin costs about 30 times more than leucovorin and capecitabine costs about 140 times more than 5-FU for 1 cycle of colon cancer treatment. There are also “hidden costs” in terms of additional hours spent by staff trying to manage these shortages, she said. ASCO Survey: Only Small Improvements Seen ASCO also surveyed its members in October and November 2012 (n = 390) and again in March and April 2013 (n = 462) to assess the impact of shortages over those 6 months and

to determine whether recent legislative and regulatory efforts to address the problem are working. Results of the second survey suggested that chemotherapy drug shortages have eased slightly, but oncologists still need to substitute drugs. Moreover, respondents expressed growing concern over the shortage of drugs used in supportive care, such as antiemetics, pain medications, and basic intravenous fluids and electrolytes, reported Richard L. Schilsky, MD, chief medical officer of ASCO.2 The most commonly reported substitutions were levoleucovorin for leucovorin (cited by 38% of respondents giving examples) and capecitabine for 5-FU (12%), comparable to what Gogineni reported from her survey. “The cost implications of these are significant,” Schilsky agreed. In addition to critical chemotherapy substitutions, other substitutions include oral formulations for intravenous agents in nearly a dozen drugs. In supportive care, a few of the substitutions used are ganciclovir for acyclovir, Lomotil for atropine, and methylprednisolone and prednisone for dexamethasone. The second survey also found: • 59% of respondents were aware of ongoing drug substitutions in their community in 2013, versus 70% in 2012 • 17% said the situation is worse now, while 16% said the situation is unchanged, and 9% said some shortages improved but others worsened • More than one-third (37%) in both surveys had no institutional policy for drug allocation during a shortage The Cancer and Leukemia Group B (CALGB) clinical trials group reported that 23 study protocols have been affected by drug shortages, he said. CALGB is delaying registration of new patients, borrowing drugs from neighboring institutions, substituting alternative drugs, and omitting drugs in short supply. According to Schilsky, while the US Food and Drug Administration has stopgap measures in place to ease the situation, “Permanent solutions will require enhancing the business model of generic drug manufacturing.” l References

1. Emanuel EJ, Shuman K, Chinn D, et al. Impact of oncology drug shortages. J Clin Oncol. 2013;31(suppl):Abstract CRA6510. Presented at: 2013 American Society of Clinical Oncology Annual Meeting; May 31-June 4, 2013; Chicago, IL. 2. Schilsky RL. Improvising when standard therapy is not available. Presented at: 2013 American Society of Clinical Oncology Annual Meeting; May 31-June 4, 2013; Chicago, IL.

www.TheOncologyPharmacist.com

CANCER CENTER PROFILE

Memorial Sloan-Kettering Cancer Center Continued from cover What is your job description? Richard Tizon (RT): Our clinical program began in 2008 under our pharmacy director, Charles Lucarelli, and our clinical pharmacy manager, Nelly Adel, who is also our PGY-2 oncology residency director. The program has successfully expanded from 3 clinical specialists covering leukemia and transplant, to over 20 specialists who are integrated into multiple services within leukemia, transplant, lymphoma, and neuro-oncology. We also have clinical pharmacy specialists in our ancillary services, such as infectious disease, geriatrics, and pain and palliative care. I joined MSKCC as a clinical pharmacy specialist in 2008, and I recently assumed a managerial role within the program earlier this year. On the dayto-day level, I coordinate the activities of the clinical pharmacy specialists, collaborate with other health professionals in the institution to promote pharmacy services, and develop strategies to expand clinical pharmacy support to new oncology service teams, particularly in the solid tumors. Over the next 3 years, we will be expanding coverage into the breast medical oncology, head and neck cancer, sarcoma, and melanoma services, with the ultimate goal of providing fully integrated clinical pharmacists to all the hospital teams. How does the multidisciplinary team approach improve patient care? RT: We are unique in that we have highly specialized services dedicated to specific disease states; instead of treating all hematologic malignancies grouped together, leukemia, lymphoma, and stem cell transplant are treated separately. This allows for greater ability to tailor patient care. In my experience, the collaborative approach provides a great advantage to physicians and to all the team members, including physicians, nurses, pharmacists, and a growing body of mid-level practitioners, including nurse practitioners, physician assistants, and clinical pharmacy specialists. Few things can fall between the cracks with a team approach. What are you excited about in the field of oncology right now? RT: Improved understanding of the molecular biology of tumors has moved the field forward so that targeted therapies and targeted immunotherapies are now available to treat a variety of cancers. We are able to benefit quickly from research at MSKCC involving new drug targets as our ability to design smaller, more relevant (to a specific target) clinical trials has increased. This world of targeted therapy comes

www.TheOncologyPharmacist.com

with more challenges and complexities in treating and supporting cancer patients. We need to keep up-to-date as new agents become available and are used in the clinic. We have to learn how to manage side effects and interactions of these newer agents. Many targeted therapies come in an oral formulation, so patient adherence is a major factor to the success of the therapy. As a team, we have to be vigilant in how we counsel and educate patients.

How has the role of the oncology pharmacist changed in the past 5 years? RT: The most obvious change is integrating pharmacists into the front lines of clinical care and including them in the consults on patients’ treatment plans and support. We have gone from being in the back room preparing and dispensing drugs to the patient’s bedside. Recently New York, through no small effort from our pharmacy leadership, has finally joined many other states in allowing collaborative drug therapy management between physicians and pharmacists. I think this is a major step forward in relieving some of the workload from

our traditional providers while maintaining work flow and patient safety.

What inspired you to become an oncology pharmacist? RT: Although oncology is sometimes perceived as a depressing specialty, I believe it is a calling that requires not only a high level of expertise, but also compassion and commitment. Throughout high school and pharmacy school, I worked at a retail pharmacy, and I was able to have meaningful contact with patients. I wanted to continue to have that experience. A mentor in pharmacy school encouraged me to become an oncology pharmacist to reclaim contact with patients by providing education and counseling. The better job we do with patient contact, the more improved patient adherence to therapy and outcomes will be. Once I decided to become an oncology pharmacist, I never looked back. What advice would you give to someone entering the field? RT: Oncology pharmacists are asked to wear many hats. They also have to deal with drug shortages, which are not going away anytime soon. We need to

develop policies and practice standards to ensure that our drug supplies go to the right patient. Also, we provide support in designing clinical trials and take a front-end position in drafting protocols for use of new technology. Oncology pharmacists are increasingly asked to wear many hats in service to the hospital. In response to the unfortunate reality of drug shortages and the accelerated availability of new treatments, pharmacists are playing a larger role in developing policies and guidelines that affect practice on a larger scale. With the trend toward smaller, more efficient, clinical trials, I see pharmacists assuming a larger supportive role in research. Lastly, the ushering of healthcare into the digital and information age is revealing many complex challenges that should be met with a pharmacist’s perspective. To meet these challenges, I would advise the person to adopt skills outside their comfort zone; for example, in business training, computer science, and informatics. This is in addition to the oncology pharmacy residency and board certification. Expanding your skill set beyond pharmacy will add greater depth and dimension to your expertise. l

LUNG CANCER

Second-Generation ALK Inhibitor Regresses CNS Metastases in NSCLC By Alice Goodman

novel ALK/EGFR (anaplastic lymphoma kinase/ epidermal growth factor receptor) inhibitor— AP26113 (ARIAD Pharmaceuticals, Inc.)— achieved good responses in crizotinib-resistant and crizotinib-naive patients with non-small cell lung cancer (NSCLC) as well as radiographic regression of central nervous system (CNS) metastases in these patients. The results of the first-in-human phase 1/2 dose-finding study of AP26113 were presented by D. Ross Camidge, MD, University of Colorado, Denver, at the European Cancer Congress (ESMO/ECCO/ESTRO), held September 27October 1, 2013, in Amsterdam, the Netherlands. Half of all ALK-positive patients with NSCLC who develop crizotinib resistance become resistant in the brain, suggesting that crizotinib has inadequate CNS exposure. Systemic progression typically occurs later in the course of disease. Phase 1 was a 3x3 dose escalation study in 30 to 60 patients with various advanced malignancies. In phase 2, there were 5 cohorts—4 with NSCLC (n = 85 total) and 1 with other cancers amenable to ALK inhibition (n = 20). The identified dose of 180 mg/day was used in phase 2 initially, but some patients developed pulmonary symptoms at that level, which resolved with steroids over 1 week. The decision was made to use a step-up approach of

90 mg/day for the first week on drug, and then move to 180 mg/day, Camidge said. Other adverse events included gastrointestinal disturbances, and these were mainly mild. Elevated liver enzymes were reported in 12% of patients. Treatmentemergent grade 3 or higher adverse events were reported in 2% to 4% of patients across all dose levels. Objective response rate was 65%. Response rate in patients previously treated with crizotinib was 61%; all 3 crizotinib-naive patients responded (100%), 1 with a complete response. Eight of 10 patients with CNS metastasis had radiographic evidence of regression, and this improvement lasted from 8 to 40 weeks. Responses were seen in some patients with the T290M mutation who were treated with the drug. Among 12 treated patients with the T790M mutation, 5 had stable disease, 4 had progressive disease, and 3 discontinued the study before receiving treatment. These data are preliminary. More experience is needed to determine if the drug will be an improvement on crizotinib. At least 2 other second-generation ALK inhibitors are in development, and these drugs also appear to achieve radiographic regression in CNS metastases. l

OCTOBER 2013 I VOL 6, NO 4

Now enrolling

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

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

Secondary Endpoints

• Overall response rate

• • • • • • • •

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

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

NCT#01889186 Reference: ClinicalTrials.gov.

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