TOP AUGUST 2013 by The Oncology Pharmacist

August 2013

www.TheOncologyPharmacist.com

Vol 6, No 3

COMPLIMENTARY CE Considerations in Multiple Myeloma—Ask the Experts: Combination Versus Sequential Therapy

see page 24

Side Effects Management

Cancer Center Profile

Barnes-Jewish Hospital

Oncology Pharmacy in the Era of Targeted Therapy By Alice Goodman

arnes-Jewish Hospital in St. Louis, Missouri, is affiliated with the Siteman Cancer Center and Washington University School of Medicine. Barnes-Jewish Hospital has made the US News & World Report list of the 100 best hospitals in the United State for the past 21 years. It is the only hospital in St. Louis and the state of Missouri to have this designation. The hospital attracts some of the nation’s top doctors, is known for nursing excellence and the use of outcome and quality measures, and Sara K. Butler, PharmD, BCPS, BCOP features the latest technology and research. Sara K. Butler, PharmD, BCPS, BCOP, Clinical Pharmacist, Medical Oncology Clinical Supervisor, PGY2 Oncology Residency Program Director at Barnes-Jewish Hospital, talks about some of the programs at her institution and changes in the field of oncology.

What is your job description? Sara Butler (SB): I am a clinical oncology pharmacist at Barnes-Jewish Hospital, working mainly with patients who have solid tumors or lymphoma. My job requires frequent collaboration with oncologists and medical residents about how to care for patients. Many of the patients I see are admitted for symptom management and complications of cancer therapy. I make recommendations based on their specific symptoms and the types of therapy they are receiving. For example, if a patient with newly diagnosed colon cancer has significant peripheral neuropathy, I would recommend FOLFIRI rather than Continued on page 35

Conference News

Highlights From the Multinational Association of Supportive Care in Cancer Annual Meeting By Alice Goodman

ith the growing number of cancer survivors in the United States and around the world, supportive care has become of even greater importance for these patients. At the recent Multinational Association of Supportive Care in Cancer (MASCC) annual meeting, held June

27-29, 2013, in Berlin, Germany, more than 1400 attendees could choose from a wealth of presentations to enhance their knowledge of supportive care and improve cancer care outcomes. Below are selected brief summaries of highlights from the meeting.

Superior Efficacy Shown for Novel Fixed-Dose Antiemetic Combination By Caroline Helwick

novel fixed-dose combination of netupitant and palonosetron, referred to as NEPA, was found to be highly effective in preventing chemotherapy-induced nausea and vomiting in 2 studies presented at the 2013 American Society of Clinical Oncology (ASCO) Annual Meeting. “NEPA, a fixed-dose combination of netupitant, a new NK1 receptor antagonist, and palonosetron, a 5-HT3 receptor

antagonist, targets dual antiemetic pathways and has been shown to uniquely work synergistically in vitro,” said principal investigator Matti S. Aapro, MD, of the Clinique de Genolier in Switzerland.1 Netupitant is believed to work by blocking the action of substance P, an endogenous neurotransmitter (high concentrations of which are found in the vomiting center of the brainstem) that Continued on page 12

The Patient’s Voice

Can I Trust You? By MMA

do not think my situation is unique. I live in a large city with horrendous healthcare. If you do not live in such a city, you may not believe that I live in the United States. I do. Most of you, I imagine, live in places—urban, suburban, or rural—similar to mine. Hopefully, because you have not been seriously ill, you do not know it. I started going to an oncologist a full year before I was told that I was really sick. He was recommended as the best oncologist in the city. For a full year,

even after he got a biopsy result that said I was really sick, he told me on my monthly visits that one morning I would wake up and all my tumors would be gone. He constantly asked me, “Do you want me to give you chemotherapy?” “Only if I need it,” I would reply, assuming that as a board-certified doctor he would know. I never got chemotherapy in my home city. In September, he recommended I go to a major cancer center 700 miles from my Continued on page 20

inside Raising Awareness of Cancer Anorexia-Cachexia Syndrome in Patients With Lung Cancer. . . . . . . .

Breast Cancer

Additional Analyses of Eribulin Study Find Quality of Life, Survival Benefits. . . . . . . . . . . . . . . . . . . . .

Prostate Cancer . . . . . . . . . . . . .

Paroxetine Does Not Reduce Tamoxifen’s Effectiveness in Breast Cancer Survivors. . . . . . . . . . . 10

Abiraterone in Untreated Metastatic Castration-Resistant Prostate Cancer

Side Effects Management

Enzalutamide Promising in Hormone-Naive Prostate Cancer

Afatinib’s Dermatologic Adverse Events Can Be Managed . . . . . . . . .

15 21

Coming soon

Another option in short-acting G-CSF therapy

Âť FDA and EMA approved Brought to you by Tevaâ&#x20AC;&#x201D;a global leader experienced in developing and manufacturing biologics. Teva has a substantial portfolio of more than 50 oncology products in the US.

Learn more at tbofilgrastim.com Indication Tbo-filgrastim is a leukocyte growth factor indicated for reduction in 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. Important Safety Information Splenic rupture, including fatal cases, can occur following the administration of human granulocyte colony-stimulating factors (hG-CSFs). Discontinue tbo-filgrastim and evaluate for an enlarged spleen or splenic rupture in patients who report upper abdominal or shoulder pain after receiving tbo-filgrastim. Acute respiratory distress syndrome (ARDS) can occur in patients receiving hG-CSFs. Evaluate patients who develop fever and lung infiltrates or respiratory distress after receiving tbo-filgrastim for ARDS. Discontinue tbo-filgrastim in patients with ARDS. Serious allergic reactions, including anaphylaxis, can occur in patients receiving hG-CSFs. Reactions can occur on initial exposure. Permanently discontinue tbo-filgrastim in patients with serious allergic reactions. Do not administer tbo-filgrastim to patients with a history of serious allergic reactions to filgrastim or pegfilgrastim. 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 tbo-filgrastim in patients with sickle cell disease. Discontinue tbo-filgrastim in patients undergoing a sickle cell crisis. The granulocyte colony-stimulating factor (G-CSF) receptor, through which tbo-filgrastim acts, has been found on tumor cell lines. The possibility that tbo-filgrastim acts as a growth factor for any tumor type, including myeloid malignancies and myelodysplasia, diseases for which tbo-filgrastim is not approved, cannot be excluded. The most common treatment-emergent adverse reaction that occurred in patients treated with tbo-filgrastim at the recommended dose with an incidence of at least 1% or greater and two times more frequent than in the placebo group was bone pain. Please see brief summary of Prescribing Information on adjacent page.

Noteworthy Numbers

Melanoma Protecting the skin from the sun should be considered a year-round necessity because our skin is constantly exposed to the sun’s ultraviolet rays and is thus susceptible to melanoma. However, it’s summertime, the season in which sun protection is viewed as most essential, so before heading out for some fun in the sun, take a closer look at these melanoma statistics.

The American Cancer Society (ACS) reports that “about 76,690 new melano-

mas will be diagnosed (about 45,060 in men and 31,630 in women) and about 9480

BRIEF SUMMARY OF PRESCRIBING INFORMATION FOR tbo-filgrastim Injection for subcutaneous use SEE PACKAGE INSERT FOR FULL PRESCRIBING INFORMATION 1 INDICATIONS AND USAGE Tbo-filgrastim is indicated to reduce the duration of severe neutropenia in patients with nonmyeloid 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 tbo-filgrastim, discontinue tbo-filgrastim 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 tbo-filgrastim, for ARDS. Discontinue tbo-filgrastim 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 tbo-filgrastim in patients with serious allergic reactions. Do not administer tbo-filgrastim 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 tbo-filgrastim 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 tbo-filgrastim acts has been found on tumor cell lines. The possibility that tbo-filgrastim acts as a growth factor for any tumor type, including myeloid malignancies and myelodysplasia, diseases for which tbo-filgrastim 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 tbo-filgrastim 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. Tbo-filgrastim 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 52% of patients were male, the median age was 55 years, and 88% of patients were Caucasian. In all three studies a placebo (Cycle 1 of the breast cancer study only) or a non-US-approved filgrastim product were used as controls. Both tbo-filgrastim 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 tbo-filgrastim at the recommended dose and was numerically two times more frequent

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people are expected to die of melanoma (about 6280 men and 3200 women)” in 2013.1

than in the placebo group. The overall incidence of bone pain in Cycle 1 of treatment was 3.4% (3.4% tbo-filgrastim, 1.4% placebo, 7.5% non-USapproved 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 tbo-filgrastim. 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 tbo-filgrastim has not been adequately determined. 7 DRUG INTERACTIONS No formal drug interaction studies between tbo-filgrastim 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 tbo-filgrastim 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. Tbo-filgrastim 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 tbo-filgrastim 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 tbo-filgrastim in pediatric patients have not been established. 8.5 Geriatric Use Among 677 cancer patients enrolled in clinical trials of tbo-filgrastim, 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 tbo-filgrastim 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 tbo-filgrastim have not been studied in patients with hepatic impairment. 10 OVERDOSAGE No case of overdose has been reported.

Manufactured by: Sicor Biotech UAB Vilnius, Lithuania U.S. License No. 1803 Distributed by: Teva Pharmaceuticals USA North Wales, PA 19454 Product of Israel FIL-40085

August 2012

This brief summary is based on the tbo-filgrastim full Prescribing Information.

Job Number: 20040 Revision No: 0 Date: 6/13/13

According to the American Society of Clinical Oncology, the overall 5-year survival rate for melanoma is 91%, and some patients require only an initial surgery to remove the tumor.2 However, melanoma that has metastasized to other organs has a survival rate of only 15%.2 For patients with metastatic or unresectable melanoma, the drugs dabrafenib (Tafinlar) and trametinib (Mekinist) were approved by the US Food and Drug Administration on May 29, 2013.3 According to the Cancer. Net website, the first sign of melanoma is often a change in the color, feel, shape, or size of a mole on the skin.4 Monthly self-examinations of the skin can help detect this deadly disease at an early stage, allowing for a greater chance of survival, the ACS advises.5 The National Cancer Institute’s Cancer Trends Progress Report–2011/2012 Update states, “The percentage of adults who report being sunburned has increased since 2005,” however, by some measures “70% of adults…protect themselves from the sun.”6 Sources 1. http://www.cancer.org/cancer/skincancer-melanoma/ detailedguide/melanoma-skin-cancer-key-statistics. 2. http://www.cancer.net/cancer-types/melanoma/statistics. 3. http://www.fda.gov/NewsEvents/Newsroom/PressAnn ouncements/ucm354199.htm. 4. http://www.cancer.net/cancer-types/melanoma/symptoms. 5. http://www.cancer.org/cancer/skincancer-melanoma/ detailedguide/melanoma-skin-cancer-new-research. 6. http://progressreport.cancer.gov/doc_detail. asp?pid=1& did=2011&chid=101&coid=1011&mid=#links.

August 2013 I VOL 6, NO 3

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

August 2013 I VOL 6, NO 3

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

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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

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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 .

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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

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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

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

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, we present our coverage from the 2013 annual meetings of the Multinational Association of Supportive Care in Cancer (MASCC) and the American Society of Clinical Oncology (ASCO). Our MASCC highlights include updates about treatment to help manage oral mucositis and opioid-induced constipation as well as information about a nutritional supplement that may lower prostate-specific antigen levels. We also tell you about the latest news regarding tamoxifen and SSRIs. Our news from ASCO includes coverage about abiraterone and enzalutamide for treating patients with prostate cancer.

Be sure to read The Patient’s Voice column by MMA. She gives us the patient’s point of view about our profession, and it is not all good. She notes that an oncology pharmacist at the cancer center where she has been treated told her, “There are retail and research pharmacists. Obviously, research requires higher qualifications.” Because of her experiences as a cancer patient, she has difficulty trusting some of the information she is given. How can we help build trust with patients like MMA? This is the topic of our new reader poll (see below). Please visit our website, www.TheOncologyPharmacist. com. Participate in our reader poll and let us know what you think. l

Reader Poll

President/CEO Brian Tyburski Chief Operating Officer Pam Rattananont Ferris Vice President of Finance Andrea Kelly Director, Human Resources Blanche Marchitto

Do you have to build trust with patients?

Associate Editorial Director, Projects Division Terri Moore Director, Quality Control Barbara Marino Quality Control Assistant Theresa Salerno 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

August 2013 I VOL 6, NO 3

o Yes

o No

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n The Patient’s Voice column, MMA asks the question, “Can I trust you?” Her experiences with the healthcare system have made her leery about many aspects of her oncology care. She details some of the issues she had with her medications and her interactions with pharmacists—

at the cancer center where she was treated and at her hometown retail pharmacy. Have you worked with patients like MMA? If so, how do you work to build trust with these patients? Are the suggestions MMA offers realistic?

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 Communi cations, 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.

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

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

9.2 months

All responders (n=74)

(95% CI: 7.1, 10.8)

Patients who achieved a CR/CRu

10.4 months

(95% CI: 9.3, 13.6)

8.3 months

Patients who achieved a PR

(95% CI: 6.3, 10.8)

Months

The efficacy of TREANDA was evaluated in a single-arm study of 100 patients with indolent B-cell NHL that had progressed during or within six months of treatment with rituximab or a rituximab-containing regimen. In 2 single-arm studies of patients with indolent B-cell NHL that had progressed (N=176), the most common non-hematologic adverse reactions (frequency ≥30%) were nausea (75%), fatigue (57%), vomiting (40%), diarrhea (37%), and pyrexia (34%). The most common hematologic abnormalities (frequency ≥15%) were lymphopenia (99%), leukopenia (94%), anemia (88%), neutropenia (86%), and thrombocytopenia (86%). TREANDA is indicated for the treatment of patients with indolent B-cell non-Hodgkin lymphoma (NHL) that has progressed during or within 6 months of treatment with rituximab or a rituximab-containing regimen. • TREANDA is administered with a convenient dosing schedule – The recommended dose is 120 mg/m² administered intravenously over 60 minutes on Days 1 and 2 of a 21-day treatment cycle, up to 8 cycles Important Safety Information • Serious adverse reactions, including myelosuppression, infections, infusion reactions and anaphylaxis, tumor lysis syndrome, skin reactions including SJS/TEN, other malignancies, and extravasation, have been associated with TREANDA. Some reactions, such as myelosuppression, infections, and SJS/TEN (when TREANDA was administered concomitantly with allopurinol and other medications known to cause SJS/TEN), have been fatal. Patients should be monitored closely for these reactions and treated promptly if any occur • Adverse reactions may require interventions such as decreasing the dose of TREANDA, or withholding or delaying treatment • TREANDA is contraindicated in patients with a known hypersensitivity to bendamustine or mannitol. Women should be advised to avoid becoming pregnant while using TREANDA • The most common non-hematologic adverse reactions for NHL (frequency ≥15%) are nausea, fatigue, vomiting, diarrhea, pyrexia, constipation, anorexia, cough, headache, weight decreased, dyspnea, rash, and stomatitis. The most common hematologic abnormalities (frequency ≥15%) are lymphopenia, leukopenia, anemia, neutropenia, and thrombocytopenia Learn more www.TREANDAHCP.com Learnatmore at www.TREANDAHCP.com Please see accompanying brief summary of full Prescribing Information. ©2013 Cephalon, Inc., a wholly owned subsidiary Reference: 1. Data on file. Teva Pharmaceuticals.

Breast Cancer

Additional Analyses of Eribulin Study Find Quality of Life, Survival Benefits By Caroline Helwick

urther analyses of Study 301, which compared eribulin to capecitabine in the treatment of

advanced breast cancer, showed greater improvements in quality of life (QOL) with eribulin, and overall survival (OS)

Brief Summary of Prescribing Information for Indolent B-cell Non-Hodgkin Lymphoma That Has Progressed INDICATION AND USAGE: TREANDA for Injection is indicated for the treatment of patients with indolent B-cell non-Hodgkin lymphoma (NHL) that has progressed during or within six months of treatment with rituximab or a rituximab-containing regimen. CONTRAINDICATIONS: TREANDA is contraindicated in patients with a known hypersensitivity (eg, anaphylactic and anaphylactoid reactions) to bendamustine or mannitol. [See Warnings and Precautions] WARNINGS AND PRECAUTIONS: Myelosuppression. Patients treated with TREANDA are likely to experience myelosuppression. In the two NHL studies, 98% of patients had Grade 3-4 myelosuppression (see Table 2). Three patients (2%) died from myelosuppression-related adverse reactions; one each from neutropenic sepsis, diffuse alveolar hemorrhage with Grade 3 thrombocytopenia, and pneumonia from an opportunistic infection (CMV). In the event of treatment-related myelosuppression, monitor leukocytes, platelets, hemoglobin (Hgb), and neutrophils closely. In the clinical trials, blood counts were monitored every week initially. Hematologic nadirs were observed predominantly in the third week of therapy. Hematologic nadirs may require dose delays if recovery to the recommended values have not occurred by the first day of the next scheduled cycle. Prior to the initiation of the next cycle of therapy, the ANC should be ≥ 1 x 109/L and the platelet count should be ≥ 75 x 109/L. [See Dosage and Administration]. Infections. Infection, including pneumonia and sepsis, has been reported in patients in clinical trials and in post-marketing reports. Infection has been associated with hospitalization, septic shock and death. Patients with myelosuppression following treatment with TREANDA are more susceptible to infections. Patients with myelosuppression following TREANDA treatment should be advised to contact a physician if they have symptoms or signs of infection. Infusion Reactions and Anaphylaxis. Infusion reactions to TREANDA have occurred commonly in clinical trials. Symptoms include fever, chills, pruritus and rash. In rare instances severe anaphylactic and anaphylactoid reactions have occurred, particularly in the second and subsequent cycles of therapy. Monitor clinically and discontinue drug for severe reactions. Patients should be asked about symptoms suggestive of infusion reactions after their first cycle of therapy. Patients who experienced Grade 3 or worse allergic-type reactions were not typically rechallenged. Measures to prevent severe reactions, including antihistamines, antipyretics and corticosteroids should be considered in subsequent cycles in patients who have previously experienced Grade 1 or 2 infusion reactions. Discontinuation should be considered in patients with Grade 3 or 4 infusion reactions. Tumor Lysis Syndrome. Tumor lysis syndrome associated with TREANDA treatment has been reported in patients in clinical trials and in post-marketing reports. The onset tends to be within the first treatment cycle of TREANDA and, without intervention, may lead to acute renal failure and death. Preventive measures include maintaining adequate volume status, and close monitoring of blood chemistry, particularly potassium and uric acid levels. Allopurinol has also been used during the beginning of TREANDA therapy. However, there may be an increased risk of severe skin toxicity when TREANDA and allopurinol are administered concomitantly. Skin Reactions. A number of skin reactions have been reported in clinical trials and post-marketing safety reports. These events have included rash, toxic skin reactions and bullous exanthema. Some events occurred when TREANDA was given in combination with other anticancer agents, so the precise relationship to TREANDA is uncertain. In a study of TREANDA (90 mg/m2) in combination with rituximab, one case of toxic epidermal necrolysis (TEN) occurred. TEN has been reported for rituximab (see rituximab package insert). Cases of Stevens-Johnson syndrome (SJS) and TEN, some fatal, have been reported when TREANDA was administered concomitantly with allopurinol and other medications known to cause these syndromes. The relationship to TREANDA cannot be determined. Where skin reactions occur, they may be progressive and increase in severity with further treatment. Therefore, patients with skin reactions should be monitored closely. If skin reactions are severe or progressive, TREANDA should be withheld or discontinued. Other Malignancies. There are reports of pre-malignant and malignant diseases that have developed in patients who have been treated with TREANDA, including myelodysplastic syndrome, myeloproliferative disorders, acute myeloid leukemia and bronchial carcinoma. The association with TREANDA therapy has not been determined. Extravasation. There are postmarketing reports of bendamustine extravasations resulting in hospitalizations from erythema, marked swelling, and pain. Precautions should be taken to avoid extravasations, including monitoring of the intravenous infusion site for redness, swelling, pain, infection, and necrosis during and after administration of TREANDA. Use in Pregnancy. TREANDA can cause fetal harm when administered to a pregnant woman. Single intraperitoneal doses of bendamustine in mice and rats administered during organogenesis caused an increase in resorptions, skeletal and visceral malformations, and decreased fetal body weights. ADVERSE REACTIONS: The data described below reflect exposure to TREANDA in 176 patients who participated in two single-arm trials for the treatment of indolent B-cell NHL. Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice. The following serious adverse reactions have been associated with TREANDA in clinical trials and are discussed in greater detail in other sections [See Warnings and Precautions] of the label: Myelosuppression; Infections; Infusion Reactions and Anaphylaxis; Tumor Lysis Syndrome; Skin Reactions; Other Malignancies. Clinical Trials Experience in NHL. The data described below reflect exposure to TREANDA in 176 patients with indolent B-cell NHL treated in two single-arm studies. The population was 31-84 years of age, 60% male, and 40% female. The race distribution was 89% White, 7% Black, 3% Hispanic, 1% other, and <1% Asian. These patients received TREANDA at a dose of 120 mg/m2 intravenously on Days 1 and 2 for up to 8 21-day cycles. The adverse reactions occurring in at least 5% of the NHL patients, regardless of severity, are shown in Table 1. The most common non-hematologic adverse reactions (≥30%) were nausea (75%), fatigue (57%), vomiting (40%), diarrhea (37%) and pyrexia (34%). The most common non-hematologic Grade 3 or 4 adverse reactions (≥5%) were fatigue (11%), febrile neutropenia (6%), and pneumonia, hypokalemia and dehydration, each reported in 5% of patients. Table 1: Non-Hematologic Adverse Reactions Occurring in at Least 5% of NHL Patients Treated With TREANDA by System Organ Class and Preferred Term (N=176). System organ class, preferred term, and number (%) of patients* are shown. Total number of patients with at least 1 adverse reaction— All Grades: 176 (100); Grade 3/4: 94 (53). Cardiac disorders, All Grades and Grade 3/4—Tachycardia: 13 (7), 0. Gastrointestinal disorders, All Grades and Grade 3/4—Nausea: 132 (75), 7 (4); Vomiting: 71 (40), 5 (3); Diarrhea: 65 (37), 6 (3); Constipation: 51 (29), 1 (<1); Stomatitis: 27 (15), 1 (<1); Abdominal pain: 22 (13), 2 (1); Dyspepsia: 20 (11), 0; Gastroesophageal reflux disease: 18 (10), 0; Dry mouth: 15 (9), 1 (<1); Abdominal pain upper: 8 (5), 0; Abdominal distension: 8 (5), 0. General disorders and administration site conditions, All Grades and Grade 3/4—Fatigue: 101 (57), 19 (11); Pyrexia: 59 (34), 3 (2); Chills: 24 (14), 0; Edema peripheral: 23 (13), 1 (<1); Asthenia: 19 (11), 4 (2); Chest pain: 11 (6), 1 (<1); Infusion site pain: 11 (6), 0; Pain: 10 (6), 0; Catheter site pain: 8 (5), 0. Infections and infestations, All Grades and Grade 3/4—Herpes zoster: 18 (10), 5 (3); Upper respiratory tract infection: 18 (10), 0; Urinary tract infection: 17 (10), 4 (2); Sinusitis: 15 (9), 0; Pneumonia: 14 (8), 9 (5); Febrile Neutropenia: 11 (6), 11 (6); Oral Candidiasis: 11 (6), 2 (1); Nasopharyngitis: 11 (6), 0. Investigations, All Grades and Grade 3/4—Weight decreased: 31 (18), 3 (2). Metabolism and nutrition disorders, All Grades and Grade 3/4—Anorexia: 40 (23), 3 (2); Dehydration: 24 (14), 8 (5); Decreased appetite: 22 (13), 1 (<1); Hypokalemia: 15 (9), 9 (5). Musculoskeletal and connective tissue disorders, All Grades and Grade 3/4—Back pain: 25 (14), 5 (3); Arthralgia: 11 (6), 0; Pain in extremity: 8 (5), 2 (1); Bone pain: 8 (5), 0. Nervous system disorders, All Grades and Grade 3/4—Headache: 36 (21), 0; Dizziness: 25 (14), 0; Dysgeusia: 13 (7), 0. Psychiatric disorders, All Grades and Grade 3/4—Insomnia: 23 (13), 0; Anxiety: 14 (8), 1 (<1); Depression: 10 (6), 0. Respiratory, thoracic and mediastinal disorders, All Grades and Grade 3/4—Cough: 38 (22), 1 (<1); Dyspnea: 28 (16), 3 (2); Pharyngolaryngeal pain: 14 (8), 1 (<1); Wheezing: 8 (5), 0; Nasal congestion: 8 (5), 0. Skin and subcutaneous tissue disorders, All Grades and Grade 3/4—Rash: 28 (16), 1 (<1); Pruritus: 11 (6), 0; Dry skin: 9 (5), 0; Night sweats: 9 (5), 0; Hyperhidrosis: 8 (5), 0. Vascular disorders, All Grades and Grade 3/4—Hypotension: 10 (6), 2 (1). *Patients may have reported more than 1 adverse reaction. NOTE: Patients counted only once in each preferred term category and once in each system organ class category.

August 2013 I VOL 6, NO 3

benefits in subsets of patients. The open-label, randomized, phase 3 Study 301 compared the therapies in

Hematologic toxicities, based on laboratory values and CTC grade, in NHL patients treated in both single arm studies combined are described in Table 2. Clinically important chemistry laboratory values that were new or worsened from baseline and occurred in >1% of patients at Grade 3 or 4, in NHL patients treated in both single arm studies combined were hyperglycemia (3%), elevated creatinine (2%), hyponatremia (2%), and hypocalcemia (2%). Table 2: Incidence of Hematology Laboratory Abnormalities in Patients Who Received TREANDA in the NHL Studies Percent of patients Hematology Variable All Grades Grade 3/4 Lymphocytes Decreased 99 94 Leukocytes Decreased 94 56 Hemoglobin Decreased 88 11 Neutrophils Decreased 86 60 Platelets Decreased 86 25 In both studies, serious adverse reactions, regardless of causality, were reported in 37% of patients receiving TREANDA. The most common serious adverse reactions occurring in ≥ 5% of patients were febrile neutropenia and pneumonia. Other important serious adverse reactions reported in clinical trials and/or post-marketing experience were acute renal failure, cardiac failure, hypersensitivity, skin reactions, pulmonary fibrosis, and myelodysplastic syndrome. Serious drug-related adverse reactions reported in clinical trials included myelosuppression, infection, pneumonia, tumor lysis syndrome, and infusion reactions. [See Warnings and Precautions] Adverse reactions occurring less frequently but possibly related to TREANDA treatment were hemolysis, dysgeusia/taste disorder, atypical pneumonia, sepsis, herpes zoster, erythema, dermatitis, and skin necrosis. Post-Marketing Experience. The following adverse reactions have been identified during post-approval use of TREANDA. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure: anaphylaxis; and injection or infusion site reactions including phlebitis, pruritus, irritation, pain, and swelling. Skin reactions including SJS and TEN have occurred when TREANDA was administered concomitantly with allopurinol and other medications known to cause these syndromes. [See Warnings and Precautions] OVERDOSAGE: The intravenous LD of bendamustine HCl is 240 mg/m2 in the mouse and rat. Toxicities included sedation, tremor, ataxia, convulsions and respiratory distress. Across all clinical experience, the reported maximum single dose received was 280 mg/m2. Three of four patients treated at this dose showed ECG changes considered dose-limiting at 7 and 21 days post-dosing. These changes included QT prolongation (one patient), sinus tachycardia (one patient), ST and T wave deviations (two patients), and left anterior fascicular block (one patient). Cardiac enzymes and ejection fractions remained normal in all patients. No specific antidote for TREANDA overdose is known. Management of overdosage should include general supportive measures, including monitoring of hematologic parameters and ECGs. DOSAGE AND ADMINISTRATION: Dosing Instructions for NHL. Recommended Dosage: The recommended dose is 120 mg/m2 administered intravenously over 60 minutes on Days 1 and 2 of a 21-day cycle, up to 8 cycles. Dose Delays, Dose Modifications and Reinitiation of Therapy for NHL: TREANDA administration should be delayed in the event of a Grade 4 hematologic toxicity or clinically significant ≥ Grade 2 non-hematologic toxicity. Once non-hematologic toxicity has recovered to ≤ Grade 1 and/or the blood counts have improved [Absolute Neutrophil Count (ANC) ≥ 1 x 109/L, platelets ≥ 75 x 109/L], TREANDA can be reinitiated at the discretion of the treating physician. In addition, dose reduction may be warranted. [See Warnings and Precautions] Dose modifications for hematologic toxicity: for Grade 4 toxicity, reduce the dose to 90 mg/m2 on Days 1 and 2 of each cycle; if Grade 4 toxicity recurs, reduce the dose to 60 mg/m2 on Days 1 and 2 of each cycle. Dose modifications for non-hematologic toxicity: for Grade 3 or greater toxicity, reduce the dose to 90 mg/m2 on Days 1 and 2 of each cycle; if Grade 3 or greater toxicity recurs, reduce the dose to 60 mg/m2 on Days 1 and 2 of each cycle. Reconstitution/Preparation for Intravenous Administration. • Aseptically reconstitute each TREANDA vial as follows: • 25 mg TREANDA vial: Add 5 mL of only Sterile Water for Injection, USP. • 100 mg TREANDA vial: Add 20 mL of only Sterile Water for Injection, USP. Shake well to yield a clear, colorless to a pale yellow solution with a bendamustine HCl concentration of 5 mg/mL. The lyophilized powder should completely dissolve in 5 minutes. If particulate matter is observed, the reconstituted product should not be used. • Aseptically withdraw the volume needed for the required dose (based on 5 mg/mL concentration) and immediately transfer to a 500 mL infusion bag of 0.9% Sodium Chloride Injection, USP (normal saline). As an alternative to 0.9% Sodium Chloride Injection, USP (normal saline), a 500 mL infusion bag of 2.5% Dextrose/0.45% Sodium Chloride Injection, USP, may be considered. The resulting final concentration of bendamustine HCl in the infusion bag should be within 0.2–0.6 mg/mL. The reconstituted solution must be transferred to the infusion bag within 30 minutes of reconstitution. After transferring, thoroughly mix the contents of the infusion bag. The admixture should be a clear and colorless to slightly yellow solution. • Use Sterile Water for Injection, USP, for reconstitution and then either 0.9% Sodium Chloride Injection, USP, or 2.5% Dextrose/0.45% Sodium Chloride Injection, USP, for dilution, as outlined above. No other diluents have been shown to be compatible. • Parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration whenever solution and container permit. Any unused solution should be discarded according to institutional procedures for antineoplastics. Admixture Stability. TREANDA contains no antimicrobial preservative. The admixture should be prepared as close as possible to the time of patient administration. Once diluted with either 0.9% Sodium Chloride Injection, USP, or 2.5% Dextrose/0.45% Sodium Chloride Injection, USP, the final admixture is stable for 24 hours when stored refrigerated (2-8°C or 36-47°F) or for 3 hours when stored at room temperature (15-30°C or 59-86°F) and room light. Administration of TREANDA must be completed within this period. DOSAGE FORMS AND STRENGTHS: TREANDA for Injection single-use vial containing either 25 mg or 100 mg of bendamustine HCl as white to off-white lyophilized powder. HOW SUPPLIED/STORAGE AND HANDLING: Safe Handling and Disposal. As with other potentially toxic anticancer agents, care should be exercised in the handling and preparation of solutions prepared from TREANDA. The use of gloves and safety glasses is recommended to avoid exposure in case of breakage of the vial or other accidental spillage. If a solution of TREANDA contacts the skin, wash the skin immediately and thoroughly with soap and water. If TREANDA contacts the mucous membranes, flush thoroughly with water. Procedures for the proper handling and disposal of anticancer drugs should be considered. Several guidelines on the subject have been published. There is no general agreement that all of the procedures recommended in the guidelines are necessary or appropriate. How Supplied. TREANDA (bendamustine hydrochloride) for Injection is supplied in individual cartons as follows: NDC 63459-390-08 TREANDA (bendamustine hydrochloride) for Injection, 25 mg in 8 mL amber single-use vial and NDC 63459-391-20 TREANDA (bendamustine hydrochloride) for Injection, 100 mg in 20 mL amber single-use vial. Storage. TREANDA may be stored up to 25°C (77°F) with excursions permitted up to 30°C (86°F) (see USP Controlled Room Temperature). Retain in original package until time of use to protect from light. 50

Distributed by: Cephalon, Inc. Frazer, PA 19355 TREANDA is a trademark of Cephalon, Inc., or its affiliates. All rights reserved. ©2008-2012 Cephalon, Inc., or its affiliates. TRE-2486c November 2012 (Label Code: 00016287.06) This brief summary is based on TRE-2527 TREANDA full Prescribing Information.

1102 women with locally advanced or metastatic breast cancer previously treated with no more than 2 regimens, including anthracyclines and taxanes. Median OS was numerically but not significantly improved with eribulin in the overall population: 15.9 versus 14.5 months (hazard ratio [HR] = 0.88; P = .056). The additional analyses of Study 301 were presented at the 2013 American Society of Clinical Oncology (ASCO) Annual Meeting.1,2 New Findings on Quality of Life in Study 301 Study 301 included QOL as a secondary end point, exploring patients’ experience of symptoms, functions, and overall well-being. The analysis found significantly greater improvements in QOL among patients treated with eribulin, reported Javier Cortes, MD, of Vall D’Hebron University Hospital in Barcelona, Spain. QOL was assessed with the European Organisation for Research and Treatment of Cancer Quality of Life Questionnaire Core 30 (EORTC QLQC30) and the breast cancer–specific supplementary measure (QLQ-BR23), administered at baseline, 6 weeks, and 3, 6, 12, 18, and 24 months after the start of treatment (or until progressive disease or treatment change) and at unscheduled visits. End points included the absolute change from baseline for Global Health Status (GHS), overall QOL, and for each functional domain and symptoms score. Functional domains and symptoms were standardized into a scale from 0 (worst) to 100 (best). An increase in scores indicated improvement in functional domains and deterioration of symptoms. GHS and overall QOL scores were low at baseline for both arms (approximately 55) but they improved to a significantly greater degree for patients receiving eribulin than for those receiving capecitabine, with an estimated treatment effect of 6.52 (P = .048), Cortes reported. “Over time, GHS and overall QOL scores improved in both arms but significantly more so for eribulin, suggesting subjective patient benefit,” he said. Patients receiving eribulin also had significantly better cognitive functioning (P <.001), whereas emotional functioning significantly improved for patients receiving capecitabine (P = .033). The estimated treatment effect for cognitive functioning was quite large, 15.33. The treatment effect for

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Breast Cancer capecitabine with regard to emotional functioning was 3.29. “Changes in symptoms appeared to mirror the adverse event profiles of the 2 drugs,” Cortes indicated. “As expected, advantages in parameters linked to gastrointestinal effects were observed with eribulin, while advantages in parameters related to hair loss were observed with capecitabine.” Symptom changes favoring eribulin included improvements in nausea and vomiting (P = .032) and diarrhea (P = .001), while systemic adverse effects (P <.001) and upset related to hair loss changes (P = .023) favored capecitabine. Change in body image was improved more with capecitabine (P <.01). Pain was comparable between the treatments at baseline and diminished at each visit. The EORTC QLQ-C30 and QLQBR23 questionnaires are widely used in international clinical trials to assess the QOL of patients with breast cancer. The QLQ-C30 includes 5 functional scales, 3 symptom scales, and 1 GHS scale. The QLQ-BR23 is a specific questionnaire containing 23 items measuring functioning and symptoms related to breast cancer. Overall Survival Improvements While the primary analysis of OS did not meet the predefined criterion for statistical significance in Study 301, the investigators hypothesized that significant differences might be observed within certain patient subgroups. The 1102 patients were randomized to receive eribulin or capecitabine as their first- (20.0%), second- (52.0%), or third-line treatment (27.2%) for advanced disease. The median number of treatment cycles was 6 for eribulin and 5 for capecitabine. “A nonsignificant trend favoring improved overall survival with eribulin compared with capecitabine, consistent with the results of the overall population, was maintained over most patient subgroups, including those receiving study treatment as their first-, second-, or third-line regimen for advanced disease,” according to Peter A. Kaufman, MD, of the Norris Cotton Cancer Center at DartmouthHitchcock Medical Center, Lebanon, New Hampshire, who presented the study at ASCO. Some patient subgroups seemed to have a greater benefit in survival with eribulin compared with capecitabine. In particular, median OS was improved by eribulin in patients with the following characteristics: • Human epidermal growth factor receptor 2 (HER2) negative (15.9 vs 13.5 months: HR = 0.84; P = .03)

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“As expected, advantages in parameters linked to gastrointestinal effects were observed with eribulin, while advantages in parameters related to hair loss were observed with capecitabine.” Javier Cortes, MD

• Estrogen receptor–negative (14.4 vs 10.5 months: HR = 0.78; P = .02) • Triple negative (14.4 vs 9.4 months: HR = 0.70; P = .01) Also deriving relatively more ben-

efit from eribulin were patients who were Latin American, had nonvisceral disease only, had more than 2 organs involved, had progressed more than 6 months after their last chemotherapy, and had received an anthracycline

and/or taxane in the metastatic setting (versus the neoadjuvant or adjuvant setting), he said. l References

1. Cortes J, Awada A, Kaufman PA, et al. Quality of life (QoL) in patients (pts) with locally advanced or metastatic breast cancer (MBC) previously treated with anthracyclines and taxanes who received eribulin mesylate or capecitabine: a phase III, open-label, randomized study. J Clin Oncol. 2013;31(suppl):Abstract 1050. Presented at: 2013 American Society of Clinical Oncology Annual Meeting; May 31-June 4, 2013; Chicago, IL. 2. Kaufman PA, Cortes J, Awada A, et al. A phase III, open-label, randomized study of eribulin mesylate versus capecitabine in patients with locally advanced or metastatic breast cancer (MBC) previously treated with anthracyclines and taxanes: subgroup analyses. J Clin Oncol. 2013;31(suppl):Abstract 1049. Presented at: 2013 American Society of Clinical Oncology Annual Meeting; May 31-June 4, 2013; Chicago, IL.

Pharmacokinetics/Pharmacodynamics

Branded Versus Generic Enoxaparin: Biological Activity May Differ By Caroline Helwick

hile branded and generic enoxaparin share many traditional characteristics of low-molecular-weight heparins (LMWHs), they differ in several parameters that are relevant to an antithrombotic effect, according to researchers from Loyola University Medical Center, Maywood, Illinois, who presented their findings at the 54th Annual Meeting of the American Society of Hematology. “While the traditional characteristics of average molecular weight, anti-FXa, and anti-FIIa potencies were not dissimilar for the generic and branded enoxaparins, other activities of this complex biological drug differed,” Jeanine Walenga, PhD, said. LMWHs are anticoagulants whose heterogeneity in saccharide chain length and in the composition (sulfate, acetyl), content, and location of functional groups can impact their multiple biological activities. This study was conducted to compare the activity profile of the most widely used LMWH, branded enoxaparin (Lovenox), and the first United States–approved generic enoxaparin (Sandoz US). Five batches each of branded and generic enoxaparin were studied in parallel. In addition to the anti-factor Xa (FXa) and anti-FIIa potencies, a battery of assays relevant to the antithrombotic activity of LMWHs was employed, covering molecular weight profiling, in vitro activities, and ex vivo pharmacodynamic responses. The concentration response of each batch of branded or generic drug was determined with blood from the same donor. Prefilled syringes containing 40 mg of enoxaparin were purchased through hospital pharmacies. Similarities and Differences Observed No significant differences were seen in the average molecular weight between branded and generic enoxaparins. However, both in vitro and in vivo/ex vivo activity differences were found in several parameters known to be relevant to the antithrombotic effect of LMWH, in particular, thrombin generation inhibition and tissue factor pathway inhibitor (TFPI) release, Walenga reported. The investigations also demonstrated a wider variation in anticoagulant response to generic enoxaparin in

comparison to branded enoxaparin. This variation was due to the response of the individual subject as well as to the batch of the product, she said. Differences appear to be more related to activities associated with the anti-FIIa (higher molecular weight) component of the LMWH. The investigators summarized the main differences between branded and generic enoxaparin: • In vitro investigations Anti-FXa and anti-FIIa potencies were similar; u however, in the thromboelastography, fibrinokinetic, and thrombin generation inhibition assays, the generic compared with the branded enoxaparin showed: n More variation in the individual’s anticoag ulant response n More batch-to-batch variation n Less predictable concentration-dependent and linear response n A lower overall anticoagulant effect • Ex vivo pharmacodynamic investigations u Generic compared with the branded enoxaparin demonstrated: n Less thrombin generation inhibition n Less TFPI release n More inhibition of the active form of throm bin-activatable fibrinolysis inhibitor “These findings suggest that simple analytical characterization (average molecular weight, anti-FXa, anti-FIIa) can establish good quality control in manufacturing but may not assume similarity in biological performance between branded and generic enoxaparins,” Walenga said. Besides the routinely required characterization, the inclusion of additional tests for biological activities and pharmacodynamic profiling of generics in animal models might provide useful information on the bioequivalence of the generic versions, the investigators suggested. l Reference

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

August 2013 I VOL 6, NO 3

Breast Cancer

Paroxetine Does Not Reduce Tamoxifenâ&#x20AC;&#x2122;s Effectiveness in Breast Cancer Survivors By Alice Goodman

reast cancer survivors who suffer study presented at the 2013 annual meetfrom depression can safely take ing of the Multinational Association of both tamoxifen and a concomi- Supportive Care in Cancer. tant selective serotonin reuptake inhibDepression affects about half of all itor (SSRI) antidepressant, according to women with breast cancer, and many of 11:12 AM Page 1 a GBC2013Asize20813_Layout large population-based1 2/8/13 observational them take antidepressants to alleviate

their mood symptoms. Depressed mood is a potential side effect in women with estrogen receptorâ&#x20AC;&#x201C;positive (ER+) breast cancer who are typically treated with hormonal therapy to prevent recurrence. So, while tamoxifen reduces the risk

ANNUAL CONFERENCE

"! ! !

! Professor Rob Coleman, MBBS, MD, FRCP Yorkshire Cancer Research Professor of Medical Oncology Director, Sheffield Cancer Research Centre Associate Director, National Institute for Health Research Cancer Research Network Department of Oncology, Weston Park Hospital Sheffield, United Kingdom

* 3:00 pm - 7:00 pm

Registration

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Symposium/Product Theater

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

8:15 am - 11:45 am

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

12:00 pm - 1:00 pm

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1:15 pm - 4:30 pm

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

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

4:30 pm - 6:30 pm

Meet the Experts/Networking/Exhibits

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

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

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

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

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7:00 am - 8:00 am

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

12:00 pm - 1:00 pm

Symposium/Product Theater/Exhibits

1:15 pm - 3:00 pm

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

The Medical Learning Institute Inc designates this live activity for a maximum of 12.5 AMA PRA Category 1 Creditsâ&#x201E;˘. Physicians should claim only the credit commensurate with the extent of their participation in the activity. This activity has been planned and implemented in accordance with the Essential Areas and policies of the Accreditation Council for Continuing Medical Education through the joint sponsorship of the Medical Learning Institute Inc and the Center of Excellence Media, LLC. The Medical Learning Institute Inc is accredited by the Accreditation Council for Continuing Medical Education to provide continuing medical education for physicians.

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The Medical Learning Institute Inc is accredited by the Accreditation Council for Pharmacy Education as a provider of continuing pharmacy education. Completion of this knowledge-based activity provides for 12.5 contact hours (1.25 CEUs) of continuing pharmacy education credit. The Universal Activity Number for this activity is (To be determined).

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

3:00 pm

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August 2013 I VOL 6, NO 3

Reference

PMPMERSONALIZED EDICINE IN ONCOLOGY O

www.globalbiomarkersconsortium.com

of breast cancer, it can also have effects on mood that lead women to use antidepressants. SSRIs, however, are known to inhibit CYP 2D6, an enzyme needed to metabolize tamoxifen, raising concerns about whether concomitant SSRIs interfere with the protective effects of tamoxifen. However, no large studies had previously addressed breast cancer recurrence in women who take both tamoxifen and antidepressants. â&#x20AC;&#x153;Depression is commonly treated with antidepressants, especially SSRIs. Women and their providers can gain reassurance from this study that using an SSRI and tamoxifen at the same time does not pose a greater risk of breast cancer recurrence,â&#x20AC;? stated lead author Reina Haque, PhD, of Kaiser Permanente Southern California. About 7000 women in the Kaiser Permanente managed care system are diagnosed with breast cancer each year, she explained. â&#x20AC;&#x153;Nearly 50% of women with a recent breast cancer diagnosis experience depression, and the incidence of depression increased 4-fold in breast cancer survivors compared to women with no history of breast cancer,â&#x20AC;? she said. The present study, Antidepressants and Breast Cancer Pharmacoepidemiology (ABC2), examined this association in a cohort of 16,887 breast cancer survivors diagnosed between 1996 and 2007, and followed through 2009. The study was based on electronic health records of these survivors. Median age at diagnosis was 63 years; about 6% had ductal carcinoma in situ; 50% had stage I disease; and 44% had stage II. Subsequent breast cancer was reported in 2946 women; 2504 developed recurrent or metastatic disease, and 457 developed contralateral breast cancer. A multivariate analysis found no increased risk of subsequent breast cancer among 16,887 women who took both paroxetine and tamoxifen for at least 25% of the days for each of the 5 years on tamoxifen. The same results were found among 12,076 women with good adherence to tamoxifen who also took paroxetine for at least 25% of the 5 years of tamoxifen treatment. â&#x20AC;&#x153;Using one of the most complete pharmacologic databases of insured patients, we observed no significantly increased risk of subsequent breast cancer in women who used paroxetine and tamoxifen concurrently. This study demonstrates the safety of using SSRIs and tamoxifen together,â&#x20AC;? Haque stated. â&#x20AC;&#x153;This study has implications for clinical decision-making and improving quality of life among breast cancer survivors,â&#x20AC;? she said. l

Haque R, Shi J, Fletcher SW, et al. Tamoxifen & antidepressant drug interactions in a cohort of breast cancer survivors cared for in large healthcare delivery systems in California. Support Care Cancer. 2013;21(suppl 1):S205. Abstract 0586. Presented at: 2013 Multinational Association of Supportive Care in Cancer Annual Meeting; June 27-29, 2013; Berlin, Germany.

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2ND ANNUAL

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CONQUERING THE CANCER CARE

CONTINUUM

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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 CANCER CARTHE I E CONT 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 RIES SE 13 spiritual.” (http://www.who.int/cancer/ management and offer expert stake20 THE INTopics UE ISS palliative/en/). D holder commentaries. will THIR For too long, however, the image of include: palliative care, pain manageNU AL AN ND O comprehensive ™ palliative care has been tied exclusively SE Ccare, ment, hospice 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 surgical in pharm spite drato overco aceasuticancer procedure provideddie for wh theile dying. providers as well as patients) uncom- we still hav me it effe cal agecare s des 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 sucD.alf Shockney, of our pat RN, nes I wasLillie scare theirforlov ien ciated with quality-of-life alled t their greatest fea ers, too, comto speak with members of our palliative rec ly wa ts. MAS r is having one in gre tching a few utes of an entBS, to wit at pai old, blackcancer patients and survivors, no mat- ease care team at Johns Hopkins and learned ern and-white minthe suffer n without a way movie. A ing. Fam to west-clinical outcome. cowboy ter what their that the word “palliative” comes from the fear these byword ily memb a gun“palliare,” will be the slinger, and had been shot final image ers tor att patients may not tell you about the sidewitness before which means to disguise or cloak. Centuries ago, this word as theYour em towncancer s they pted to rem their docove 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 of ine pra and wh s cisk In many cases they may simply assume that the discomfor flag—the drape is no longer referred to this term.a helping hisby teeth. I’m knife to bite betwe ey providers the purpose of sure back fort “comes effective age pain The World Health Organizationwamodified s how peoits origin the day enwith the disease.” However, with the imly associate ple coped this d with can manits inal definition of palliative care as quo follows: “Palliative witprovements r to nu cer and h pain – in medicine and the power of science, it treatment. The mb lithem and fol pro harthe d toquality doesn’t anymore. Docall not wait for your patients vide you with a lowing articles care is an approach that improves life 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 r tive of hospithrough enviro est thatat the time you are planer initiate soon and thisrequ discussion sociatedyou withthe life-threatening thenm prethat thoughines. They also pro tools a to even next edition illness, entafte He did , ond me. wheth atient g to aterallitand he s an inp mote tful care brin tion Thi to s. un rma resp be to serie ilege it info sur Lilli be taken um e D. Sho e that all for me or a clinic visrated all of the wastor t is my priv to enCare Continu ice options, their doc ckney, ney reite cer of it I jour , wit us Can ne. are long the RN add h pho can ask , hosp ress with cer patien pain me ed to com talk by about theLLC BS,ther weasu Conquering MAS me Hill Healthcare Communications, told specifically on to read. Hopee- �� Green our ple ts rem toge ses had te the focu ent ured exp a ch end pai too that his wife had eriencin of wheth nt issue, whi provides g and im n they are er they are l he and vitally importa age 30. at be s to to nosi som eve ple relieve it. presently her initial diag gree. Pat will be is one I beli ressio i ien e in pain, and e expon Pain steals ment ways n cliniof her tim s addressed here ripti what to cir ts have trosinc of away soc ubl what de- tness,ph his descto fully, concept it ysical enduran e, psychological e,dho onwe better ways cle (a hap ial Base and aler ver ted we ce new , limi tua ll-b pain was and can ma interpret n and l cancer e or adopted as I lly absent for bad in the py faccal con ing a ditio ke quali eing, and gravely ill. terminally il 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 ass ment ne doctor. Fur took a pain pillwas ent for eff ing an nowght that I thou patients and before ed to be himcom ective pai essment years ago gett He self thatthehe priorities himbeviewed by thermore, is thitold n manageessetod see I recall several distring swinf for all of so ati theer after hiscancer field. anyone dur as orm named Bill. man a ling on us and to working from act ing I fee sometime difficultually re- g this nex rnet and e-mail t l con it So ir vis dit? in s it is not. thefoun via the Inte pro is ing fident you will fin metimnesregardin Certainl had found me ing that his young it is, what hevok d these art and contai f conversatio stat that will assaist cer patien y one of the greate brie icles though cancan Mary. And wrote to me ststep ts is the you in rea ning valuable inf but fearsfor t astatic breast r, a drug exp met not fea orm had we res is sse y, r on ll sed ati e ssin of v Mar as develo r li painnow ing herby canwife, (He andplac ice. ping more g your current pat on that gressed to he was suffer o hosp r p ed fut d a ing h call ure t a h effective and the ients as cer t n. She eipatients hav special program before eiways e 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 ockney, hospital and D. Sh hav the in ing y at d RN entl pai fuse I bega , BS, MAS curr n ef©ther , he .)3As 201 Greenefits was awake, con hospice care of alth Hil He ckney, RN, more than she “had still lie, my car, e“Lil the key ben land Lillie D. Sho weight, but Comm said l t unicati untifou MAS times, losing chemotherapy he got very upse 8 years old. I ons, LLC rth issue of BS, g doctor been receivin Conquering ot die. We have 2 sons, 6 and him that she wrote that the Colast He nti told y.” cann the nu then erda wife I um Ca the yest e.” for nce Care ser thiad s n care of her would work with dresse raise themr alon meet himies nin e and cansnot sitIua who had take Treat g Thro ice staff and 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 rapy frien paon 2 erkefor preC outco is optimal y art ld ling him tore morning in her onthe uum.ily members and me icl e, to pro ims. roltewou medical identify fam hasized the im the cologis taking places of the emp him vid I were Th . ns help e boys ere cli e ins that usually ussio nic saidphthat ad disc are – adigh intthes giss ofas e type armacolo o the duccal help him traise doctor al in a row nowsome considerat ld ks a me wou f. 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CONTIN

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FOURTH

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Conquering t Cancer Carehe CONTI

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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 nt, i g 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 soon read tie learn why. lea Lilli nts ve e wa D. the nt to and Shockney ir family in , RN, de ep alt And speaki BS, MAS debt, and hough we have enter ng of the tea ed an excitin that the pat era of person 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 tre atm ve en pa bee t plan st. Even pri not be doing n accustom we must be nor treatmen been daunti things to a ed doing thing patient; t regimen ng from a s with a pat patients, of s 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 t atment at the patien y tried to care, 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 mission. s about tre and patients atmen , oncologist s, pharmaco t are a must, logists, pa © 2013 Gr lliative een Hill He althcare Co mmunicatio ns, LLC

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Side Effects Management

Superior Efficacy Shown for Novel Fixed-Dose... Continued from cover can stimulate the vomiting reflex. NEPA was developed to improve the convenience of administering guideline-based antiemetic prophylaxis, according to David Ettinger, MD, who reviewed the 2 studies at a poster discussion session. The optimal dose of NEPA was initially determined in a study led by Paul Hesketh, MD, of the Lahey Hospital & Medical Center in Burlington, Massachusetts.2 At ASCO, Aapro presented a late-breaking abstract examining the efficacy of NEPA at a fixed dose of 300 mg, which had proved most effective in the earlier study. The dose-finding study was a randomized, double-blind comparison of 3 oral doses of NEPA (netupitant 100, 200, or 300 mg plus palonosetron 0.5 mg), compared with palonosetron 0.5 mg alone, in 694 previously untreated patients receiving cisplatin-based, highly emetogenic chemotherapy. The antiemetics were all given on day 1, and all patients received oral dexamethasone on days 1 to 4. An exploratory arm included aprepitant plus ondansetron and dexamethasone. The primary end point was complete response (ie, no emesis and no rescue medication). “Each NEPA dose resulted in superior complete response rates compared with palonosetron,” Hesketh reported.

Table Complete Response Rates1 Outcome

NEPA 300 mg (%) Palonosetron (%) (N=724) (N=725) P Value

Delayed emesis (25-120 h)

76.9

69.5

.001

Acute emesis (0-24 h)

88.4

85.0

.047

Overall CR (0-120 h)

74.3

66.6

.001

Overall (including no significant nausea)

64.0

58.0

.020

Abbreviations: CR, complete response; NEPA, netupitant plus palonosetron.

Complete responses were observed in 89.6% of patients receiving NEPA at the most effective dose of 300 mg, compared with 76.5% of the palonosetron group (P = .004). The percentage of patients protected from acute emesis was 98.5% with NEPA compared with 89.7% with palonosetron (P = .007). Delayed emesis protection was observed in 90.4% versus 80.1%, respectively (P = .018), and overall complete protection (no emesis, no significant nausea) in 83.0% versus 69.9% (P ≤.05). Late-Breaking Abstract: NEPA 300 mg in Patients Receiving Anthracyclines Aapro presented findings from a multinational, randomized, double-blind study assessing the efficacy of a single

oral dose of NEPA 300 mg versus palonosetron 0.5 mg in 1455 chemotherapy-naive patients receiving anthracycline-based (moderately emetogenic) chemotherapy; 98% were female and 97% had breast cancer. In addition to NEPA or palonosetron, dexamethasone was given on day 1 in a dose of 12 mg to patients on the NEPA arm and 20 mg to those receiving palonosetron. The primary end point of this study was complete response during the delayed phase (ie, 25 to 120 hours post chemotherapy). “NEPA showed superior complete response rates as compared to palonosetron during the delayed, acute, and overall phases,” Aapro reported (Table). “NEPA was also superior to

palonosetron during the delayed/overall phases for complete protection, no emesis, and no significant nausea.” The most frequently reported study drug–related adverse events for NEPA included headache (3.3%) and constipation (2.1%), the majority being mild to moderate. Severe adverse events were rare (0.7%). Ettinger, the Alex Grass Professor of Oncology at the Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins, Baltimore, Maryland, said these were “good studies” that showed NEPA 300 mg to be more efficacious and more convenient than its comparators. He suggested that future studies compare NEPA plus dexamethasone with the guideline-recommended antiemetic regimen of aprepitant/palonosetron/dexamethasone. l References

1. Aapro MS, Rossi G, Rizzi G, et al. Phase III study of NEPA, a fixed-dose combination of netupitant (NETU) and palonosetron (PALO), versus PALO for prevention of chemotherapy-induced nausea and vomiting (CINV) following moderately emetogenic chemotherapy (MEC). J Clin Oncol. 2013;31(suppl):Abstract LBA9514. Presented at: 2013 American Society of Clinical Oncology Annual Meeting; May 31-June 4, 2013; Chicago, IL. 2. Hesketh PJ, Rossi G, Rizzi G, et al. Efficacy of NEPA, a novel combination of netupitant (NETU) and palonosetron (PALO), for prevention of chemotherapy-induced nausea and vomiting (CINV) following highly emetogenic chemotherapy (HEC). J Clin Oncol. 2013;31(suppl):Abstract 9512. Presented at: 2013 American Society of Clinical Oncology Annual Meeting; May 31-June 4, 2013; Chicago, IL.

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Side Effects Management

Afatinib’s Dermatologic Adverse Events Can Be Managed By Alice Goodman

ermatologic adverse events are frequently reported in patients treated with epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs), dual EGFR/human epidermal growth factor receptor 2 (HER2) blockers, and ErbB family blockers. So it is not surprising to learn that afatinib (Gilotrif; Boehringer Ingelheim)—a potent oral irreversible inhibitor of EGFR, HER2, and ErbB4 receptor kinases—is also associated with dermatologic adverse events. Afatinib was recently approved by the US Food and Drug Administration for first-line treatment of patients who have lung cancer with EGFR mutations. Its approval is based on data from the pivotal LUX-Lung 3 trial, comparing afatinib to chemotherapy with pemetrexed/cisplatin. Data from LUX-Lung 3 showed about a 4.2-month progression-free survival (PFS) advantage compared with pemetrexed/cisplatin. Patients with non–small cell lung cancer (NSCLC) with tumors harboring the 2 most common EGFR mutations (Del19 or L858R) taking afatinib lived for well over a year without disease progression (PFS of 13.6 months) versus just over half a year (PFS of 6.9 months) for those in the comparator arm. Afatinib is also being studied in breast cancer and head and neck cancer. Because afatinib more widely targets the ErbB family kinases, the drug may replace erlotinib and gefitinib as first-line therapy for patients with advanced NSCLC, explained Mario E. Lacouture, MD, Memorial Sloan-Kettering Cancer Center, New York City. Therefore, it is important to educate patients about these dermatologic adverse events and provide optimal management leading to the best symptom control, thereby promoting adherence. Lacouture discussed the dermatologic adverse events associated with afatinib, as well as management recommendations, at the 2013 Annual Meeting of the Multinational Association of Supportive Care in Cancer.1 This topic is also the subject of a recent article with Lacouture as the lead author in Expert Reviews in Anticancer Therapy.2 In a large analysis of phase 1, 2, and 3 trials of afatinib in NSCLC (including the LUX-Lung clinical trials program), 4 main dermatologic adverse events were associated with afatinib therapy: (1) papulopustular (acneiform) rash, (2) xerosis, (3)

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pruritus, and (4) paronychia. These effects have also been reported with other EGFR TKIs, Lacouture said. Patients taking afatinib (and other EGFR TKIs) should take precautions for skin protection, including using

of patients had any grade of xerosis and none was severe. Over-the-counter moisturizing cream and ammonium lactate cream or salicylic acid (grade 2 only) are recommended for grade 1/2 xerosis. If grade 3 or higher xero-

Afatinib was recently approved by the US Food and Drug Administration for first-line treatment of patients who have lung cancer with EGFR mutations.

An important observation from trials of other EGFR inhibitors is that patients who experience dermatologic adverse events are more likely to benefit from EGFR-inhibitor therapy, and the severity of rash is correlated with improved survival. This association has not yet been established with afatinib, however, but it is likely to be similar. It is important to maintain an effective dose of EGFR-inhibitor therapy. Therefore, timely identification and appropriate management of dermatologic adverse events will help keep patients on therapy, Lacouture said. l References

alcohol-free skin-based products, minimizing sun exposure, wearing sun protective clothing and a hat, and using a sunscreen with SPF >30 and UVA/UVB protection when planning to be outdoors. Dose modifications or interruptions can be used to manage severe dermatologic adverse events (ie, grade 3 or higher), but a hiatus of longer than 28 days of treatment is not recommended. If, however, the adverse event remains at grade 3 or is an intolerable grade 2 reaction despite interventions and a 28-day interruption, afatinib should be discontinued. In the LUX-1 and LUX-2 NSCLC trials (totaling more than 500 patients), all grades of papulopustular (acneiform) rash were reported in 78% to 94% of patients (severe grade 3 in 14%-28%). Drugs used to treat this rash include topical and oral steroids and antibiotics. For grades 1/2, afatinib can be continued at the current dose. Nail effects (paronychia) of all grades were reported in 39% to 86% of patients, with grade 3 in 5% to 8% of patients in LUX-1 and LUX-2. These can be treated with topical antibiotics, vinegar soaks, and topical ultrapotent steroids. For more severe paronychia, nail avulsion and systemic antibiotics can be considered. Pruritus was reported in 18% to 60% of patients enrolled in LUX-1 and LUX2. Severe pruritus is quite rare, <1%. Topical, oral, or systemic steroids, antihistamines, or gamma-aminobutyric acid (GABA) antagonists are recommended as treatment. Xerosis is less frequently reported than the other 3 adverse events of interest discussed. In the LUX-2 trial, only 11%

sis occurs, the stated measures plus topical steroid to eczematous areas, as well as afatinib treatment interruption and referral to a dermatologist, are suggested.

1. Schadendorf D, Lacouture ME, Chu CY, et al. Management of dermatological adverse events associated with afatinib, an oral ErbB family blocker. Support Care Cancer. 2013;21(suppl 1):S248. Abstract 0709. 2. Lacouture ME, Schadendorf D, Chu CY, et al. Dermatologic adverse events associated with afatinib: an oral ErbB family blocker. Expert Rev Anticancer Ther. 2013;13(6):721-728.

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Conference News: NCCN

The Changing Oncology Landscape: Evolution or Revolution? By Audrey Andrews

Panelists at the NCCN roundtable discussion.

anelists at the 2013 Annual Conference of the National Comprehensive Cancer Network (NCCN) view the oncology world as rapidly changing, and the impact of this—for better or for worse—will be felt by healthcare providers, payers, and patients alike. “Certainly, this landscape is shifting beneath our feet,” said Clifford Goodman, PhD, senior vice president and principal of the Lewin Group, a healthcare consulting firm based in Falls Church, Virginia, who moderated the panel discussion. “There are tectonic forces, and these are unsteady times,” he said.

the workplace with a higher risk profile or more advanced disease. Susan A. Higgins, MD, MS, associate director of the Department of Therapeutic Radiology Residency Training Program at Yale Cancer Center, New Haven, Connecticut, added that in her practice at Yale, she is seeing stage IV cervical cancer (a “third-world country disease”) among her underprivileged patients. In contrast, her affluent patients are moving into concierge practices. While the Affordable Care Act will “ballast the very bottom,” Higgins said, high copays for everyone else means “the bottom of the middle class is falling down.”

Coverage Continuum The population in the United States is not getting any healthier, despite broadening access to care and efforts to eliminate disparities, the panelists agreed. This is largely because the socioeconomic gap is widening and healthcare is becoming less affordable, especially to the middle class. “In 3 years, the person who makes an average US salary will have to spend 50% of it to cover his out-of-pocket expenses and healthcare premium,” Lee N. Newcomer, MD, senior vice president of UnitedHealth Group, Minneapolis, Minnesota, pointed out. John Fox, MD, MHA, senior medical director of Priority Health, Grand Rapids, Michigan, further predicted, “In the future, there will be healthcare exchanges and subsidies for low-income persons, but the middle class may be squeezed. Their out-of-pocket costs could be up to $6000 for an individual or $12,000 for a family. Even Medicare and Medicaid will experience more cost-sharing. This is a new disparity.” One result of this is a population of persons who bypass preventive care and screening, and thus enter or reenter

The population in the US is not getting any healthier, despite broadening access to care and efforts to eliminate disparities....This is largely because the socioeconomic gap is widening and healthcare is becoming less affordable, especially to the middle class.

August 2013 I VOL 6, NO 3

Roy Beveridge, MD, chief medical officer of McKesson Specialty Health, predicted that healthcare reform will increase coverage for previously uninsured persons, “but it is going to create other types of problems for how we care for them.” Newcomer predicted it will broaden access to care but not affect the escalating cost of care. “Access may not be worth much if people cannot afford the deductible,” he pointed out. Involving the Patient Greater attention must be paid to early integration of palliative care, both for quality-of-life reasons and as a way to reduce the cost of end-of-life care. Fox suggested that before cancer outcomes

can be improved, oncology stakeholders need to determine “which outcomes are most valuable.” At Priority Health, he said, they are “those that are most valuable to our patients,” and this is not necessarily longer life expectancy. The patient’s list of priorities must be front and center of clinical decision-making, and any treatment should be consistent with them. “The only way to know this is to ask the patient,” Fox said. Beveridge saw other obstacles to the successful integration of palliative care or end-of-life care: the lack of manpower to effectively deliver it, and the

fact that patients often fail to grasp its meaning. “Patients don’t want to make their caregivers unhappy. We have found in interviews that many will accept a third or fourth line of futile therapy because they don’t want to let their doctors down. Interestingly, physicians say they are giving futile therapy because they don’t want to let their patients down,” he said. Newcomer called this a “philosophical barrier.” “Americans still think death is an option,” he said. “We have a whole culture that says it is wrong to stop [treatment],” and this impedes a full and open exchange about prognosis. “When you throw in the family and cultural dynamic, you almost need the Department of State as a negotiator,”

Beveridge added. “We have found that it is frequently better to have a nurse practitioner or social worker introduce the topic, because we as physicians are not trained to do this, and we don’t do it particularly well.” Tools to help initiate these discussions are becoming available, including the American Board of Internal Medicine Foundation’s Choosing Wisely program, which includes the American Society of Clinical Oncology’s “Top Five” list of common, costly procedures in oncology that are not supported by evidence and that should be questioned. Some practices in the UnitedHealth network are asking patients to complete the Choosing Wisely form on hospital admission. “These practices are achieving much more patient-oriented outcomes, far fewer days in the ICU [intensive care unit], and more deaths at home, because they are having this discussion,” Newcomer reported. He said that he recently used the Choosing Wisely tool with his own parents and was surprised at what he learned. “I changed my viewpoint about their end-of-life care. This can be done,” Newcomer said. “It doesn’t require an army of palliative care specialists but a cultural commitment.” Some employers are beginning to see the value of palliative care and have expanded benefits accordingly. Some are even subsidizing advanced care directives and living wills. “At Pitney Bowes, we provide incentives for this,” offered John J. Mahoney, MD, MPH, consultant to Pitney Bowes. How “Big Data” May Personalize Medicine “Big data” will revolutionalize cancer care, panelists predicted. The power of tools like Watson is already being realized, said Marty Kohn, MD, MS, of IBM. Watson is a computer learning system that self-corrects and self-improves with little human input. “Watson can read and comprehend thousands of articles in a few seconds,” according to Kohn. Watson’s future role in therapeutic decision-making can be demonstrated in a joint venture between Memorial Sloan-Kettering Cancer Center and WellPoint. Watson is being taught to understand the critical attributes of a cancer patient’s history, to consult the literature and evidence-based guidelines, and to come up with treatment recommendations. But big data and tools like Watson do far more than accumulate information, Kohn pointed out. They draw from

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Conference News: NCCN multiple pathways to create a basis for making personalized decisions that are more likely to have value. It is not just “lots of data” but data that encompass volume, velocity, variety, and variability. More real-world than Watson was the example given by Newcomer, who noted that UnitedHealth Group has access to a decade’s worth of information on 70 to 80 million people that can be integrated with state tumor registries and insurance claims data to create longitudinal records for individuals. This will be used to profile chemotherapy regimens and their progression-free survival rates, he said. He expects this registry to be a more realistic picture than is gained from clinical trial data and to be useful to third-party payers in determining coverage. Among the panelists, Andrew von Eschenbach, MD, president of Samaritan Health Initiatives, Montgomery, Texas, and adjunct professor at MD Anderson Cancer Center, Houston, Texas, was particularly enthusiastic. “Big data is the most critically important thing we could be talking about,” he said. “If we have any hope of improving outcomes, it’s in the big data.”

“Our current incentives and disincentives are not providing for optimal care.” Clifford Goodman, PhD

The capturing of big data will revolutionize basic research and allow for modeling in silico cellular processes, biological processes, and multiple oncologic pathways. In clinical research, big data will allow for more sophisticated analyses that will “move us from information to real knowledge,” von Eschenbach predicted. “Then, with physician engagement and interpretation, we get to wisdom,” he said, which should lead to the ultimate goal of giving the right treatment to the right patient for the right reason. “That is the difference between rational medicine and rationed medicine.” Others on the panel were more cautious. “The trick is not to acquire data alone,” according to Beveridge, but to assure that the integrity of the data is strong. Fox emphasized that data should not be used “in a vacuum,” but in the context of patient preferences, which may include no active intervention. “We think about how to improve overall survival, but the challenge is for us to think differently. Overall survival is not the sine qua non of cancer care.”

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How to Brave the New World: The Evolving Ecosystem The future of cancer care requires a reformed “ecosystem,” in the words of Goodman. This means the integration of components in a multidisciplinary approach and a competitive collaboration to problem solving. The evolving ecosystem is no longer centered on individual excellence but rather on interoperable performance. “We were trained to play golf. The game has switched to basketball,” von Eschenbach said. “It’s about interoperability [and] how to work together so that I

can’t be as good as I need to be without Lee Newcomer.” Goodman noted that von Eschenbach once headed up the National Cancer Institute: “many competing cancer institutions doing research.” The ideal scenario, von Eschenbach said, would not have been “61 separate phenomenal cancer centers, but 61 playing together like a well-orchestrated team.” “As we look toward a brave new world in oncology, it’s tempting to look at all the high-tech stuff we have for discovering the next cure, but in this roundtable we saw that in order to get to the next

level, we can’t forget that we have disparities in care that drag the system down,” Goodman concluded. “We need to hold up that part of our at-risk population at the same time we advance the cutting edge with big data and reorganizing the cancer ecosystem. Our current incentives and disincentives are not providing for optimal care.” l Reference

Goodman C, Beveridge R, Fox J, et al. The changing oncology landscape: evolution or revolution? Presented at: 2013 Annual Conference of the National Comprehensive Cancer Network; March 15, 2013; Hollywood, FL. Roundtable discussion.

Side Effects Management

Raising Awareness of Cancer AnorexiaCachexia 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 to a retrospective, single-institution study presented at the 2013 Annual Meeting of the Multinational Association of Supportive Care in Cancer. 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 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, anorexia-cachexia 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):S285. Abstract 0808.

August 2013 I VOL 6, NO 3

Conference News: MASCC Continued from cover

Prophylactic Subcutaneous Fentanyl for Dyspnea A preliminary double-blind, randomized, controlled clinical trial suggests that prophylactic use of subcutaneous fentanyl can improve dyspnea, the ability to walk, and respiratory rate in ambulatory patients with breakthrough dyspnea. The findings of this preliminary study justify a larger randomized, controlled trial for confirmation, said lead author David Hui, MD, Palliative Care and Rehabilitation Medicine, University of Texas MD Anderson Cancer Center, Houston. “Dyspnea is one of the most common and distressing symptoms in cancer patients, and often worsens with breakthrough episodes on exertion. We

“Dyspnea is one of the most common and distressing symptoms in cancer patients.” David Hui, MD

hypothesized that subcutaneous fentanyl given before exertion could alleviate breakthrough dyspnea,” Hui said. Twenty ambulatory patients were enrolled in the trial and all stayed on study. They were asked to perform a baseline 6-minute walk test (6MWT), and then were assigned to subcuta-

neous fentanyl or placebo before taking another 6MWT. The investigators measured change in dyspnea numeric rating scale, walk distance, vital signs, and adverse events between the first and second 6MWTs. Subcutaneous fentanyl was associated with significant improvements in a

dyspnea numeric rating score at the end of the second 6MWT, with a mean change of –1.8 (P = .02). Significant improvements were also seen in dyspnea at rest 15 minutes after drug administration (P = .04), fatigue Borg Scale after the 6MWT (P = .04), 6MWT distance (+37.2 m, P = .03), and respiratory rate (–2.4, P = .03). No adverse events were observed. Hui noted that there was a large, but nonsignificant, placebo effect in the trial. Reference

Hui D, Xu A, Frisbee-Hume S, et al. Prophylactic subcutaneous fentanyl for exercise-induced breakthrough dyspnea: a preliminary double-blind, randomized controlled trial. Support Care Cancer. 2013;21(suppl 1):S191. Abstract 0542.

High Marks for Nutritional Supplement in Localized Prostate Cancer A food supplement containing pomegranate seed, green tea, broccoli, and turmeric taken twice a day significantly lowered prostate-specific antigen (PSA) levels compared with placebo in men with localized prostate cancer, according to the results of a double-blind, placebo-controlled clinical trial. Use of the supplement allowed more men to remain on observation alone, without having to resort to salvage surgery, radiation, or androgen-deprivation therapy (ADT).

Called Pomi-T, the supplement is commercially available. Previous animal models and phase 2 studies demonstrated that these polyphenolrich foods have anticancer effects. The study presented at MASCC 2013 is the first adequately powered, randomized, controlled phase 3 trial of Pomi-T (natureMedical Products) in men with localized prostate cancer. The study was also presented at the 2013 American Society of Clinical Oncology Annual Meeting.

The investigators enrolled 203 men (average age, 74 years) whose PSA was rising after radiotherapy or surgery for localized prostate cancer. They were managed with active surveillance (59%) or watchful waiting (41%), and randomized to receive 2 capsules of Pomi-T per day or placebo for 6 months. At 6 months of follow-up, median rise in PSA was 14.7% in the Pomi-T group versus 78.5% in the placebo group, representing a 63.8% difference favoring the supplement (P = .0008).

Lymphedema in Head and Neck Cancer Although little is known about the prevalence of lymphedema in head and neck cancer (HNC), a series of studies found that three-quarters of patients with HNC have problematic lymphedema, both internally and externally. “Lymphedema is a significant problem affecting a majority of HNC patients. Treatments such as surgery, chemotherapy, radiation, and combined modality therapy can damage lymphatic structures, leading to scar tissue and fibrosis. Lymphedema can be detected noninvasively, and this can inform clinical practice,” stated Sheila Ridner, PhD, RN, FAAN, Vanderbilt University School of Nursing, Nashville, Tennessee. The studies examined prevalence, symptoms, measurement techniques, and symptom assessment tools. Study 1 included 81 patients at least 3 months out from treatment. After a posttreatment interval of a median of 17.7 months, 75.3% had late-effect lymphedema; of these patients, 9.8% had external lymphedema exclusively, 39.4% had internal edema exclusively, and 50.8% had both types. Study 2 included 25 patients with HNC. Swelling (both internal and external) was measured before and after treatment at 6 and 12 weeks using digital photography and National Cancer Institute Common Terminology Criteria for Adverse Events (CTCAE) v.4.02. At baseline, digital photography identified external swelling more often than did CTCAE. Internal swelling was identified at baseline

August 2013 I VOL 6, NO 3

in 10 patients, and only 4 had been treated with surgery. Digital photography captured 100% of cases of internal swelling and 92% of cases identified by CTCAE. Study 3 included 100 patients and followed the time course and patterns of internal and external swelling over 36 weeks. Preliminary findings regarding external lymphedema using 3 different tools (Foldi, CTCAElymphedema, CTCAE-fibrosis) showed that by 36 weeks post treatment for HNC, >50% had lymphedema. Internal lymphedema, as documented via scoping procedures on the Patterson scale, was present in a few structures in 10% to 20% of patients prior to treatment. At 36 weeks post treatment, about 30% of patients had internal lymphedema, and this was observed in more structures than noted prior to treatment. Study 4 included 30 patients and found that 10 major symptoms were reported by >50% of patients. Taken together, these studies help characterize the prevalence, patterns, and assessment of lymphedema in HNC. Ridner said that patients should be educated about lymphedema before, during, and after treatment. Internal and external examinations should be conducted to look for lymphedema, and signs and symptoms of lymphedema should be evaluated at each clinic visit. Patients should be referred to lymphedema treatments when indicated. Reference

Ridner S, Deng J, Murphy BA, et al. Lymphedema in patients with head and neck cancer. Support Care Cancer. 2013;21(suppl 1):S196. Abstract 0558.

PSA levels were stable or lower than baseline in significantly more men in the supplement group: 46% versus 14%, representing a 32% difference (P = .00001). At follow-up, fewer men taking Pomi-T were assigned to any form of radiation, surgery, or ADT (7.4% vs 26%; P = .01). There were no significant differences between the 2 groups in laboratory measurements of cholesterol, blood pressure, serum glucose, C-reactive protein, or adverse events. Taking the supplement allowed more men to continue on active surveillance: 92.6% for Pomi-T versus 74% for placebo. “These results are awesome. We didn’t expect such a big response. This can change practice, because men and their doctors look at their PSA as a deciding factor in whether to continue on active management,” stated lead author Robert Thomas, MD, consulting oncologist at Bedford Hospital and Addenbrooke’s, part of Cambridge University Hospitals, United Kingdom. Importantly, this supplement is well tolerated and may even improve digestion and urinary symptoms, Thomas said. It is easy for men to stay on therapy with the supplement, and men are more amenable to taking a nutritional supplement than an active drug, especially hormone therapy. This product does not appear to act on hormones. The investigators plan to study Pomi-T in men with different stages of prostate cancer, as well as those taking ADT. The study was not funded by the makers of Pomi-T. Reference

Thomas R, Williams M, Bellamy P. A polyphenol rich whole food supplement reduces PSA progression in men with prostate cancer in a double blind placebo controlled RCT—the UK national Pomi-T study. Support Care Cancer. 2013;21(suppl 1):S33. Abstract 0040.

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Conference News: MASCC Importance of Evaluating Swallowing in Advanced Cancer A study reported that about 1 in 5 patients with advanced cancer have difficulty swallowing when admitted to the hospital; even at discharge, some still have problems. Difficulty swallowing is an independent predictor of survival in advanced cancer. These findings highlight the critical need for regular evaluation to ensure adequate nutrition and patient care, according to lead author Shiva Shrotriya, MD, Harry R. Horvitz Center for Palliative Medicine at the Cleveland Clinic Taussig Cancer Institute, Ohio. The study was based on electronic medical records of 249 patients with

solid tumors treated in an acute palliative medical unit from 2008 through 2011. Patients’ ability to swallow was evaluated

a sip of water without aspiration and a 3-ounce cup of water without aspiration. Mean age was 68 years, 57% were

Patients’ ability to swallow was evaluated by a routine swallow screen, preswallow test questionnaires, and a clinical swallow test.

by a routine swallow screen, preswallow test questionnaires, and a clinical swallow test. The clinical swallow test included

female, 71% were white, 25% were African American, and 4% “other”; 47% had metastatic disease. Mean length of

hospital stay was 8 to 10 days. On admission, 6% had difficulty swallowing, and 6% also had difficulty swallowing at discharge; 21% had difficulty swallowing during the hospital stay. “Most patients who underwent a formal clinical swallow test failed the routine swallow screen, and pneumonia/respiratory and gastrointestinal problems were common among those with difficulty swallowing,” Shrotriya stated. Reference

Shrotriya S, Thomas S, Timmer R, et al. Prevalence and incidence of difficulty swallowing in advanced cancer. Support Care Cancer. 2013;21(suppl 1):S188. Abstract 0535.

Naloxegol for Opioid-Induced Constipation Two large well-designed studies of patients with opioid-induced constipation (OIC) demonstrated that naloxegol rapidly improved stool frequency and did not compromise opioid-mediated analgesia. In both KODIAC-04 and KODIAC-05, participants were not patients with cancer, and AstraZeneca plans to study naloxegol to establish its safety and efficacy in patients with cancer pain. “Opioid-induced constipation is a major challenge in palliative care medicine for patients taking opioid analgesics who develop persistent constipation that does not respond to available treatments. Naloxegol holds promise for the treatment of OIC without interfering with opioid analgesia for pain,” said lead author Jan Tack, MD, PhD, Translational Research Center for Gastrointestinal Disorders, University of Leuven, Belgium. The KODIAC studies are part of a large development program for naloxegol, a peripherally acting mu-opioid– receptor antagonist under investigation for the treatment of patients with OIC. KODIAC-04 and KODIAC-05 were identically designed, phase 3 randomized, double-blind, placebo-controlled pivotal trials that evaluated 2 daily doses of this novel oral agent: 12.5 mg and 25 mg. In both studies, the 25 mg dose of naloxegol met both primary and secondary end points, but in KODIAC-05, the 12.5 mg dose failed to achieve statistical significance. KODIAC-04 included 641 patients taking 30 to 1000 morphine equivalents each week for pain who were randomized 1:1:1 to receive placebo or naloxegol 12.5 mg/day or 25 mg/day. Response was defined as having at least 3 spontaneous bowel movements per week, with an increase of at least 1 spontaneous bowel movement over baseline for at least 9 weeks and for at least 3 of the previous 4 weeks. Response rates

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were 29.4% for placebo, 40.8% for the lower dose (P = .015 vs placebo), and 44.4% for the higher dose (P = .001 vs placebo). KODIAC-05 included 696 patients similar to the population in KODIAC-04. Response rates were 29.3% for placebo, 34.9% for the 12.5 mg dose, and 39.7% for the 25 mg dose. Only the 25 mg dose was statistically significant compared with placebo (P = .021). For both trials, median time to first postdose laxation was significantly shorter for both doses of naloxegol compared with placebo (P <.001). No increase in pain scores or need for higher doses of opioids was observed in patients taking naloxegol. Adverse events (AEs) were more

frequent on naloxegol 25 mg and included abdominal pain, diarrhea, nausea and vomiting, and flatulence. Major cardiovascular events were rare and were similar across treatment groups. In KODIAC-04,

The KODIAC studies are part of a large development program for naloxegol. any AEs were reported in 46.9% of patients receiving placebo, 49.3% of patients taking naloxegol 12.5 mg, and 61.2% of those taking naloxegol 25 mg.

In KODIAC-05, any AEs were reported in 58.9%, 59.6%, and 69.0% of patients, respectively. Discontinuations due to AEs were higher in the 25 mg dose groups; in both trials about 5% of patients receiving either placebo or naloxegol 12.5 mg discontinued therapy because of AEs, compared with about 10% of those receiving the higher naloxegol dose. The rates of serious AEs were low in both trials, and occurred more frequently in the placebo and 12.5 mg dose groups than in the 25 mg dose groups. Reference

Tack J, Gralla R, Webster L, et al. Efficacy and safety of naloxegol in patients with opioid-induced constipation (OIC): results from 2 identical phase 3, prospective, randomized, multicenter, double-blind, controlled trials. Support Care Cancer. 2013;21(suppl 1):S260. Abstract 0737.

Managing Oral Mucositis MuGard has been approved in Europe for the prevention and treatment of oral mucositis (OM). It was found to be safe and effective in alleviating the signs and symptoms of OM in an interim analysis of the first patients enrolled in a randomized controlled clinical trial. The final results will be presented in the future and will be based on 120 patients. “There is no accepted prophylaxis or therapy for OM—a frequent and debilitating adverse event of concomitant chemoradiotherapy. Saline bicarbonate [SBC] rinse is recommended by the NCI [National Cancer Institute] as a standard for care for HNC [head and neck cancer]. We compared SBC versus MuGard to attenuate OM symptoms,” explained lead author Ron R. Allison, MD, 21st Century Oncology Carolina Radiation Medicine, Greenville, North Carolina. MuGard is a mucoadhesive oral wound rinse used to manage OM or stomatitis caused by radiotherapy and/ or chemotherapy and other types of oral mouth sores. Classified as a medical device, MuGard is a hydrated polymer system (oral hydrogel). When gently distributed within the mouth, the mucoadhesive formulation results in the formation of a protective coating over the oral mucosa. MuGard was previously shown to reduce the

incidence and severity of mucositis in patients with HNC undergoing radiation therapy, compared with data from historical control groups. In the study presented at MASCC 2013, 70 patients were treated with MuGard rinse every 3 hours up to 6 times per day over a period of 6 to 8 weeks versus SBC given on the same schedule. Patients completed the validated Oral Mucositis Daily Questionnaire (OMDQ) reporting mouth and throat soreness and other symptoms. The primary end point compared the efficacy of the 2 identically packaged oral rinses on reducing OM symptoms as determined by the area under the curve (AUC) of mouth and throat soreness as defined by the OMDQ. The interim analysis showed that treatment with oral MuGard was significantly superior to SBC, with a mean AUC of 58.9 versus 92.1 in the SBC group (P = .041). MuGard was also significantly better than SBC in alleviating other associated symptoms of OM. l Reference

Allison RR, Ambrad AA, Arshoun YM, et al. The multi-institutional, randomized, double-blind, placebo-controlled trial to assess the efficacy of MuGard in mitigating oral mucositis (OM) in chemoradiation-treated (CRT) head and neck cancer patients. Support Care Cancer. 2013;21(suppl 1):S211. Abstract 0605.

August 2013 I VOL 6, NO 3

Identifying and Tracking Febrile Neutropenia

lthough the development of new and effective chemotherapy regimens has significantly improved tumor response rates for a number of solid and hematologic cancers, the prognosis for patients may be compromised by chemotherapy-induced myelosuppression and its complications, including febrile neutropenia (FN).1 FN is a potentially life-threatening condition that can develop in cancer patients treated with myelosuppressive chemotherapy and result in increased risk of infection, hospitalization of up to 12 days, reduced chemotherapy dose intensity due to dose delays or reductions (in up to 25% of patients), and mortality.1-4 For many outpatient chemotherapy regimens, the nadir in ANC occurs 5 to 10 days after the last dose, corresponding to the highest risk for developing FN.5 Moreover, NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines®) have identified 4 determinants of risk for developing FN: 1. disease type, 2. chemotherapy regimen (High-dose, Dose-dense and Standard-dose therapy), 3. patient risk factors, and 4. treatment intent (curative vs. palliative).6 In this regard, NCCN Guidelines have identified chemotherapy regimens that place patients into high-, intermediate-, and low-risk categories for developing FN:6 • Examples of high risk disease settings and chemotherapy regimens include bladder cancer treated with MVAC, breast cancer treated with taxane/anthracycline regimens, esophageal and gastric cancers treated with docetaxel/cisplatin/fluorouracil, and Hodgkin lymphoma (HL) treated with BEACOPP • Examples of intermediate risk diseases and chemotherapy regimens include breast cancer treated with taxane-based regimens, esophageal and gastric cancers treated with platinum-based therapies, and HL treated with ABVD or Stanford V protocols ®

Just as important, there are patient and treatment-intent risk factors to consider in assessing risk for chemotherapy-induced FN. Patient risk factors for developing FN include age ≥65 years, pre-existing neutropenia, previous chemotherapy or radiation therapy, recent surgery, tumor with bone marrow involvement, and poor performance status.6 Comorbid conditions that significantly increase the risk of FN include the presence of open wounds, active tissue infection, renal disease (manifested by diminished glomerular filtration rate), lung disease (especially chronic obstructive pulmonary disease [COPD]), cardiovascular disease, liver disease (manifested by increased alkaline phosphatase or total bilirubin), and diabetes mellitus.6,7 Patients with FN with one or more comorbidities are also more likely to die in-hospital than patients without any major comorbidities. Whereas patients without any comorbidities had a 2.6% risk of in-patient mortality, the presence of 1 or >1 comorbidity was associated with an in-patient mortality rate of

10.3% and ≥21.4%, respectively.8 Finally, based on the chemotherapy regimen and patient-related risk factors, the patient is assigned to a high risk group, an intermediate group or low risk group.6 Every adult patient with solid tumors and non-myeloid malignancies should be proactively evaluated for these risk factors prior to their first chemotherapy cycle and following each round of chemotherapy.6 The clinical presentation of FN includes a single oral temperature of ≥38.3°C (101°F), or temperatures of ≥38.0°C (100.4°F) measured 1 hour apart, and an ANC <500/mm3 or <1000/mm3 with a predicted decline to <500/mm3 over the next 48 hours.5,6 A patient’s reduced ability to mount an inflammatory response can limit localizing signs and symptoms, and fever may be the only abnormal finding at presentation. Approximately half of patients with FN harbor an occult infection, and at least 20% of all patients with an ANC <100/mm3 are bacteremic.5 Early infections in

It is critical that all healthcare providers who manage cancer patients are familiar with the NCCN Guidelines® or their own institutional guidelines for the identification of patients at risk for FN. patients with FN are primarily bacterial in origin, although subsequent infections may include antibiotic-resistant bacteria and fungal or viral infections (including herpes simplex virus, varicella-zoster virus, cytomegalovirus, or hepatitis B).9 The consequences associated with FN include hospitalization; according to a subset of an observational retrospective cohort study of 1188 cancer patients admitted with neutropenia, FN, or neutropenia plus infection, the mean number of days in hospital ranged from 5.5 days in patients with primary breast cancer, 9.5 days for those with lung and bronchial cancers, and 12.0 days in NHL.4 Moreover, empiric IV antibiotic treatment is utilized in these patients and is often continued after discharge from the hospital. Just as important, a delay or dose reduction in the next round of chemotherapy is often necessary, resulting in reduced dose intensity, affecting long-term clinical outcomes for the primary malignancy as well as the patient’s quality of life.3,7,10

Morbidities, Mortalities, and Costs Associated With FN

In cancer patients hospitalized for FN plus infection, all-cause mortality during hospitalization was approximately 20% for hematologic malignancies and metastatic breast cancer, 21%

for lung or bronchial cancer.4 However, maintaining the dose and schedule are also of central concern in the delivery of chemotherapy, since delivering higher doses of chemotherapy agents reduces the survival probability of chemotherapy-resistant clones of cancer cells.10 Thus, reduction in relative dose intensity due to FN can have a significant impact on the patients’ quality of life and overall survival. Moreover, there are significant costs associated with the evaluation and treatment of FN. In an observational retrospective cohort study of cancer patients hospitalized in the United States for neutropenia, FN or neutropenia plus infection, the mean costs were $18,042 in those with neutropenia, rising to $22,839 in patients with neutropenia plus fever, and $27,587 for those with neutropenia plus infection.4 A review of current literature in cancer patients with FN who were compared with cancer patients without FN found that mean health resource utilization was $9,628 per patient-month in FN patients compared with $8,478 per patient-month in the non-FN patients.11 The largest cost difference by categorical source of care between the 2 groups was for hospitalization, and the costs associated with inpatient services for FN were significantly higher than for outpatient care (average of $22,086 for inpatient encounters vs $985 for outpatient encounters).11 Thus, the need for hospitalization is a significant contributor to costs associated with the management of FN. Hospitalization costs for FN also vary by cancer type. The highest costs are associated with hematologic malignancies other than NHL (mean of $52,579), lowest for primary breast cancer ($8,413), and intermediate for metastatic breast cancer ($14,341) and lung and bronchial cancer ($17,382).4 Thus, effective methods for identifying cancer patients who are at risk for neutropenic complications and implementing measures for preventing FN represent delivery of high-quality medicine and involve a critical role for the oncology pharmacist.

Tracking FN: Two New Approaches

Previous models that have been developed in an effort to track the incidence and consequences of FN requiring inpatient care made use of healthcare claims or hospital administrative databases; unfortunately, these methodologies suffered from a number of drawbacks, including being based on clinical practice of more than a decade ago and not taking into account FN treated in an outpatient setting.1,8,12 These limitations have called into question the accuracy of the data from these models. Recently, two new approaches have been described that may provide new ideas to track FN. Some of the limitations described above may be overcome by using electronic health records (EHR) that include point-of-care information in the inpatient and outpatient settings. In this regard, the data obtained from Humedica’s National EHR-Derived patient database during 2007-2010

showed that 19% of 2131 patients with various malignancies, including breast, lung, genitourinary or colorectal cancer or non-Hodgkin lymphoma, experienced an episode of FN, most frequently in the first or second cycle of chemotherapy.12 In the Humedica database, among the 8999 cycles of chemotherapy evaluated, 83.2% of the FN events were initially treated in the inpatient setting and 16.8% were initially treated in the outpatient setting, although 3.9% required subsequent hospitalization.12 Among FN patients initially treated in the inpatient setting, mean hospital length of stay was 8.4 days, and for those initially treated in the outpatient setting, mean number of FN-related outpatient management visits was 2.6, most in the physician’s office or the emergency department.12 In the Humedica database, among the FN events initially treated in the inpatient setting, inpatient mortality was 8.1%.12 A second approach to tracking FN involved a retrospective cohort study from a database maintained by Premier containing service records from more than 400 geographically diverse US hospitals, for hospitalization of 16,273 cancer patients for FN.13 This database employed a composite of information, including ICD-9 codes for neutropenia with fever or infection, and receipt of intravenous antibiotics, in an effort to understand clinical outcomes as well as expenses and resources entailed in caring for patients with FN in the involved institutions. This study showed that 19% of the FN patients were treated in an intensive care unit (ICU) setting, with an average length of stay of 5.2 days in the ICU.13 For all tumor types, hospitalization costs ranged from $18,479 to $19,281, with a mean case fatality rate of 10.6% and a mean length of stay of 8.6 days.13 The models taken from the database identified certain cancers and comorbidities as potential risk factors for higher rates of inpatient mortality and higher economic burden, including breast cancer patients with diagnosed septicemia/ bacteremia, and non-Hodgkin lymphoma patients with renal disease. The FN-related 30-day readmission rate after the index hospitalization was 5.9% for all tumor types studied.13 Indeed, substantial differences in the clinical and economic burden of FN existed depending on tumor types, infection types, and comorbidities.13 These unique models, derived from point-of-care information and hospital discharge data, afford real-time information about recent practices, and may provide guidance to institutions desiring to implement novel approaches for quality improvement initiatives in tracking the clinical characteristics, resource utilization, and outcomes in patients with FN.

Identifying and Implementing Measures to Reduce the Consequences of FN

Despite frequent planned reductions from standard relative dose intensity, the incidence of FN

remains high in community oncology practice in the United States, and improved methods of pretreatment assessment of patient risk factors for FN are needed.3 Healthcare providers who manage cancer patients should be aware of the pertinent patient data that should be collected on all cancer patients to assess their risk for FN to help reduce the incidence and consequences of FN, and thereby improve quality of care. Potential areas for quality improvement in tracking patients with FN include: • Implementing electronic medical records with physician order entry to avoid missing patients who are admitted to the hospital for hydration or chemotherapy and develop FN while in-hospital • Use of ICD codes indicative for FN (currently, ICD-9 codes are not specific for FN, and only allow coding for 288.00-288.09 Neutropenia; 780.6 Fever; 041.0-041.9 Bacterial infection; 038.0-038.9 Septicemia; 790.7 Bacteremia; 780.6 Fever of unknown origin; and 999.3 Other infection).14 • Involving oncology pharmacists in evaluating risk for FN, working in an interdisciplinary team to ensure appropriate supportive patient care, and continuing to track patients in the outpatient setting. In a recent survey of oncology nurses, while 99% of the respondents agreed that assessment of chemotherapy-induced neutropenia and its life-threatening complications are critical to quality patient care, only about half of the clinicians reported that they were able to access the NCCN Guidelines® for assessing risk of FN in their patients.2 Thus, it is critical that all healthcare providers who manage cancer patients are familiar with the NCCN Guidelines® or their own institutional guidelines for the identification of patients at risk for FN, their assessment and workup, and their management. Furthermore, it should be part of every institution’s process-related quality-of-care policy that the NCCN Guidelines® or validated institutional guidelines on the identification, assessment, and management of cancer patients at risk for FN are understood and followed.

Summary of Abbreviations

ABVD=doxorubicin + bleomycin + vinblastine + dacarbazine ANC=absolute neutrophil count BEACOPP=bleomycin + etoposide + doxorubicin + cyclophosphamide + vincristine + procarbazine + prednisone ECOG=Eastern Cooperative Oncology Group EHR=electronic health records FN=febrile neutropenia HL=Hodgkin lymphoma MVAC=methotrexate + vinblastine + doxorubicin + cisplatin NCCN=National Comprehensive Cancer Network NHL=non-Hodgkin lymphoma

References 1.

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Amgen was the exclusive financial sponsor of the article and had complete editorial control over its content.

Lyman GH, Delgado DJ. Risk and timing of hospitalization for febrile neutropenia in patients receiving CHOP, CHOP-R, or CNOP chemotherapy for intermediate-grade non-Hodgkin lymphoma. Cancer. 2003;98:2402-2409. Nirenberg A, Reame NK, Cato KD, et al. Oncology nurses’ use of National Comprehensive Cancer Network clinical practice guidelines for chemotherapy-induced and febrile neutropenia. Oncol Nurs Forum. 2010;37: 765-773. Crawford J, Dale DC, Kuderer NM, et al. Risk and timing of neutropenic events in adult cancer patients receiving chemotherapy: the results of a prospective nationwide study of oncology practice. J Natl Compr Canc Netw. 2008;6:109-118. Schilling NB, Parks C, Deeter RG. Costs and outcomes associated with hospitalized cancer patients with neutropenic complications: a retrospective study. Exp Ther Med. 2011;2:859-866. Lewis MA, Hendrickson AW, Moynihan TJ. Oncologic emergencies: pathophysiology, presentation, diagnosis, and treatment. CA Cancer J Clin. 2011;61: 287-314. Referenced with permission from The NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines®) for Myeloid Growth Factors V.1.2013. © National Comprehensive Cancer Network, Inc. 2013. All rights reserved. http://www.nccn.org/professionals/physician_gls/pdf/ myeloid_growth.pdf. Accessed April 12, 2013. To view the most recent and complete version of the guideline, go online to www.nccn.org. NATIONAL COMPREHENSIVE CANCER NETWORK®, NCCN®, NCCN GUIDELINES®, and all other NCCN Content are trademarks owned by the National Comprehensive Cancer Network, Inc. Nirenberg A, Bush AP, Davis A, et al. Neutropenia: state of the knowledge part I. Oncol Nurs Forum. 2006;33: 1193-1201. Kuderer NM, Dale DC, Crawford J, et al. Mortality, morbidity, and cost associated with with febrile neutropenia in adult cancer patients. Cancer. 2006; 106:2258-2266. Referenced with permission from The NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines®) for Prevention and Treatment of Cancer-Related Infections V.1.2012. © National Comprehensive Cancer Network, Inc 2013. All rights reserved. http://www.nccn.org/ professionals/physician_gls/pdf/infections.pdf. Accessed April 11, 2013. To view the most recent and complete version of the guideline, go online to www. nccn.org. NATIONAL COMPREHENSIVE CANCER NETWORK®, NCCN®, NCCN GUIDELINES®, and all other NCCN Content are trademarks owned by the National Comprehensive Cancer Network, Inc. Loibl S, Skacel T, Nekljudova V, et al. Evaluating the impact of relative total dose intensity (RTDI) on patients’ short and long-term outcome in taxane- and anthracycline-based chemotherapy of metastatic breast cancer—a pooled analysis. BMC Cancer. 2011;11:131. Michels SL, Barron RL, Reynolds MW, et al. Costs associated with febrile neutropenia in the US. Pharmacoeconomics. 2012;30:809-823. Weycker D, Barron R, Kartashov A, et al. Incidence, treatment and consequences of chemotherapy-induced febrile neutropenia in inpatient and outpatient settings. Presented at the 54th ASH Annual Meeting and Exposition, December 8-11, 2012, Atlanta, GA. Abstract 4232. Dulisse B, Li X, Gayle JA, Barron RL, Ernst FR, et al. A retrospective study of the clinical and economic burden during hospitalizations among cancer patients with febrile neutropenia. J Med Econ. 2013(epub ahead of print):1-26. 2013 ICD-9-CM Medical Diagnostic Codes Lookup and Search; 2013 medical coding data. http://www.icd9data. com. Accessed March 27, 2013. 68602-R1-V1

The Patient’s Voice

Can I Trust You? Continued from cover city, the closest reputable cancer hospital that my insurance covers. I asked if it was an emergency. He told me it was not. Due to work considerations, I decided to go in December and kept seeing him every month. By the time I got to the cancer center, my cancer had turned highly aggressive (studies say this happened in September, but I was never alerted). I am still in treatment with an uncertain prognosis. After 8 months living in another city to get care, supporting 2 households, uprooting some of my children and forcing others to pass almost an entire school year without their mother, modifying my employment conditions, and accruing tens of thousands of dollars in medical and living expense debt, I am back in my home city because I have to be: my employment and my younger children are here. When my story got out through the grapevine, I heard other tales of healthcare woe from numerous friends and acquaintances. For example, a friend in my city brought her toddler daughter in to her pediatrician suspecting she had diabetes and was told to give the child apple slices with honey on them, which sent the toddler into a comatose state, requiring a frantic transport to the hospital, where she was diagnosed with diabetes. An acquaintance’s mother had lost most kidney function and was given medicine by the specialist treating her for her kidney problem—this medicine further reduced her kidney function. My son’s friend’s mother was given medicine for her supposed bipolar disorder (apparently diagnosed based on the doctor’s “extensive experience” in detecting the disorder), fell asleep for 3 days without moving, was brought back to her doctor who conducted no tests and told the family not to worry, still did not wake up, was rushed to the hospital 24 hours later by her son, and died of an aggressive brain tumor 3 months after her wrong diagnosis. The stories kept piling up, and the outcomes kept being the same: those who stayed in my city got worse/died, and those with the resources (insurance coverage, time, and money) traveled hundreds of miles and accrued debts big and small, to get treated. Mind you, I live in a city, not in a rural area. So, now I am back here. I am shell-

shocked, nervous, and sick. I have prescriptions that are running out and need to be filled. I called my local pharmacy to transfer my prescriptions. The assistant told me he would call me in a few hours when he confirmed the transfer. He never called. I called back the next day to find out what had happened. Another person answered the phone this time. She told me my prescription was ready. I went to the drive-through window. I got my prescriptions through the metal drawer, placed in the drugstore’s marketing-laden bag, stapled shut. “Do you want to talk to the pharmacist?” the teller asked me. I saw no reason to do so. I had been taking these medicines for almost 8 months, now. What would I have to ask the pharmacist?

15 minutes waiting, someone answered. “Hold on for the pharmacist,” she said. I waited another 2 minutes. The pharmacist finally answered. Upset because of both the labeling issue and the long wait time, I had little patience left. “Are these the correct medicines or are they not?” I demanded. Kindly, he had me read the labels on the 2 bottles, one from my cancer center, one from the retail outlet that employed him. “Yes,” he told me. “They are the same medicines.” “Thank you,” I told him and hung up. This experience did little to encourage my trust in the pharmacies/pharmacists in my city. I know that for whatever reason, not all pharmacists want to go into research or become a doctor of

Trust between the patient and his/her medical team is crucial. Pharmacists, as part of that team, need to build trust. When I got home, I realized I should have asked some questions. The medicines I was used to had been substituted with, I imagine, ones that are generic. I did not recognize any of the names. I opened the bottles. The pills looked nothing like the ones I normally took; mine had both been white, and one of these was blue. The label did not have the same instructions as the original bottle. I started to panic. Had some sort of mistake been made? My interaction with the medical establishment in this city had conditioned me to not trust the work of the medical experts. I called the pharmacy. The recording told me to hold on as the pharmacy was “serving other customers.” My call, it said, was very important. I waited. Five minutes passed. Ten minutes passed. I got annoyed and hung up. The comment of a pharmacist at my cancer center rang through my head. “There are retail and research pharmacists,” he told me. “Obviously, research requires higher qualifications.” I called back. I heard the same recording. This time I vowed to wait. Eventually, after almost

pharmacology. For many, the PharmD degree and other legal requirements to be a pharmacist suffice. This is probably better for patients, too, who may not always need someone with a PhD. I know, too, that no medical research takes place in my city; everything is retail based. But, regardless, it would be really nice if pharmacists (research or retail) could acknowledge a few basic facts: 1. Patients, by the time they get to the pharmacist, have often been traumatized. Perhaps they have just found out they have cancer or another life-threatening illness. Perhaps, as in my case, they have had horrific experiences with the medical establishment in their region. Perhaps their lives have been changed and then changed again, over and over, as they look for the alternatives they can afford for care. Regardless, even though as a pharmacist at a retail outlet you may be under lots of pressure to make a larger profit by getting out as much medicine as possible to as many patients as possible, please make answering phone calls promptly a priority. If even in a retail

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August 2013 I VOL 6, NO 3

establishment part of your job requires serving patients, please do so by not making them wait for extended periods of time. Disgruntled customers can really eat away at profits! 2. Dealing with the familiar helps patients, most of whom have nowhere near your knowledge of their medicines. Within the legal requirements, when working with a transferred prescription, include as much similar information on one bottle as on the next. Since you have to call to confirm the prescription anyway, can you simply ask for what information is on the previous bottle’s label? For example, on my original prescription bottle, the instructions said “Take on Monday, Wednesday, and Friday.” The new label contains none of that information. However, because I kept both the new and the old bottle, I know it. 3. Train the frontline window people to explain a little bit about the medicines they are giving out. Much of my concern could have easily been averted had I been told that one medicine had been replaced by a generic one. I know it is legal to do this and supposedly causes no harm to the patient, yet I still would have liked to have been told that it had been done. Also, I would have liked to have known that one of my medicines could come in different colors. If I had simply been told at the drive-through window something like, “This medicine comes in different colors. I do not know what color your other pills were that you got from your previous pharmacy, but these are blue,” my doubts would have been allayed. I may have still called the pharmacy to double-check that all was as it should be, but I also certainly would have appreciated a little additional information right from the start. Trust between the patient and his/her medical team is crucial. Pharmacists, as part of that team, need to build trust. I do not even want to feel that the question “Can I trust you?” is one I need to ask. I want to have complete confidence in your abilities. Help me build it. l MMA is undergoing treatment for cancer. She wishes to use her initials.

October 4-6, 2013 The Seaport Boston Hotel 1 Seaport Lane Boston, MA 02210

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Prostate Cancer

Abiraterone in Untreated Metastatic Castration-Resistant Prostate Cancer Longer-Term Analysis of Pivotal Trial Confirms Safety and Efficacy By Alice Goodman

biraterone plus prednisone reduces the risk of disease progression and delays the time to opiate use and chemotherapy versus prednisone alone in men with metastatic castration-resistant prostate cancer (mCRPC) who had not received chemotherapy for metastatic disease, according to a long-term analysis of the COU-AA-302 trial presented at the 2013 American Society of Clinical Oncology (ASCO) Annual Meeting. Treatment with abiraterone plus prednisone was safe, and no new safety concerns emerged with longer follow-up. Abiraterone plus prednisone received expanded approval from the US Food and Drug Administration in December 2012 for men with chemotherapynaive mCRPC, based on updated interim results of COU-AA-302. “Building on an increased understanding of the continued relevance of the androgen signaling pathway in CRPC, abiraterone impairs androgen synthesis by selective inhibition of the CYP17 enzyme complex and is now approved for the treatment of mCRPC across the spectrum of disease states,” said lead author Dana Rathkopf, MD, of Memorial Sloan-Kettering Cancer Center in New York City. Rathkopf presented updated safety and efficacy results from COU-AA-302 at ASCO. The study evaluated 1082 men with asymptomatic or mildly symptomatic progressive mCRPC not treated with prior chemotherapy. They were randomized to receive abiraterone plus prednisone versus prednisone alone. The phase 3 multinational, randomized, double-blind, placebo-controlled study was conducted at 151 sites in 12 countries, enrolling patients from April 2009 to June 2010. Median duration of follow-up was 27.1 months. An interim analysis showed that abiraterone plus prednisone significantly improved radiographic progression-free survival (rPFS; P <.0001). A nonsignificant trend was seen for improved overall survival (OS) with abiraterone treatment. Results of the longer-term analysis were similar to those reported at the interim analysis. Abiraterone significantly improved rPFS versus prednisone alone, reducing the risk of disease progression by 48%: median of 16.5 months versus 8.2 months, respectively (P <.0001). OS was a median of 35.3 months in the abiraterone-treated group versus 30.1 months in the pred-

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nisone-alone group (not significant). Significant differences favoring abiraterone plus prednisone were observed for time to opiate use (P = .0002), time to chemotherapy initiation (P <.0001), time to deterioration in ECOG Performance Status (P = .0052), and time to prostate-specific antigen (PSA) progression (P <.0001).

The percentage of grades 3 and 4 adverse events was low, despite more than 2 years of exposure to abiraterone. The cumulative incidence of all grades of adverse events was similar across both treatment groups. Rates of infection were high in both treatment groups; the majority of grades 1 and 2 infections were of

the upper respiratory tract and upper urinary tract. l Reference

Rathkopf DE, Smith MR, De Bono JS, et al. Long-term safety and efficacy analysis of abiraterone acetate (AA) plus prednisone (P) in metastatic castration-resistant prostate cancer (mCRPC) without prior chemotherapy (COU-AA-302). J Clin Oncol. 2013;31(suppl):Abstract 5009. Presented at: 2013 American Society of Clinical Oncology Annual Meeting; May 31-June 4, 2013; Chicago, IL.

Enzalutamide Promising in Hormone-Naive Prostate Cancer

romising results were obtained with enzalutamide monotherapy in patients with hormone-naive prostate cancer. The drug prevented biochemical failure in more than 90% of patients enrolled in a phase 2 trial, and enzalutamide appears to have an improved adverse event profile compared with standard androgen deprivation therapy (ADT). A phase 3 trial will be needed to determine the role of enzalutamide vis-à-vis standard ADT. Enzalutamide, an oral androgen receptor antagonist, is approved by the US Food and Drug Administration for the treatment of metastatic castration-resistant prostate cancer that progresses on docetaxel. The phase 2 trial, reported at the 2013 American Society of Clinical Oncology Annual Meeting, sought to evaluate the role of this novel agent earlier in the course of disease. “Enzalutamide monotherapy achieved high PSA responses and PSA declines in men with hormonenaive prostate cancer. We believe the results of this trial compare favorably with ADT. By contrast with ADT, patients treated with enzalutamide had stable bone mineral density (BMD) and only modest changes in serum triglycerides. The effects seen in this phase 2 trial are consistent with those seen with potent ADT inhibition, and support the role of enzalutamide as monotherapy in prostate cancer,” stated Matthew R. Smith, MD, Dana-Farber Cancer Institute and Massachusetts General Hospital in Boston. ADT is considered the mainstay of treatment for recurrent or metastatic prostate cancer, but men find the side effects difficult to tolerate, including frequent hot flashes, fatigue, loss of libido and erectile function, gynecomastia, increased risk of BMD loss, decreased muscle mass, and decreased insulin sensitivity. Some of these side effects are risk factors for diabetes mellitus and cardiovascular disease. It would be desirable to have an effective therapy with fewer adverse events, Smith told listeners. The study included patients with hormone-naive prostate cancer for which ADT is indicated. At baseline, patients had testosterone levels ≥230 ng/mL, prostate-specific antigern (PSA) ≥2 ng/mL, and a life expectancy of at least 12 months. The men received enzalutamide monotherapy for 25 weeks; then an analysis of primary efficacy was performed. Patients deemed eligible could continue on therapy. The study included 67 men, with a median age of 73 years,

median body mass index (BMI) 26.2 kg/m2, median baseline PSA 18.2 ng/mL, and median duration of prostate cancer since diagnosis of 1 year; 51% had a Gleason score of 7, and 24% had a Gleason score ≥8 at entry. At study entry, 39% had metastasis, and more than one-third had prior prostatectomy. Enzalutamide monotherapy achieved marked and rapid PSA declines in 92.5% of patients; median PSA decrease was –99.6%; and 62/67 (92.5%) achieved the primary end point of PSA decline ≥80% at week 25, regardless of the presence of metastasis at baseline. Four of 5 patients deemed nonresponders were actually withdrawals prior to evaluating response. Among 16 patients evaluable for objective responses with measurable disease, complete response plus partial response was 50%. Although BMD declines of 3% to 4% are observed during the first year of ADT, no significant changes in BMD were found after 25 weeks of treatment with enzalutamide. In fact, slight increases in BMD were observed at the femoral neck and other sites. After 25 weeks of enzalutamide monotherapy, mean BMI decreased by 4.2%, and body fat increased by 6.9%. Moderate increases were seen in serum triglycerides (6.5%) and total cholesterol levels (4.6%), but Smith noted that these are smaller increases than occur with ADT. Discussant’s Comments The study was positive, with a high rate of PSA decline and an improved side effect profile for enzalutamide compared with ADT, said formal discussant Michael Carducci, MD, of the Johns Hopkins School of Medicine in Baltimore, Maryland. Enzalutamide is 1 of 6 new drugs approved for metastatic castration-resistant prostate cancer, and the use of each of these drugs will also be studied earlier in the course of disease, Carducci continued. He said that advances in survival will come from learning how to optimize sequencing of the new drugs as well as older therapies. The emphasis will be on how best to combine agents. Several studies are under way to examine this question. l —AG Reference

Smith MR, Borre M, Rathenborg P, et al. Efficacy and safety of enzalutamide (ENZA) monotherapy in hormone-naive prostate cancer (HNPC). J Clin Oncol. 2013;31(suppl):Abstract 5001. Presented at: 2013 American Society of Clinical Oncology Annual Meeting; May 31-June 4, 2013; Chicago, IL.

August 2013 I VOL 6, NO 3

Prostate Cancer

Prostate Cancer in the News By Alice Goodman

Radium-223 Improves Survival in Castration-Resistant Prostate Cancer Radium-223 (Xofigo), a radioactive isotope, improved survival in men with castration-resistant prostate cancer (CRPC) and symptomatic bone metastases, according to results of a randomized, phase 3, double-blind, placebo-controlled pivotal trial. The study was halted early, when an interim analysis showed a clear survival benefit for radium-223. Updated results of the trial were published in the New England Journal of Medicine. Radium-223 homes to the bone, where it emits alpha particles that cause DNA damage, sparing normal tissue. The drug

Radium-223 was approved by the US Food and Drug Administration earlier in 2013 based on this study. has a half-life of 11.4 days, which is much shorter than other alpha-emitting isotopes. Radium-223 was approved by the US Food and Drug Administration earlier in 2013 based on this study, which is the first to show a survival benefit for an alpha-emitting isotope in CRPC.

The trial enrolled 921 participants randomized 2:1 to receive radium-223 intravenously every 4 weeks for 6 cycles or placebo in combination with the best available standard care. Best available standard care included radiotherapy, antiandrogen therapy, estrogen, estramus-

Gleason Scoring May Provide Better Management and Prognosis The Gleason score (GS) assigned at a comprehensive guided prostate biopsy at a referring institution. Patients cancer center allowed better biochemical failure risk were treated with radiation therapy alone (no androgen stratification and prognostic information for patients deprivation therapy) between 1994 and 2007. Pathology treated with external-beam radiotherapy compared with slides of all patients diagnosed at a referring institution were the GS of the referring institution. A confirmatory reviewed at FCCC by an oncologic pathologist with special second pathologic review (SPR) at a dedicated compre- expertise in GU pathology. Follow-up comprised serial proshensive cancer center by a pathologist who specializes tate-specific antigen (PSA) determinations every 6 months in genitourinary (GU) malignancies led to a change in and annual digital rectal examinations. Biochemical failure overall GS grouping in 13% of patients. An SPR per- was determined by the American Society for Radiation formed at Fox Chase Cancer Center (FCCC) changed Oncology definition (PSA nadir plus 2 ng/mL). the National Comprehensive Cancer Network risk group Median follow-up was 64 months, and median folassignment in 144 men (9%): 92 low-up PSA interval was 6.2 men (64%) to lower risk and 52 months. Median age of patients Several studies, as well (36%) to higher risk. was 68 years. About 80% had “These changes all have the stage T1/2 prostate cancer and as anecdotal reports, potential to alter management and PSA <10 ng/mL. note discordance rates prognosis. The GS assigned based on Overall, the GS assigned by the SPR provided greater prognosFCCC upgraded 8% of patients of up to 40% between tication of biochemical failure risk. and downgraded 6% of patients the GS assigned by a Patients may benefit from national compared with the GS assigned by standards encouraging an SPR at a their referring institution. Among general pathologist and comprehensive cancer center,” wrote patients originally assigned to GS the GS subsequently the authors. Natasha C. Townsend, 6 by the referring institution, 8% MD, of FCCC, was lead author. At were upgraded to the intermediassigned by a GU present, nationwide standards do not ate category (ie, GS 7). A greater pathology specialist. call for an SPR at a comprehensive impact was observed in patients cancer center. originally assigned to GS 7 by This retrospective study, pubthe referring institution; 20% were lished in the July 2013 issue of the Journal of the National downgraded by FCCC to GS 6 and 2% upgraded to GS Comprehensive Cancer Network, is the largest regarding 8-9. The authors note that the greatest impact of an SPR by the impact of an SPR on the GS and the only report on FCCC was in the group of men originally assigned to GS 8-9: the impact of an SPR on the GS in patients treated with 58% were downgraded to GS 6 (12%) or GS 7 (88%). radiotherapy. The data show an improvement in overall prediction Several studies, as well as anecdotal reports, note dis- of biochemical failure with the GS assigned by FCCC cordance rates of up to 40% between the GS assigned by a compared with the GS assigned by the referring institugeneral pathologist and the GS subsequently assigned by tion. “Overall, these data support a routine SPR, prefa GU pathology specialist. Taken together, studies to date erably at a dedicated comprehensive cancer center with suggest that central review by a specialist in GU pathology a pathologist specializing in the diagnosis of prostate will provide a more accurate estimate of the GS than that cancer,” the authors wrote. assigned by general pathologists. The retrospective study included 1649 men diagnosed Reference Townsend NC, Ruth K, Al-Saleem T, et al. Gleason scoring at a comprehensive with prostate cancer based on a transrectal ultrasound– cancer center: what’s the difference? J Natl Compr Canc Netw. 2013;11(7):812-819.

August 2013 I VOL 6, NO 3

tine, and ketoconazole; men who were taking antiandrogen therapy at baseline continued it during the trial. Median age was 71 years; 94% were white; 87% were Eastern Cooperative Oncology Group (ECOG) performance status 0-1; 58% had previously received docetaxel; 54% were taking opioids for pain relief; 44% were taking nonopioids for pain relief. Overall survival (OS) was the primary end point. At the time of the interim analysis, when 314 deaths had occurred, median OS was significantly in favor of radium-223: 14 months versus 11.2 months, respectively (P = .002). An updated analysis in the New England Journal of Medicine, when 528 deaths were reported, confirmed that radium-223 achieved a significant OS benefit, with a median OS of 14.9 months for patients treated with radium-223 versus 11.3 months for the placebo group (P <.001). Patients treated with radium-223 were 30% less likely to die: 54% died versus 64% in the placebo group (P <.001). Median time to first symptomatic skeletal event—a key secondary end point—was significantly improved with radium-223: 15.6 months versus 9.8 months, respectively (P <.001). Adverse events, including grade 3 or 4 adverse events, serious adverse events, and drug discontinuations due to adverse events, were numerically lower in the group treated with radium-223. The most commonly reported adverse events (at least 5% frequency) with radium-223 included nausea, diarrhea, vomiting, and peripheral edema. The most common hematologic laboratory abnormalities were anemia, thrombocytopenia, and neutropenia. In an accompanying editorial in the New England Journal of Medicine, Neha Vapiwala, MD, and Eli Glatstein, MD, University of Pennsylvania, Philadelphia, wrote that the properties of radium-223, including its halflife and safety, make it an important new anticancer weapon. They noted that it is not clear what the ultimate role of radium-223 will be; perhaps it will be combined with other agents to further improve outcomes. Additional trials combining radium-223 with other drugs, including docetaxel, are being planned. Reference

Parker C, Nilsson S, Heinrich D, et al; ALSYMPCA Investigators. Alpha emitter radium-223 and survival in metastatic prostate cancer. N Engl J Med. 2013;369(3):213-223.

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Prostate Cancer Campaign Reduces Unnecessary Tests for Low-Risk Prostate Cancer The rate of unnecessary cancer imaging scans for low-risk prostate cancer was drastically reduced by a joint campaign in Sweden aimed at curtailing those tests. Such tests account for a significant proportion of healthcare funds in the United States. The campaign was initiated in 2000 by the Swedish County Councils and the National Prostate Cancer Register (NCPR) of Sweden to reduce inappropriate diagnostic imaging in men with this cancer. Men diagnosed with low-risk prostate cancer are unlikely to harbor metastases. Despite guidelines and quality measures from various policy organizations and professional societies that stipulate that extensive cancer scans for metastases are discouraged for these patients, many physicians continue to order these scans, said lead author Danil V. Makarov, MD, assistant professor at NYU Langone Medical Center, New York City.

The authors note that imaging is important to detect metastases in men with high-risk prostate cancer. However, most prostate cancer is diagnosed at an early stage, when it is unlikely to have spread.

records of almost 100,000 Swedish men diagnosed with prostate cancer from 1998 to 2009. Imaging rates at institutions in Sweden were published and compared with best practices, giving providers an incentive not to be cited

In the US, inappropriate prostate cancer imaging ranges from 22% to 62%, depending on the geographic region, according to a study published in 2012. The study was a collaboration between Makarov; his colleague at NYU, Stacy Loeb, MD; investigators at Memorial Sloan-Kettering Cancer Center; and Swedish investigators at Uppsala University Hospital and the Karolinska Institute. The authors examined the

for ordering unnecessary imaging tests for low-risk prostate cancer. These data were also presented at urology meetings in Sweden. During the study period, the percentage of inappropriate scans among patients with low-risk prostate cancer

dropped from 45% at the beginning of the campaign to 3% at the end. But the rate of appropriate scans for high-risk patients also dropped from 63% to 47% over the study period. Makarov said that it is important to emphasize the appropriate use of scans, along with the inappropriate use. He believes that the Swedish campaign demonstrates that targeted educational efforts can reduce the number of inappropriate tests. Such efforts could be implemented at urology conferences and in collaboration with the government, he suggested. In the US, inappropriate prostate cancer imaging ranges from 22% to 62%, depending on the geographic region, according to a study published in 2012. Reference

Makarov DV, Loeb S, Ulmert D, et al. Prostate cancer imaging trends after a nationwide effort to discourage inappropriate prostate cancer imaging. J Natl Cancer Inst. 2013 Jul 13. Epub ahead of print.

Medicare Report on Costly Radiation Therapy for Prostate Cancer Another study reveals the growing use of expensive treatment for prostate cancer. In July 2013, the Government Accountability Office (GAO) released a report, “Medicare: Higher Use of Costly Prostate Cancer Treatment by Providers Who Self-Refer Warrants Scrutiny,” requested by bipartisan leaders in Congress. The report focused on specialty urology groups’ use of intensity-modulated radiation therapy (IMRT) from 2006 to 2010. The report showed that IMRT utilization among self-referring groups increased by 456% over the study period. IMRT utilization among non–self-referring physicians decreased by 5%, in line with national recommendations calling for judicious use of IMRT for treating prostate cancer. The number of IMRT services performed by limited urology groups increased by 609%, while use by true multispecialty groups decreased 3.8%. Along with these trends, IMRT spending by self-referral groups increased by approximately $138 million, compared with a $91 million decrease in non– self-referral groups. These increases in IMRT utilization among self-referring practices were not attributable to patient preferences, age, geographic area, or patients’ health status. The report concludes that financial incentives were a major factor responsible for increased referrals for IMRT. Moreover, financial incentives were responsible for self-referral groups not ordering other appropriate but less expen-

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sive treatments, such as brachytherapy, prostatectomy, and active surveillance when appropriate. These factors result in higher costs to Medicare and beneficiaries, and the costs when driven by providers’ financial

interest are difficult to justify, states the GAO report. Congress is currently considering a law called “Promoting Integrity in Medicare Act of 2013” that addresses the findings of the GAO to improve patient care and

save billions of dollars in Medicare funds. Reference

US Government Accountability Office. Medicare: Higher Use of Costly Prostate Cancer Treatment by Providers Who Self-Refer Warrants Scrutiny. July 2013. http://www.gao. gov/products/GAO-13-525. Accessed August 5, 2013.

Hormone Therapy and Kidney Damage The risk of acute kidney injury was increased in men with achieved by ADT is known to increase the risk of heart nonmetastatic prostate cancer treated with androgen disease and diabetes. Reducing testosterone to castrate deprivation therapy (ADT), according to a retrospective levels may also affect blood vessels in the kidney and analysis reported online in the Journal of the American cause estrogen deficiency, leading to adverse effects on Medical Association. Current use of ADT more than renal tubular function. This association has not been doubled the odds of acute kidney injury compared with well studied previously, the authors noted. men who did not receive ADT. The renal effects of ADT were The highest rate of acute kidney analyzed in a nested case-control damage was reported with comstudy of men with nonmetastatic ADT will remain a bined use of gonadotropin-releasprostate cancer. The study was based mainstay of treatment ing hormone (GnRH) agonists and on a national hospital database that antiandrogens. Effects were also included 10,250 men followed up for for nonmetastatic seen with estrogen, other combinaa mean of 4.1 years. Of these men, prostate cancer, but tion therapies, and GnRH mono232 developed acute kidney injury at therapy. a rate of 5.5 per 1000 patient-years; these findings should ADT will remain a mainstay 40 men (17.2%) never received ADT. raise concern about of treatment for nonmetastatic Controls were 2721 patients who did prostate cancer, but these findnot develop acute kidney injury. potential effects on ings should raise concern about Overall, current ADT use increased the kidney. potential effects on the kidney. the likelihood of developing acute Hormonal therapy should be used kidney injury by 2.48 compared with judiciously to avoid potentialcontrols. The association was conly serious adverse events, noted author Samy Suissa, sistently elevated, with the highest odds during the first PhD, of Jewish General Hospital in Montreal, Quebec, year of treatment with ADT. Past treatment with ADT Canada, and coauthors. did not increase the risk of acute kidney injury. l ADT is widely used to treat men with prostate cancer, but can lead to serious adverse events. For example, met- Reference Lapi F, Azoulay L, Niazi MT, et al. Androgen deprivation therapy and risk of acute abolic disturbances induced by the hypogonadal state kidney injury in patients with prostate cancer. JAMA. 2013;310(3):289-296.

August 2013 I VOL 6, NO 3

CONTINUING EDUCATION 6th Annual

AUGUST 2013 • VOLUME 6 • NUMBER 3

CONSIDERATIONS in

Multiple Myeloma

™

ASK THE EXPERTS: Combination Versus Sequential Therapy PUBLISHING STAFF Group Director, Sales & Marketing John W. Hennessy john@greenhillhc.com Editorial Director Susan A. Berry susan@coexm.com Senior Copy Editor BJ Hansen Copy Editors Dana Delibovi Rosemary Hansen Grants/Project Associate Susan Yeager The Lynx Group President/CEO Brian Tyburski Chief Operating Officer Pam Rattanonont Ferris Vice President of Finance Andrea Kelly 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 sixth annual “Considerations in Multiple Myeloma” newsletter series, we continue to explore unresolved issues related to the management of the disease and new directions in treatment. To ensure an interprofessional perspective, our faculty is comprised of physicians, nurses, and pharmacists from leading cancer institutions, who provide their insight, knowledge, and clinical experience related to the topic at hand. In this third issue, experts from the Winship Cancer Institute of Emory University answer questions related to the use of combination and sequential therapies for 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

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FACULTY

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

Ajay K. Nooka, MD, MPH, FACP Assistant Professor of Hematology and Medical Oncology Winship Cancer Institute Emory University School of Medicine Atlanta, GA

Charise Gleason, MSN, ANP-BC, AOCNP Nurse Practitioner Winship Cancer Institute Emory University Atlanta, GA

Katherine Sanvidge Shah, PharmD, BCOP Hematology/Oncology Pharmacy Specialist Winship Cancer Institute Emory University Atlanta, GA

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

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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

August 2013 I VOL 6, NO 3

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CONSIDERATIONS IN MULTIPLE MYELOMA Sponsors This activity is jointly sponsored by Medical Learning Institute Inc and Center of Excellence Media, LLC. Commercial Support Acknowledgment This activity is supported by educational grants from Onyx Pharmaceuticals and Millennium: The Takeda Oncology Company. Target Audience The activity was developed for physicians, nurses, and pharmacists involved in the treatment of patients with multiple myeloma (MM). Purpose Statement The purpose of this activity is to enhance competence of physicians, nurses, and pharmacists concerning the treatment of MM. Physician Credit Designation The Medical Learning Institute Inc designates this enduring material for a maximum of 1.0 AMA PRA Category 1 Credits™. Physicians should claim only the credit commensurate with the extent of their participation in the activity. This activity has been planned and implemented in accordance with the Essential Areas and policies of the Accreditation Council for Continuing Medical Education through the joint sponsorship of the Medical Learning Institute Inc and the Center of Excellence Media, LLC. The Medical Learning Institute Inc is accredited by the Accreditation Council for Continuing Medical Education to provide continuing medical education for physicians. Registered Nurse Designation Medical Learning Institute Inc Provider approved by the California Board of Registered Nursing, Provider Number 15106, for 1.0 contact hour. Registered Pharmacy Designation The Medical Learning Institute Inc is accredited by the Accreditation Council for Pharmacy Education as a provider of continuing pharmacy education. Completion of this application-based activity provides for 1.0 contact hour (0.1 CEU) of continuing pharmacy education credit. The Universal Activity Number for this activity is 0468-9999-13-016-H01-P. Learning Objectives Upon completion of this activity, the participant will be able to: • Discuss existing and emerging therapeutic options for patients with newly diagnosed or relapsed/refractory MM and how to tailor therapy for individual patients

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

vestigational use for the following products/devices: MLN9708, ONX0912, vorinostat, panobinostat, and romidepsin. 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/P13008C. 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: August 16, 2013 Valid for CME/CPE/CE credit through: August 16, 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

Understanding Combination and Sequential Therapy in Multiple Myeloma Ajay K. Nooka, MD, MPH, FACP

Assistant Professor of Hematology and Medical Oncology Winship Cancer Institute Emory University School of Medicine, Atlanta, GA

Introduction Over the past decade, an increased knowledge of multiple myeloma (MM) and of the physiologic factors affecting its growth and proliferation have led to the development and approval of numerous targeted agents, including bortezomib, thalidomide, lenalidomide, carfilzomib, and pomalidomide. Given the expanding treatment armamentarium for the disease, physicians are often faced with the question of whether to offer patients combination or sequential therapy. In this article, Ajay K. Nooka, MD, MPH, FACP, discusses this issue in the context of the latest data from clinical trials, and provides insights on practices that contribute to optimal patient care.

What are the advantages and disadvantages of sequential versus combination therapy in MM? The term sequential therapy refers to treatment with drug regimens administered one after another in a chronological fashion rather than concomitantly,

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while the term combination therapy alludes to more than one drug treatment administered concurrently. The best example of combination therapy in the era of modern antimyeloma treatment originates from combining a proteasome inhibitor (PI) with an immunomodulatory drug (IMiD). The PI bortezomib combined with the IMiD lenalidomide exhibited synergy in preclinical models, and newly diagnosed patients in a phase 1/2 trial achieved high overall response rates (ORRs) of 100% with greater than one-third of patients achieving a complete response (CR)/near-complete response.1 These results are not limited to the induction setting. For example, consolidation with bortezomib/thalidomide/ dexamethasone (VTD) following autologous stem cell transplantation (ASCT) has induced molecular responses by upgrading the quantitative polymerase chain reaction (qPCR)-positivity to qPCR-negativity, suggesting that combination therapies may be able to deliver molecular responses, where conventional agents failed to achieve similar responses.2 Sequential therapy can be interpreted in more than one way. First, it can mean sequential administration of therapies, switching to a new regimen following disease progression. Second, it can mean a predefined sequence of therapies, each new regimen following the previous therapy without evidence of disease progression. The best example in recent myeloma literature is that of a phase 2 feasibility study in which sequential bortezomib and dexamethasone (VD) for 6 cycles, followed by thalidomide and dexamethasone (TD) maintenance therapy until progression following ASCT, demonstrated that a prolonged sequential weekly regimen is feasible and well tolerated, with post-ASCT CR upgraded by more than one-third during maintenance therapy, with no further increase in grade 3/4 peripheral neuropathy (PN).3

August 2013 I VOL 6, NO 3

CONTINUING EDUCATION The underlying concept of sequential therapy arises from the idea of preserving therapeutic options for later use in the disease course. Another potential advantage of sequential therapy is to limit the toxicities associated with combination therapies. This notion presumes that curing the disease is not the primary goal, and that progression-free survival (PFS) as well as overall survival (OS) are equivalent with both sequential and combination therapies. This argument is largely supported by data from historical ineffective combinations of chemotherapy when compared with a standard melphalan and prednisone (MP) regimen. Due to the low ORR for any of these historical regimens, it is not surprising that the use of sequential therapy was as ineffective as combination therapy. However, with the use of newer, more active agents such as IMiDs and PIs, as well as a better understanding of the biology of the disease, reconsideration of sequential therapy is warranted. Combination approaches with currently available highly effective regimens are more effective at inducing durable responses than sequential single agents. The rationale seems logical: myeloma cells follow Gompertzian rather than exponential kinetics, which forms the basis for ASCT, suggesting enhanced susceptibility to combination therapies with the goal of minimizing residual tumor burden and deepening the response. In addition, combination therapies have allowed for targeting induced-pathway dependence. The exposure of malignant cells to a single agent often results in preferential overactivation of a survival pathway that can be targeted by using the second agent as part of a combination strategy. Also, combination therapies can lead to synergistic mechanisms of tumor apoptosis, allowing for better overall response and depth of response when compared with single-agent therapy. This notion presumes that achieving depth of response with a safe and tolerable durable therapy actually results in survival improvement. The downside to this approach is the lack of long-term data confirming that combination therapies provide a survival advantage over singleagent therapy. However, with a better understanding of clonal dynamics and recent description of “clonal tides,” along with evidence of the existence of clonal heterogeneity at diagnosis, the argument is in favor of combination therapies over sequential therapies, especially when the intent is to eradicate both the dominant and minor clones that emerge at relapse.4 Which factors can affect the order of agents used in a sequential approach to therapy? In the current fast-paced era of antimyeloma therapies, with practices rapidly adapting to novel combination treatment strategies, it may not be feasible to conduct a study randomizing to sequential or combination therapies with a primary end point of OS, especially when data suggest that improved depth of response translates to PFS and OS advantage. A retrospective outcomes analysis evaluated whether the sequence of treating with lenalidomide-based therapy followed by bortezomib-based therapy versus bortezomib-based therapy followed by lenalidomide-based therapy improved outcomes. This study included 208 patients and reported that sequence of therapy was not predictive of OS, except in patients with renal failure, where bortezomib-based first-line therapy was recommended.5 In another study, the Myeloma Research Council XI randomized patients receiving cyclophosphamide/thalidomide/dexamethasone (CTD) or cyclophosphamide/lenalidomide/dexamethasone (CRD) who had not achieved at least a partial response to receive either no further therapy or a triplet combination of cyclophosphamide/bortezomib/dexamethasone (CVD). A mean paraprotein reduction of 74% from the start of CVD was observed, suggesting that a bortezomib-based combination therapy would have delivered these responses at the start.6 These results were confirmed in a meta-analysis of phase 3 trials of bortezomib-based induction therapies, suggesting that the addition of bortezomib to the induction regimen not only improved response rates but also resulted in prolonged PFS and OS.7 Similar data in transplant-ineligible patients were reported in the phase 3 VISTA trial.8 OS was prolonged with the combination of bortezomib/melphalan/prednisone (VMP) compared with patients who received first-line MP followed by salvage bortezomib, suggesting a survival advantage with combination therapies. OS from start of subsequent therapy was similar following the VMP and MP regimens, suggesting that combination therapies do not induce more resistant relapses.9 These observations add strength to the argument that combination therapies—especially those including bortezomib in the induction setting—improve response rates and further outcomes. As myeloma is mainly a disease of elderly patients, with a median age at diagnosis of 69 years,8 approximately 50% of patients are not transplant eligible at

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the time of diagnosis. Also, due to the prevalence of MM in the elderly, it is not uncommon to encounter patients who are frail, exhibit poor functional status, and have multiple comorbidities. These patients are more susceptible to treatment-related adverse events, may have lower tolerability for full drug doses, and may be on other medications that interact with their antimyeloma treatment. The question of whether these patients can tolerate combination therapies is always challenging. Taking age into consideration, beneficial results of the VISTA trial demonstrated a median survival advantage of 13 months with combination therapies.9 Taking frailty into consideration, a gentler approach of combination therapies with lower intensity dosage regimens improves the safety profile and thus optimizes treatment outcomes. A plan for further reduction in dosages is recommended with close monitoring.10 One of the most notable concepts to which the myeloma community has quickly adapted in recent years is the recognition of risk stratification, spanning from the most indolent to the most aggressive forms on the MM spectrum. The majority of myeloma-treating physicians accept genetically defined risk stratification and the fact that high-risk patients have poorer survival outcomes compared with other patients with MM. At the least, combination therapies, preferably including an IMiD and a PI, are agreed upon as best for induction in this high-risk patient group. Early genomic data support this approach of targeting all coexisting disease subclones with aggressive combination therapies and avoiding sequential single-agent therapy in high-risk patients.4 Moreover, data also suggest that by using sequential therapy early in the disease course, early suboptimal treatment of myeloma may sometimes preferentially eradicate the more indolent clone, thus leaving room for expansion of the aggressive clone.4 A similar rationale supports combination therapies in the maintenance setting in high-risk patients; early clinical data concur with these findings.11 What are the latest data regarding the safety and efficacy of combination regimens in MM? In newly diagnosed myeloma patients, triplet regimens have been proven to be highly effective in delivering high-quality durable responses with a satisfactory toxicity profile. The combinations of IMiDs and a PI demonstrated synergy as previously described and resulted in quality responses.1 With the use of next-generation PIs and IMiDs, much deeper response rates have been observed. Moving a step further, combinations of newer monoclonal antibodies and histone deacetylase inhibitors have the potential to augment the quality of responses and translate into improved PFS and OS. Figure 1 illustrates the upgraded responses achieved with doublets to triplets with various combinations of newer agents and signifies the importance of combination therapies.1,12-16 In contrast to the robust evidence supporting the advantages of treating newly diagnosed patients with combination therapies, using a similar approach when treating patients with relapsed/refractory MM has proven more challenging. Often these patients have already been treated with multiple agents and may have more comorbidities secondary to the disease itself or due to prior treatment-related effects. Salvage regimens used in this setting previously resulted in inadequate responses and shorter duration of response, as shown in Figure 2.17-28 However, the addition of liposomal doxorubicin to bortezomib prolonged median PFS to 9.3 months among bortezomib-naive patients versus 6.5 months for bortezomib alone, showing the value of a combination approach.23 More recently, a phase 3 trial in the relapsed setting comparing VTD with TD reported PFS of 19 months for the VTD arm, representing the longest PFS in a relapsed setting and highlighting the importance of combination therapy.28 Various methods have been utilized to address the issue of overlapping toxicity with combination therapy (eg, increased grade 3 PN): dose or schedule modification of the agents, route of administration of bortezomib, newer IMiDs to decrease PN, and newer PIs such as carfilzomib and oprozomib are potential options. However, the key principle of combination therapy yielding effective reduction of disease burden and improving PFS will guide us in defining future studies. The role of quadruplet therapies remains unclear at this time. In both transplant-eligible and -ineligible populations, regimens such as lenalidomide/bortezomib/cyclophosphamide/dexamethasone (RVCD), bortezomib/cyclophosphamide/ thalidomide/dexamethasone (VCTD), lenalidomide/bortezomib/doxorubicin/ dexamethasone (RVDD), and bortezomib/melphalan/prednisone/thalidomide (VMPT) have been evaluated, with outcomes similar to triplet therapies, albeit with higher toxicities. With appropriate dosage modifications to reduce the risk of toxicity, these regimens can be administered in some patients, if the objective is to

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CONSIDERATIONS IN MULTIPLE MYELOMA

Figure 2. Upgraded responses observed with doublets to triplets in combination therapy for patients with relapsed/ refractory myeloma.17-28

achieve greater depth of response, demonstrated as higher molecular remissions. Rather than using the historically ineffective alkylator-based therapy in these combination regimens, investigational biological agents hold promise. ♦ References

1. 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. 2. Cavo M, Pantani L, Petrucci MT, et al. Bortezomib-thalidomide-dexamethasone is superior to thalidomide-dexamethasone as consolidation therapy after autologous hematopoietic stem cell transplantation in patients with newly diagnosed multiple myeloma. Blood. 2012;120:9-19. 3. Sahebi F, Frankel PH, Farol L, et al. Sequential bortezomib, dexamethasone, and thalidomide maintenance therapy after single autologous peripheral stem cell transplantation in patients with multiple myeloma. Biol Blood Marrow Transplant. 2012;18:486-492. 4. Keats JJ, Chesi M, Egan JB, et al. Clonal competition with alternating dominance in multiple myeloma. Blood. 2012;120:1067-1076. 5. Patel AM, Ho VQ, Shain KH, et al. Sequence of therapy in multiple myeloma: does it matter?: retrospective evaluation of patients with multiple myeloma who have received bortezomib followed by lenalidomide or vice versa. Blood (ASH Annual Meeting Abstracts). 2011;118: Abstract 3979. 6. Pawlyn C, Davies FE, Gregory WM, et al. Sequential immunomodulatory drug (IMiD) and proteosome inhibitor therapy improves response rates in newly diagnosed multiple myeloma: preliminary results from the Myeloma XI trial. Blood (ASH Annual Meeting Abstracts). 2012;120:Abstract 335. 7. Nooka AK, Kaufman JL, Behera M, et al. The improved efficacy of bortezomib containing induction regimens (BCIR) versus non-bortezomib containing induction regimens (NBCIR) in transplant-eligible patients with multiple myeloma (MM): meta-analysis of phase III randomized controlled trials (RCTs). Blood (ASH Annual Meeting Abstracts). 2011;118:Abstract 3994. 8. San Miguel JF, Schlag R, Khuageva NK, et al; for the VISTA Trial Investigators. Bortezomib plus melphalan and prednisone for initial treatment of multiple myeloma. N Engl J Med. 2008;359:906-917. 9. San Miguel JF, Schlag R, Khuageva NK, et al. Continued overall survival benefit after 5 years’ follow-up with bortezomib-melphalan-prednisone (VMP) versus melphalan-prednisone (MP) in patients with previously untreated multiple myeloma, and no increased risk of second primary malignancies: final results of the phase 3 VISTA trial. Blood (ASH Annual Meeting Abstracts). 2011;118:Abstract 476. 10. 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. 11. Kaufman JL, Nooka AK, Muppidi S, et al. Survival outcomes of early autologous stem cell transplant (ASCT) followed by lenalidomide, bortezomib, and dexamethasone (RVD) maintenance in patients with high-risk multiple myeloma (MM). J Clin Oncol (ASCO Annual Meeting Proceedings). 2012;30(15 suppl):Abstract 8100. 12. 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. 13. Cavo M, Tacchetti P, Patriarca F, et al. Bortezomib with thalidomide plus dexamethasone compared with thalidomide plus dexamethasone as induction therapy before, and consolida-

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D VT

el ot

um ab

no VD

CR/nCR indicates complete response/near-complete response; C, cyclophosphamide; D, dexamethasone; PR, partial response; R, lenalidomide; T, thalidomide; V, bortezomib; VGPR, very good partial response.

PL D bi no st at

os rin

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D CR

D RV

D VT

≥VGPR ≥PR

V-

CR/nCR ≥VGPR ≥PR

100 90 80 70 60 50 40 30 20 10 0 T

100

Response Rates (%)

120

Figure 1. Upgraded responses observed with doublets to triplets in combination therapy for patients with newly diagnosed myeloma.1,12-16

C indicates cyclophosphamide; D, dexamethasone; PLD, pegylated liposomal doxorubicin; PR, partial response; R, lenalidomide; T, thalidomide; V, bortezomib; VGPR, very good partial response.

tion therapy after, double autologous stem-cell transplantation in newly diagnosed multiple myeloma: a randomised phase 3 study. Lancet. 2010;376:2075-2085. 14. Rajkumar SV, Jacobus S, Callander NS, et al; for the Eastern Cooperative Oncology Group. 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. 15. Jakubowiak AJ, Dytfeld D, Griffith KA, et al. A phase 1/2 study of carfilzomib in combination with lenalidomide and low-dose dexamethasone as a frontline treatment for multiple myeloma. Blood. 2012;120:1801-1809. 16. Kaufman JL, Shah JJ, Laubach JP, et al. Lenalidomide, bortezomib, and dexamethasone (RVD) in combination with vorinostat as front-line therapy for patients with multiple myeloma (MM): results of a phase 1 study. Blood (ASH Annual Meeting Abstracts). 2012;120:Abstract 336. 17. Singhal S, Mehta J, Desikan R, et al. Antitumor activity of thalidomide in refractory multiple myeloma. N Engl J Med. 1999;341:1565-1571. 18. Richardson PG, Schlossman RL, Weller E, et al. Immunomodulatory drug CC-5013 overcomes drug resistance and is well tolerated in patients with relapsed multiple myeloma. Blood. 2002;100:3063-3067. 19. Richardson PG, Sonneveld P, Schuster MW, et al; for the Assessment of Proteasome Inhibition for Extending Remissions (APEX) Investigators. Bortezomib or high-dose dexamethasone for relapsed multiple myeloma. N Engl J Med. 2005;352:2487-2498. 20. Dimopoulos MA, Zervas K, Kouvatseas G, et al. Thalidomide and dexamethasone combination for refractory multiple myeloma. Ann Oncol. 2001;12:991-995. 21. Weber DM, Chen C, Niesvizky R, et al. Lenalidomide plus dexamethasone for relapsed multiple myeloma in North America. N Engl J Med. 2007;357:2133-2142. 22. Jagannath S, Barlogie B, Berenson J, et al. A phase 2 study of two doses of bortezomib in relapsed or refractory myeloma. Br J Haematol. 2004;127:165-172. 23. Orlowski RZ, Nagler A, Sonneveld P, et al. Randomized phase III study of pegylated liposomal doxorubicin plus bortezomib compared with bortezomib alone in relapsed or refractory multiple myeloma: combination therapy improves time to progression. J Clin Oncol. 2007;25:3892-3901. 24. Richardson PG, Alsina M, Weber DM, et al. Phase II study of the pan-deacetylase inhibitor panobinostat in combination with bortezomib and dexamethasone in relapsed and bortezomib-refractory multiple myeloma (PANORAMA 2). Blood (ASH Annual Meeting Abstracts). 2011;118:Abstract 814. 25. Richardson PG, Jagannath S, Jakubowiak AJ, et al. Phase II trial of lenalidomide, bortezomib, and dexamethasone in patients (pts) with relapsed and relapsed/refractory multiple myeloma (MM): updated efficacy and safety data after >2 years of follow-up. Blood (ASH Annual Meeting Abstracts). 2010;116:Abstract 3049. 26. Davies FE, Wu P, Jenner M, Srikanth M, Saso R, Morgan GJ. The combination of cyclophosphamide, Velcade and dexamethasone (CVD) induces high response rates with comparable toxicity to Velcade alone (V) and Velcade plus dexamethasone (VD). Haematologica. 2007;92: 1149-1150. 27. Lonial S, Jakubowiak AJ, Jagannath S, et al. A phase 2 study of elotuzumab in combination with lenalidomide and low-dose dexamethasone in patients with relapsed/refractory multiple myeloma. Blood (ASH Annual Meeting Abstracts). 2011;118:Abstract 303. 28. Garderet L, Iacobelli S, Moreau P, et al. Superiority of the triple combination of bortezomib-thalidomide-dexamethasone over the dual combination of thalidomide-dexamethasone in patients with multiple myeloma progressing or relapsing after autologous transplantation: the MMVAR/IFM 2005-04 randomized phase III trial from the Chronic Leukemia Working Party of the European Group for Blood and Marrow Transplantation. J Clin Oncol. 2012;30: 2475-2482.

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CONTINUING EDUCATION

Nursing Considerations for Combination Therapy in Multiple Myeloma Charise Gleason, MSN, ANP-BC, AOCNP Nurse Practitioner Winship Cancer Institute Emory University, Atlanta, GA

Introduction Although there has been significant clinical benefit seen with newer regimens for multiple myeloma (MM), challenges remain, including the occurrence of adverse events (AEs). As a member of the cancer care team, it is the nurse’s responsibility to anticipate which toxicities and complications are likely to occur with treatment, to employ the necessary interventions, and to counsel patients accordingly. In this article, Charise Gleason, MSN, ANP-BC, AOCNP, discusses effective nursing strategies in the setting of combination antimyeloma therapy, and shares her perspectives on preventing and managing side effects related to the use of specific novel agents.

What are some of the effective supportive care strategies that can be used for controlling AEs associated with frontline combination regimens in transplant-eligible patients? Management of MM has changed dramatically with the introduction of newer therapies.1 There are currently several frontline regimens available for the treatment of transplant-eligible patients, as outlined in the latest guidelines from the National Comprehensive Cancer Network.2 Common induction regimens include bortezomib, thalidomide, and dexamethasone (VTD), lenalidomide, bortezomib, and dexamethasone (RVD), bortezomib plus dexamethasone (VD), and cyclophosphamide, bortezomib, and dexamethasone (CyBorD).2 Treatment for symptomatic myeloma is first stratified based on transplant eligibility. Clinical considerations when choosing an induction regimen include tumor burden, hypercalcemia, renal status, cytogenetic abnormalities, performance status, and preexisting comorbidities.2-4 During induction, patients may develop treatment-related toxicities such as peripheral neuropathy (PN), infection, gastrointestinal (GI) toxicities, and thrombosis (deep vein thrombosis/pulmonary embolism [DVT/PE]), all of which require careful monitoring and effective management strategies. Peripheral Neuropathy Neuropathy remains a major challenge in the treatment of patients with MM. The nursing implications related to this toxicity are far-reaching and encompass patient education, frequent monitoring of symptoms, and participation in multidisciplinary decisions to adjust drug dose or schedule, and in some cases, to interrupt or discontinue treatment. Obtaining an accurate assessment of PN at baseline is critical to patient follow-up. After baseline evaluation, close monitoring at each visit promotes early detection.5 Patient education is actually an important component of this process, since a well-informed patient knows what signs and symptoms to report to the cancer care team. Nurses must distinguish between neuropathy related to the myeloma disease process and neuropathy that is related to treatment.5 Myeloma-related PN is mainly sensory or sensorimotor; typical symptoms include paresthesias, hyperesthesias, numbness, and tingling that typically start distally and move proximally.5-8 Treatment-related PN, on the other hand, is typically symmetrical, distal, and progressive, and symptoms may vary depending on the agent being administered.5,9-15 For example, the 2 antimyeloma agents most commonly associated with PN—bortezomib and thalidomide—have different PN symptom profiles.

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Bortezomib-induced PN is predominantly sensory and mild, although up to 15% of patients report severe sensory and motor PN.5 Symptoms of bortezomib-induced PN include burning, hyperesthesia, hypoesthesia, paresthesia, discomfort, numbness, pain, and weakness.5,12,13 In contrast, thalidomide-induced PN may be permanent, and symptoms may even occur after the cessation of therapy.5,9,10 PN associated with thalidomide tends to be sensory/sensorimotor neuropathy, with tingling or painful distal paresthesia affecting the feet or hands, with a loss of sensation in the lower limbs.5 Muscle weakness or tremor may also occur.5 Both bortezomib and thalidomide have been associated with lower-extremity weakness, although this symptom is more commonly seen with thalidomide use.14,15 Bortezomib has traditionally been administered by the intravenous (IV) route, but recent data suggest that the subcutaneous (SC) route may help to minimize PN in bortezomib-treated patients.15,16 SC administration of bortezomib is comparable to IV administration in systemic availability and response rates.15,16 A randomized trial by Moreau and colleagues reported a reduction in bortezomib-induced PN with the SC route, from 53% to 38% for all grades of PN, and from 16% to 6% in grade 3 /4 PN. At our center, we are now using SC bortezomib in our induction regimens and have found a significant decrease in patient chair time. Pharmacologic treatment of PN includes the use of pregabalin, gabapentin, tricyclic antidepressants, opioids, duloxetine, and topical interventions such as local lidocaine patches, cocoa butter, or menthol ointment.17,18 Duloxetine is the first drug to be evaluated in a randomized trial to treat painful chemotherapy-induced PN. In this trial (N=231),19 Smith and colleagues observed that 5 weeks of duloxetine treatment decreased pain severity compared with placebo among patients with grade ≥1 sensory neuropathy. When documenting PN, nurses can grade severity via National Cancer Institute (NCI) toxicity criteria for neuropathy.20 These criteria are listed for peripheral motor and peripheral sensory neuropathy and are available at http://ctep. cancer.gov. Grading ranges from grade 1 (asymptomatic neuropathy with clinical observation of some deficits) to severe, symptomatic neuropathies of grade ≥3. Infection Patients with MM are at an increased risk for infection, which is the leading cause of death in this patient population.21 Any treatment that produces myelosuppression—including lenalidomide, cyclophosphomide, dexamethasone, and bortezomib—can further increase the risk of opportunistic infections. Patients need to be educated on the importance of infection control practices such as good general hygiene, hand washing, oral care, and central line maintenance. Prompt reporting of symptoms and appropriate treatment are essential to avoid severe infections and treatment interruption. Herpes zoster reactivation has been reported with bortezomib-containing regimens.22,23 Therefore, prophylaxis with an antiviral agent (eg, acyclovir) is important in regimens containing bortezomib and is effective in reducing the risk for zoster reactivation. The herpes zoster vaccination is not recommended, although patients should receive the pneumococcal and influenza vaccines.24 The use of IV immunoglobulin may help with recurrent infections, although no randomized trials support this practice. Gastrointestinal Toxicities GI toxicities such as nausea and vomiting, diarrhea, and constipation can occur with numerous antimyeloma therapies, including lenalidomide, thalidomide, and bortezomib.25 In the transplant-eligible patient who receives melphalan for conditioning in autologous stem cell transplantation, these AEs can be very severe and may lead to life-threatening GI mucositis.26 Toxicities such as these have a marked impact on quality of life and may lead to poor adherence to therapy, loss of appetite, decreased function, anxiety, and social isolation.25 The International Myeloma Foundation Nurse Leadership Board recommends routine assessment and active intervention to manage the GI effects of

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CONSIDERATIONS IN MULTIPLE MYELOMA

lenalidomide, thalidomide, and bortezomib.25 Recommended assessment methodology applies NCI grading criteria to findings from history-taking, symptom self-report, examination, and laboratory testing for electrolytes and other chemistries.25 Assessment should always include an evaluation of patient-related factors that may predispose individuals to GI effects, as these may lead to exacerbation of symptoms during antimyeloma therapy. These include age (eg, >65 years for constipation and diarrhea, but <50 years for nausea) and improper diet (eg, low fiber intake for constipation), as well as additional medications, comorbidities, and surgical/medical procedures (eg, radiation therapy for emesis).25 At the outset of therapy, it is important for nurses to educate patients and caregivers on the risk for GI toxicities and on the importance of good hydration, a diet with sufficient fiber, and the basics of proper nutrition. When a GI event occurs, education on appropriate interventions such as the use of antiemetics, laxatives, or antidiarrheals should be provided, and reinforced as needed. Patients may need robust support from nurses to help them cope with the physical and psychosocial effects of these AEs and to adhere to bowel regimens and other protocols. Venous Thromboembolic Events Thrombosis is a complication observed with certain malignancies and their treatment, and it is especially common in myeloma, which may be associated with a “background” incidence of venous thromboembolic events of 5% to 10%.27,28 The immunomodulatory drugs (IMiDs) thalidomide and lenalidomide further elevate the risk of thrombosis.27-29 A review of select studies that were conducted without mandated antithrombotic prophylaxis suggests that the risk of thrombosis with thalidomide plus dexamethasone ranges from 12% to 15%— about 4 to 5 times higher than with single-agent dexamethasone.27 Similar results have been seen with lenalidomide and dexamethasone.27 Individual risk factors, quite apart from MM or antimyeloma therapy, may add substantially to patients’ risk. These additional factors include older age, previous DVT/PE, immobilization, trauma, central venous catheter, surgery, and some medications (eg, erythropoietin).28-30 Moreover, certain drugs in combination with an IMiD elevate risk; notable among these are high-dose dexamethasone and doxorubicin.30 Antithrombotic prophylaxis is generally recommended for patients receiving therapy that includes an IMiD. The current recommendation for patients with low (0-1) additional risk factors is aspirin 81 mg to 325 mg once daily; when a patient has high (≥2) additional risk factors, recommended prophylaxis is either low-molecular-weight heparin (enoxaparin 40 mg/day or its equivalent) or warfarin to an international normalized ratio of 2 to 3.30 What are some common toxicities associated with newer agents being used in the relapsed/refractory setting? At our center, we treat patients experiencing relapsed/refractory disease with several novel agents, including carfilzomib and pomalidomide. It is imperative that nurses become familiar with the toxicity profiles of these and other therapies being utilized in this setting for MM. Carfilzomib is a next-generation IV proteasome inhibitor,31 approved by the US Food and Drug Administration (FDA) for relapsed and/or refractory MM. In pivotal clinical trials, the most common AEs of all grades reported with this agent include fatigue (55.5%), anemia (46.8%), nausea (44.9%), thrombocytopenia (36.3%), dyspnea (34.6%), diarrhea (32.7%), and pyrexia (30.4%).32 Carfilzomib is associated with a lower incidence of severe PN than thalidomide or the other available proteasome inhibitor, bortezomib; incidence of grade 3 PN was 1% in clinical trials.32 Nurses who administer carfilzomib must be alert to rare but potentially serious infusion reactions and tumor lysis syndrome.32 To ward off these problems, slower infusion (eg, over ≥10 minutes), prehydration, and optional posthydration fluids, and pretreatment steroid prophylaxis are recommended approaches. Pomalidomide is a next-generation oral immunomodulatory agent that has been approved by the FDA for the treatment of relapsed and refractory MM. Pomalidomide in combination with low-dose dexamethasone has demonstrated clinical activity in patients following relapse after multiple lines of therapy, including patients who are refractory to lenalidomide and bortezomib.33-36 Common AEs reported in pivotal trials with single-agent pomalidomide include fatigue/asthenia (55%), neutropenia (52%), anemia (38%), constipation

(36%), nausea (36%), diarrhea (34%), dyspnea (34%), upper respiratory tract infection (32%), and back pain (32%).37 The risk for PN is lower with this agent than with thalidomide; the incidence of neuropathy was 10% in pivotal trials with single-agent pomalidomide. Data from a recent phase 1/2 trial showed comparable AEs with pomalidomide alone (POM) or in combination with low-dose dexamethasone (POM+LoDex).36 Discontinuations due to AEs were 7% and 12% for the 2 treatment groups, respectively. Incidence rates of PN, DVT, and renal failure reported with POM compared with POM+LoDex, respectively, were as follows: 7% vs 10%, 2% vs 1%, and 2% vs 1%. Pomalidomide should be taken without food and given at least 2 hours before/ after meals.37 Nurses should educate patients and caregivers on antithrombotic prophylaxis, infection risk, fatigue, and the importance of adhering to a consistent schedule. ♦ 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. National Comprehensive Cancer Network (NCCN). NCCN Clinical Practice Guidelines in Oncology™: Multiple Myeloma. V2.2013. http://www.nccn.org. Accessed June 2, 2013. 3. Stadtmauer EA. Tailoring initial treatment for newly diagnosed, transplantation-eligible multiple myeloma. Oncology. 2010;24(suppl 2):7-13. 4. Niesvizky R, Coleman M, Mark T. Best practices in the management of newly diagnosed multiple myeloma patients who will not undergo transplant. Oncology. 2010;24(suppl 2):14-21. 5. Richardson PG, Delforge M, Beksac M, et al. Management of treatment-emergent peripheral neuropathy in multiple myeloma. Leukemia. 2012;26:595-608. 6. Kyle RA. Monoclonal proteins in neuropathy. Neurol Clin. 1992;10:713-734. 7. Ropper AH, Gorson KC. Neuropathies associated with paraproteinemia. N Engl J Med. 1998;338:1601-1607. 8. Palumbo A, Facon T, Sonneveld P, et al. Thalidomide for treatment of multiple myeloma: 10 years later. Blood. 2008;111:3968-3977. 9. Mothy B, El-Cheikh J, Yakoub-Agha I, et al. Peripheral neuropathy and new treatments for multiple myeloma: background and practical recommendations. Haematologica. 2010;95: 311-319. 10. Thalomid [package insert]. Summit, NJ: Celgene Corporation; February 2013. 11. San Miguel JF, Richardson PG, Orlowski RZ, et al. Risk of second primary malignancies (SPMs) following bortezomib (Btz)-based therapy: analysis of four phase 3 randomized controlled trials in previously untreated or relapsed multiple myeloma (MM). Blood (ASH Annual Meeting Abstracts). 2011;118:Abstract 2933. 12. Richardson PG, Briemberg H, Jagannath S, et al. Frequency, characteristics, and reversibility of peripheral neuropathy during treatment of advanced multiple myeloma with bortezomib. J Clin Oncol. 2006;24:3113-3120. 13. Richardson PG, Sonneveld P, Schuster MW, et al. Bortezomib or high-dose dexamethasone for relapsed multiple myeloma. N Engl J Med. 2005;352:2487-2498. 14. Sonneveld P, Jongen JLM. Dealing with neuropathy in plasma-cell dyscrasias. Hematology (ASH Education Program Book). 2010:423-430. 15. Berkowitz A, Walker S. Bortezomib-induced peripheral neuropathy in patients with multiple myeloma. Clin J Oncol Nurs. 2012;16:86-89. 16. Moreau P, Pylypenko H, Grosicki S, et al. Subcutaneous versus intravenous administration of bortezomib in patients with relapsed multiple myeloma: a randomised, phase 3, non-inferiority study. Lancet Oncol. 2011;12:431-440. 17. Tariman J, Love G, McCullagh E, et al. Peripheral neuropathy associated with novel therapies in patients with multiple myeloma: consensus statement of the IMF Nurse Leadership Board. Clin J Oncol Nurs. 2008;12(suppl):29-35. 18. Delforge M, Bladé J, Dimopoulos MA, et al. Treatment-related peripheral neuropathy in multiple myeloma: the challenge continues. Lancet Oncol. 2010;11:1086-1095. 19. Smith EM, Pang H, Cirrincione C, et al. Effect of duloxetine on pain, function, and quality of life among patients with chemotherapy-induced painful peripheral neuropathy: a randomized clinical trial. JAMA. 2013;309:1359-1367. 20. National Cancer Institute Cancer Therapy Evaluation Program. Common Terminology Criteria for Adverse Events (CTCAE), v4.03. http://ctep.cancer.gov/protocolDevelopment/electronic_ applications/ctc.htm. Accessed August 7, 2013. 21. Ludwig H, Zojer N. Supportive care in multiple myeloma. Best Pract Res Clin Haematol. 2007; 20:817-835. 22. Kim SJ, Kim K, Kim BS, et al. Bortezomib and the increased incidence of herpes zoster in patients with multiple myeloma. Clin Lymphoma Myeloma. 2008;8:237-240. 23. Chanan-Khan A, Sonneveld P, Schuster MW, et al. Analysis of herpes zoster events among bortezomib-treated patients in the phase III APEX study. J Clin Oncol. 2008;26:4784-4790. 24. Wood SK, Payne JK. Cancer-related infections. J Adv Pract Oncol. 2011;2:356-371. 25. Smith LB, Bertolotti P, Curran K, et al. Gastrointestinal side effects associated with novel therapies in patients with multiple myeloma: consensus statement of the IMF Nurse Leadership Board. Clin J Oncol Nurs. 2008;12:37-51. 26. Sharma SK, Handoo A, Choudhary D, Dhamija G, Gupta N. Severe gastrointestinal mucositis following high dose melphalan therapy for multiple myeloma. World J Gastroenterol. 2013;19:784-785. 27. Zonder JA. Thrombotic complications of myeloma therapy. Hematology (ASH Education Program Book). 2006:348-355.

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August 2013 I VOL 6, NO 3

CONTINUING EDUCATION

Pharmacologic Considerations in the Era of Novel Therapies for Multiple Myeloma Katherine Sanvidge Shah, PharmD, BCOP Hematology/Oncology Pharmacy Specialist Winship Cancer Institute Emory University, Atlanta, GA

Introduction The development of more effective drugs has led to better response rates and prolonged survival in multiple myeloma (MM). When choosing among these therapies, it is essential to consider factors such as pharmacologic profiles and drug–drug interactions to ensure optimal patient outcomes. In this article, Katherine Sanvidge Shah, PharmD, BCOP, discusses new directions in antimyeloma treatment and provides insight into the mechanism of action of both approved and investigational agents being used in combination and sequential therapies.

What are some of the drug–drug and drug–dietary interactions that may occur with commonly used agents for MM? When patients are treated with the proteasome inhibitor (PI), bortezomib, it is important to counsel them on possible dietary modifications they may need to make. In vitro and in vivo data suggest that several components of green tea and green tea extract can antagonize the antimyeloma effectiveness of this agent.1 In MM cell lines, epigallocatechin gallate and several other polyphenols have interfered with the proteasome-inhibiting actions of bortezomib and prevented tumor cell death.2 Patients should be instructed to avoid consuming green tea and its extract while receiving concomitant bortezomib. Ascorbic acid or vitamin C is another supplement of concern.3 Studies have shown that vitamin C can inhibit the activity of bortezomib through direct binding between the hydroxyl group of the antioxidant agent and the boronic acid of the PI. This binding decreases the affinity of the PI for the chymotrypsin-like subunit of the proteasome, thus decreasing the anticancer effect.4 This was confirmed in a study by Perrone and colleagues, which showed that a dose-dependent effect of ascorbic acid decreased the effectiveness of bortezomib.5 It is recommended that patients do not exceed 500 mg of ascorbic acid a day and that they separate administration by at least 12 hours before or after bortezomib administration, given the fact that the half-life of oral ascorbic acid is 10 hours.5 In general, it is probably best to instruct patients to avoid extra vitamin C supplementation and vitamin C–containing multivitamins during bortezomib therapy. St. John’s wort (hypericum perforatum) should also be avoided, since it has the potential to induce the cytochrome P450 34A enzyme system and therefore decrease bortezomib plasma concentrations.6 A drug–drug interaction that is unavoidable due to the therapeutic efficacy of the regimen is the one that occurs when the immunomodulatory drug (IMiD) lenalidomide is combined with dexamethasone. The concern with this regimen is the significantly increased risk of thromboembolism. In 2 studies of patients with relapsed or refractory MM, the incidence of grade 3/4 venous thromboembolic events (VTEs) was significantly higher when these agents were used together than when dexamethasone was administered alone (11.4%-14.7% vs 3.4%4.6%, respectively).7,8 Currently, it appears the best options for VTE prophylaxis with this combination are low-molecular-weight heparin or warfarin (with a targeted international normalized ratio of 2-3), especially in cases in which highdose dexamethasone is prescribed.9 Aspirin is another option for VTE prophylaxis, particularly when low-dose dexamethasone is utilized.10 Of course, it is also essential to educate patients on the signs and symptoms of VTE, such as erythematous, warm, swollen, or painful extremities for deep vein thrombosis, and shortness of breath, pain upon inspiration, and cough for pulmonary embolism.10

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Can you discuss how next-generation agents may help to improve outcomes in MM? Several new agents are allowing for extended, durable responses and disease control, which are allowing patients with MM to live longer. PIs have been proven to be one of the major milestones in the MM treatment landscape, leading to improved outcomes in the frontline as well as relapsed/refractory settings. Carfilzomib, a next-generation PI, differs from bortezomib in that it exhibits irreversible and sustained inhibition on the proteasome, is more potent, and is more selective in its action, which may translate to fewer side effects such as neuropathy.11 On July 20, 2012, the US Food and Drug Administration granted accelerated approval to carfilzomib for the treatment of patients with MM who have received at least 2 prior therapies, including bortezomib and an IMiD, and have demonstrated disease progression on or within 60 days of the completion of the last therapy. Approval was based on results of the open-label, single-arm phase 2b study, PX-171-003-A1. The overall response rate (ORR) was 22.9%, with a duration of response of 7.8 months.11 Although carfilzomib is currently approved at a standard dose of 27 mg/m2 infused over 2 to 10 minutes, it is being investigated at higher doses with a prolonged infusion time of 30 minutes to prevent infusion-related reactions. Due to the projected shortage of oncologists/nurses and the potential for decreased availability of infusion sites, increased efforts into the safety and efficacy of oral chemotherapeutic options is essential. Fortunately, there are several orally bioavailable PIs currently under investigation. MLN9708 (ixazomib), an orally available, second-generation PI, is a dipeptidyl boronic acid that is rapidly hydrolyzed in water and converts into MLN2238, the active form which potently, reversibly, and selectively inhibits the proteasome, primarily binding to the β5 subunit of the 20S proteasome. MLN9708 exhibits a shorter proteasome dissociation half-life (18 minutes vs 110 minutes), a larger volume of distribution, and increased pharmacodynamic effects in tissues compared with bortezomib.12 This agent is the first oral PI to enter clinical trials, and it is currently being evaluated in both once-weekly and biweekly schedules in the relapsed/refractory setting.13-15 In addition, the upcoming phase 3, randomized, double-blind, multicenter, TOURMALINEMM2 trial will compare MLN9708 plus lenalidomide and dexamethasone with placebo plus lenalidomide and dexamethasone in nontransplant patients with newly diagnosed MM. Another orally available PI currently under investigation is ONX-0912 (oprozomib), a structural analog of carfilzomib that is currently being investigated in phase 1 and 2 trials (See Table).16 Pomalidomide is a novel, third-generation IMiD, with immunomodulatory, antiangiogenic, and direct antimyeloma activity. Created by chemical modifications to the structural backbone of thalidomide, pomalidomide exhibits more potent anti-inflammatory activity and appears to demonstrate a more favorable toxicity profile.17 This has translated into clinical efficacy even in heavily pretreated patients. For example, Jagannath and colleagues recently reported on results of a multicenter, randomized, open-label phase 2 study (MM-002) evaluating the safety and efficacy of pomalidomide (POM) alone or in combination with low-dose dexamethasone (POM+LoDEX) in 221 patients with relapsed and refractory MM who have received multiple prior therapies, including lenalidomide and bortezomib.18 ORRs were 34% in the POM+LoDEX group and 15% in the POM alone group. The median duration of response (for patients who achieved ≥PR) was 45 months in the POM+LoDEX group and 31 months in the POM group. Results of a subanalysis based on age (≥65 years vs <65 years) showed that age had no impact on the duration or depth of response. The median progression-free survival for the overall population was 4.6 months for those who received POM+LoDEX and 2.6 months for those who received POM.

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CONSIDERATIONS IN MULTIPLE MYELOMA

Table. Next-generation Oral Proteasome Inhibitors for MM16

or improvement to PR. Grade 3/4 AEs included thrombocytopenia (64%) and peripheral neuropathy (8%).23 ♦

Proteasome Inhibitor

References

Type

Pattern of Inhibition

Clinical Trial Investigation

MLN9708 (ixazomib)

Boronic acid

Reversible

Phase 1, 2, and 3

Fatigue, thrombocytopenia, N/V, diarrhea

ONX-0912 (oprozomib)

Epoxyketone

Irreversible

Phase 1 and 2

N/V, diarrhea, abdominal pain, fatigue, decreased appetite

Adverse Events

MM indicates multiple myeloma; N/V, nausea/vomiting.

What investigational histone deacetylase inhibitors are showing promise in MM? Histone deacetylase (HDAC) inhibitors promote the acetylation of histone proteins, thereby decondensing chromatin to its active form and reversing epigenetic silencing of transcription factors and tumor suppressor genes which regulate cell growth. HDAC inhibitors have been shown to inhibit proliferation and induce apoptosis in MM cell lines. Although HDAC inhibitors have failed to improve outcomes when used as single agents, they appear to be synergistic both in vitro and in vivo when combined with other anti-MM agents, particularly PIs. The molecular basis underlying this synergism appears to be multifactorial and involves interference with protein degradation as well as the interaction of myeloma cells with microenvironment.19 Vorinostat has been evaluated in the Vorinostat Clinical Trials in Hematologic and Solid Malignancies (VANTAGE) study program. The phase 2 VANTAGE 095 trial evaluated this agent in combination with bortezomib in bortezomib-refractory patients with MM (>2 prior therapies, N=143).20 Results suggest that the combination of vorinostat and bortezomib is active in patients whose disease is considered refractory to prior bortezomib and IMiDs, with an ORR of 17% reported in this trial. The median overall survival (OS) was 11.2 months with a 2-year OS rate of 32%. This combination therapy was generally well tolerated, with thrombocytopenia and gastrointestinal toxicities being the most common adverse events (AEs) reported. The safety and efficacy of panobinostat in combination with carfilzomib is being evaluated in a phase 1/1b trial in patients with relapsed/refractory MM.21 The primary grade ≥3 toxicities were hematologic (thrombocytopenia, anemia, and neutropenia) and were manageable. Clinical benefit rate was determined to be 38%. Additionally, the triplet combination of panobinostat, bortezomib, and dexamethasone is currently being evaluated in a phase 3, randomized, placebo-controlled trial (PANORAMA-1).22 Romidepsin has also been investigated as triple therapy with bortezomib and dexamethasone in a phase 1/2 trial of patients with relapsed or refractory MM (patients having received ≥1 previous therapy). Encouraging activity was observed, with 72% of patients experiencing a minor response or better, and 4 of 6 patients (67%) who were refractory to bortezomib achieving disease stability

1. Liu FT, Agrawal SG, Movasaghi Z, et al. Dietary flavonoids inhibit the anticancer effects of the proteasome inhibitor bortezomib. Blood. 2008;112:3835-3846. 2. Golden EB, Lam PY, Kardosh A, et al. Green tea polyphenols block the anticancer effects of bortezomib and other boronic acid-based proteasome inhibitors. Blood. 2009;113:5927-5937. 3. Catley L, Anderson KC. Velcade and vitamin C: too much of a good thing? Clin Cancer Res. 2006;12:3-4. 4. Llobet D, Eritja N, Encinas M, et al. Antioxidants block proteasome inhibitor function in endometrial carcinoma cells. Anticancer Drugs. 2008;19:115-124. 5. Perrone G, Hideshima T, Ikeda H, et al. Ascorbic acid inhibits antitumor activity of bortezomib in vivo. Leukemia. 2009;23:1679-1686. 6. Velcade (bortezomib) for Injection. Detailed View: Safety Labeling Changes Approved by FDA Center for Drug Evaluation and Research (CDER). www.fda.gov/Safety/MedWatch/ SafetyInformation/SafetyRelatedDrugLabelingChanges/ucm123444.htm. Accessed August 6, 2013. 7. Dimopoulos M, Spencer A, Attal M, et al. Lenalidomide plus dexamethasone for relapsed or refractory multiple myeloma. N Engl J Med. 2007;357:2123-2132. 8. Weber DM, Chen C, Niesvizky R, et al. Lenalidomide plus dexamethasone for relapsed multiple myeloma in North America. N Engl J Med. 2007;357:2133-2142. 9. Palumbo A, Rajkumar SV, Dimopoulos MA, et al. Prevention of thalidomide- and lenalidomide-associated thrombosis in myeloma. Leukemia. 2008;22:414-423. 10. Hirsh J. Risk of thrombosis with lenalidomide and its prevention with aspirin. Chest. 2007;131:275-277. 11. diCapua Siegel DS, Martin T, Wang M, et al. Results of PX-171-003-A1, an open-label, single-arm, phase 2 (Ph 2) study of carfilzomib (CFZ) in patients (pts) with relapsed and refractory multiple myeloma (MM). Blood (ASH Annual Meeting Abstracts). 2010;116:Abstract 985. 12. Kupperman E, Lee EC, Cao Y, et al. Evaluation of the proteasome inhibitor MLN9708 in preclinical models of human cancer. Cancer Res. 2010;70:1970-1980. 13. Kumar S, Bensinger WI, Reeder CB, et al. Weekly dosing of the investigational oral proteasome inhibitor MLN9708 in patients with relapsed and/or refractory multiple myeloma: results from a phase 1 dose-escalation study. Blood (ASH Annual Meeting Abstracts). 2011;118:Abstract 816. 14. Richardson PG, Baz R, Wang L, et al. Investigational agent MLN9708, an oral proteasome inhibitor, in patients (Pts) with relapsed and/or refractory multiple myeloma (MM): results from the expansion cohorts of a phase 1 dose-escalation study. Blood (ASH Annual Meeting Abstracts). 2011;118:Abstract 301. 15. Lonial S, Baz RC, Wang M, et al. Phase I study of twice-weekly dosing of the investigational oral proteasome inhibitor MLN9708 in patients (pts) with relapsed and/or refractory multiple myeloma (MM). J Clin Oncol. 2012;30:Abstract 8017. 16. Lawasut P, Chauhan D, Laubach J, Hayes C, et al. New proteasome inhibitors in myeloma. Curr Hematol Malig Rep. 2012;7:258-266. 17. Schey S, Ramasamy K. Pomalidomide therapy for myeloma. Expert Opin Investig Drugs. 2011;20:691-700. 18. Jagannath S, Richardson PG, Hofmeister C, et al. Pomalidomide with or without low-dose dexamethasone in relapsed and refractory multiple myeloma: updated analysis. Haematologica. 2013;13(suppl 1):S143-S144. Poster P-210. 19. Hideshima T, Richardson PG, Anderson KC. Mechanism of action of proteasome inhibitors and deacetylase inhibitors and the biological basis of synergy in multiple myeloma. Mol Cancer Ther. 2011;10:2034-2042. 20. Siegel DS, Dimopoulos MA, Yoon SS, et al. VANTAGE 095: Final results from a global, single-arm, phase 2b trial of vorinostat in combination with bortezomib in salvage multiple myeloma patients. Haematologica. 2012;97(supp 1):119. Abstract 0294. 21. Shah JJ, Thomas SK, Weber DM, et al. Phase 1/1b study of the efficacy and safety of the combination of panobinostat + carfilzomib in patients with relapsed and/or refractory multiple myeloma. Blood (ASH Annual Meeting Abstracts). 2012;120:Abstract 4081. 22. Panobinostat or placebo with bortezomib and dexamethasone in patients with relapsed multiple myeloma (PANORAMA-1). NCT01023308. http://clinicaltrials.gov/ct2/show/NCT01023308. Accessed August 6, 2013. 23. Harrison SJ, Quach H, Link E, et al. A high rate of durable responses with romidepsin, bortezomib, and dexamethasone in relapsed or refractory multiple myeloma. Blood. 2011; 118:6274-6283.

Nursing Considerations for Combination Therapy in Multiple Myeloma

Continued from page 29

28. Kristinsson SY. Thrombosis in multiple myeloma. Hematology (ASH Education Program Book). 2010:437-444. 29. Boyle EM, Fouquet G, Manier S, et al. Immunomodulator drug-based therapy in myeloma and the occurrence of thrombosis. Expert Rev Hematol. 2012;5:617-626. 30. Palumbo A, Rajkumar SV, Dimopoulos MA, et al. Prevention of thalidomide- and lenalidomide-associated thrombosis in myeloma. Leukemia. 2008;22:414-423. 31. Nooka A, Gleason C, Casbourne D, Lonial S. Relapsed and refractory lymphoid neoplasms and multiple myeloma with a focus on carfilzomib. Biologics Targets Ther. 2013;7:13-32. 32. Kyprolis [package insert]. South San Francisco, CA: Onyx Pharmaceuticals; July 2012. 33. Lacy MQ, Hayman SR, Gertz MA, et al. Pomalidomide (CC4047) plus low dose dexamethasone (Pom/dex) is active and well tolerated in lenalidomide refractory multiple myeloma (MM). Leukemia. 2010;24:1934-1939.

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34. Lacy M, Gertz MA, Hayman SR, et al. Activity of pomalidomide plus dexamethasone (Pom/ dex) in dual lenalidomide/bortezomib refractory multiple myeloma (MM). J Clin Oncol (ASCO Annual Meeting Proceedings). 2010;28(suppl):Abstract 8002. 35. Lacy MQ, Hayman SR, Gertz MA, et al. Pomalidomide (CC4047) plus low-dose dexamethasone (Pom/dex) is highly effective therapy in relapsed multiple myeloma. Blood (ASH Annual Meeting Abstracts). 2008;112:Abstract 866. 36. Richardson PG, Siegel DS, Vij R, et al. Randomized, open label phase 1/2 study of pomalidomide (POM) alone or in combination with low-dose dexamethasone (LoDex) in patients (pts) with relapsed and refractory multiple myeloma who have received prior treatment that includes lenalidomide (LEN) and bortezomib (BORT): phase 2 results. Blood (ASH Annual Meeting Abstracts). 2011;118:Abstract 634. 37. Pomalyst [package insert]. Summit, NJ: Celgene Corporation; February 2013.

August 2013 I VOL 6, NO 3

Melanoma

Immunotherapies Take Center Stage in Melanoma By Audrey Andrews Data continue to build for the use of immunotherapy in the treatment of patients with metastatic melanoma. At the 2013 American Society of Clinical Oncology (ASCO) Annual Meeting, several sessions focused on recent advances in melanoma, including new ways to boost the activity of current therapies, the development of a new class of immunotherapy, and a new form of immunotherapy—an oncolytic vaccine.

cacy and safety were similar in ipilimumab-naive patients and those who had received prior treatment with ipilimumab,” Ribas noted.

F. Stephen Hodi, Jr, MD

Lynn M. Schuchter, MD

Growth Factors Give Ipilimumab a Boost Investigators presented data showing that the activity of ipilimumab was boosted by the addition of granulocyte macrophage colony-stimulating factor (GM-CSF). The phase 2 study reported improved overall survival (OS) with the combination versus ipilimumab alone.1 “Adding GM-CSF to ipilimumab improved survival and also tolerability of treatment. These data represent an important avenue for combining cytokine therapy with immune checkpoint blockade,” said F. Stephen Hodi, Jr, MD, director of the Melanoma Center at Dana-Farber Cancer Institute, Boston, Massachusetts, speaking at an ASCO press briefing. GM-CSF works within the immune system by enhancing granulocytes and macrophages, while the antibody ipilimumab “takes the brakes off” immune blockade, allowing the body itself to fight the tumor, Hodi explained. The Eastern Cooperative Oncology Group (ECOG) E1608 trial randomly assigned 245 patients with previously treated metastatic melanoma to receive ipilimumab and maintenance treatment, or the same plus the growth factor sargramostim. The addition of GM-CSF to ipilimumab significantly improved OS from a median time of 12.7 months with ipilimumab alone to 17.5 months, a 36% reduction in mortality (P = .014). A surprising and encouraging finding was that tolerability was actually better with the combination than with the single agent, he reported. “With both drugs commercially available, these findings have implications for the current treatment of melanoma patients,” Hodi suggested. “At the same time, we still need to clarify the best way to apply these findings in everyday practice.” Lynn M. Schuchter, MD, program

August 2013 I VOL 6, NO 3

Mario Sznol, MD

leader of the Melanoma and Cutaneous Malignancies Program at Abramson Cancer Center of the University of Pennsylvania, Philadelphia, commented that because both drugs are approved, physicians could start using this combination immediately, though she questioned whether third-party payers would reimburse for the growth factors. New Class of Anti–PD-1 Blockade Agents May Be a Blockbuster A new class of immunotherapeutic agents blocks the programmed death-1 (PD-1) and PD-1 ligand (PD-L1), and helps keep T cells primed and ready to attack

Kim A. Margolin, MD

(the dose chosen for further development), and median OS was 20 months for this population; responses were prompt and averaged 24 months in duration, Sznol reported. “We are in an era of remarkable advances for melanoma,” he said. “Median survival with vemurafenib is 16 months. For ipilimumab it is similar. But here, with nivolumab it’s 16.8 months [across all dose levels], and the median duration of response of 2 years [across all dose levels] is one of the highest numbers I have seen.” Antonio Ribas, MD, associate professor of hematology-oncology and

“Adding GM-CSF to ipilimumab improved survival and also tolerability of treatment. These data represent an important avenue for combining cytokine therapy with immune checkpoint blockade.” F. Stephen Hodi, Jr, MD

tumor cells. This class of agents is poised to again change the standard of care in melanoma, according to melanoma experts. Interest in these agents is so great that an entire clinical science symposium was devoted to this drug class at ASCO. Long-term follow-up of an expanded phase 1 trial of the PD-1 inhibitor nivolumab in heavily pretreated patients showed that median OS approached 17 months across all dose levels (0.1, 0.3, 1, 3, or 10 mg/kg), with a very favorable toxicity profile, reported Mario Sznol, MD, professor of medical oncology in the Melanoma Program at the Yale Cancer Center, New Haven, Connecticut.2 In this study of 107 patients who received nivolumab, response rates reached 41% among those patients receiving the optimal dose of 3 mg/kg

surgical oncology at the University of California Los Angeles, presented early data for lambrolizumab, the anti–PD-1 agent that recently received “breakthrough therapy” status by the US Food and Drug Administration (FDA). He discussed preliminary results of an ongoing phase 1b expansion trial of patients with melanoma at the clinical science symposium on anti–PD-1.3 Lambrolizumab was administered every 2 or 3 weeks until disease progression or unacceptable toxicity. Of the 294 enrolled patients, 179 did not receive ipilimumab and 115 patients were pretreated with ipilimumab. As of December 2012, the median response duration had not been reached, and only 2 patients discontinued because of adverse events. “We found that effi-

Dual Blockade With PD-1 Packs Bigger Punch By combining the cytotoxic Tlymphocyte antigen-4 (CTLA-4)– blocking antibody ipilimumab and the PD-1 blocker nivolumab, investigators achieved deep, rapid, and durable tumor responses in a phase 1 study presented by Jedd D. Wolchok, MD, PhD, an oncologist at Memorial Sloan-Kettering Cancer Center, New York City.4 The study results were published online simultaneously with the presentation.5 Among the 53 patients receiving concurrent treatment, 53% had an objective response at the maximum dose associated with an acceptable level of adverse events, with ≥80% tumor reduction, including 18% who achieved a complete response. After a median follow-up of 13 months, 90% of responders were still stable. The estimated 1-year survival rate with this regimen was 82%. Grade 3 or 4 adverse events were reported in 53% of the patients in the concurrent-regimen group. “The proportion of patients with a rapidly declining tumor burden is reminiscent of responses to targeted pathway inhibitors, yet the durability of these responses maintains consistency with the long-lasting nature of immunotherapy in prior studies,” Wolchok said at the ASCO clinical science symposium on anti–PD-1. The paper’s discussant, Walter J. Urba, MD, PhD, director of cancer research at Providence Cancer Center in Oregon, predicted that PD-1 blockade is “certainly going to change the state of the care of patients with melanoma once again.” Harnessing an Oncolytic Virus The cancer-killing virus talimogene laherparepvec (T-VEC) is the first oncolytic virus to produce a treatment benefit in melanoma. T-VEC directly kills tumor cells and elicits a host response that indirectly targets distant metastases as well, explained Howard I. Kaufman, MD, cancer program director at Rush University Medical Center, Chicago, Illinois.6 Continued on page 34

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Melanoma

Immunotherapies Take Center Stage in Melanoma Continued from page 32 The phase 3 OncoVEX Pivotal Trial in Melanoma (OPTiM) study randomized 436 patients with advanced melanoma to receive intratumoral injections of T-VEC or subcutaneous injections of GM-CSF. The virus significantly improved durable responses

(≥6 months) compared with GM-CSF (16.3% vs 2.1%; P <.0001), meeting the study’s end point, Kaufman reported. Median time to treatment failure was 8.2 months versus 2.9 months with GM-CSF, a 58% reduction in progression (P <.0001). In the interim

analysis, median OS was 23.3 months with T-VEC and 19.0 months with GM-CSF. The treatment was also very well tolerated, he said. Kim A. Margolin, MD, of the Seattle Cancer Care Alliance, commented that because GM-CSF is not a standard

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CONSIDERATIONS in

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LETTER

FROM THE

EDITOR-IN-CHIEF

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

to learn more!

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

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

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

Houry Leblebjian, PharmD, BCOP Clinical Pharmacy Specialist in MARCH 2013 • VOLUME 4 • NUMBER 2 Hematology/Oncology Dana-Farber Cancer Institute Boston, MA

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The Elodia Kehm Chair of Hematology Professor of Medicine Director, Lymphoma Program Rush University Medical Center/Rush University Chicago, IL

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Mitchell R. Smith, MD, PhD Director of Lymphoid Malignancies Program Taussig Cancer Institute Cleveland Clinic Cleveland, OH

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Assistant Attending Medical Oncologist Lymphoma, Cutaneous Lymphomas, T-Cell Lymphoma Memorial Sloan-Kettering Cancer Center New York, NY

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Two New Therapies Approved for Advanced Melanoma On May 29, 2013, just before the ASCO meeting, the FDA approved 2 new therapies, which do not target the immune system, for patients with advanced melanoma and BRAF mutation: dabrafenib (Tafinlar) targets patients with the V600E mutation, and trametinib (Mekinist) targets patients with the BRAF V600E or V600K mutation. Both therapies were approved by the FDA with a companion diagnostic test. l References

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treatment for metastatic melanoma, it may not be a good comparator for the novel therapy. She suggested the best use of T-VEC may be in combination with another immune mediator such as ipilimumab. “Targeting immunoinhibitory pathways is providing a new strategy for immunotherapy….There are synergies among inhibitory pathways. Coblockade enables better rescue of exhausted T cells and therapeutic efficacy than blockade of a single inhibitory pathway,” said Arlene H. Sharpe, MD, PhD, codirector of the Harvard Institute of Translational Immunology at Harvard Medical School, Boston, at the ASCO clinical science symposium. According to Sharpe and other melanoma experts, combinations of these expensive novel therapies may prove the most efficacious, and a number of such regimens are entering clinical trials.

August 2013 I VOL 6, NO 3

1. Hodi FS, Lee SJ, McDermott DF, et al. Multicenter, randomized phase II trial of GM-CSF (GM) plus ipilimumab (Ipi) versus Ipi alone in metastatic melanoma: E1608. J Clin Oncol. 2013;31(suppl):Abstract CRA9007. Presented at: 2013 American Society of Clinical Oncology Annual Meeting; May 31-June 4, 2013; Chicago, IL. 2. Sznol M, Kluger HM, Hodi SF, et al. Survival and long-term follow-up of safety and response in patients (pts) with advanced melanoma (MEL) in a phase I trial of nivolumab (anti-PD-1; BMS-936558; ONO-4538). J Clin Oncol. 2013;31(suppl):Abstract CRA9006. Presented at: 2013 American Society of Clinical Oncology Annual Meeting; May 31-June 4, 2013; Chicago, IL. 3. Ribas A, Robert C, Daud A, et al. Clinical efficacy and safety of lambrolizumab (MK-3475, Anti-PD-1 monoclonal antibody) in patients with advanced melanoma. J Clin Oncol. 2013;31(suppl):Abstract 9009. Presented at: 2013 American Society of Clinical Oncology Annual Meeting; May 31-June 4, 2013; Chicago, IL. 4. Wolchok JD, Kluger HM, Callahan MK, et al. Safety and clinical activity of nivolumab (anti-PD-1, BMS936558, ONO-4538) in combination with ipilimumab in patients (pts) with advanced melanoma (MEL). J Clin Oncol. 2013;31(suppl):Abstract 9012. Presented at: 2013 American Society of Clinical Oncology Annual Meeting; May 31-June 4, 2013; Chicago, IL. 5. Wolchok JD, Kluger H, Callahan MK, et al. Nivolumab plus ipilimumab in advanced melanoma. N Engl J Med. 2013;369(2):122-133. 6. Andtbacka RHI, Collichio FA, Amatruda T, et al. OPTiM: a randomized phase III trial of talimogene laherparepvec (T-VEC) versus subcutaneous (SC) granulocyte-macrophage colony-stimulating factor (GM-CSF) for the treatment (tx) of unresected stage IIIB/C and IV melanoma. J Clin Oncol. 2013;31(suppl):Abstract LBA9008. Presented at: 2013 American Society of Clinical Oncology Annual Meeting; May 31-June 4, 2013; Chicago, IL.

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Cancer Center Profile

Barnes-Jewish Hospital Continued from cover FOLFOX, because FOLFIRI does not exacerbate peripheral neuropathy since it does not contain oxaliplatin.

What is the approach to patient care at Barnes-Jewish Hospital? SB: Barnes-Jewish Hospital is affiliated with Siteman Cancer Center—a National Cancer Institute–designated comprehensive cancer center—and Washington University in St. Louis, Missouri. Our approach to patient care is collaborative and incorporates teamwork from several types of specialists, including physicians, pharmacists, nurses, nurse practitioners, dietitians, physical therapists, and social workers. How does this translate to improved patient care? SB: The team approach provides different perspectives and addresses medical and nonmedical issues, so that patient management is more holistic. What is exciting to you in the field of oncology? SB: The shift to targeted therapy over the past decade is a major advance. We’ve known for many years that receptors and pathways are important in the development and proliferation of cancer but we were unable to exploit these targets. In the era of targeted therapy, we now have many [treatments] specific to different cancer types. For example, in melanoma we have immunotherapy and other newer drugs that are being used in combination to extend the lives of patients. Other well-known examples are the multitargeted tyrosine kinase inhibitors for chronic myeloid leukemia, trastuzumab as well as newer drugs that target the HER2 receptor in HER2-positive breast cancer, and crizotinib for ALKpositive non–small cell lung cancer. How has the role of the oncology pharmacist changed over the past 5 to 10 years? SB: With conventional chemotherapy, we had to manage adverse events like nausea, vomiting, diarrhea, alopecia, and

The Siteman Cancer Center at Barnes-Jewish Hospital and Washington University School of Medicine in St. Louis, Missouri.

peripheral neuropathy, but targeted therapies have distinct side effect profiles. We have had to extend our knowledge and clinical experience to manage new symptoms associated with specific targeted therapies; for example, the immune effects of ipilimumab in patients with myeloma include autoimmune colitis or inflammation of other organ systems. In the past, the oncology pharmacist didn’t have to manage these types of effects, which are specific to the drug. We need to learn whether to stop the drug, put it on hold, or continue treatment when adverse effects occur with targeted therapy. It can be challenging to keep on top of specific pathways and potential adverse effects.

What inspired you to become an oncology pharmacist?

SB: My inspiration was 2-fold: a family member with cancer and a fourthyear clinical rotation in oncology at pharmacy school. I was drawn to the field because I enjoy working with patients and find it rewarding to talk to patients who may be highly anxious about their therapy and to reassure them about side effects and the ability to manage them. On the inpatient side at our hospital, a clinical pharmacist is assigned to every inpatient, and we augment the education that nurses provide.

What advice would you give to a pharmacist just entering the field? SB: I would say to keep an open mind and to look for opportunities on the inpatient and outpatient sides where you will be collaborating with

physicians. The multidisciplinary approach is rewarding, and now pharmacy schools are increasing the number of oncology residency programs. Oncology is a high-cost area, and the expertise of pharmacists can help provide care efficiently and reduce inappropriate care.

If you weren’t a pharmacist, what would you be doing? SB: I have always wanted to work in the medical field. Working in my hometown pharmacy during a summer when I was in college clinched my decision to become a pharmacist. Even though some patients may not survive, it is uplifting to be able to make patients feel better while they are undergoing treatment for their disease. l

Take action: get YOUR cancer center profiled! We are looking to interview oncology pharmacists from cancer centers around the country. It’s an easy process—a short phone interview and you need to submit some photos.

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

August 2013 I VOL 6, NO 3

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.