Special Issue May 2012, VOL 5, NO 4

4th ANNUAL REVIEW ISSUE

A Look at Recent Advances in Cancer Care

LymphomasBrentuximab Vedotin for the Treatment of Relapsed/Refractory HodgkinLymphoma and Anaplastic Large Cell LymphomaColleen Erb, MSN, CRNP, ACNP-BC, AOCNP Barbara Barnes Rogers, CRNP, MN, AOCN, ANP-BC

Multiple MyelomaManaging Bortezomib Therapy in Patients With Multiple MyelomaLinda Caldwell, RN, MS; Cass Hammond, RN, MSN, CRNP; Kathleen Colson, RN, BSN, BS

Prostate CancerMetastatic Castrate-Resistant Prostate Cancer—Treatment OverviewShari L. Black, MAN, CNP

Hematologic MalignanciesMyelofibrosis—A Myeloproliferative NeoplasmCatherine Bishop, DNP, NP, AOCNP

Supportive CarePrevention and Treatment of Thromboembolism in Patients With CancerAaron D. Dush, PharmD, CACPP

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MAY 2012 www.TheOncologyNurse.com VOL 5, NO 4

©2012 Green Hill Healthcare Communications, LLC

TON_May2012_v7_TON 5/21/12 1:09 PM Page 1

7% 8%CR

43% 42%

ORRPrimary Endpoint

11% 12%

CR

53% 51%

ORR

SC (n=148)IV (n=74)

Subcutaneous VELCADE Demonstrated Efficacy Consistent With IV for the Primary Endpoint

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RESPONSE RATES† IN RELAPSED MULTIPLE MYELOMA (MM): SUBCUTANEOUS AND IV

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▼ The study met its primary non-inferiority objective that single-agent subcutaneous VELCADE retained at least 60% of the overall response rate after 4 cycles relative to single-agent IV VELCADE

SUBCUTANEOUS VS IV TRIAL: a non-inferiority, phase 3, randomized (2:1), open-label trial compared the efficacy and safety of VELCADE administered subcutaneously (n=148) with VELCADE administered intravenously (n=74) in patients with relapsed MM. The primary endpoint was overall response rate at 4 cycles. Secondary endpoints included response rate at 8 cycles, median TTP and PFS (months), 1-year overall survival (OS), and safety.

* INDICATIONS: VELCADE is indicated for the treatment of patients with multiple myeloma. VELCADE is indicated for the treatment of patients with mantle cell lymphoma who have received at least 1 prior therapy.

†Responses were based on criteria established by the European Group for Blood and Marrow Transplantation.1

VELCADE IMPORTANT SAFETY INFORMATIONCONTRAINDICATIONSVELCADE is contraindicated in patients with hypersensitivity to bortezomib, boron, or mannitol. VELCADE is contraindicated for intrathecal administration.

WARNINGS, PRECAUTIONS AND DRUG INTERACTIONS ▼ Peripheral neuropathy, including severe cases, may occur – manage with dose modification or discontinuation. Patients

with preexisting severe neuropathy should be treated with VELCADE only after careful risk-benefit assessment ▼ Hypotension can occur. Use caution when treating patients receiving antihypertensives, those with a history of syncope,

and those who are dehydrated▼ Closely monitor patients with risk factors for, or existing heart disease ▼ Acute diffuse infiltrative pulmonary disease has been reported▼ Nausea, diarrhea, constipation, and vomiting have occurred and may require use of antiemetic and antidiarrheal

medications or fluid replacement▼ Thrombocytopenia or neutropenia can occur; complete blood counts should be regularly monitored throughout treatment▼ Tumor Lysis Syndrome, Reversible Posterior Leukoencephalopathy Syndrome, and Acute Hepatic Failure have been reported

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a less-dose-intense schedule, or discontinuation. Please see full Prescribing Information for dose modification g

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AT 24 WEEKS (AFTER 8 CYCLES) VELCADE±dexamethasone

AT 12 WEEKS (AFTER 4 CYCLES)Single-agent VELCADE® (bortezomib)

NOW APPROVED FOR SUBCUTANEOUS ADMINISTRATION IN ALL INDICATIONS*


6%16%

GRADE ≥3

38%53%

SC (n=147)

IV (n=74)

ALL GRADES

Difference in Incidence of Peripheral Neuropathy With Subcutaneous VELCADE

PERIPHERAL NEUROPATHY (PN) IN RELAPSED MM: SUBCUTANEOUS AND IVR

Please see Brief Summary for VELCADE on next page.

For Patient Assistance Information or Reimbursement Assistance, call 1-866-VELCADE (835-2233), Option 2, or visit VELCADEHCP.comReference: 1. 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(5):431-440.

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▼ Starting VELCADE® (bortezomib) subcutaneously may be considered for patients with preexisting PN or patients at high risk for PN. Patients with preexisting severe neuropathy should be treated with VELCADE only after careful risk-benefit assessment

▼ Treatment with VELCADE may cause PN that is predominantly sensory. However, cases of severe sensory and motor PN have been reported. Patients should be monitored for symptoms of neuropathy, such as a burning sensation, hyperesthesia, hypoesthesia, paresthesia, discomfort, neuropathic pain, or weakness

▼ Patients experiencing new or worsening PN during therapy with VELCADE may require a decrease in the dose, a less-dose-intense schedule, or discontinuation. Please see full Prescribing Information for dose modification guidelines for PN

WARNINGS, PRECAUTIONS AND DRUG INTERACTIONS CONTINUED▼ Women should avoid becoming pregnant while being treated with VELCADE. Pregnant women should be apprised of the

potential harm to the fetus

▼ Closely monitor patients receiving VELCADE in combination with strong CYP3A4 inhibitors. Concomitant use of strong CYP3A4 inducers is not recommended

ADVERSE REACTIONS Most commonly reported adverse reactions (incidence ≥30%) in clinical studies include asthenic conditions, diarrhea, nausea, constipation, peripheral neuropathy, vomiting, pyrexia, thrombocytopenia, psychiatric disorders, anorexia and decreased appetite, neutropenia, neuralgia, leukopenia, and anemia. Other adverse reactions, including serious adverse reactions, have been reported

IN ALL INDICATIONS*

1 3


VELCADE, MILLENNIUM and are registered trademarks of Millennium Pharmaceuticals, Inc. Other trademarks are property of their respective owners.Millennium Pharmaceuticals, Inc., Cambridge, MA 02139 Copyright © 2012, Millennium Pharmaceuticals, Inc.All rights reserved. Printed in USA

Brief Summary

INDICATIONS:VELCADE® (bortezomib) for Injection is indicated for the treatment of patients with multiple myeloma. VELCADE® (bortezomib) for Injection is indicated for the treatment of patients with mantle cell lymphoma who have received at least 1 prior therapy.

CONTRAINDICATIONS:VELCADE is contraindicated in patients with hypersensitivity to bortezomib, boron, or mannitol. VELCADE is contraindicated for intrathecal administration.

WARNINGS AND PRECAUTIONS:VELCADE should be administered under the supervision of a physician experienced in the use of antineoplastic therapy. Complete blood counts (CBC) should be monitored frequently during treatment with VELCADE.

Peripheral Neuropathy: VELCADE treatment causes a peripheral neuropathy that is predominantly sensory. However, cases of severe sensory and motor peripheral neuropathy have been reported. Patients with pre-existing symptoms (numbness, pain or a burning feeling in the feet or hands) and/or signs of peripheral neuropathy may experience worsening peripheral neuropathy (including ≥ Grade 3) during treatment with VELCADE. Patients should be monitored for symptoms of neuropathy, such as a burning sensation, hyperesthesia, hypoesthesia, paresthesia, discomfort, neuropathic pain or weakness. In the Phase 3 relapsed multiple myeloma trial comparing VELCADE subcutaneous vs. intravenous the incidence of Grade ≥ 2 peripheral neuropathy events was 24% for subcutaneous and 41% for intravenous. Grade ≥ 3 peripheral neuropathy occurred in 6% of patients in the subcutaneous treatment group, compared with 16% in the intravenous treatment group. Starting VELCADE subcutaneously may be considered for patients with pre-existing or at high risk of peripheral neuropathy.

Patients experiencing new or worsening peripheral neuropathy during VELCADE therapy may benefit from a decrease in the dose and/or a less dose-intense schedule. In the single agent phase 3 relapsed multiple myeloma study of VELCADE vs. Dexamethasone following dose adjustments, improvement in or resolution of peripheral neuropathy was reported in 51% of patients with ≥ Grade 2 peripheral neuropathy in the relapsed multiple myeloma study. Improvement in or resolution of peripheral neuropathy was reported in 73% of patients who discontinued due to Grade 2 neuropathy or who had ≥ Grade 3 peripheral neuropathy in the phase 2 multiple myeloma studies. The long-term outcome of peripheral neuropathy has not been studied in mantle cell lymphoma.

Hypotension: The incidence of hypotension (postural, orthostatic, and hypotension NOS) was 13%. These events are observed throughout therapy. Caution should be used when treating patients with a history of syncope, patients receiving medications known to be associated with hypotension, and patients who are dehydrated. Management of orthostatic/postural hypotension may include adjustment of antihypertensive medications, hydration, and administration of mineralocorticoids and/or sympathomimetics.

Cardiac Disorders: Acute development or exacerbation of congestive heart failure and new onset of decreased left ventricular ejection fraction have been reported, including reports in patients with no risk factors for decreased left ventricular ejection fraction. Patients with risk factors for, or existing heart disease should be closely monitored. In the relapsed multiple myeloma study of VELCADE vs. dexamethasone, the incidence of any treatment-emergent cardiac disorder was 15% and 13% in the VELCADE and dexamethasone groups, respectively. The incidence of heart failure events (acute pulmonary edema, cardiac failure, congestive cardiac failure, cardiogenic shock, pulmonary edema) was similar in the VELCADE and dexamethasone groups, 5% and 4%, respectively. There have been isolated cases of QT-interval prolongation in clinical studies; causality has not been established.

Pulmonary Disorders: There have been reports of acute diffuse infiltrative pulmonary disease of unknown etiology such as pneumonitis, interstitial pneumonia, lung infiltration and Acute Respiratory Distress Syndrome (ARDS) in patients receiving VELCADE. Some of these events have been fatal. In a clinical trial, the first two patients given high-dose cytarabine (2 g/m2 per day) by continuous infusion with daunorubicin and VELCADE for relapsed acute myelogenous leukemia died of ARDS early in the course of therapy. There have been reports of pulmonary hypertension associated with VELCADE administration in the absence of left heart failure or significant pulmonary disease. In the event of new or worsening cardiopulmonary symptoms, a prompt comprehensive diagnostic evaluation should be conducted.

Reversible Posterior Leukoencephalopathy Syndrome (RPLS): There have been reports of RPLS in patients receiving VELCADE. RPLS is a rare, reversible, neurological disorder which can present with seizure, hypertension, headache, lethargy, confusion, blindness, and other visual and neurological disturbances. Brain imaging, preferably MRI (Magnetic Resonance Imaging), is used to confirm the diagnosis. In patients developing RPLS, discontinue VELCADE. The safety of reinitiating VELCADE therapy in patients previously experiencing RPLS is not known.

Gastrointestinal Adverse Events: VELCADE treatment can cause nausea, diarrhea, constipation, and vomiting sometimes requiring use of antiemetic and antidiarrheal medications. Ileus can occur. Fluid and electrolyte replacement should be administered to prevent dehydration.

Thrombocytopenia/Neutropenia: VELCADE is associated with thrombocytopenia and neutropenia that follow a cyclical pattern with nadirs occurring following the last dose of each cycle and typically recovering prior to initiation of the subsequent cycle. The cyclical pattern of platelet and neutrophil decreases and recovery remained consistent over the 8 cycles of twice weekly dosing, and there was no evidence of cumulative thrombocytopenia or neutropenia. The mean platelet count nadir measured was approximately 40% of baseline. The severity of thrombocytopenia was related to pretreatment platelet count. In the relapsed multiple myeloma study of VELCADE vs. dexamethasone, the incidence of significant bleeding events (≥Grade 3) was similar on both the VELCADE (4%) and dexamethasone (5%) arms. Platelet counts should be monitored prior to each dose of VELCADE. Patients experiencing thrombocytopenia may require change in the dose and schedule of VELCADE. There have been reports of gastrointestinal and intracerebral hemorrhage in association with VELCADE. Transfusions may be considered. The incidence of febrile neutropenia was <1%.

Tumor Lysis Syndrome: Because VELCADE is a cytotoxic agent and can rapidly kill malignant cells, the complications of tumor lysis syndrome may occur. Patients at risk of tumor lysis syndrome are those with high tumor burden prior to treatment. These patients should be monitored closely and appropriate precautions taken.

Hepatic Events: Cases of acute liver failure have been reported in patients receiving multiple concomitant medications and with serious underlying medical conditions. Other reported hepatic events include increases in liver enzymes, hyperbilirubinemia, and hepatitis. Such changes may be reversible upon discontinuation of VELCADE. There is limited re-challenge information in these patients.

Hepatic Impairment: Bortezomib is metabolized by liver enzymes. Bortezomib exposure is increased in patients with moderate or severe hepatic impairment; these patients should be treated with VELCADE at reduced starting doses and closely monitored for toxicities.

Use in Pregnancy: Pregnancy Category D. Women of childbearing potential should avoid becoming pregnant while being treated with VELCADE (bortezomib). Bortezomib administered to rabbits during organogenesis at a dose approximately 0.5 times the clinical dose of 1.3 mg/m2 based on body surface area caused post-implantation loss and a decreased number of live fetuses.

ADVERSE EVENT DATA: Safety data from phase 2 and 3 studies of single-agent VELCADE 1.3 mg/m2/dose administered intravenously twice weekly for 2 weeks followed by a 10-day rest period in 1163 patients with previously treated multiple myeloma (N=1008, not including the phase 3, VELCADE plus DOXIL® [doxorubicin HCI liposome injection] study) and previously treated mantle cell lymphoma (N=155) were integrated and tabulated. In these studies, the safety profile of VELCADE was similar in patients with multiple myeloma and mantle cell lymphoma.

In the integrated analysis, the most commonly reported adverse events were asthenic conditions (including fatigue, malaise, and weakness); (64%), nausea (55%), diarrhea (52%), constipation (41%), peripheral neuropathy NEC (including peripheral sensory neuropathy and peripheral neuropathy aggravated); (39%), thrombocytopenia and appetite decreased (including anorexia); (each 36%), pyrexia (34%), vomiting (33%), anemia (29%), edema (23%), headache, paresthesia and dysesthesia (each 22%), dyspnea (21%), cough and insomnia (each 20%), rash (18%), arthralgia (17%), neutropenia and dizziness (excluding vertigo); (each 17%), pain in limb and abdominal pain (each 15%), bone pain (14%), back pain and hypotension (each 13%), herpes zoster, nasopharyngitis, upper respiratory tract infection, myalgia and pneumonia (each 12%), muscle cramps (11%), and dehydration and anxiety (each 10%). Twenty percent (20%) of patients experienced at least 1 episode of ≥Grade 4 toxicity, most commonly thrombocytopenia (5%) and neutropenia (3%). A total of 50% of patients experienced serious adverse events (SAEs) during the studies. The most commonly reported SAEs included pneumonia (7%), pyrexia (6%), diarrhea (5%), vomiting (4%), and nausea, dehydration, dyspnea and thrombocytopenia (each 3%).

In the phase 3 VELCADE + melphalan and prednisone study in previously untreated multiple myeloma, the safety profile of VELCADE administered intravenously in combination with melphalan/prednisone is consistent with the known safety profiles of both VELCADE and melphalan/prednisone. The most commonly reported adverse events in this study (VELCADE+melphalan/prednisone vs melphalan/prednisone) were thrombocytopenia (52% vs 47%), neutropenia (49% vs 46%), nausea (48% vs 28%), peripheral neuropathy (47% vs 5%), diarrhea (46% vs 17%), anemia (43% vs 55%), constipation (37% vs 16%), neuralgia (36% vs 1%), leukopenia (33% vs 30%), vomiting (33% vs 16%), pyrexia (29% vs 19%), fatigue (29% vs 26%), lymphopenia (24% vs 17%), anorexia (23% vs 10%), asthenia (21% vs 18%), cough (21% vs 13%), insomnia (20% vs 13%), edema peripheral (20% vs 10%), rash (19% vs 7%), back pain (17% vs 18%), pneumonia (16% vs 11%), dizziness (16% vs 11%), dyspnea (15% vs 13%), headache (14% vs 10%), pain in extremity (14% vs 9%), abdominal pain (14% vs 7%), paresthesia (13% vs 4%), herpes zoster (13% vs 4%), bronchitis (13% vs 8%), hypokalemia (13% vs 7%), hypertension (13% vs 7%), abdominal pain upper (12% vs 9%), hypotension (12% vs 3%), dyspepsia (11% vs 7%), nasopharyngitis (11% vs 8%), bone pain (11% vs 10%), arthralgia (11% vs 15%) and pruritus (10% vs 5%).

In the phase 3 VELCADE subcutaneous vs. intravenous study in relapsed multiple myeloma, safety data were similar between the two treatment groups. The most commonly reported adverse events in this study were peripheral neuropathy NEC (38% vs 53%), anemia (36% vs 35%), thrombocytopenia (35% vs 36%), neutropenia (29% vs 27%), diarrhea (24% vs 36%), neuralgia (24% vs 23%), leukopenia (20% vs 22%), pyrexia (19% vs 16%), nausea (18% vs 19%), asthenia (16% vs 19%), weight decreased (15% vs 3%), constipation (14% vs 15%), back pain (14% vs 11%), fatigue (12% vs 20%), vomiting (12% vs 16%), insomnia (12% vs 11%), herpes zoster (11% vs 9%), decreased appetite (10% vs 9%), hypertension (10% vs 4%), dyspnea (7% vs 12%), pain in extremities (5% vs 11%), abdominal pain and headache (each 3% vs 11%), abdominal pain upper (2% vs 11%). The incidence of serious adverse events was similar for the subcutaneous treatment group (36%) and the intravenous treatment group (35%). The most commonly reported SAEs were pneumonia (6%) and pyrexia (3%) in the subcutaneous treatment group and pneumonia (7%), diarrhea (4%), peripheral sensory neuropathy (3%) and renal failure (3%) in the intravenous treatment group.

DRUG INTERACTIONS:Bortezomib is a substrate of cytochrome P450 enzyme 3A4, 2C19 and 1A2. Co-administration of ketoconazole, a strong CYP3A4 inhibitor, increased the exposure of bortezomib by 35% in 12 patients. Therefore, patients should be closely monitored when given bortezomib in combination with strong CYP3A4 inhibitors (e.g. ketoconazole, ritonavir). Co-administration of omeprazole, a strong inhibitor of CYP2C19, had no effect on the exposure of bortezomib in 17 patients. Co-administration of rifampin, a strong CYP3A4 inducer, is expected to decrease the exposure of bortezomib by at least 45%. Because the drug interaction study (n=6) was not designed to exert the maximum effect of rifampin on bortezomib PK, decreases greater than 45% may occur. Efficacy may be reduced when VELCADE (bortezomib) is used in combination with strong CYP3A4 inducers; therefore, concomitant use of strong CYP3A4 inducers is not recommended in patients receiving VELCADE. St. John’s Wort (Hypericum perforatum) may decrease bortezomib exposure unpredictably and should be avoided. Co-administration of dexamethasone, a weak CYP3A4 inducer, had no effect on the exposure of bortezomib in 7 patients. Co-administration of melphalan-prednisone increased the exposure of bortezomib by 17% in 21 patients. However, this increase is unlikely to be clinically relevant.

USE IN SPECIFIC POPULATIONS:Nursing Mothers: It is not known whether bortezomib is excreted in human milk. Because many drugs are excreted in human milk and because of the potential for serious adverse reactions in nursing infants from VELCADE, a decision should be made whether to discontinue nursing or to discontinue the drug, taking into account the importance of the drug to the mother.

Pediatric Use: The safety and effectiveness of VELCADE in children has not been established.

Geriatric Use: No overall differences in safety or effectiveness were observed between patients ≥ age 65 and younger patients receiving VELCADE; but greater sensitivity of some older individuals cannot be ruled out.

Patients with Renal Impairment: The pharmacokinetics of VELCADE are not influenced by the degree of renal impairment. Therefore, dosing adjustments of VELCADE are not necessary for patients with renal insufficiency. Since dialysis may reduce VELCADE concentrations, VELCADE should be administered after the dialysis procedure. For information concerning dosing of melphalan in patients with renal impairment, see manufacturer’s prescribing information.

Patients with Hepatic Impairment: The exposure of bortezomib is increased in patients with moderate and severe hepatic impairment. Starting dose should be reduced in those patients.

Patients with Diabetes: During clinical trials, hypoglycemia and hyperglycemia were reported in diabetic patients receiving oral hypoglycemics. Patients on oral antidiabetic agents receiving VELCADE treatment may require close monitoring of their blood glucose levels and adjustment of the dose of their antidiabetic medication.

Please see full Prescribing Information for VELCADE at VELCADEHCP.com.

V-12-0017a 03/12


May 2012 I VOL 5, NO 4 5www.TheOncologyNurse.com

Editorial Board

EDITOR-IN-CHIEFBeth Faiman,PhD(c), MSN, APRN-BC, AOCNCleveland Clinic TaussigCancer InstituteCleveland, OH

Elizabeth Bilotti,RN, MSN, APRN,BC, OCNJohn Theurer Cancer CenterHackensack UniversityMedical CenterHackensack, NJ

Catherine Bishop,DNP, NP, AOCNPLansdowne, VA

Deena DamskyDell, MSN, RN-BC,AOCN, LNCFox Chase Cancer CenterPhiladelphia, PA

Wendy DiSalvo,DNP, APRN, AOCNGenentechNew London, NH

DeniceEconomou, RN,MN, CNS, AOCNCity of Hope NationalMedical CenterDuarte, CA

ConstanceEngelking, RN,MS, CNS, OCNThe CHE ConsultingGroup, Inc.Mt. Kisco, NY

Amy Ford, RN,BSN, OCNQuintilesDallas, TX

Sharon S. Gentry,RN, MSN, AOCNDerrick L. Davis ForsythRegional Cancer CenterWinston-Salem, NC

Cassandra J.Hammond, RN,MSN, CRNPAvid Education Partners,LLCSharpsburg, MD

Shannon Hazen,RN, BSN, OCNNovant HealthPresbyterian CancerCenterCharlotte, NC

Patricia IrouerHughes, RN, MSN,BSN, OCNPiedmont HealthcareRex, GA

Taline Khoukaz,NP, MSN, ACNP-CUniversity of SouthernCaliforniaNorris Cancer Center &HospitalLos Angeles, CA

Sandra E. Kurtin,RN, MS, AOCN,ANP-CArizona Cancer CenterTucson, AZ

Ann McNeill,MSN, RN, NP-C,OCNJohn Theurer Cancer CenterHackensack UniversityMedical CenterHackensack, NJ

Kena C. Miller,RN, MSN, FNPRoswell Park CancerInstituteBuffalo, NY

Patricia Molinelli,MS, RN, APN-C,AOCNSSomerset Medical CenterSomerville, NJ

Ellen A. Neylon,MSN, FNP, CCRP,OCNColumbia UniversityMedical CenterCenter for LymphoidMalignanciesNew York, NY

Dolores “Jeff”Nordquist, RN, MS,CS, FNPMayo ClinicRochester, MN

MelindaOberleitner, RN,DNS, APRN, CNSCollege of Nursing andAllied Health ProfessionsUniversity of LouisianaLafayette, LA

Jayshree Shah, NPJohn Theurer Cancer CenterHackensack UniversityMedical CenterHackensack, NJ

Gary Shelton,MSN, NP, ANP-BC,AOCNPNYU Clinical CancerCenterNew York, NY

Lori Stover, RN,BSNWestern PennsylvaniaCancer Institute Pittsburgh, PA

Joseph D.Tariman, PhD,APRN, BCNorthwestern UniversityMyeloma ProgramChicago, IL

Jacqueline MarieToia, RN, MS, DNPNorthwestern UniversityMyeloma ProgramChicago, IL

Pamela HallquistViale, RN, MS,CS, ANP, AOCNSaratoga, CA

Connie Visovsky,RN, PhD, APRNUniversity of South Florida College of Nursing Tampa, FL

Rita Wickham,PhD, RN, AOCNNorthern MichiganUniversity Independent Oncology &Palliative Care ConsultantMarquette, MI

Karla Wilson, RN,MSN, FNP-C, CPONCity of Hope NationalMedical CenterDuarte, CA

PharmacyJohn F. Aforismo,BSc Pharm, RPh,FASCPRJ Health SystemsInternational, LLCWethersfield, CT

NutritionKaren Connelly,RD, CSOSomerset Medical CenterSomerville, NJ

Patient AdvocatePeg FordOvarian Cancer AdvocacyAllianceCoronado, CA

Social WorkCarolyn Messner,DSW, MSW, LCSW-R, BCDCancerCareNew York, NY

Managed Care andPharmaceuticalManagementBurt Zweigenhaft,BSBioPharma Partners LLCNew York, NY

Isabell Castellano, RNBristol-Myers Squibb Children’s HospitalRobert Wood Johnson University HospitalNew Brunswick, NJ

Jeanne Westphal, RNMeeker County Memorial HospitalLitchfield, MN


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The Oncology Nurse-APN/PA®, ISSN 1944-9798 (print);ISSN 1944-9801 (online) is published 11 times a year byGreen Hill Healthcare Communications, LLC, 241Forsgate Drive, Suite 205C, Monroe Twp, NJ 08831.Telephone: 732.656.7935. Fax: 732.656.7938. Copyright©2012 by Green Hill Health care Com munications,LLC. All rights reserved. The Oncology Nurse-APN/PA®

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do not necessarily reflect those of the Editorial Board, theEditorial Director, or the Publisher. Publication of anadvertisement or other product mention in The OncologyNurse-APN/PA® should not be construed as an endorse-ment of the product or the manufacturer’s claims.Readers are encouraged to contact the manufacturer withquestions about the features or limitations of the productsmentioned. Neither the Editorial Board nor the Publisherassumes any responsibility for any injury and/or damageto persons or property arising out of or related to any useof the material contained in this periodical. The reader isadvised to check the appropriate medical literature andthe product information currently provided by the manu-facturer of each drug to be administered to verify thedosage, the method and duration of administration, orcontraindications. It is the responsibility of the treatingphysician or other healthcare professional, relying onindependent experience and knowledge of the patient, todetermine drug dosages and the best treatment for thepatient. Every effort has been made to check generic andtrade names, and to verify dosages. The ultimate respon-sibility, however, lies with the prescribing physician.Please convey any errors to the Editorial Director.

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6 May 2012 I VOL 5, NO 4 www.TheOncologyNurse.com

About the Editor

All of us here at The OncologyNurse-APN/PA (TON) arepleased to announce that our

editor-in-chief, Beth Faiman, was therecipient of the 2012 Oncology

Nursing Society (ONS) Excellence inMed ical Oncology Award. She washonored during the opening cere-monies at the ONS 37th AnnualCongress, held in New Orleans,Louisiana.The award recognizes accomplish-

ments in the advancement of nurs-ing knowledge within hematologyand medical oncology. Beth clearlymet the criteria, as an active author,educator, mentor, and researcher inthe field. She is currently an AdultNurse Practitioner in the MultipleMyeloma Program at the TaussigCancer Institute of the ClevelandClinic.Beth commented on receiving the

award, “Every day I am inspired bynurses, patients, caregivers, andmembers of the healthcare team. It istruly an honor to win this prestigiousaward and represent each and every

nurse who is as deserving of thishonor as I am.” She added that dealing with her

patients’ problems is especiallyimportant to her. “Being recognizedas recipient of the 2012 ONSExcellence in Medical OncologyAward will allow me to achieve oneof many goals, which is to become anurse researcher with a focus on can-cer symptom management. My edu-cation enables me to conductresearch and investigation into mypatients’ problems,” she said. “I aspireto become a nurse researcher in theCancer Institute. Many supportivetreatments will go uninvestigated dueto a lack of researchers. I am the for-tunate recipient of NIH funding tocontinue my education and achievemy goal.” Congratulations, Beth! You are truly

deserving of this recognition. �

About This Issue

This month’s Fourth AnnualReview Issue of The OncologyNurse-APN/PA (TON) high-

lights some of the advances in cancercare over the past year. While this issuepresents several of the most noteworthydevelopments, we could only scratchthe surface of all that has happened inthe world of oncology. One needs onlyto look at the total number of abstractspresented at the American Society ofHematology and the American Societyof Clinical Oncology annual meetingsto know how much potentially prac-tice-changing research is in thepipeline. Some of these developmentshave been presented in previous issueswhile others will be featured in upcom-ing issues as researchers release updateddata from ongoing studies.Although each issue of TON fea-

tures articles that illustrate how rapidlypractices are changing—everythingfrom the expanding use of oral oncolyt-

ics to the increasing role of personal-ized medicine in oncology—this issuein particular points out how impor-tant it is for oncology nurses to beaware of all these advances, both forthemselves and for their patients.Newer therapies bring about changesto daily practice, and informed nursescan better help their patients under-stand these treatments.As we did in last month’s issue, we

present the 4 finalists for the secondannual Oncology Nurse Excellenceaward. The 4 finalists—Darcie Deaver,MSN, NP-C; Wendy Miano, RN,

MSN, DNP, DN; Patricia (Patti)Palmer, RN, MS, AOCN; andDeborah Thompson, BSN, ONC—were selected from among the manynominations we received. The out-standing contributions of each finalistare representative of all the accom-plishments of those who are part of theoncology nursing profession. If youhaven’t already done so, go towww.TheOncologyNurse.com/awardto vote for your choice as the recipientof the Oncology Nurse Excellenceaward. The winner will be announcedin the June issue. �

Visit our Web site to vote for

the recipient of the second annual

Oncology Nurse Excellence award.

Beth Faiman, PhD(c), MSN, APRN-BC, AOCNEditor-in-Chief

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www.TheOncologyNurse.com8 May 2012 I VOL 5, NO 4

News Briefs

Pazopanib, an angiogenesisinhibitor, achieved meaning-ful responses in about three-

quarters of patients with refractoryurothelial cancer in preliminaryclinical trial results presented at apress briefing during the 2012Annual Meeting of the AmericanAssociation for Cancer Research(AACR) in Chicago, Illinois.

According to lead author of thestudy, Andrea Necchi, MD,Instituto Nazionale dei Tumori,Milan, Italy, this is the first target-ed therapy to demonstrate mean-ingful clinical activity in patientswith refractory urothelial cancer.He called the 76% rate of diseasestabilization “remarkable,” notingthat data on other efficacy out-comes are needed in the future.

The study also provided somenew information on interleukin-8(IL-8) levels as a potential biomark-er for response. Elevated levels of IL-8, as well as rising IL-8 levels duringthe first 4 weeks of pazopanib treat-ment, were associated with tumorprogression and shorter overall sur-vival. These data need to be con-firmed in further trials.

“Our data indicate that pazopanibseems to be a legitimate drug in thisdisease. Most interestingly, our bio-marker analysis clearly pointed outthe role of rising levels of circulatinginterleukin-8 as an early and poten-tially practice-changing indicator oftumor resistance and poor survival,”he said, as reported in a news releasefrom AACR.

Second-line therapies thus farhave been disappointing inadvanced urothelial cancer, whichhas a poor prognosis. Median over-all survival is about 4 to 5 months.

TREANDA® is her chemo. This is her therapy.

Five-year overall survival of metastaticurothelial cancer is about 10% to 15%.

Although targeted therapies are theoret-ically attractive in bladder cancers, thus

far no beneficial strategies have beenidentified until this trial.

“Our biomarker

analysis clearly

pointed out the role of

rising levels of

circulating interleukin-8

as an early and

potentially practice-

changing indicator of

tumor resistance and

poor survival.”

—Andrea Necchi, MD

Pazopanib Potential Treatment for Refractory Urothelial CancerBy Alice Goodman



News Briefs

*TREANDA (95% CI: 11.7, 23.5) vs chlorambucil (95% CI: 5.6, 8.6).† HR=hazard ratio.‡CI=confidence interval.

§ Independent Review Committee assessment was based on modified International Working Group response criteria (IWG-RC). Modifications to IWG-RC specified that persistently positive bone marrow in patients who met all other criteria for complete response (CR) would be scored as partial response (PR). Bone marrow sample lengths were not required to be ≥20 mm.

Important Safety Information

l

LEARN MORE AT WWW.TREANDA.COM Please see accompanying brief summary of full Prescribing Information.

Oncology

20100 30 4025155

PROGRESSION-FREE SURVIVAL (PFS): CHRONIC LYMPHOCYTIC LEUKEMIA (CLL)

35

TREANDA(n=153)

Chlorambucil(n=148)18 months

median PFS

45

0.10.20.30.40.5

Surv

ival

dis

tribu

tion

func

tion

0.60.70.80.91.0

Months

HR†=0.27 (95% CI‡: 0.17, 0.43) P<.0001

6 monthsmedian PFS

Discover the elements of efficacy and safety

Patients responding (%)

(n=57)

(n=17)

0 20 40 60 80 100

ORR§: INDOLENT B-CELL NHL THAT HAS PROGRESSED

PR

CR/CRu 17%

57%74%Total ORR

(95% CI: 64.3, 82.3)

Single-agent TREANDA produced a 74% ORR§ in patients with indolent B-cell NHL that had progressed

Single-agent TREANDA tripled median PFS in patients with CLL*

during or within 6 months of treatment with rituximab or a rituximab-containing regimen. Patients were scheduled

2 21-day treatment cycle, up to 8 cycles

non-hematologic adverse reactions (frequency ≥30%)

common hematologic abnormalities (frequency ≥

(88%), neutropenia (86%), and thrombocytopenia (86%)

randomized, open-label, phase 3 trial in treatment-naïve

2 intravenously on

up to 6 cycles

common non-hematologic adverse reactions (frequency ≥

abnormalities (frequency ≥

Built for Action®

The phase 2, open-label, proof-of-concept study enrolled 41 patients withadvanced or metastatic urothelial can-cer. Fifty percent progressed on second-line therapy. Patients received daily

pazopanib 800 mg once a day untildevelopment of disease progression orunacceptable toxicity, or withdrawal.

According to RECIST criteria (fortumor shrinkage), objective responses

were seen in 7 patients and stable dis-ease in 24 patients (total disease stabi-lization, 31 out of 41 patients: 76%).Median progression-free survival(PFS) was 2.6 months and median

overall survival was 4.7 months. At 2months, 61% of patients were free ofprogression, and durable PFS was seenin 10% of patients at a median follow-up of 19 months. �



News Briefs

Brief Summary of Prescribing Information

INDICATIONS AND USAGE: TREANDA is indicated for the treatment of patients with chronic lymphocytic leukemia (CLL). Efficacy relative to first line therapies other than chlorambucil has not been established. TREANDA for Injection is indicated for the treatment of patients with indolent B-cell non-Hodgkin’s 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. 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 349 patients who participated in an actively-controlled trial (N=153) for the treatment of CLL and two single-arm studies (N=176) 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 CLL. The data described below reflect exposure to TREANDA in 153 patients. TREANDA was studied in an active-controlled trial. The population was 45-77 years of age, 63% male, 100% white, and had treatment naïve CLL. All patients started the study at a dose of 100 mg/m2 intravenously over 30 minutes on days 1 and 2 every 28 days. Adverse reactions were reported according to NCI CTC v.2.0. In the randomized CLL clinical study, non-hematologic adverse reactions (any grade) in the TREANDA group that occurred with a frequency greater than 15% were pyrexia (24%), nausea (20%), and vomiting (16%). Other adverse reactions seen frequently in one or more studies included asthenia, fatigue, malaise, and weakness; dry mouth; somnolence; cough; constipation; headache; mucosal inflammation; and stomatitis. Worsening hypertension was reported in 4 patients treated with TREANDA in the randomized CLL clinical study and none treated with chlorambucil. Three of these 4 adverse reactions were described as a hypertensive crisis and were managed with oral medications and resolved. The most frequent adverse reactions leading to study withdrawal for patients receiving TREANDA were hypersensitivity (2%) and pyrexia (1%). Table 1 contains the treatment emergent adverse reactions, regardless of attribution, that were reported in ≥ 5% of patients in either treatment group in the randomized CLL clinical study.

Table 1: Non-Hematologic Adverse Reactions Occurring in Randomized CLL Clinical Study in at Least 5% of Patients

Number (%) of patients TREANDA Chlorambucil (N=153) (N=143)System organ class Preferred term All Grades Grade 3/4 All Grades Grade 3/4Total number of patients with at least 1 adverse reaction 121 (79) 52 (34) 96 (67) 25 (17)Gastrointestinal disordersNausea 31 (20) 1 (<1) 21 (15) 1 (<1)Vomiting 24 (16) 1 (<1) 9 (6) 0 Diarrhea 14 (9) 2 (1) 5 (3) 0

Table 1: Non-Hematologic Adverse Reactions Occurring in Randomized CLL Clinical Study in at Least 5% of Patients (continued)

Number (%) of patients TREANDA Chlorambucil

(N=153) (N=143)System organ class Preferred term All Grades Grade 3/4 All Grades Grade 3/4 General disorders and administration site conditionsPyrexia 36 (24) 6 (4) 8 (6) 2 (1)Fatigue 14 (9) 2 (1) 8 (6) 0Asthenia 13 (8) 0 6 (4) 0Chills 9 (6) 0 1 (<1) 0Immune system disordersHypersensitivity 7 (5) 2 (1) 3 (2) 0Infections and infestationsNasopharyngitis 10 (7) 0 12 (8) 0Infection 9 (6) 3 (2) 1 (<1) 1 (<1)Herpes simplex 5 (3) 0 7 (5) 0Investigations Weight decreased 11 (7) 0 5 (3) 0Metabolism and nutrition disorders Hyperuricemia 11 (7) 3 (2) 2 (1) 0Respiratory, thoracic and mediastinal disorders Cough 6 (4) 1 (<1) 7 (5) 1 (<1)Skin and subcutaneous tissue disorders Rash 12 (8) 4 (3) 7 (5) 3 (2) Pruritus 8 (5) 0 2 (1) 0

The Grade 3 and 4 hematology laboratory test values by treatment group in the randomized CLL clinical study are described in Table 2. These findings confirm the myelosuppressive effects seen in patients treated with TREANDA. Red blood cell transfusions were administered to 20% of patients receiving TREANDA compared with 6% of patients receiving chlorambucil.

Table 2: Incidence of Hematology Laboratory Abnormalities in Patients Who Received TREANDA or Chlorambucil in the Randomized CLL Clinical Study

TREANDA Chlorambucil (N=150) (N=141)

Laboratory Abnormality All Grades Grade 3/4 All Grades Grade 3/4 n (%) n (%) n (%) n (%)Hemoglobin Decreased 134 (89) 20 (13) 115 (82) 12 (9)Platelets Decreased 116 (77) 16 (11) 110 (78) 14 (10)Leukocytes Decreased 92 (61) 42 (28) 26 (18) 4 (3)Lymphocytes Decreased 102 (68) 70 (47) 27 (19) 6 (4)Neutrophils Decreased 113 (75) 65 (43) 86 (61) 30 (21)

In the randomized CLL clinical study, 34% of patients had bilirubin elevations, some without associated significant elevations in AST and ALT. Grade 3 or 4 increased bilirubin occurred in 3% of patients. Increases in AST and ALT of Grade 3 or 4 were limited to 1% and 3% of patients, respectively. Patients treated with TREANDA may also have changes in their creatinine levels. If abnormalities are detected, monitoring of these parameters should be continued to ensure that significant deterioration does not occur. 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 3. 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 3: 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 Number (%) of patients*Preferred term All Grades Grade 3/4Total number of patients with 176 (100) 94 (53)at least 1 adverse reaction Cardiac disordersTachycardia 13 (7) 0Gastrointestinal disordersNausea 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) 0Gastroesophageal reflux disease 18 (10) 0Dry mouth 15 (9) 1 (<1)Abdominal pain upper 8 (5) 0Abdominal distension 8 (5) 0General disorders and administration site conditionsFatigue 101 (57) 19 (11)Pyrexia 59 (34) 3 (2)Chills 24 (14) 0Edema peripheral 23 (13) 1 (<1)Asthenia 19 (11) 4 (2)Chest pain 11 (6) 1 (<1)Infusion site pain 11 (6) 0Pain 10 (6) 0Catheter site pain 8 (5) 0

Aspecific subgroup of womenwith early-stage breast cancermay be able to avoid adjuvant

radiation, according to a presentation

at the 2012 Annual Meeting of theAmerican Association for CancerResearch (AACR) held in Chicago,Illinois. Women with the luminal A

subtype of breast cancer, particularlythose older than age 60, had fewerlocal recurrences at 10 years whentreated with tamoxifen alone versus

tamoxifen plus radiation therapy in apost hoc analysis of a randomizedtrial that compared these 2 forms oftreatment.

N

N G

18 (10) 5 (3)U 18 (10) 0U 17 (10) 4 (2)S 15 (9) 0P 14 (8) 9 (5)F

11 (6) 2 (1)N 11 (6) 0I

31 (18) 3 (2) M

22 (13) 1 (<1)H 15 (9) 9 (5)M

25 (14) 5 (3)A 11 (6) 0P 8 (5) 2 (1)B 8 (5) 0N

13 (7) 0

P

14 (8) 1 (<1)D 10 (6) 0R

38 (22) 1 (<1)D 28 (16) 3 (2)P 14 (8) 1 (<1)W 8 (5) 0N 8 (5) 0S

28 (16) 1 (<1)P 11 (6) 0D 9 (5) 0N 9 (5) 0H 8 (5) 0V

10 (6) 2 (1)

*

I

greater toxicity, reduce the dose to

Cephalon, Inc.

T Frazer, PA 19355

T

Luminal A Subtype Breast Cancer: Forgo Radiation?



News Briefs

Senior author of this paper, Fei-FeiLiu, MD, radiologist at PrincessMargaret Hospital, senior scientist atthe Ontario Cancer Institute, and pro-fessor at the University of Toronto,

Canada, cautioned that local radiationtherapy is still the standard of care forall other breast cancer subtypes.Liu commented that avoiding radia-

tion therapy in these patients, who

account for about 25% of all newly diag-nosed breast cancer cases in NorthAmerica, could achieve an estimated$400 million in savings for the health-care system in the United States.

The luminal A subtype of breast can-cer is defined as estrogen receptor–posi-tive, progesterone receptor–positive,HER2-negative, and low Ki-67 (<14%),a proliferation marker. The study wasbased on molecular subtyping analysis of304 tumor blocks from 769 women withearly T1 or T2, node-negative breastcancer who participated in a randomizedcontrolled trial comparing tamoxifenplus whole-breast radiation therapy ver-sus tamoxifen alone. Using immunohis-tochemistry, the researchers classifiedtumors into 6 categories: luminal A,luminal B, luminal-HER2, HER2-enriched, basal-like, or triple-negativephenotype nonbasal.Overall, breast cancer recurrence at

10 years was 13.8% with tamoxifenalone compared with 5% for tamoxifenplus breast radiation. The luminal Asubtype had the best outcome of anysubgroup, with a 10-year risk of localrelapse of 8% with tamoxifen alone ver-sus 4.6% with tamoxifen and radiation.Luminal A patients older than age 60had a 10-year local recurrence rate of4.3% on tamoxifen alone versus 6% forcombined modality therapy. Grade 1/2luminal A tumors had a similar rate ofrecurrence regardless of treatment; 4.9%with tamoxifen versus 5.5% with tamox-ifen plus radiation. The researchers saidthat these findings suggest that localbreast radiation therapy did not affectthe outcome of older patients with theluminal A subtype. By contrast, radiation therapy had a

positive impact on other breast cancersubtypes. For example, women withluminal B tumors had a 10-year recur-rence rate of 16.1% with tamoxifenalone versus 3.9% with tamoxifen plusradiation therapy. A similar trend wasseen for HER2, HER2-enriched, andbasal-like tumors, but the numbers ineach group were small. These findings have implications for

personalized cancer medicine, suggest-ing that Ki-67 be added to the currentstandard testing for hormone receptorand HER2 status in newly diagnosedpatients with breast cancer. If thesedata on the luminal subtype A tumorsare validated, that would pave the wayfor discussions with patients with thissubtype about the need to undergoradiation therapy in addition totamoxifen or other adjuvant therapy.In a news release from AACR, Liu

was quoted as saying: “This is yetanother powerful example of ‘personal-ized cancer medicine.’ When thisinformation is combined with well-conducted randomized clinical trials,significant advances can be madewhereby we can truly start to tailortherapies, based on new molecularmarkers, which can be introduced intoroutine clinical practice.” � —AG

Table 3: Non-Hematologic Adverse Reactions Occurring in at Least 5% of NHL Patients Treated With TREANDA by System Organ Class and Preferred Term (N=176) (continued)

System organ class Number (%) of patients*Preferred term All Grades Grade 3/4 Infections and infestationsHerpes zoster 18 (10) 5 (3)Upper respiratory tract infection 18 (10) 0Urinary tract infection 17 (10) 4 (2)Sinusitis 15 (9) 0Pneumonia 14 (8) 9 (5)Febrile Neutropenia 11 (6) 11 (6)Oral Candidiasis 11 (6) 2 (1)Nasopharyngitis 11 (6) 0InvestigationsWeight decreased 31 (18) 3 (2) Metabolism and nutrition disordersAnorexia 40 (23) 3 (2)Dehydration 24 (14) 8 (5)Decreased appetite 22 (13) 1 (<1)Hypokalemia 15 (9) 9 (5)Musculoskeletal and connective tissue disordersBack pain 25 (14) 5 (3)Arthralgia 11 (6) 0Pain in extremity 8 (5) 2 (1)Bone pain 8 (5) 0Nervous system disordersHeadache 36 (21) 0Dizziness 25 (14) 0Dysgeusia 13 (7) 0Psychiatric disordersInsomnia 23 (13) 0Anxiety 14 (8) 1 (<1)Depression 10 (6) 0Respiratory, thoracic and mediastinal disordersCough 38 (22) 1 (<1)Dyspnea 28 (16) 3 (2)Pharyngolaryngeal pain 14 (8) 1 (<1)Wheezing 8 (5) 0Nasal congestion 8 (5) 0Skin and subcutaneous tissue disordersRash 28 (16) 1 (<1)Pruritus 11 (6) 0Dry skin 9 (5) 0Night sweats 9 (5) 0Hyperhidrosis 8 (5) 0Vascular disordersHypotension 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.

Hematologic toxicities, based on laboratory values and CTC grade, in NHL patients treated in both single arm studies combined are described in Table 4. 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 4: Incidence of Hematology Laboratory Abnormalities in Patients Who Received TREANDA in the NHL Studies

Percent of patientsHematology Variable All Grades Grade 3/4Lymphocytes Decreased 99 94Leukocytes Decreased 94 56Hemoglobin Decreased 88 11Neutrophils Decreased 86 60Platelets 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 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 LD50 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 CLL. Recommended Dosage: The recommended dose is 100 mg/m2 administered intravenously over 30 minutes on Days 1 and 2 of a 28-day cycle, up to 6 cycles. Dose Delays, Dose Modifications and Reinitiation of Therapy for CLL:

TREANDA administration should be delayed in the event of 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 3 or greater toxicity, reduce the dose to 50 mg/m2 on Days 1 and 2 of each cycle; if Grade 3 or greater toxicity recurs, reduce the dose to 25 mg/m2 on Days 1 and 2 of each cycle. Dose modifications for non-hematologic toxicity: for clinically significant Grade 3 or greater toxicity, reduce the dose to 50 mg/m2 on Days 1 and 2 of each cycle. Dose re-escalation in subsequent cycles may be considered at the discretion of the treating physician. 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.

Sterile Water for Injection, USP 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.

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

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

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.

Manufactured by: Manufactured for:Pharmachemie B.V. Cephalon, Inc.The Netherlands Frazer, PA 19355

TREANDA is a trademark of Cephalon, Inc., or its affiliates.

©2008-2011 Cephalon, Inc., or its affiliates. TRE-2263 March 2011(Label Code: 00016287.03) All rights reserved.This brief summary is based on TREANDA full Prescribing Information.



News Briefs

Contemporary treatment optionshave improved survival in cancerpatients, making it more impor-

tant than ever to focus on quality-of-lifeissues such as fertility in survivors ofchildbearing age. The majority of radiol-ogists and medical oncologists appear to

appreciate the need for attention to fer-tility in age-appropriate patients, accord-ing to a study published online ahead ofprint in Practical Radiation Oncology(Gwede C, et al. 2012). The survey foundthat more than 80% of radiation oncolo-gists and medical oncologists discuss the

impact of treatment on fertility withpatients of childbearing age.

“These findings are particularly impor-tant for radiation oncologists, who mayhave a unique role in communicating fer-tility preservation options to theirpatients, since their patients have daily

interaction with staff and weekly treat-ment exams with the radiation oncologyphysician and nurse,” stated senior authorof this paper, Gwendolyn P. Quinn, PhD,Moffitt Cancer Center, Tampa, Florida.

As the authors point out, with success-ful treatment, survival is increased. In thepast, the clinical focus was on keepingpatients alive, but now attention hasshifted to survival with good quality oflife. Chemotherapy, radiotherapy, andsurgery can impact fertility. Thus, optionsfor preserving fertility should be discussedprior to initiation of cancer treatmentwith patients who may want to have afirst child or an additional child.

Unfortunately, previous studies sug-gested that less than 50% of adult cancerpatients of childbearing age are givenadequate information about fertility-pre-serving options prior to cancer treatment,and less than 35% of women stated thatthey discussed risk of infertility during orafter cancer treatment.

The present study sought to examinepatterns of discussion of fertility preserva-tion and referrals among medical oncolo-gists, radiation oncologists, and surgicaloncologists. These professionals were sur-veyed about whether they “always/often,”“sometimes,” or “rarely/never” initiateddiscussions on the impact of treatment onfuture fertility.

Radiation and medical oncologistswere more proactive than surgical oncol-ogists in having fertility discussions withpatients; 83% of radiation oncologistsand 84% of medical oncologists discussedfertility options with patients “always/often,” compared with only 51% of surgi-cal oncologists. None of the radiationoncologists, 4% of medical oncologists,and 20% of surgical oncologists said they“never” discussed it with their patients.

Surprisingly, in view of the fertility dis-cussion rates, referral rates for fertilitypreservation among the 3 specialties weresimilar: 40% of radiologists, 45% of med-ical oncologists, and 46% of surgicaloncologists reported referring patients ofchildbearing age to fertility specialists“always/often.” � —AG

Radiologists and Medical Oncologists Attend toFertility Issues in Younger Survivors

Options for preserving

fertility should be

discussed prior to initiation

of cancer treatment with

patients who may want to

have a first child or an

additional child.

TARGET AUDIENCEThis initiative will target medical oncologists, hematologists, breast surgeons, radiationoncologists, oncology nurses, advanced practice nurses, nurse practitioners, physicianassistants, oncology pharmacists, managed care professionals, and others with clinicalresearch and management interest in treatment of ductal carcinoma in situ (DCIS) andearly-stage breast cancer.

STATEMENT OF NEEDAbility to detect DCIS has dramatically improved in recent decades, and the current inci-dence of DCIS is several-fold higher than in the 1970s and 1980s, largely due to increaseduse of mammography screening.1,2 However, attempts to identify subsets of DCIS womenwho may be spared radiotherapy and perhaps treated with surgery alone have heretoforebeen unsuccessful. This inability to predict which patients will develop recurrent DCIS orinvasive disease has complicated DCIS management. Many clinicians and other health-care professionals dealing with patients diagnosed with DCIS are unaware or incomplete-ly knowledgeable about the most recent results from a clinical trial examining the abilityof the 12-gene assay, using a prespecified DCIS algorithm, to predict recurrence risk, andthe implications these findings may have for management of their patients with DCIS. 1. Kerlikowske K. Epidemiology of ductal carcinoma in situ. J Natl Cancer Inst Monogr. 2010;2010:139-141.2. Virnig BA, Tuttle TM, Shamliyan T, Kane RL. Ductal carcinoma in situ of the breast: a systematic review of incidence,treatment, and outcomes. J Natl Cancer Inst. 2010;102:170-178.

EDUCATIONAL OBJECTIVESAfter completion of this activity, participants will be better able to:

• Identify approaches currently available or in development to predict recurrence riskin DCIS patients

• Explain how the 12-gene expression assay for DCIS was developed and how it compares with the 21-gene assay for early invasive breast cancer

• Describe the design and findings of the ECOG 5194 validation study• Apply the 12-gene assay for DCIS into clinical decision-making• Explain relevant information about the 12-gene DCIS assay and DCIS score topatients

Individualizing Treatment for DCIS of the Breast: New Molecular Approaches

www.coexm.com/ace09LOG ON TODAY TO PARTICIPATE

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

FACULTYChair:Lawrence J. Solin, MD, FACR,FASTROChairman Department of Radiation OncologyAlbert Einstein Medical CenterPhiladelphia, PA

E. Shelley Hwang, MD, MPHProfessor and Chief, Breast SurgeryDuke University Medical CenterDurham, NC

Kathy D. Miller, MDAssociate Professor Department of MedicineIU School of MedicineIndianapolis, IN

ACCREDITATIONPhysicians: Creative Educational Concepts, Inc. (CEC) is accredited by the Accreditation Council for Continuing MedicalEducation (ACCME) to provide continuing medical education for physicians. CEC designates this enduring educational activityfor a maximum of 1.0 AMA PRA Category 1 Credits™. Physicians should only claim credit commensurate with the extent of theirparticipation in the activity.Nurses:CEC is accredited as a provider of continuing nursing education by the American Nurses Credentialing Center’s (ANCC)Commission on Accreditation. CEC provides this activity for 1.0 contact hour. Learners are advised that accredited status doesnot imply endorsement by the provider or ANCC of any commercial products displayed in conjunction with an activity.Case Managers: This activity has been approved for 1.0 clock hour through 12/31/12 by the Commission for Case ManagerCertification. Case Managers number 790005057.

This activity is supported by an educational grant from Genomic Health, Inc.

��

� � ��



Lymphomas

Brentuximab vedotin was ap -proved by the US Food and DrugAdministration (FDA) on August

18, 2011, for the treatment of Hodgkinlymphoma (HL) that has relapsed afterautologous stem cell transplant(ASCT) as well as for the managementof relapsed anaplastic large cell lym-phoma (ALCL).1 It is an anticancerantibody conjugated to a cytotoxicagent, monomethyl auristatin E(MMAE). The antibody component isa chimeric antibody that targets CD30,a member of the tumor necrosis factorreceptor superfamily. Because of its lim-ited expression on healthy tissue, CD30is an attractive target for monoclonalantibody therapy.1 CD30 expression isrestricted to activated B and T lympho-cytes in healthy individuals; however,the function of CD30 is poorly under-stood. No diseases in humans have beenlinked to defects in CD30 genes.2 TheCD30 antigen is expressed in bothbenign and malignant disorders. Thenonmalignant disorders in which CD30is expressed include lymphomatoidpapulosis and disorders with virallytransformed B cells, such as infectiousmononucleosis, hepatitis C, and HIV,and in human T-lymphotropic virus 1–associated lymphoma cells. Malignantdisorders in which CD30 is expressedinclude ALCL, thyroid carcinoma,embryonal carcinomas, and select sub-types of B-cell–derived non-Hodgkinlymphomas and mature T-cell lym-phomas. Other lymphoid malignanciesin which CD30 is expressed include pri-mary mediastinal B-cell lymphoma, pri-mary effusion lymphoma harboring thehuman herpesvirus 8, immunoblasticlymphoma and multiple myeloma, adultT-cell lymphoma/leukemia, and mycosis

fungoides.2 HL and ALCL are the 2most common tumors expressing CD30.Attempts to target the CD30 antigen

with an unconjugated monoclonal anti-body have demonstrated minimal activ-ity. To enhance the antitumor effect ofCD30-directed therapy, the monoclon-al antibody SGN-30 was modified bythe addition of a valine-citrulline dipep-tide linker to enable attachment of theantitubulin agent MMAE, resulting inthe CD30 antibody-drug conjugate(ADC) brentuximab vedotin (SGN-35).1 ADCs combine the specificity oftargeting found with monoclonal anti-

bodies with the ability to deliver a high-ly toxic chemotherapy agent that can-not be administered systemically.1Brentuximab vedotin is designed to bestable in the bloodstream but to releaseMMAE once it is internalized intoCD30-expressing tumor cells. MMAEbinds to tubulin and disrupts the micro-tubule network within the cell andinduces cell cycle arrest and apoptoticcell death (Figure).1,3 In vitro, the drugis potent and selective against CD30-positive tumor cell lines. The recom-mended dose is 1.8 mg/kg administeredover 30 minutes every 3 weeks. The

maximum dose is 180 mg. It is adminis-tered as an intravenous (IV) infusion,not as a bolus or IV push. Treatment canbe continued to a maximum of 16cycles.4Two phase 1 clinical trials have been

completed using different schedulesincluding either 1- or 3-week intervals.In the initial phase 1 dose-escalationstudy in CD30-positive hematologicmalignancies, brentuximab vedotin wasadministered to 45 patients (42 withHL, 2 with ALCL, and 1 with CD30-positive angioimmunoblastic T-celllymphoma) every 3 weeks at dose levelsfrom 0.1 to 3.6 mg/kg. The phase 2 dosewas determined to be 1.8 mg/kg admin-istered every 3 weeks. Objectiveresponses, including 11 completeresponses, were noted in 17 patients.Objective responses were noted in 6patients (50%) who received the 1.8mg/kg dose. Tumor regression was notedin 86% of evaluable patients. The medi-an duration of response was at least 9.7months. Most patients (88%) withobjective responses demonstratedresponses within 4 treatment cycles.Median progression-free survival (PFS)was at least 5.9 months, and a trendtoward longer PFS was seen in patientswho received doses of ≥1.2 mg/kg. Thedrug was well tolerated overall acrossdose levels. Dose-limiting toxicitiesincluded neutropenia and hyper-glycemia. The most common treat-ment-related adverse events werefatigue (36%), pyrexia (33%), neu-tropenia (22%), peripheral neuropathy

Brentuximab Vedotin for the Treatmentof Relapsed/Refractory HL and ALCLBy Colleen Erb, MSN, CRNP, ACNP-BC, AOCNP, and Barbara Barnes Rogers, CRNP, MN, AOCN, ANP-BCFox Chase Cancer Center—Medical Oncology, Philadelphia, Pennsylvania

Case StudyBS is a 63-year-old male who was well until the summer of 2008 when he developed right calf discomfort along with the sen-sation of his foot feeling cold. He had throbbing discomfort that led him to the emergency room. A Doppler ultrasound wascompleted of the right lower extremity that showed no evidence of a deep vein thrombosis. Due to evidence of a distinct masson the right calf on MRI, an excisional biopsy was completed, and he was diagnosed with anaplastic large cell lymphoma(ALCL), stage IE. He was treated with 3 cycles of cyclophosphamide, doxorubicin, vincristine, and prednisone (CHOP) ther-apy. Following CHOP, he received involved-field radiation therapy (XRT) and was noted to be in complete remission. In thefall of 2009 (approximately 6 months after the completion of his initial therapy), he developed right upper arm discomfort. Afluorodeoxyglucose-avid lesion was noted on PET/CT, and a biopsy was performed that demonstrated recurrent ALCL. Hewas treated with XRT to the right upper arm. While receiving XRT, he developed lymphadenopathy that was biopsied andfound to be positive for ALCL. He was started on pralatrexate on a clinical trial but had progression of disease during the firstcycle. He was then treated with mesna, ifosfamide, mitoxantrone, and etoposide (MINE) but experienced disease progressionduring the second cycle. He was started on brentuximab vedotin and achieved a complete response while on therapy. Hereported numbness of his fingers and toes and experienced the sensation of his hands and feet feeling cold. He had a dosereduction after 10 cycles but completed 16 cycles. He remains in complete response 6 months after completion of therapy.

Figure. Mechanism of Action of Brentuximab Vedotin3

The antibody-drug conjugate (ADC) brentuximab vedotin binds to CD30 proteinson the cell surface. ADC then forms a complex with CD30 and enters the cell.Inside the cell, the ADC’s chemotherapy component is released and kills the cancer cell.

Colleen Erb, MSN, CRNP, ACNP-BC, AOCNP

Barbara Barnes Rogers, CRNP, MN, AOCN, ANP-BC

Continued on page 14


(PN) (22%), nausea (22%), and diar-rhea (22%). The adverse events wereprimarily grade 1 or 2. Fatigue, neu-tropenia, and PN were considered to bedose related.5In the second phase 1 study, brentux-

imab vedotin was administered weeklyfor 3 weeks with 1 week off (4-weekcycle). A total of 44 patients were treat-ed, with 38 of the patients having HL, 5 ALCL, and 1 peripheral T-cell lym-phoma. Doses ranged from 0.4 to 1.4mg/kg, with the maximum tolerateddose determined to be 1.2 mg/kg. Themost common side effects were periph-eral sensory neuropathy (66%), fatigue(52%), nausea (50%), diarrhea (32%),arthralgia (27%), and pyrexia (25%).Grade 3 adverse events occurring in ≥2patients were peripheral sensory neu-ropathy, anemia, neutropenia, peripher-al motor neuropathy, hyperglycemia,diarrhea, and vomiting. Grade 4 adverseevents occurred in 3 patients andincluded hyperglycemia, low potassiumand magnesium, and neutropenia. Theoverall objective response rate (ORR)was 59%, with 34% of patients attain-ing a complete response. Tumor regres-sion occurred in 85% of patients.6Two phase 2 clinical trials have been

completed in patients with relapsedHL and relapsed ALCL. In the firststudy, the efficacy of brentuximabvedotin was evaluated in patients withrelapsed or refractory HL who experi-

enced disease progression after under-going ASCT.7 Patients received bren-tuximab vedotin 1.8 mg/kg every 3weeks as a 30-minute infusion. Themaximum number of cycles was 16.The median age of the 102 patientstreated was 31 years. Patients hadreceived a median of 3.5 prior thera-pies and must have had failure with anASCT. The ORR was 75%, with 34%

achieving a complete response.Treatment-related toxicities includedperipheral sensory neuropathy, nausea,fatigue, neutropenia, and diarrhea.Adverse events that were grade 3 orhigher and occurred in ≥5% of patientsincluded neutropenia, peripheral sen-sory neuropathy, thrombocytopenia,and anemia.7In the second phase 2 study,8 58

patients with relapsed systemic ALCLwere treated with brentuximab vedotin1.8 mg/kg every 3 weeks for up to 16

cycles. The median age of the patientswas 52 years. Patients had received amedian of 2 prior regimens. The major-ity of patients (62%) had primaryrefractory disease, and 50% were refrac-tory to their most recent therapy.Seventy-two percent of the patients inthe trial had ALK-negative disease. TheORR was 86%, with 53% of thepatients achieving a complete response.

The median duration of response hadnot been reached. Of the 15 patientswith malignant cutaneous lesions atbaseline, 93% had resolution of alllesions. The median time to resolutionwas about 5 weeks.8Since a significant number of patients

who receive brentuximab vedotinachieve a complete response, an impor-tant question is whether patients can besuccessfully re-treated with brentux-imab vedotin. Bartlett and colleaguesreported on patients who were re-treated

with brentuximab vedotin in 3 multi-center studies.9 Patients who had anylevel of tumor response with prior bren-tuximab vedotin treatment and subse-quently experienced relapse were re-treated with brentuximab vedotin.Patients were treated at a dose of either 1mg/kg once a week or 1.8 mg/kg every 3weeks, depending on their original treat-ment schedule. Seven patients re-treatedhad a total of 8 retreatment experiences,with 2 complete responses, 4 partialresponses, and 2 stable disease.Therefore, it is believed that no signifi-cant resistance is developed to brentux-imab vedotin after the initial treatment.9The most common side effects of

brentuximab vedotin (≥20%) are neu-tropenia, peripheral sensory neuropa-thy, fatigue, nausea, anemia, upper res-piratory tract infection, diarrhea,pyrexia, rash, thrombocytopenia,cough, and vomiting (Table 1).4 Themost common grade 3/4 side effectsinclude neutropenia, peripheral sensoryneuropathy, thrombocytopenia, andanemia. MMAE is a strong inhibitor ofCYP3A4. Administration of brentux-imab vedotin along with ketoconazolecaused increased exposure to MMAE ofapproximately 34%. Therefore, patientstaking strong CYP3A4 inhibitors alongwith brentuximab vedotin should beclosely monitored for adverse reac-tions.4 In January 2012, the FDA noti-fied healthcare professionals that 2additional cases of progressive multifo-cal leukoencephalopathy (PML) hadbeen reported associated with brentux-imab vedotin, now totaling 3 cases ofPML.10 PML is a rare but serious braininfection that can result in death.Symptoms can include changes inmood or usual behavior; confusion;thinking problems; loss of memory;changes in vision, speech, and walking;and decreased strength or weakness inone side of the body. Due to its serious-ness, the FDA required a BoxedWarning to highlight this risk.Additionally, a new contraindicationwarning was added against using bren-tuximab vedotin with bleomycin dueto inceased risk of pulmonary toxici-ty.4,10 This was noted in a clinical trialevaluating combination therapy in HL.Noninfectious pulmonary toxicity wasmore common with brentuximabvedotin plus ABVD (doxorubicin,bleomycin, vinblastine, and dacar-bazine), with an incidence of 40%,than with brentuximab plus AVD(doxorubicin, vinblastine, and dacar-bazine) with an incidence of 0%.Other literature evaluating bleomycin-based regimens without brentuximabvedotin for HL have indicated theincidence of pulmonary toxicity to bebetween 10% and 25%.10,11


Lymphomas

Brentuximab Vedotin for the Treatment... Continued from page 13

Table 1 Common Toxicities of Brentuximab Vedotin Occurring in ≥20% of Patients4

Hodgkin Lymphoma Anaplastic Large Cell Lymphoma

Toxicity Any Grade Grade 3/4 Any Grade Grade 3/4

Blood and lymphatic system disordersNeutropenia 54% 21% 55% 21%Anemia 33% 10% 52% 2%Thrombocytopenia 28% 9% 16% 10%

Nervous system disorders

Peripheral sensory neuropathy 52% 8% 53% 10%

General disorders and administration site conditions

Fatigue 49% 3% 41% 4%Pyrexia 29% 2% 38% 2%

Infections and infestations

Upper respiratory tract infection 47% 0% 12% 0%

Gastrointestinal disorders

Nausea 42% 0% 38% 2%

Diarrhea 36% 1% 29% 3%

Abdominal pain 25% 3% 9% 2%

Vomiting 22% 0% 17% 3%

Skin and subcutaneous tissue disorders

Rash 27% 0% 31% 0%

Respiratory, thoracic, and mediastinal disorders

Cough 25% 0% 17% 0%

Management of side effects is of particular

importance when caring for patients

receiving brentuximab vedotin.



Lymphomas

Management of ToxicitiesManagement of side effects is of particu-lar importance when caring for patientsreceiving brentuximab vedotin. Grade3/4 side effects, including neutropenia,peripheral sensory neuropathy, thrombo-cytopenia, and anemia, are among themost commonly occurring toxicitiesrelated to brentuximab vedotin,4 requir-ing close monitoring and early assess-ment to prevent complications.Anemia is caused by the reduction of

circulating red blood cells due to damageto existing stem cells in the bone mar-row. Normally, when there is increaseddemand for red blood cell production,the bone marrow responds to thedemand by increasing production. Thiscompensatory response is diminished inpatients receiving cytotoxic therapy (eg,brentuximab vedotin) because of dam-age to the precursor cells in the bonemarrow.12 Monitoring for side effects ofanemia, including increased fatigue,lightheadedness, dizziness, palpitations,and shortness of breath, is important.One important intervention in the

management of chemotherapy-inducedanemia is transfusion of packed redblood cells. Transfusion criteria vary byinstitution, but generally, transfusion ofpacked red blood cells is ordered tomaintain hemoglobin between 7 g/dLand 9 g/dL in asymptomatic patientswith no significant comorbidities orbetween 8 g/dL and 10 g/dL in patientswith acute coronary syndrome, cere-brovascular disease, chronic obstructivepulmonary disease or hypoxemia, tachy-cardia, fever, or angina.12 The most com-mon risks related to red blood cell trans-fusions are transfusion reactions(including hemolytic, febrile, and non-hemolytic transfusion reactions as well astransfusion-related acute lung injury),congestive heart failure (especially if thepatient has known cardiac disease), virustransmission (though this risk isextremely low), bacterial contamination,iron overload, and increased thromboticevents.13 Informed consent should beobtained prior to administering bloodtransfusions.13 In addition to transfusionof packed red blood cells, erythrocyte-stimulating agents can be used in the pal-liative setting at provider discretion.13Thrombocytopenia, caused by a

reduction in the rate of platelet produc-tion, can be due to marrow injury frommyelosuppressive medications that leadto destruction of the precursormegakaryocytes.14 Patients receivingbrentuximab vedotin are at risk forthrombocytopenia during their treat-ment. Thrombocytopenia commonlyoccurs 10 to 14 days following theadministration of chemotherapy. Insome patients, dose decreases or delaysare necessary due to delayed platelet

recovery. Patients may not have anysymptoms until platelets fall below20,000/µL. Symptoms include petechi-ae, ecchymosis, hemorrhagic bullae onmucous membranes, gingival bleeding,epistaxis, menorrhagia, hematuria, GIbleeding, and bleeding from injectionsites. In patients with prolonged throm-bocytopenia, there is risk of cranialhemorrhage.15 Indications for prophy-lactic platelet transfusion are controver-sial. In general, evidence-based practiceleads to a trigger for platelet transfusionat levels <10,000/µL unless there areother risk factors making this unreason-able, including fever, increased whiteblood cell (WBC) count, coagulopathy,bleeding, or invasive procedures.15Neutropenia is also associated with

brentuximab vedotin. Neutropenia isdefined as an absolute neutrophilcount (ANC) <500 neutrophils/µL or<1000 neutrophils/µL and a predicteddecline to ≤500 neutrophils/µL overthe next 48 hours.16 The severity andduration of neutropenia correlate withpatient outcomes and influence thefrequency and severity of infection aswell as the response to chemotherapy.14Patients with prolonged severe neu-tropenia are at significantly increasedrisk of developing severe bacterial,viral, and fungal infections.14 The management of neutropenia

includes the use of growth factors toincrease the WBC count, as well as pre-venting and treating infections relatedto neutropenia. Myeloid growth factors,including filgrastim and sargramostim,have been approved by the FDA for usein the prevention of neutropenia relat-ed to chemotherapy administration.Both effectively increase the ANC, butthey have different side effect profiles.Filgrastim is a granulocyte colony-stim-ulating factor (G-CSF) and is more spe-cific for activation of neutrophils.17Filgrastim is available in a pegylatedform (pegfilgrastim) that has a half-lifeof 46 to 62 hours, compared with theplasma half-life of 3 to 4 hours for fil-grastim.18 Sargramostim is a granulo-

cyte-macrophage colony-stimulatingfactor (GM-CSF) that stimulatesmonocytes, eosinophils, and neu-trophils, prolongs their half-lives, andenhances their function.18 In patientswho have had neutropenic complica-tions during a prior cycle of brentux-imab vedotin without CSF support,CSFs can be instituted to decrease theneed for dose reductions or treatmentdelays. Dosing of filgrastim is 5µg/kg/day subcutaneously until an ANClevel >5000/µL is reached or pegfilgras-tim 6 mg subcutaneously once, with

both to be administered at least 24 hoursafter chemotherapy infusion. Admin -istration of CSFs during chemotherapyor within 24 hours of chemotherapy mayexpose the rapidly dividing myeloid cellsto the cytotoxic chemotherapy andresult in more profound neutropenia.The most common side effect of CSFs isbone pain,18 which can be treated suc-cessfully with NSAIDs or acetamino-phen if not contraindicated.19 Other,infrequent side effects include fever,petechiae, rash, splenomegaly, increasedliver enzymes, epistaxis, hypertension orhypotension, cardiac arrhythmias,headache, nausea, vomiting, peritonitis,leukocytosis, and transfusion reactions.19Of all the side effects of brentuximab

vedotin noted, peripheral sensory neu-ropathy can affect quality of life themost. PN can require dose reductions ordelays and can significantly impactdaily life.20 PN related to brentuximabvedotin is similar to that experienced bypatients receiving microtubule-target-ing agents (MTAs),5 such as vinca alka-

loids, taxanes, and the recently intro-duced epothilone analog, ixabepilone.21MTAs interfere with the normal func-tion and structure of the microtubulesin cells, leading to tumor cell death byarresting the cell cycle.21 This mecha-nism of action leads to interruption ofthe active transport of proteins andother components within the neurons,thereby affecting axonal transport inthe neurons. Neurons depend on thistransport of proteins for survival.21Because the peripheral nerves havelonger axon length and more perme-ability due to their structure, they aremore frequently and quickly affected bythis interruption, causing neuropathy.21PN is manifested in most patients

receiving brentuximab vedotin by sen-sory findings, including paresthesia,pain or burning, allodynia, hyperesthe-sia or numbness, decreased vibratorysensation, and reduced or absent deeptendon reflexes. There may also bemotor findings consistent with neuropa-thy that include generalized muscleweakness, decreased fine motor skills,and vocal cord dysfunction. Lastly,autonomic findings, though less likely,can include abdominal cramping, con-stipation, severe ileus, and urinaryretention. Grading usually takes intoaccount the effect on quality of life anddaily activities (Table 2).21,22Preexisting PN from any other causes

increases the risk and severity of PNrelated to treatment.22 Certain condi-tions that put patients at increased riskof developing PN from brentuximabvedotin include diabetes, alcoholism,nutritional deficiencies, and infectiousdiseases such as AIDS or Lyme disease.21Assessment of patients in whom there issuspicion of neuropathy should includeevaluation for signs of decreasedstrength or diminished reflexes; symp-toms including pain, paresthesia, orhyperesthesia; and any interferencewith activities of daily living.20 In mostcases of neuropathy, signs or symptomswill begin in the distal extremities and

Table 2 NCI CTCAE Version 4.03 Grading of Peripheral Neuropathy21,22

Grade 1 Grade 2 Grade 3 Grade 4 Grade 5

Peripheral motor neuropathy

Asymptomatic;clinical or diagnosticobservations only;intervention notindicated

Moderate symp-toms; limitinginstrumental ADL

Severe symptoms; limiting self-careADL; assistivedevice indicated

Life-threateningconsequences;urgent intervention indicated

Death

Peripheral sensory neuropathy

Asymptomatic; loss of deep tendonreflexes or paresthesia

Moderate symp-toms; limitinginstrumental ADL

Severe symptoms;limiting self-careADL

Life-threateningconsequences;urgent intervention indicated

Death

Abbreviations: ADL, activities of daily living; CTCAE, Common Terminology Criteria for Adverse Events; NCI,National Cancer Institute.

Of all the side effects of

brentuximab vedotin

noted, peripheral sensory

neuropathy can affect

quality of life the most.




Lymphomas

progress proximally in a stocking-glovedistribution.20 The only proven treatment methods

for PN are discontinuation, delay, or dosereduction of brentuximab vedotin.5 Inone study, resolution of PN was noted in10 of 16 patients (63%) at the last safetyassessment, approximately 30 days fromthe last dose of brentuximab vedotin; theonly grade 3 event, which was observedin a patient in the 2.7-mg cohort,returned to grade 1 after approximately 4months.5 In most cases, neuropathy willresolve after discontinuation of therapyor by decreasing the dose of brentuximabvedotin, but in some cases it becomessevere and irreversible.21Other interventions have been used

in the treatment of chemotherapy-induced PN (CIPN), but none havebeen proven by prospective randomizedclinical trial data, and none are FDAapproved at this time. Some of theseinclude tricyclic antidepressants, includ-ing amitriptyline, desipramine, andimipramine, that modulate sodiumchannels and inhibit reuptake of norepinephrine and serotonin, whichleads to decreased pain.23 Anti -convulsants, including gabapentin, arealso often used, although there havebeen no data to show true reduction ofpain.20 Opioid pain medication has beenused to treat CIPN, with good reliefreported by patients. Opioids can betitrated to achieve maximal reduction ofpain. Once maximal relief is achieved,the preferred plan of care includes a long-acting opioid analgesic with a short-act-ing medication used only for break-through pain.20 Other compounds underinvestigation specifically for neuropathycaused by MTAs include amifostine, glu-tamine, and gluta thione.21 There are nolarge randomized trials demonstratingefficacy of these agents and, in general,all evidence and current clinical guide-lines do not recommend using amifos-tine.21 Glutamine and glutathione haveshown some promise in reducing theseverity of PN, but again, there are nolarge trials to support their use.21 In gen-eral, continued assessment and earlyintervention are key to preventingsevere, irreversible PN, and patientsshould be advised to report symptomsimmediately.21

Nursing management of patientsreceiving brentuximab vedotin includesgood assessment and patient education.Patients should be educated to reportsymptoms early and should be askedabout symptoms of PN or myelosuppres-sion at each visit, as early interventionwill prevent serious complications.Patients should be educated about earlydetection of PN and how to avoidfalling or other harmful situationsshould they lose sensation, propriocep-tion, or reflexes.21 Patient educationshould also include defining myelosup-pression for the patient, listing symp-toms to report, and explaining the rou-

tine of laboratory evaluations andchemotherapy treatments. Nursesshould also take time before the start oftreatment to teach patients about thepotential for and consequences of neu-tropenia. They should tell patients toreport signs and symptoms of infectionor any fever immediately to their physi-cian or nurses and let patients knowabout prevention of infection by way ofhand washing and avoiding contactwith anyone who appears ill.24Nurses can also help define fatigue-

fighting strategies such as prioritizingtasks and taking breaks to rest if neces-sary.25 Many studies have been conduct-ed to evaluate the use of exercise incombating fatigue. There is strong evi-dence supporting the benefits of exer-cise in managing fatigue.26 Exercise caneffectively reduce fatigue in many set-tings, including fatigue resulting fromchemotherapy. In this case, home-basedmoderate exercise, both aerobic andstrength training, has been proven to bebeneficial.26 The current recommenda-tion from the National Comp rehensiveCancer Network (NCCN) is to start

with low-intensity exercise of shortduration and then increase and modifythe plan as conditions change.27Currently, data are insufficient to rec-ommend specific amounts of time foractivity, but the US Surgeon Generaldoes recommend 30 minutes of activityon most days for all populations.27 Withthis in mind, caution should be taken inpatients with comorbidities such as res-piratory or cardiac disease and in thosewith bone metastasis, thrombocytopenia,anemia, and fever.27 In these patients,activity regimens should be closely mon-itored and individualized based on cur-rent physical activity level and ability.27Brentuximab vedotin is a novel ADC

that targets CD30. Responses have beenshown in patients with Hodgkin lym-phoma and anaplastic large cell lym-phoma that is relapsed or refractory toprior therapy. Responses have also beenshown in the retreatment setting. Whileoverall the therapy is tolerable, signifi-cant side effects (grade 3 or greater) withbrentuximab vedotin can include neu-tropenia, peripheral sensory neuropathy,thrombocytopenia, and anemia. Nursingassessment to detect side effects earlymay be useful in attenuating their sever-ity. In addition, interventions should beinitiated to minimize the impact of ther-apy on the patient’s quality of life. �

References1. Katz J, Janik JE, Younes A. Brentuximab vedotin(SGN-35). Clin Cancer Res. 2011;17:6428-6436.2. Younes A. CD30-targeted antibody therapy. Curr OpinOncol. 2011;23:587-593.3. Phillips C. Special report: trial suggests new treatmentoption for Hodgkin lymphoma. NCI Cancer Bulletin.2010;7(24):5. http://www.cancer.gov/ncicancerbulletin/121410/page5. Accessed February 12, 2012.4. Adcetris [package insert]. Bothell, WA: SeattleGenetics, Inc; 2012.5. Younes A, Bartlett NL, Leonard JP, et al. Brentuximabvedotin (SGN-35) for relapsed CD30-positive lym-phomas. N Engl J Med. 2010;363:1812-1821.6. Fanale MA, Forero-Torres A, Rosenblatt JD, et al. Aphase I weekly dosing study of brentuximab vedotin inpatients with relapsed/refractory CD30-positive hema-tologic malignancies. Clin Cancer Res. 2012;18:248-255.7. Chen RW, Gopal AK, Smith SE, et al. Results froma pivotal phase II study of brentuximab vedotin (SGN-35) in patients with relapsed or refractory Hodgkin lym-phoma (HL). J Clin Oncol (ASCO Meeting Abstracts).2011;29(suppl):Abstract 8031.8. Pro B, Advani R, Brice P, et al. Durable remissionwith brentuximab vedotin (SGN-35): updated results ofa phase II study in patients with relapsed or refractorysystemic anaplastic large cell lymphoma (sALCL). J Clin Oncol (ASCO Meeting Abstracts). 2011;29(suppl):Abstract 8032.9. Bartlett N, Grove LE, Kennedy DA, et al. Objectiveresponses with brentuximab vedotin (SGN-35) retreat-

ment in CD30-positive hematologic malignancies: acase series. J Clin Oncol (ASCO Meeting Abstracts).2010;28(suppl):Abstract 8062.10. FDA (2012). FDA drug safety communication: newboxed warning and contraindication for Adcetris (bren-tuximab vedotin). http://www.fda.gov/Drugs/DrugSafety/ucm287668.htm. Accessed April 6, 2012.11. Younes A, Connors JM, Park SI, et al. Frontlinetherapy with brentuximab vedotin combined withABVD or AVD in patients with newly diagnosedadvanced stage Hodgkin lymphoma. Blood (Proc ASH).2011;118(suppl):Abstract 955.12.Means RT Jr. Anemias secondary to chronic diseaseand systemic disorders. In: Greer JP, Foerster J, RodgersGM, et al, eds. Wintrobe’s Clinical Hematology. Vol 1.12th ed. Philadelphia, PA: Lippincott Williams &Wilkins, a Wolters Kluwer business; 2009:1221-1238.13. National Comprehensive Cancer Network. NCCNClinical Practice Guidelines in Oncology™: Cancer- andChemotherapy-Induced Anemia. V2.2012. http://www.nccn.org/professionals/physician_gls/pdf/anemia.pdf.Accessed August 20, 2011.14. Alvandi F, Klein HG. Blood transfusion. In:Rodgers GP, Young NS, eds. Bethesda Handbook ofClinical Hematology. Philadelphia, PA: LippincottWilliams & Wilkins; 2005:341-354.15. Lynch MP, Rogers BB. Thrombocytopenia. In:Camp-Sorrell D, Hawkins RA, eds. Clinical Manual forthe Oncology Advanced Practice Nurse. Pittsburgh, PA:Oncology Nursing Society; 2006:859-864.16. Galel SA, Nguyen DD, Fontaine MJ, et al.Transfusion medicine. In: Greer JP, Foerster J, RodgersGM, et al, eds. Wintrobe’s Clinical Hematology. Vol 1.12th ed. Philadelphia, PA: Lippincott Williams &Wilkins, a Wolters Kluwer business; 2009:689.17. National Comprehensive Cancer Network. NCCNClinical Practice Guidelines in Oncology™: MyeloidGrowth Factors. V1.2011. http://www.nccn.org/professionals/physician_gls/pdf/myeloid_growth.pdf. AccessedAugust 21, 2011.18. Green MD, Koelbl H, Baselga J, et al. A randomizeddouble-blind multicenter phase III study of fixed-dosesingle-administration pegfilgrastim versus daily filgras-tim in patients receiving myelosuppressive chemothera-py. Ann Oncol. 2003;14:29-35.19. Mohebtash M, Arlen PM. Hematopoietic growthfactors. In: Abraham J, Gulley JL, Allegra CJ, eds. TheBethesda Handbook of Clinical Oncology. Philadelphia,PA: Lippincott Williams & Wilkins; 2010:433-440.20. Quirion E. Filgrastim and pegfilgrastim use inpatients with neutropenia. Clin J Oncol Nurs.2009;13:324-328.21. Carlson K, Ocean AJ. Peripheral neuropathy withmicrotubule-targeting agents: occurrence and manage-ment approach. Clin Breast Cancer. 2011;11:73-81.22. US Department of Health and Human Services.National Cancer Institute Common Terminology Criteriafor Adverse Events (CTCAE); V4.03. 2010.23. Wickham R. Chemotherapy-induced peripheralneuropathy: a review and implications for oncologynursing practice. Clin J Oncol Nurs. 2007;11:361-376.24. O’Leary C. Neutropenia and infection. In: BrownCG, ed. Guide to Oncology Symptom Management.Pittsburgh, PA: Oncology Nursing Society; 2010:347-362.25. Miller S. Anemia. In: Brown CG, ed. Guide toOncology Symptom Management. Pittsburgh, PA:Oncology Nursing Society; 2010:29-47.26. Barsevick AM, Newhall T, Brown S. Managementof cancer-related fatigue. Clin J Oncol Nurs. 2008;12(5suppl):21-25.27. National Comprehensive Cancer Network. NCCNClinical Practice Guidelines in Oncology™: Cancer-RelatedFatigue. V1.2012. http://www.nccn.org/professionals/physician_gls/pdf/fatigue.pdf. Accessed August 20,2011.

Nursing management

of patients

receiving brentuximab

vedotin includes

good assessment and

patient education.

Brentuximab Vedotin for the Treatment... Continued from page 15


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Finalist Wendy Miano becameinterested in nursing as an under-graduate student when she had

the opportunity to volunteer at a hos-pice and was “struck by the notion ofthe patient and family as a unit of care,focusing on quality of life and empower-ment.” This focus has continued throughher career as an oncology nurse atUniversity Hospitals, Case MedicalCenter (UH/CMC), beginning in 1984.Wendy has practiced in adult and pedi-atric acute care oncology and adult andpediatric hospice, in addition to con-tributing to the development of newnurses as an instructor of medical/surgi-cal nursing. Her career path turned tonursing leadership in 1996 when shebecame Administrative Director of theIreland Cancer Center AmbulatoryServices and, in 2008, Chief NursingOfficer for Cancer Services atUH/CMC. Wendy believes the mostimportant qualities in an oncology

nurse are critical thinking skills andemotional maturity that accompany afocus on holistic communication withpatients to help them successfully navigate the complex multimodalitynature of cancer treatment.Wendy’s colleagues view her as a key

member of the team that collaboratedto design, construct, and open theSeidman Cancer Center in 2011. Thisfreestanding cancer hospital contains144 inpatient beds, ambulatory clinics,and support services. In writing theirnomination, they emphasized thatWendy was “truly a leader and rolemodel who effectively utilized clinicalknowledge in cancer patient care tocreate a new physical and programmat-ic model of oncology patient care, aunique achievement accomplishedrarely in this field.” Staying true to herearly impressions as an undergraduatestudent, Wendy attributes the successof the new facility to the input of 15 to

20 patient and family volunteers whowere involved in all facets of the designprocess, “sitting as partners with orga-nizational leaders.” Based on thisinput, the new facility has comfortablerooms outside each patient roomwhere family and friends can be closeto the patient, while also being able tohave personal time meeting their ownneeds and attending to other responsi-bilities. Even a small detail such asincluding a small safe in each roomallows what Wendy characterizes as a“monumental shift in how patients andfamilies move within the space.”When asked to reflect on what she

would be if not a nurse, Wendy wouldsee herself as an oceanographer, caringfor the earth through the interaction ofwater and animals. It is unmistakablethat Wendy Miano considers the bigpicture, while emphasizing the impor-tance of the individual, no matter whatthe situation.

OncologyNurse ExcellenceAward Finalists

It was a difficult process, but we have selected 4 finalists from among the peers you nominated for the second annual Oncology Nurse Excellence (ONE) award. All the nominees were outstanding, but these 4 individuals stood out for their display of leadership and compassion and for their commitment to evidence-based practices. Now it’s your turn. After you read about each finalist, please go to www.TheOncologyNurse.com/award and tell us your pick for the ONE award. We will announce the readers’ choice in the June issue of The Oncology Nurse-APN/PA.

Vote Now for Your Choicewww.TheOncologyNurse.com/award

Darcie Deaver, MSN, NP-CMoffitt Cancer CenterTampa, Florida

Darcie Deaver has been an oncol-ogy nurse since 2003, when shebegan her career as a staff nurse

in the inpatient bone marrow transplantunit. She completed a master of sciencedegree in nursing at the University ofSouth Florida (USF) in 2006 and is cur-rently a nurse practitioner in the malig-nant hematology program at MoffittCancer Center in Tampa, Florida.According to her colleagues, she “hasbeen a rock of support for our patients,our physicians, and our nurses. Sheconsistently communicates with andincludes the primary care team in thepatient care plan.” The most importantinformation she gives patients is thetruth, explaining the disease in a waythat makes sense to them, focusing onthe facts, research, and reality. Her col-

leagues say Darcie’s delivery of thisinformation is what makes her unique.She loves her job of caring for patients,and they experience her confidenceand compassion. If she weren’t a nurse,Darcie would probably go to medicalschool.

Valuing a quest for knowledge andexhibiting a never quitting spirit, Darcie

is also a doctoral candidate at USF. Shenow spends most of her day seeingpatients for her research. She has exten-sive knowledge about cutaneous T-celllymphoma, peripheral T-cell lymphoma,mycosis fungoides, and Sézary syndromeand has given many presentations onthese topics. Darcie has received a num-ber of awards, including an OncologyNursing Society commendation for out-standing achievement for her article“The Development of PericarditisFollowing Peripheral Blood Stem CellTransplantation: A Case Report” andMoffitt’s 2010 Advanced Practice Pro -fessional. In nominating her for the ONEaward, Darcie’s colleagues em phasize she“is always professional in her demeanor,gets along well with her peers, andalways gives her best to patient care.”

The most importantinformation Darciegives patients is thetruth, explaining thedisease in a way thatmakes sense to them.

Wendy Miano, RN, MSN, DNP,DNUniversity HospitalsCase Medical CenterCleveland, Ohio



theONE Award

When nominating Patti Palmerfor the ONE award, her col-leagues described her as an

exceptional oncology nurse educatorwho, during the past 2 years, guidedthe inpatient oncology team at theUniversity of California Davis MedicalCenter through Putting Evidence IntoPractice initiatives that improved sat-isfaction scores for communication

from 40% to 92%, teamwork from 57%to 81%, cohesiveness from 30% to81%, and overall excellent quality ofcare from 40% to 92%. Patti isinvolved with many aspects of oncolo-gy care at the Medical Center, includ-ing daily huddles with the medicaloncology, surgical oncology, and stem

cell transplant multidisciplinary teams,for whom she identifies patients whomay need to be seen for education oremotional support. She participates ininstitutional committees for the onlinechemotherapy order project, the sharedgovernance research committee, thescientific review committee for theCancer Center, and the clinical nursespecialist group.

Patti has been an oncology nurse for38 years. When she was preparing togo to college, she thought nursing wasa good fit for someone like herself wholikes science and math. Over the yearsshe has found that “empathy, compas-sion, caring, and a mind with a never-satisfied thirst for learning” are impor-

tant qualities for an oncology nurse topossess. She strives to get to know herpatients as individuals so she can makea plan of care that is uniquely suited tothem. In the future, Patti believes thatthe patient’s treatment experience canbe changed for the better by improv-ing teamwork from outpatient to in -patient and back again. Patti enjoysoncology as an ever-changing special-ty and has noticed that in the begin-ning she spent “a lot of time helpingpeople die (and not doing it verywell), and now we really focus on liv-ing full lives until and if you die.” Shesees 2012 as a very exciting time foroncology and a great time to be anoncology nurse.

If she weren’t a nurse, Patti enthusi-astically proclaimed that she would seeherself as a small and large animal vet-erinarian. This would be in addition tokeeping her current hobby as a fiberartist. Combining science and soft-ness, calculations and caring are char-acteristics that make Patti Palmer aworthy nominee for the ONE award.

When Deborah Thompsondescribes the connections she hopes to form with her

patients, she calls them “her familymembers.” She explains that her firstpriority is to help the patient developtrust in her and comfort within theenvironment, because when they firstcome to the infusion center where sheworks, they are afraid. To create this,Deborah talks about “taking part inthe journey together” with thepatients, their family, and theirfriends, and she has found that whenshe refers to her patients as familymembers, they view her differently.Other important qualities for anoncology nurse, according to Deborah,are compassion, honesty, integrity,dedication, and dependability. As evi-dence that Deborah practices what shepreaches, one of her patients wrote aletter of appreciation to Eric Shinseki,Secretary of Veterans Affairs, com-mending the care she rendered to him.

For the past 29 years, Deborah hasbeen an oncology staff nurse at theAtlanta Veterans AdministrationMedical Center. In the infusion center,

Deborah and her coworkers administerchemotherapy, immunotherapy, andblood products to 35 to 45 patients perday. In almost 3 decades of practice,she has seen many improvements inmedications available to the oncologypatient. She relates that when she firststarted practicing, patients becamedeathly ill with nausea and vomitingafter chemotherapy, and that is rarenow. She has seen a significant shift inchemotherapy administration from the

inpatient to the outpatient setting, andmost importantly, patients are livingmuch longer after treatment. Ac -cording to her colleagues, Deborah is adedicated nurse who is “enthusiasticabout educating her peers, the veterans,and the community, as evidenced byher consistent educational offerings.”

The importance of education is alsomanifest by Deborah’s other possiblecareer choice if not a nurse, that of ahealth reporter. She feels that increasedknowledge in the community aboutdiseases, and the importance of regularcheck-ups and early reporting of prob-lems, is very important.

Deborah believes in the importanceof providing patients with hope andencourages them to keep a positive atti-tude during their journey toward an

end goal. In fact, each day she writes apositive affirmation on the wall. Two ofour ONE award nominee’s favorites are“A word of encouragement can meanthe difference between giving up andgoing on” and “When life knocks youdown, try to land on your back, becauseif you can look up, you can get up.”

Deborah believes in the importance of providing patients with hope and encouragesthem to keep a positive attitude during theirjourney toward an end goal.

Patti believes that the patient’s treatment experience can be changed for the better byimproving teamwork from outpatient to inpatient and back again.

Deborah Thompson, BSN,ONCVeterans Administration Medical Center AtlantaDecatur, Georgia

Patricia (Patti) Palmer, RN,MS, AOCNUniversity of California Davis Medical CenterSacramento, California


Joann Ackler, RN, OCNAlbert Einstein Cancer CenterKhaled Alqawasmeh, MSNTawam HospitalRebecca Amirian, BSN Roswell Park Cancer InstituteToni Armstrong, BSN, ACLSTerrebonne General Medical CenterMonica Averia, MSN, ACNP, NPUSC Kenneth Norris Cancer HospitalGayle Balmaceda, RN, BSN, ANP-BC, GNP-BCUniversity of Texas MD Anderson Cancer CenterAnne Beatie, BSN, ONC, OCNUCDMC, Adult Infusion CenterPatricia Bluml, MSN, ARNP, OCNVia Christi Hospitals, Wichita-Blood and MarrowTransplant Center of KansasCarolyn Bowers, RN, OCNOchsner Baptist Radiation Oncology Megan BrownMethodist Infusion CenterMichele Brown, NPSt. Luke’s Mountain State Tumor Institute Tess Buckles, RN, OCNSouth Carolina Oncology AssociatesDyane Bunnell, MSN, RN-BC, CPON, AOCNSNemours/Alfred I. duPont Hospital for ChildrenMatthew Burke, MBA, RN, MSN, APRN-BCSmilow Cancer Hospital at Yale Joan Burnham, RNMethodist WillobrookDorothy Cafran, RN, BSN, OCNS, CHPNNorthern Westchester HospitalKim Calabro, BSN, RN, OCNOSF Saint Anthony Medical Center-Center forCancer CarePamela Calarese, MS, RN, CS, OCNDana Farber Cancer InstituteMahnaz Capps, BSNWalter Reed National Military Medical CenterSherry Cesati, RNLRGHealthcare OncologyCarlin Cialino, BSN, OCNAbramson Cancer Center, Hospital of theUniversity of PAFreda Clark, RN, OCNGrady Memorial HospitalMark Clark, RN, OCN, AOCN, MSN, FNP-BCNortheast Georgia Diagnostic ClinicKathleen Clifford, RN, MSN, C-FNP, AOCNSaint Luke’s Health SystemLinda Cothron, BSN, MSN, FNP, OCNChapters HealthcareCyndi Cramer, BA, RN, OCN, PCRNTampa General HospitalTracey Curtis, MSN, Board Certified, FamilyPractice Hematology/Oncology NPFlorida Cancer SpecialistsJulie Dartez White, RN, BSN, OCNCancer Care AssociatesBeth Delaney, APRN, OCN, BC-PCOhio State University, James Cancer CenterLourdes Dimafelix, RN, OCNMedical City DallasJanet Ditello, ADN, ACLSProvena Saint Joseph Medical CenterIryna Durnyeva, RN, BSN, OCNMaimonides Medical CenterEva Edrial, BSNProvena Saint Joseph Medical Center

Susan Epting, MSN, AOCNGenentechSylvia S. Estrada, RNC, WHCNP, CBCN, CCRP, MSN,MSHCM, BSNSaul and Joyce Brandman Breast Center, Cedars-Sinai Medical CenterSharon Etris, MSN, NPWinship Cancer Institute of Emory UniversityTrudie Eubanks, RNForrest General HospitalHelen Evers, BSN, RNMethodist Hospital Division, Thomas JeffersonUniversity Hospital Beverly Farmer, ADN, OCNDavid Lee Cancer Center, affiliated withCharleston Area Medical CenterSara Flickner, RN, BSN, OCNNorthwestern Memorial HospitalJana Floershiem, RN, ADN, OCNMiners Colfax Medical Center Sandy Forrester, RN, OCNAuerbach Hematology-OncologyDiashea FosterMethodist Infusion CenterLana Fournier, BSMinnesota OncologySusan Foy, RN, OCNReston Hospital CenterJennifer Goldschmitt, NPNorth Shore University Hospital/Monter Cancer CenterCassie Gossett, RN, BSN, OCNUniversity Medical Center BrackenridgeDeborah Hancock, RNGrady Memorial HospitalShannon Hazen, RN, BSN, OCNPresbyterian Hospital Kimberly Hess, ANP, OCNCoastal Carolina Health Care, New Bern Cancer CareSarah Holmes, RN, OCNAuerbach Hematology-OncologyChristine Hull, MSN, AOCNSInova Loudoun HospitalArlene Jacobson, RN, BSN, OCNMaimonides Cancer CenterStephany Jacques, RN, OCNRumford HospitalRobin Johnson, RN, OCNProvidence Holy Family HospitalLisa Karem, RN, BSN, OCNUPMC Cancer CenterSarah C. Kaveney, MSN, RN, OCN, NEA-BCThe Regional Cancer CenterCheri Kennedy, RN, OCNSanta Clara Valley Medical CenterColleen Krumpe, BSN, RN, OCNSt Mary Medical CenterSandra Kurtin, RN, MS, AOCN, ANP-CThe University of Arizona Cancer CenterZoe Lambrecht, RN, OCN, ELNECTampa General HospitalCheryl Larschan, ADNRobert and Carol Weissman Cancer Center atMartin Health SystemCarol Layug, BSNProvena Saint Joseph Medical CenterToni Maria Le Donne, BSN, RNMethodist Infusion CenterColleen Lemoine, MSN/APRN-BC/CNSInterim Louisiana State University Hospital

Rita M. Levy, RN, OCNDoylestown HospitalRobin Lewis, RN, BSN, CBCNWake Forest Baptist Medical CenterJennifer Lindeman, MSRoswell ParkVera Luzietti, RN, ONSUC HealthSuzanne “Windy” Lyle, MS, FNP, AOCNP, MS, NPPortland VA Medical CenterDenise Margiotta, Acute Nurse PractitionerNew York UniversityMemorial Sloan-Kettering Cancer CenterEvangeline Masalta, BSN, APNUniversity of Texas MD Anderson Cancer CenterToni McCoy, RN, BSNLongview Regional Medical CenterSusan McDonald, BSN, OCNBrigham and Women’s HospitalMelissa McEwen, ADN, OCNTexas OncologyMyra Mcgrath, RNHalifax Health Center for OncologyHolly Meyerowich, RN, OCNJupiter Medical CenterAmy Miller, OCNPaynesville Area Health Care SystemMaryKay Moore, BSNCleveland ClinicAndrea Moran, APRNNeag Comprehensive Cancer Center University of Connecticut Health CenterSabrina Mosseau, BS, RN, OCNSamaritan Hospital Cancer Treatment CenterMary P. Murphy, RN, OCN, CBCNAlbert Einstein Cancer CenterMassey Nematollahi, BScN, MScN, RNStronack Cancer Center at SouthlakeIris Nieves, BSN, OCNNassau University Medical CenterBridget E. O’Brien, DNP, APN, FNP-BC, AOCNPNorthwestern Faculty Foundation, Robert H. Lurie Comprehensive Cancer Center of NorthwesternUniversityMarsha Opalach, RN, OCN, MeD, CHPNCentraState Medical CenterLisa Pittman, RNAdventist Hinsdale HospitalTina Pryor, RNVirginia Oncology AssociatesMeghan C. Punda, CRNPCenter for Cancer and Blood DisordersAnna Quincy, BSN, OCNProvidence Sacred Heart Medical CenterAnnette Quinn, RN, MSNUPMC Shadyside Hospital, Dept. of RadiationOncology, University of Pittsburgh CancerInstituteDenise Menonna Quinn, RN-BC, MSN, AOCNSHackensack University Medical Center andBergen Regional Medical CenterDawn Reininger, BSN, OCNUniversity of Wisconsin Hospital and ClinicsStella Rineer, RNAuerbach Hematology-OncologyMaria Rivera, RNThe Center for Cancer and Blood DisordersSusan Roche, CRNP, MSN, DNP, AOCNP, APRN-BCThe Regional Cancer CenterRonda Rogers, RN, CBPN-ICTexas Health Physician Group

Kimberly Rohan, MS, APN, AOCN, BSN, MSN, NPEdward Cancer CenterJulie Ross, NPRoswell Park Cancer InstituteKim Ryan, APRN, OCNCT Oncology GroupJulie Sanner, RN, ONS, CBCNCoborn Cancer CenterSusan Schneider, PhD, RN, AOCN, ACNS-BC, FAANDuke University School of NursingMarie Christine Seitz, RN, MSN, ANP-BC, AOCNMount St. Mary’s College Andrea Shaffer, RN, BSN, ARNP, OCNMoffitt Cancer Center and Research InstituteKathy Shine, BSN, RNIronwood Cancer & Research CentersMichelle Shriner, BSN, OCNAdams County Cancer CenterAnne Skwira-Brown, RN, CNPEssentia Duluth Clinic Cancer CenterElisabeth Smith, BSNWinship Cancer Institute, Emory UniversityMaria Solaun, BSNCity Of HopeKaren Sommers, NPUniversity of California IrvinePauline Soucy, RN, AD, OCNSouthern New Hampshire Medical CenterMaria Stir, RNBayhealth Medical Center, Kent General HospitalCristina Suarez, CPNMiami Children’s HospitalMaggie Syta, RN/NPBone Marrow Clinic at Roswell Park CancerInstituteRosemary Taormina, BSN, OCNNancy N. & J. C. Lewis Cancer and ResearchPavilionKimberly Elizabeth Thorn, RN, BSN, OCNTexas Oncology-TylerRose Tiabbi, RN, BS, OCNNorth Shore Long Island Jewish Health Systemat Glen CoveSara M. Tinsley, MS, ARNP, AOCNMoffitt Cancer CenterJennifer Tripp, BSN, OCNParkland Medical Center Julie Vaday, MSNKaiser Permanente Santa Clara Medical CenterNancy Warner, RN Minnesota OncologyWendy Waters, RN, OCNSouth Carolina Oncology AssociatesMarigo Werner, RN, BSN, OCNPikeville Medical CenterMegan Wholey, NP/OCNVirginia Hospital CenterBeverly Williams, RNRay County Memorial HospitalAlicia Wojchik, RN, MA, CNP, AOCNPMN OncologyMaryanne Yarrington, RN, OCNProvidence Hospital and Medical CentersLyn Zehner, RN, MN, AOCNSInova Alexandria HospitalJennifer Zimmerman, ADPenn State Hershey Medical Center

Oncology Nurse Excellence AwardThank you to all for Participating in the 2012



Supportive Care

The link between cancer andthrombosis has been known formany years. Recently this con-

nection has come to the forefront withincreased recognition by healthcareproviders and mandates by governingbodies. The results of a thromboembolicevent can be catastrophic in a patientwith cancer. Malignant neoplasms aloneare associated with a 4-fold increased riskof a venous thromboembolic event(VTE), and cytotoxic or immunosup-pressive chemo therapy in creases themalignant neoplasm–associated risk tomore than 6-fold.1,2 VTE leads to a sig-nificant reduction in survival3-5 and isthe second-leading cause of death inpatients with cancer.6 Patients withcancer who have a VTE are also atincreased risk of recurrence, bleedingcomplications, and morbidity.7Patients with cancer have multiple

factors that increase their risk of VTE.First, the cancer itself produces a hyper -coaguable state for these patients.Certain cancers appear to carry a high-er risk than others (malignant braintumors; adenocarcinoma of the lung,ovary, pancreas, colon, stomach,prostate, and kidney; and hematologicmalignancies),8 but all cancers willincrease the patient’s overall VTE risk.The patient’s therapy also plays a

major role in the risk of VTE. Manynewer chemotherapeutic agents, suchas bevacizumab, carry an increased riskof thromboembolism.9 VTE riskincreases 2- to 5-fold when womenwith breast cancer are treated withtamoxifen.10,11 Aromatase inhibitorsalso increase this risk, but at about halfthe rate of tamoxifen.12 Thalidomideor lenalidomide increases throm boem-bolic risk, especially when used in com-bination with chemotherapy or high-dose dexamethasone.13 All of these areadditive to the other general risk fac-tors that these patients may already beexposed to, such as decreased mobility,surgeries or procedures, age, indwellingcatheters, and other comorbidities.Due to the high risk faced by cancer

patients, many guidelines have beendeveloped to help assist in the preven-tion and treatment of thromboembolicevents in these patients. The NationalComprehensive Cancer Network(NCCN), American Society of ClinicalOncology (ASCO), and the AmericanCollege of Chest Physicians (CHEST)

have issued guidelines to help practi-tioners prevent and treat thrombosis inpatients with cancer. These guidelineshave much overlap in their recommen-dations, and rightfully so. I will attemptto give a brief summary of some of theseguidelines specific to patients with can-cer (Table). For prevention of VTE, all 3 societies

agree that pharmacologic prophylaxisshould be initiated in hospitalized cancer patients in the absence of con-traindications.14-16 Low-dose unfrac-tionated heparin (LDUH), low-molecular-weight heparin (LMWH),or fondaparinux should be utilized.Pharmacologic prophylaxis would becontraindicated in patients who arebleeding or have a high risk for majorbleeding. In these patients, considermechanical prophylaxis with graduatedcompression stockings or intermittentpneumatic compression. If the throm-botic risk persists once the bleeding riskhas subsided, the use of pharmacologicprophylaxis should be reassessed and sub-stituted for mechanical prophylaxis.

For prevention of VTE in the surgicalpatient with cancer, again all 3 societiesagree. The guidelines recommendextended prophylaxis for surgical cancerpatients for up to 4 weeks, particularly inhigh-risk abdominal or pelvic sur-gery.14,15,17 All 3 recommend LMWH.NCCN and ASCO also support unfrac-tionated heparin as an alternative, andNCCN supports fondaparinux as well.Mechanical methods can be added topharmacologic prophylaxis in patients athighest risk.For patients in the ambulatory set-

ting, the societies previously agreed thatroutine prophylactic anticoagulationwas not recommended except inpatients with multiple myeloma whowere receiving thalidomide- or lenalido-mide-based combination regimens andin whom the risk of VTE warranted pro-phylaxis.14,15 The latest additions to theCHEST guidelines have extended thisrecommendation. These guidelines sug-gest that outpatients with solid tumorswho have additional risk factors for VTEbut who have a low risk for bleeding use

prophylactic doses of LMWH or LDUHover no prophylaxis.16 The additionalrisk factors include previous thrombosis,immobilization, hormonal therapy,angiogenesis in hibitors, and againthalidomide or lenalidomide therapy.This recommendation is based on mod-erate-quality evidence of reduction inmortality and high-quality evidence ofreduction in VTE. These effects werelarger than any plausible increase inbleeding risk.For patients with cancer who have

indwelling central venous catheters(CVCs), routine prophylactic anticoagu-lation is not recommended.14-16 Over thenext few years, more evidence maybecome available on the efficacy andcost-effectiveness, and specific groups ofpatients with CVCs that may benefitfrom prophylaxis, taking into considera-tion VTE risk versus bleeding risk.

Prevention and Treatment ofThromboembolism in Patients WithCancerBy Aaron D. Dush, PharmD, CACPThe Arthur G. James Cancer Hospital and Richard J. Solove Research Institute at The Ohio State University

Aaron D. Dush, PharmD, CACP

Table Recommendations for Prevention and Treatment of VTE in Patients With Cancer

ASCO CHEST NCCN

Prevention of VTE in the hospitalized patient withcancer

Prophylactic anticoagulationconsidered for all in theabsence of contraindications

Prophylactic anticoagulationconsidered for all in theabsence of contraindications

Prophylactic anticoagulationconsidered for all in the absence of contraindications

Prevention of VTE in thesurgical patient with cancer

Extended prophylaxis up to 4 weeks postprocedure high-risk surgery



Prevention of VTE in theambulatory patient withcancer

Not recommended exceptwith thalidomide/lenalidomide-based regimens

Prophylactic anticoagulationsuggested in patients withsolid tumors who have addi-tional risk factors for VTEand who are at low risk ofbleeding

Not recommended except withthalidomide/lenalidomide-based regimens

Prevention of VTE inpatients with CVC andcancer

Not recommended Not recommended Not recommended

Treatment of VTE inpatients with cancer

LMWH preferred and treatedindefinitely as long as cancerpersists



Treatment of catheter-related thrombosis inpatients with cancer

Anticoagulation as long ascatheter is in place or at least3 months after removal

Anticoagulation as long ascatheter is in place or at least 3 months after removal

Abbreviations: ASCO, American Society of Clinical Oncology; CHEST, American College of Chest Physicians; CVC,central venous catheter; LMWH, low-molecular-weight heparin; NCCN, National Comprehensive Cancer Network;VTE, venous thromboembolic event.


TON_May2012_v7_TON 5/21/12 9:44 AM Page 21


Supportive Care

For treatment of VTE in cancerpatients, therapy is driven by the findingsof the CLOT trial.18 This trial was con-ducted over a 6-month period. It com-pared the efficacy of LMWH (dal-teparin) to oral anticoagulation in theprevention of recurrent thrombosis inpatients with cancer. The trial showed

no significant difference in bleeding riskor 6-month mortality but did show a sta-tistically significant difference in recur-rent thromboembolism at 6 monthsfavoring the LMWH group.When treating cancer patients who

have a pulmonary embolism (PE) ordeep vein thrombosis (DVT), LMWH

is the preferred agent. These patientsshould be treated indefinitely as longas they have active cancer or risk fac-tors persist.14,15,19 Well-managed vita-min K antagonists, such as warfarin,may be an acceptable alternative whenLMWH is not advisable. This may betrue in patients who cannot afford

LMWH, patients who are opposed todaily injections, or those who haverenal insufficiency.As for the dose of LMWH, in the

CLOT trial dalteparin was given at200 IU/kg once daily for the firstmonth then 150 IU/kg once daily forthe remaining 5 months.18 Enoxaparincarries an indication for inpatienttreatment of DVT with or without PEat a dose of 1 mg/kg every 12 hours or1.5 mg/kg every 24 hours. For outpa-tient DVT without PE, the indicateddose is 1 mg/kg every 12 hours.20 Bothindications are in conjuction with theinitiation/administration of warfarin.The quality of evidence comparingonce-daily versus twice-daily LMWHis low because of impression andinconsistency in studies comparing the2 types of administration. A meta-analysis of studies showed similar ratesof mortality, recurrent DVT, and majorbleeding.21 Keep in mind, these studieswere not for long-term treatment withLMWH. LMWH was administered fora period of 5 to 10 days in conjunctionwith a vitamin K antagonist. The studyby Merli and colleagues, published inAnnals of Internal Medicine in 2001,suggested that outcomes may be inferi-or with once-daily versus twice-dailyregimens.22 In the subset of patientswith malignancy, the study showed a12.2% rate of recurrence with theonce-daily dose and only a 6.4% rate ofrecurrence with the twice-daily group;however, statistical significance wasnot achieved. This study also did notinclude long-term use of LMWH.These studies did lead to the latest

CHEST recommendation for patientswith acute DVT of the leg treated withLMWH. They suggest once-daily overtwice-daily administration, but thisrecommendation applies only if theapproved once-daily regimen uses thesame total daily dose as the twice-dailyregimen.19 This would be true for dal-teparin using 200 IU/kg once daily butnot for enoxaparin that uses 1.5 mg/kgonce daily (twice-daily dose is 1 mg/ kgevery 12 hours). This recommendationcould then be interpreted as indicatingthat the preferred treatments are dal-teparin 200 IU/kg every 24 hours orenoxaparin 1 mg/kg every 12 hours.The recommendation carries a 2Cgrade from CHEST, which is a weakrecommendation with low- or verylow-quality evidence. In patients withcancer, again based on the CLOT trialthat did study long-term LMWH ther-apy, clinicians should utilize LMWHdosing where the full total daily dose isutilized. Dalteparin is the only LMWHto carry a treatment indication forpatients with cancer at 200 IU/kg dailyfor the first month, then 150 IU/kg

“Quality care iseveryone’s business.”

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Prevention and Treatment of Thromboembolism... Continued from page 21



Supportive Care

daily. If we carry this to a class indica-tion, enoxaparin should be dosed at 1mg/kg every 12 hours initially for treat-ment of VTE in patients with cancer.Also, one must remember that LMWHis eliminated renally, so dose adjust-ments may be necessary based on thepatient’s renal function.For the treatment of catheter-related

thrombosis, it is suggested that thecatheter not be removed if it is still func-tioning. The treatment for this thrombo-sis is based on whether the catheter is oris not removed. If the catheter isremoved, the patient should be treatedfor 3 months after the catheter isremoved. If the catheter is not removed,the patient should be treated with anti-coagulation therapy as long as thecatheter remains in place.15,19Two new oral anticoagulants have

recently joined the market, and moreare in the pipeline. These will mostlikely be approved in the next fewyears, as will additional indications forthe oral anticoagulants already avail-able. Two agents that have recentlybeen approved are dabigatran(Pradaxa) and rivaroxaban (Xarelto).Dabigatran is a direct thrombininhibitor, and rivaroxaban is a selec-tive inhibitor of factor Xa. Currentlyboth are approved for nonvalvular atri-al fibrillation, and rivaroxaban is alsoapproved for DVT prophylaxis postknee and hip replacement.23,24 Neitheris currently approved for the treatmentof VTE. The goal for any of the newanticoagulants is to develop an agentthat is oral, requires minimal monitor-ing, has a predictable and rapid effect,has a large therapeutic index, and hasminimal drug interactions.Dabigatran is a twice-daily medica-

tion, whereas rivaroxaban is given oncedaily. Both are eliminated by the kid-neys, so are contraindicated in patientswith renal impairment. They do have arapid onset and a larger therapeuticindex. There are no regular monitoringrecommendations with these agents.Although these medications seem to

make anticoagulation therapy simpler,there are a few things to consider inpatients with cancer. There is currentlyno reversal agent available to complete-ly reverse the anticoagulation effect ofthese agents. This plays a major role inanticoagulation therapy in patientswith cancer who are already at a higherrisk of bleeding. With the rapid onsetand rapid clearance of these agents, ashort half-life syndrome can result. Ifcompliance is an issue, patients on thesemedications can return to baseline aftermissing only 1 or 2 doses, which canrapidly increase their risk of a throm-boembolic event.An interesting phase 2 trial by

Levine and colleagues that was recentlypublished in the Journal of Thrombosis

and Haemostasis initiated patientsreceiving chemotherapy on apixaban for12 weeks.25 Apixaban is a factor Xainhibitor that is not yet approved by theFDA. These were patients without aprior history of VTE. The outcomeswere to determine major or clinicallyrelevant nonmajor bleeding, VTE, andadverse events related to the drug. Thetrial did show a low bleeding risk forthese patients and a decrease in VTE.The study protocol did potentially selectfor patients with a lower bleeding risk bynot including patients with a prolongedbleeding time or patients receiving mod-erate to high doses of aspirin or otherantiplatelet agents, and caution shouldbe used when extrapolating these resultsto a less selective population. This doesintroduce what may be on the horizonfor anticoagulation and cancer and theuse of the newer agents. Further studieswill need to be completed to supportthese findings.In cancer patients in whom bleeding

risk is already elevated, a clear picture ofthe real-life bleeding risk associated withthese agents is still not available. Lack ofmonitoring may actually be a negativein these patients. With the other agents,we have a standard laboratory value thatcan measure the extent of the patient’santicoagulation. There is no standardlaboratory value to measure the neweragents. Certain anticoagulation markersmay be elevated with therapy, but thereis no direct correlation to the actuallevel of anticoagulation. With cancerpatients receiving chemotherapy and

having frequent procedures or surgeries,we cannot assess their true bleeding risk.In patients with cancer, these medica-tions should be used with extreme cau-tion until more postmarketing data areavailable and analyzed. �

References1. Heit JA, Silverstein MD, Mohr DN, et al. Risk fac-tors for deep vein thrombosis and pulmonary embolism:a population-based case-control study. Arch Intern Med.2000;160:809-815.2. Blom JW, Doggen CJ, Osanto S, et al. Malignancies,prothrombotic mutations, and the risk of venous throm-bosis. JAMA. 2005;293:715-722.3. Alcalay A, Wun T, Khatri V, et al. Venous throm-boembolism in patients with colorectal cancer: inci-dence and effect on survival. J Clin Oncol.2006;24:1112-1118.4. Chew HK, Wun T, Harvey D, et al. Incidence ofvenous thromboembolism and its effect on survivalamong patients with common cancers. Arch Intern Med.2006;166:458-464.5. Sørensen HT, Mellemkjaer L, Olsen JH, et al.Prognosis of cancers associated with venous throm-boembolism. N Engl J Med. 2000;343:1846-1850.6. Khorana AA, Francis CW, Culakova E, et al.Thromboembolism is a leading cause of death in cancerpatients receiving outpatient chemotherapy. J ThrombHaemost. 2007;5:632-634.7. Prandoni P, Lensing AW, Piccioli A, et al. Recurrentvenous thromboembolism and bleeding complicationsduring anticoagulant treatment in patients with cancerand venous thrombosis. Blood. 2002;100:3484-3488.8. Falanga A, Donati MB. Pathogenesis of thrombosis inpatients with malignancy. Int J Hematol. 2001;73:137-144.9.Nalluri SR, Chu D, Keresztes R, et al. Risk of venousthromboembolism with the angiogenesis inhibitorbevacizumab in cancer patients: a meta-analysis. JAMA.2008;300:2277-2285.10. Lee AY, Levine MN. Venous thromboembolism andcancer: risks and outcomes. Circulation. 2003;107(23suppl 1):I17-I21.11. Fisher B, Costantino JP, Wickerham DL, et al.Tamoxifen for the prevention of breast cancer: currentstatus of the National Surgical Adjuvant Breast andBowel Project P-1 study. J Natl Cancer Inst. 2005;97:1652-1662.12. Thürlimann B, Keshaviah A, Coates AS, et al.Breast International Group (BIG)1-98. CollaborativeGroup. A comparison of letrozole and tamoxifen in

postmenopausal women with early breast cancer. N EnglJ Med. 2005;353:2747-2757.13. El Accaoui RN, Shamseddeen WA, Taher AT.Thalidomide and thrombosis. A meta-analysis. ThrombHaemost. 2007;97:1031-1036.14. Lyman GH, Khorana AA, Falanga A, et al.American Society of Clinical Oncology Guideline:Recommendations for venous thromboembolism pro-phylaxis and treatment in patients with cancer. J ClinOncol. 2007;25:5490-5505.15. National Comprehensive Cancer Network. NCCNClinical Practice Guidelines in Oncology: VenousThromboembolic Disease. Version 1.2009. http://www.oncologycast.net/guidelinecasts/NCCN_Guidelines.pdf.Accessed April 26, 2012.16. Kahn SR, Lim W, Dunn AS, et al. Prevention ofVTE in nonsurgical patients: Antithrombotic Therapyand Prevention of Thrombosis, 9th ed: AmericanCollege of Chest Physicians Evidence-Based ClinicalPractice Guidelines. Chest. 2012;141(suppl 2):e195S-e226S.17. Gould MK, Garcia DA, Wren SM, et al. Preventionof VTE in nonorthopedic surgical patients:Antithrombotic Therapy and Prevention ofThrombosis, 9th ed: American College of ChestPhysicians Evidence-Based Clinical PracticeGuidelines. Chest. 2012;141(suppl 2):e227S-e277S.18. Lee AY, Levine MN, Baker RI, et al. Low-molecu-lar-weight heparin versus a coumarin for the preventionof recurrent venous thromboembolism in patients withcancer. N Engl J Med. 2003;349:146-153.19. Kearon C, Akl EA, Comerota AJ, et al.Antithrombotic therapy for VTE disease: Anti -thrombotic Therapy and Prevention of Thrombosis, 9thed: American College of Chest Physicians Evidence-Based Clinical Practice Guidelines. Chest.2012;141(suppl 2):e419S-e494S.20. Lovenox [package insert]. Bridgewater, NJ: sanofi-aventis US LLC; 2011.21. Couturaud F, Julian JA, Kearon C. Low molecularweight heparin administered once versus twice daily inpatients with venous thromboembolism: a meta-analysis.Thromb Haemost. 2001;86:980-984.22. Merli G, Spiro TE, Olsson CG, et al. Subcutaneousenoxaparin once or twice daily compared with intra-venous unfractionated heparin for treatment of venousthromboembolic disease. Ann Intern Med. 2001;134:191-202.23. Pradaxa [package insert]. Ridgefield, CT: BoehringerIngelheim; 2012.24. Xarelto [package insert]. Leverkusen, Germany:Bayer HealthCare; 2011.25. Levine MN, Gu C, Liebman HA, et al. A ran-domized phase II trial of apixaban for the prevention ofthromboembolism in patients with metastatic cancer. J Thromb Haemost. 2012;10:807-814.

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Myelofibrosis

Myeloproliferative neoplasms(MPNs) are somewhat rarechronic hematologic malig-

nancies. There are no known cures, butthe disease itself is treatable. Accordingto the World Health Organization’srevised WHO Classification of Tumors ofthe Hematopoietic and Lymphoid Tissues,MPNs include essential thrombo-cythemia (ET), polycythemia vera(PV), and idiopathic myelofibrosis(IMF), also referred to as primarymyelofibrosis (Table 1).1 IMF, ET, andPV are considered Philadelphia chro-mosome (Ph) negative. Chronic myel-ogenous leukemia (CML) is consideredPh positive. This review article willfocus on IMF, and the new treatmentapproved by the US Food and DrugAdministration (FDA).In 1951, William Dameshek, a pre-

eminent American hematologist,described the concept of myeloprolifer-

ative disorders by grouping togetherCML, ET, PV, IMF, and erythro -leukemia. He articulated that a self-per-petuating trilineage myeloproliferationunderlined their pathogenesis.2

EtiologyIMF is a disorder of the blood cellswherein the bone marrow revealsfibrous tissue, and lab values demon-strate varying degrees and combinationsof leukopenia, anemia, and thrombocy-topenia. The disease is thought to origi-nate from the neoplastic transformationof a single hematopoietic stem cell. Thedisease presents either de novo or in thesetting of PV or ET.3 Bone marrow mor-phology is critical to the diagnosis andwill generally show a dramatic increasein reticulin fibers and collagen togetherwith a loss of normal hematopoieticcells. Additionally, normocytic anemiawith nucleated red blood cells and anincrease in megakaryocytes is seen onhistologic examination.4 The diseaseaffects both men and women equallyand is usually diagnosed in the fifth toseventh decade of life. There are noknown risk factors, but there have beenreports that myelofibrosis may be linkedto immunologic-mediated hyperplasiaof marrow suggestive of lupus erythe-matosus, and other connective tissuediseases.4 Additionally, exposure to ben-zenes or high-dose ionizing radiationhas preceded the diagnosis of primarymyelofibrosis.5 Prognosis varies accord-

ing to a set of clinical factors, includinghemoglobin level, constitutional symp-toms, circulating blasts, leukocytecount, and cytogenetics.6 Morbidity andmortality are commonly associated withleukemic transformation, infection, por-tal hypertension, and thrombohemor-rhagic events.7

Clinical Presentation and DiagnosisApproximately one-quarter of patientswith IMF are asymptomatic at the timeof diagnosis.8 Patients who are sympto-matic may present to the primary careprovider with complaints of fatigue,weakness, shortness of breath, andweight loss. Some patients may alsocomplain of left upper quadrant pain ordiscomfort due to splenomegaly.8 Labvalues can be very broad. Normocytic-

normochromic anemia is present inalmost all patients. In 1 study the hemo-globin concentration in patients atdiagnosis was 9.5 to 11.6 g/dL, with arange of 4 to 20 g/dL among a total of539 patients in 4 studies.8 Anisocytosis(variation in size) and poikilocytosis(variation in shape) are constant find-ings, as are teardrop-shaped red cells.7Prognosis worsens with increased pres-ence of the clinical manifestations list-ed above and shown in the Figure.9 In2008, WHO recommended 2 sets ofspecific criteria (major and minor) tohelp clinicians make an accurate diag-nosis (Table 2).10

Role of the Janus-AssociatedKinase (JAK) PathwayAdvances in the understanding of thepathogenesis of Ph-negative MPNssuch as IMF have led to the discovery ofthe JAK2V617F mutation as a prospec-tive therapeutic target.11 The JAK path-way plays a major role in blood cell pro-duction and immune and inflammatoryresponses.12 Overactivity or imperfec-tions in this pathway are thought to beresponsible, in part, for many diseasestates, including IMF. The JAK pathwaysends out signals from blood cell growthfactors, cytokines, or hormones outsidethe bone marrow stem cell to its nucle-us. Under normal functioning of thebone marrow, suitable blood cell devel-opment and utility are ensured.12 Thereis a strong association between abnor-

Myelofibrosis—A MyeloproliferativeNeoplasmBy Catherine Bishop, DNP, NP, AOCNP, Hematology/Oncology Nurse Practitioner

Lansdowne, Virginia

Catherine Bishop, DNP, NP, AOCNP

Table 1 WHO 2008 Revised Classification of MPNs1

CML (BCR-ABL1–positive)Polycythemia Vera (PV)

1. Chronic-phase PV2. Post-PV myelofibrosis3. Blast-phase PV

Essential Thrombocythemia (ET)1. Chronic-phase ET2. Post-ET myelofibrosis3. Blast-phase ET

Primary Myelofibrosis1. Chronic-phase primarymyelofibrosis

2. Blast-phase primary myelofibrosis

Abbreviations: CML, chronic myelogenous leukemia; MPNs, myeloproliferative neoplasms.

Adapted from Vardiman JW, Thiele J,Arber DA, et al. The 2008 revision ofthe World Health Organization (WHO)classification of myeloid neoplasms andacute leukemia: rationale and importantchanges. Blood. 2009;114:937-951.

Figure. Clinical Manifestations of Idiopathic Myelofibrosis Indicated in Worsening Prognosis9

Adapted from “Development of New Therapies for Myelofibrosis” presentation by Srdan Verstovsek, MD, PhD, Associate Professor,Department of Leukemia, University of Texas, MD Anderson Cancer Center.

Cytopenias

Low or high white cell count Transformation to acute leukemia•Blast percent

Increasing bone marrow fibrosis

Low total cholesterol Progressive splenomegaly/hepatomegaly

Weight loss Constitutional symptoms

Prognostic Factors

Approximately

one-quarter of patients

with idiopathic

myelofibrosis are

asymptomatic at the

time of diagnosis.



Myelofibrosis

mal cell signaling in the JAK pathwayand the development of MPNs.12,13

TreatmentAllogeneic stem cell transplantation(SCT) offers the possibility of cure forsome patients with IMF.14 However, therisk of graft-vs-host disease, transplant-related death, and relapse of themyelofibrosis requires careful selectionof appropriate candidates. Until recent-ly there were few, if any, treatments thatprovided hope for patients ineligible fortransplant. Most of the treatmentoptions were palliative in nature,intended to minimize anemia, neu-tropenia, or thrombocytopenia, as wellas the many constitutional symptomsexperienced by the majority of IMFpatients. Given the essential role of theJAK pathway in blood cell productionand immune function, scientists beganresearching the potential of JAK inhibi-tion for treating patients with IMF.

Approval of a New DrugOn November 16, 2011, the FDAapproved ruxolitinib (Jakafi) for thetreatment of intermediate- and high-risk myelofibrosis.15,16 The oral drug isthe first in a new class of drugs knownas JAK inhibitors. The drug inhibitsJAK1 and JAK2 pathways. Theapproval was based on results from 2randomized phase 3 trials—COM-FORT-I and COMFORT-II—whichtested the drug in patients with post-PV myelofibrosis and post-ET myelofi-brosis. Patients in both trials wereresistant or refractory to available ther-apy. Additionally, they were ineligiblefor SCT. The COMFORT trials estab-lished that patients treated with rux-olitinib experienced significant reduc-tions in splenomegaly. COMFORT-Ialso demonstrated improvements insymptoms as measured by the modifiedMyelofibrosis Symptom AssessmentForm (MFSAF) and the MFSAF TotalSymptom Score to include abdominaldiscomfort, pain under left ribs, satiety,night sweats, bone and muscle pain,and itching. Most patients on placebohad worsening of these symptoms.15At the time of approval, 75% of the

patients on study 1 and 67% on study 2who achieved at least a 35% reductionin spleen volume maintained this

reduction. The most common adverseevents in both studies were thrombo-cytopenia and anemia. These weremanageable and rarely led to discon-tinuation of the drug.16 The recom-

mended starting dose of ruxolitinib is20 mg orally twice daily for patientswith a platelet count above 200 x109/L, and 15 mg twice daily for thosewith a platelet count between 100 and200 x 109/L.16

ConclusionPatients diagnosed with IMF do notcomprise a great proportion of patientsin the oncology setting. However, theiruncommon, mostly incurable diseasemakes them at least as vulnerable asthose with the most commonly diag-nosed cancers. Science has been focus-ing on personalized medicine, and forthe few diagnosed with IMF, the JAKinhibitors represent a new option forIMF management. Based on the datafrom the COMFORT studies, ruxoli-tinib has been approved for use inpatients with intermediate/high-riskmyelofibrosis, offering patients somehope now, and for the future develop-ment of other targeted therapies. �

References1. Vardiman JW, Thiele J, Arber DA, et al. The 2008revision of the World Health Organization (WHO)classification of myeloid neoplasms and acuteleukemia: rationale and important changes. Blood.2009;114:937-951.2. Tefferi A. The history of myeloproliferative disorders:

before and after Dameshek. Leukemia. 2008;22:3-13.3. Passamonti F, Malabarba L, Orlandi E, et al.Polycythemia vera in young patients: a study on thelong-term risk of thrombosis, myelofibrosis andleukemia. Haematologica. 2003;88:13-18.4. el Mouzan MI, Ahmad MA, al Fadel Saleh M, alSohaibani MO, al Gindan YM. Myelofibrosis and pan-cytopenia in systemic lupus erythematosus. ActaHaematol. 1988;80:219-221.5. Tondel M, Persson B, Carstensen J. Myelofibrosis andbenzene exposure. Occup Med (Lond). 1995;45:51-52.6. Arana-Yi C, Quintás-Cardama A, Giles F, et al.Advances in the therapy of chronic idiopathic myelofi-brosis. Oncologist. 2006;11:929-943.7. Thiele J, Kvasnicka HM, Steinberg T, et al. Survivalin primary (idiopathic) osteomyelofibrosis, so calledagnogenic myeloid metaplasia. Leuk Lymphoma.1992;6:389.8. Lichtman MA. Idiopathic myelofibrosis (agnogenicmyeloid metaplasia). In: Beutler E, Lichtman MA,Coller BS, et al, eds. Williams Hematology. 6th ed. NewYork, NY: McGraw-Hill; 2001:chap 95. http://medtextfree.wordpress.com/2012/01/23/chapter-95.Accessed April 18, 2012.9. Verstovsek S. Development of new therapies formyelofibrosis. Presented at Mayo Clinic, Scottsdale,Arizona, February 2009.10. Swerdlow SH, Campo E, Harris NL, et al, eds. WHOClassification of Tumours of Haemopoietic and LymphoidTissues. 4th ed. Lyon, France: IARC Press; 2008.11. Quintás-Cardama A, Kantarjian H, Cortes J,Verstovsek S. Janus kinase inhibitors for the treatmentof myeloproliferative neoplasias and beyond. Nat RevDrug Discov. 2011;10:127-140.12. The JAK/STAT pathway: fact sheet. NovartisOncology Web site. http://www.novartisoncology.com/files/media/research/JAK-STAT%20Pathway%20Fact%20Sheet_FINAL.pdf. Accessed April 1, 2012.13. Tefferi A. Essential thrombocythemia, poly-cythemia vera, and myelofibrosis: current managementand the prospect of targeted therapy. Am J Hematol.2008;83:491-497.14. Bacigalupo A, Soraru M, Dominietto A, et al.Allogeneic hemopoietic SCT for patients with primarymyelofibrosis: a predictive transplant score based ontransfusion requirement, spleen size and donor type.Bone Marrow Transplant. 2010;45:458-463.15. FDA approves Incyte’s Jakafi(TM) (ruxolitinib) forpatients with myelofibrosis [press release]. Wilmington,DE: Incyte Corporation; November 16, 2011.http://investor.incyte.com/phoenix.zhtml?c=69764&p=irol-newsArticle&ID=1631201&highlight=. AccessedApril 18, 2012. 16. Pazdur R. FDA approval for ruxolitinib phosphate.National Cancer Institute Web site. http://www.cancer.gov/cancertopics/druginfo/fda-ruxolitinibphosphate.Accessed April 4, 2012.

Table 2 Diagnostic Criteria for Primary Myelofibrosis (WHO 2008)10

3 major criteria + 2 minor criteria must be met to confirm diagnosis.

Major diagnostic criteria1. Megakaryocyte proliferation and atypia*2. Not meeting WHO criteria for PV, BCR-ABL1−positive CML, MDS, orother myeloid neoplasm

3. Presence of JAK2V617F or other clonal marker or no evidence of secondarybone marrow fibrosis in absence of clonal marker

Minor diagnostic criteria1. Leukoerythroblastosis2. Increase in serum lactate dehydrogenase3. Anemia4. Splenomegaly

*Accompanied by either reticulin and/or collagen fibrosis, or in the absence of significant reticulin fibrosis, a prefibrotic cellular-phase disease.

Abbreviations: CML, chronic myelogenous leukemia; MDS, myelodysplastic syndrome;PV, polycythemia vera; WHO, World Health Organization.

Science has been focusing on personalized

medicine, and for the few diagnosed with IMF, the

JAK inhibitors represent a new option for

IMF management.

Prospective data from a recentstudy links the long-term use ofnonsteroidal anti-inflammatorydrugs (NSAIDs) with the increasedrisk for renal cell carcinoma. Theuse of acetaminophen and aspirinwas not associated with the risk for

renal cell carcinoma.

—Arch Intern Med. 2011;171:1487-1493.

Did You Know?The oral drug is the first

in a new class of

drugs known as

JAK inhibitors.






Prostate Cancer

Worldwide, there are approxi-mately 500,000 men diag-nosed with prostate cancer

each year, and in those men prostatecancer is the third most common typeof malignancy, surpassed only by cancerof the lung and stomach.1 Other thannonmelanoma skin cancer, prostatecancer is the most commonly diagnosedmale cancer in the United States.2There is disparity in risk of prostate can-cer diagnosis between races. Prostatecancer is more common in AfricanAmerican males than it is in whiteAmerican males.3 Higher mortality isassociated with late detection.4 Theprevalence of prostate-specific antigen(PSA) screening has caused a drasticreduction in the number of patientswho have distant metastatic disease atthe time of diagnosis.5 For thosepatients who present with metastaticdisease, local definitive therapy is nolonger an appropriate option. The stan-dard of care is systemic therapy.

Androgen deprivation therapy(ADT) remains the standard frontlinetreatment for metastatic prostate can-cer. Patients can be treated with single-agent therapy gonadotropin-releasinghormone (GnRH) agonists, of whichthere are several options, or with com-bined androgen blockade, pairingGnRH with an antiandrogen such asbicalutamide. This therapy is widelyeffective; however, complications orside effects can include hot flushes,fractures, anemia, fatigue, loss of mus-cle mass and strength, and loss oflibido, as well as changes in cognitivefunction. All of these side effects canpotentially alter a patient’s quality oflife (QOL), sometimes significantly. Itis important for the practitioner toobtain a complete assessment of theside effects each patient is experienc-ing, as well as the consequences thoseeffects have upon the patient’s QOL,and then to make clinical recommen-dations for palliative measures that canimprove the patient’s QOL.

The majority of hormone-dependentcancers become castrate-resistant inabout 1 to 3 years, resuming growthdespite ADT.6 In 1996, the US Foodand Drug Administration (FDA)approved mitoxantrone, at 12 mg/m2, incombination with corticosteroids, typi-cally prednisone 5 mg twice daily, forthe treatment of patients with painrelated to advanced hormone-refractoryprostate cancer, now known as castrate-

Metastatic Castrate-Resistant Prostate Cancer—Treatment OverviewBy Shari L. Black, MAN, CNP

Cleveland Clinic Foundation Taussig Cancer Center, Cleveland, Ohio

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Please see Brief Summary of full Prescribing Information, including Boxed WARNING, on the last page of this ad.REFERENCE: 1. ADCETRIS [Prescribing Information]. Bothell, WA: Seattle Genetics, Inc; 2012.US/BVP/2011/0104d

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Prostate Cancer

resistant prostate cancer (CRPC). Priorto 2004, treatments for metastaticCRPC were palliative, without anyproven survival benefit. Since thattime, several therapies have emergedthat have demonstrated a survivaladvantage.Docetaxel in combination with pred-

nisone was approved by the FDA in

2004 for the treatment of metastaticcastrate-resistant disease. The 3-armTAX 327 study, which led to FDAapproval, compared docetaxel at 75mg/m2 administered every 3 weeks, doc-etaxel at 30 mg/m2 weekly for every 5 of6 weeks, and mitoxantrone at 12 mg/m2

every 3 weeks, each with prednisone 5mg twice daily. The original analysis,

done in August 2003, showed signifi-cantly better survival and response ratesfor pain, PSA, and QOL in the every-3-week docetaxel with prednisone groupwhen compared with the mitoxantronewith prednisone group. Median survivaltime was 18.9 months (95% confidenceinterval [CI], 17.0-21.2) in the every-3-week docetaxel with prednisone arm,

17.4 months (95% CI, 15.7-19.0) in theweekly docetaxel and prednisone arm,and 16.5 months (95% CI, 14.4-18.6)in the mitoxantrone and prednisonearm.7 By March 2007, data on 310 addi-tional deaths were obtained and updat-ed. These data demonstrated a con-tinued survival benefit for the

57%complete remission(95% CI: 44%-70%)1

29%partial remission(95% CI: 18%-41%)1

sALCL: 86% ORR (95% CI: 77%-95%)1

32% complete remission(95% CI: 23%-42%)1

40%partial remission(95% CI: 32%-49%)1

HL: 73% objective response rate (ORR) (95% CI: 65%-83%)1

Important Safety Information• Progressive multifocal leukoencephalopathy (PML): JC

virus infection resulting in PML and death has been reported in ADCETRIS™ (brentuximab vedotin)–treated patients. In addition to ADCETRIS therapy, other possible contributory factors include prior therapies and underlying disease that may cause immunosuppression. Consider the diagnosis of PML in any patient presenting with new-onset signs and symptoms of central nervous system abnormalities. Evaluation of PML includes, but is not limited to, consultation with a neurologist, brain MRI, and lumbar puncture or brain biopsy. Hold ADCETRIS if PML is suspected and discontinue ADCETRIS if PML is confi rmed.

• Stevens-Johnson syndrome: Stevens-Johnson syndrome has been reported with ADCETRIS. If Stevens-Johnson syndrome occurs, discontinue ADCETRIS and administer appropriate medical therapy.

• Use in pregnancy: Fetal harm can occur. Pregnant women should be advised of the potential hazard to the fetus.

Adverse Reactions:ADCETRIS was studied as monotherapy in 160 patients in two phase 2 trials. Across both trials, the most common adverse reactions (≥20%), regardless of causality, were neutropenia, peripheral sensory neuropathy, fatigue, nausea, anemia, upper respiratory tract infection, diarrhea, pyrexia, rash, thrombocytopenia, cough and vomiting.Drug Interactions:Patients who are receiving strong CYP3A4 inhibitors concomitantly with ADCETRIS should be closely monitored for adverse reactions.

BOXED WARNINGProgressive multifocal leukoencephalopathy (PML): JC virus infection resulting in PML and death can occur in patients receiving ADCETRIS.

Contraindication:Concomitant use of ADCETRIS and bleomycin is contraindicated due to pulmonary toxicity.Warnings and Precautions:• Peripheral neuropathy: ADCETRIS treatment causes a peripheral

neuropathy that is predominantly sensory. Cases of peripheral motor neuropathy have also been reported. ADCETRIS-induced peripheral neuropathy is cumulative. Treating physicians should monitor patients for symptoms of neuropathy, such as hypoesthesia, hyperesthesia, paresthesia, discomfort, a burning sensation, neuropathic pain or weakness and institute dose modifi cations accordingly.

• Infusion reactions: Infusion-related reactions, including anaphylaxis, have occurred with ADCETRIS. Monitor patients during infusion. If an infusion reaction occurs, the infusion should be interrupted and appropriate medical management instituted. If anaphylaxis occurs, the infusion should be immediately and permanently discontinued and appropriate medical management instituted.

• Neutropenia: Monitor complete blood counts prior to each dose of ADCETRIS and consider more frequent monitoring for patients with Grade 3 or 4 neutropenia. If Grade 3 or 4 neutropenia develops, manage by dose delays, reductions or discontinuation. Prolonged (≥1 week) severe neutropenia can occur with ADCETRIS.

• Tumor lysis syndrome: Patients with rapidly proliferating tumor and high tumor burden are at risk of tumor lysis syndrome and these patients should be monitored closely and appropriate measures taken.

• Hodgkin lymphoma (HL) after failure of autologous stem cell transplant (ASCT)1

• HL in patients who are not ASCT candidates after failure of at least 2 multiagent chemotherapy regimens1

Indicated for the treatment of:• Systemic anaplastic large cell lymphoma

(sALCL) after failure of at least 1 multiagent chemotherapy regimen1

The indications for ADCETRIS™ (brentuximab vedotin) are based on response rate. There are no data available demonstrating improvement in patient-reported outcomes or survival with ADCETRIS.1

After multiple failures,

single-agent responseC

N = 102, 15-77 years (median: 31 years)1 N = 58, 14-76 years (median: 52 years)1

1 4 2:39 PM




Prostate Cancer

every-3-week docetaxel with pred-nisone group. Median survival time was19.2 months in the every-3-week doc-etaxel with prednisone arm, 17.8months in the weekly docetaxel andprednisone arm, and 16.3 months in themitoxantrone and prednisone arm (P =.004).8 The every-3-week docetaxel

with twice-daily prednisone chemother-apy regimen has remained a standard ofcare for first-line therapy for metastaticCRPC since its FDA approval.Cabazitaxel was approved by the

FDA on June 17, 2010, in combinationwith prednisone for the treatment ofpatients with castrate-resistant metastat-

ic prostate cancer previously treated witha docetaxel-containing regimen. Thiswas the first therapy found to provide sig-nificant survival benefit in second-linemetastatic castrate-resistant prostatecancer. A multinational phase 3 trial,known as TROPIC, included patientswho were progressing either during or

after docetaxel (cumulative dose ≥225mg/m2). The patients were randomizedto receive 10 mg per day of prednisonewith an every-3-week infusion of eithermitoxantrone at 12 mg/m2 or cabazitax-el at 25 mg/m2. Analysis revealed thatthe patients receiving cabazitaxel andprednisone demonstrated a statisticallysignificantly longer overall survivalcompared with those receiving mitox-antrone and prednisone (P <.0001).The median survival in the cabazitaxeland prednisone group was 15.1 monthscompared with 12.7 months in themitoxantrone and prednisone group.Progression-free survival was also foundto be statistically significantly in favorof the cabazitaxel and prednisone arm.The most frequent grade 3/4 toxicitywas neutropenia observed in 81.7% ofpatients treated with cabazitaxel andprednisone and 58.0% of those treatedwith mitoxantrone and prednisone.Rates of febrile neutropenia were 7.5%and 1.3%, respectively.9 In clinical prac-tice, one may want to consider eithergrowth-factor support or a dose reduc-tion of the cabazitaxel, or sometimesboth, in efforts to minimize the degreeof neutropenia and its sequelae.Sipuleucel-T, an autologous cellular

immunotherapy, was approved by theFDA on April 29, 2010, to treatasymptomatic or minimally sympto-matic metastatic CRPC. In a phase 3study, patients were randomly assignedin a 2:1 ratio to receive either sipuleu-cel-T or placebo every 2 weeks, for atotal of 3 infusions. Analysis showedthat in the sipuleucel-T group, therewas a relative reduction of 22% in therisk of death as compared with theplacebo group (P = .03). This reduc-tion represented a 4.1-month improve-ment in median survival. However, nosignificant effect on the time to objec-tive disease progression was observed.10The rationale for treating patients withsipuleucel-T can be a difficult conceptfor patients to understand, as it is typi-cal for patients to have neither a dropin PSA nor any improvement in theirimaging studies. Carefully detailedpatient education is warranted toensure that patients have an adequateunderstanding of the potential benefitthey may receive from this therapy.Abiraterone acetate, in combination

with prednisone, is the most recentlyapproved therapy for metastatic CRPCpatients who have received prior doc-etaxel therapy, obtaining FDAapproval on April 28, 2011. In theclinical trial that led to FDA approval,patients were randomized in a 2:1 ratioto receive abiraterone acetate, 1000mg once daily in combination withprednisone 5 mg twice daily or placeboin combination with prednisone 5 mg

ADCETRIS, SeaGen Secure and their logos are trademarks and Seattle Genetics and are US registered trademarks of Seattle Genetics, Inc. © 2012 Seattle Genetics, Inc., Bothell, WA 98021

All rights reserved. Printed in USA US/BVP/2011/0150b

Brief Summary of Prescribing Information(see Package Insert for full Prescribing Information)

WARNING: PROGRESSIVE MULTIFOCAL LEUKOENCEPHALOPATHY (PML)JC virus infection resulting in PML and death can occur in patients receiving ADCETRIS.

Indications and usageThese indications are based on response rate. There are no data available demonstrating improvement in patient reported outcomes or survival with ADCETRIS.

ADCETRIS™ (brentuximab vedotin) is indicated for treatment of patients with Hodgkin lymphoma (HL) after failure of autologous stem cell transplant (ASCT) or after failure of at least two prior multi-agent chemotherapy regimens in patients who are not ASCT candidates.

ADCETRIS is indicated for treatment of patients with systemic anaplastic large cell lymphoma (sALCL) after failure of at least one prior multi-agent chemotherapy regimen.

ContraindicationsPulmonary toxicity: Concomitant use of ADCETRIS and bleomycin is contraindicated due to pulmonary toxicity. In a clinical trial that studied ADCETRIS with bleomycin as part of a combination regimen, the rate of non-infectious pulmonary toxicity was higher than the historical incidence reported with ABVD (adriamycin, bleomycin, vinblastine, dacarbazine). Patients typically reported cough and dyspnea. Interstitial infiltration and/or inflammation were observed on radiographs and computed tomographic imaging of the chest. Most patients responded to corticosteroids.

Warnings and precautions Peripheral neuropathyADCETRIS treatment causes a peripheral neuropathy that is predominantly sensory. Cases of peripheral motor neuropathy have also been reported. ADCETRIS-induced peripheral neuropathy is cumulative. In the HL and sALCL clinical trials, 54% of patients experienced any grade of neuropathy. Of these patients, 49% had complete resolution, 31% had partial improvement, and 20% had no improvement. Of the patients who reported neuropathy, 51% had residual neuropathy at the time of their last evaluation. Monitor patients for symptoms of neuropathy, such as hypoesthesia, hyperesthesia, paresthesia, discomfort, a burning sensation, neuropathic pain or weakness. Patients experiencing new or worsening peripheral neuropathy may require a delay, change in dose, or discontinuation of ADCETRIS.

Infusion reactionsInfusion-related reactions, including anaphylaxis, have occurred with ADCETRIS. Monitor patients during infusion. If anaphylaxis occurs, immediately and permanently discontinue administration of ADCETRIS and administer appropriate medical therapy. If an infusion-related reaction occurs, the infusion should be interrupted and appropriate medical management instituted. Patients who have experienced a prior infusion-related reaction should be premedicated for subsequent infusions. Premedication may include acetaminophen, an antihistamine and a corticosteroid.

NeutropeniaComplete blood counts should be monitored prior to each dose of ADCETRIS and more frequent monitoring should be considered for patients with Grade 3 or 4 neutropenia. Prolonged (≥1 week) severe neutropenia can occur with ADCETRIS. If Grade 3 or 4 neutropenia develops, manage by dose delays, reductions, or discontinuations.

Tumor lysis syndromeTumor lysis syndrome may occur. Patients with rapidly proliferating tumor and high tumor burden may be at increased risk of tumor lysis syndrome. Monitor closely and take appropriate measures.

Progressive multifocal leukoencephalopathy JC virus infection resulting in PML and death has been reported in ADCETRIS-treated patients. In addition to ADCETRIS therapy, other possible contributory factors include prior therapies and underlying disease that may cause immunosuppression.

Consider the diagnosis of PML in any patient presenting with new-onset signs and symptoms of central nervous system abnormalities. Evaluation of PML includes, but is not limited to, consultation with a neurologist, brain MRI, and lumbar puncture or brain biopsy. Hold ADCETRIS dosing for any suspected case of PML and discontinue ADCETRIS dosing if a diagnosis of PML is confirmed.

Stevens-Johnson syndromeStevens-Johnson syndrome has been reported with ADCETRIS. If Stevens-Johnson syndrome occurs, discontinue ADCETRIS and administer appropriate medical therapy.

Use in pregnancyThere are no adequate and well-controlled studies of ADCETRIS in pregnant women. However, based on its mechanism of action and findings in animals, ADCETRIS can cause fetal harm when administered to a pregnant woman. Brentuximab vedotin caused embryo-fetal toxicities, including significantly decreased embryo viability and fetal malformations, in animals at maternal exposures that were similar to human exposures at the recommended doses for patients with HL and sALCL. If this drug is used during pregnancy, or if the patient becomes pregnant while receiving the drug, the patient should be apprised of the potential hazard to the fetus.

Adverse reactionsADCETRIS was studied as monotherapy in 160 patients in two phase 2 trials. Across both trials, the most common adverse reactions (≥10%), regardless of causality, were neutropenia, anemia, thrombocytopenia, lymphadenopathy, peripheral sensory neuropathy, peripheral motor neuropathy, headache, dizziness, fatigue, pyrexia, chills, pain, edema peripheral, upper respiratory tract infection, nausea, diarrhea, abdominal pain, vomiting, constipation, rash, pruritus, alopecia, night sweats, dry skin, cough, dyspnea, oropharyngeal pain, arthralgia, myalgia, back pain, pain in extremity, muscle spasms, insomnia, anxiety, decreased appetite and weight decreased.

ADCETRIS was studied in 102 patients with HL in a single arm clinical trial in which the recommended starting dose and schedule was 1.8 mg/kg intravenously every 3 weeks. Median duration of treatment was 27 weeks (range, 3 to 56 weeks). The most common adverse reactions (≥20%), regardless of causality, were neutropenia, peripheral sensory neuropathy, fatigue, upper respiratory tract infection, nausea, diarrhea, anemia, pyrexia, thrombocytopenia, rash, abdominal pain, cough, and vomiting. The most common serious adverse reactions experienced by patients with HL include peripheral motor neuropathy (4%), abdominal pain (3%), pulmonary embolism (2%), pneumonitis (2%), pneumothorax (2%), pyelonephritis (2%), and pyrexia (2%).

ADCETRIS™ (brentuximab vedotin) was studied in 58 patients with sALCL in a single arm clinical trial in which the recommended starting dose and schedule was 1.8 mg/kg intravenously every 3 weeks. Median duration of treatment was 24 weeks (range, 3 to 56 weeks). The most common adverse reactions (≥20%), regardless of causality, were neutropenia, anemia, peripheral sensory neuropathy, fatigue, nausea, pyrexia, rash, diarrhea, and pain. The most common serious adverse reactions experienced by patients with sALCL were septic shock (3%), supraventricular arrhythmia (3%), pain in extremity (3%), and urinary tract infection (3%).

Drug interactionsIn vitro data indicate that monomethyl auristatin E (MMAE) is a substrate and an inhibitor of CYP3A4/5.

Effect of other drugs on ADCETRIS CYP3A4 Inhibitors/Inducers: MMAE is primarily metabolized by CYP3A. Co-administration of ADCETRIS with ketoconazole, a potent CYP3A4 inhibitor, increased exposure to MMAE by approximately 34%. Patients who are receiving strong CYP3A4 inhibitors concomitantly with ADCETRIS should be closely monitored for adverse reactions. Co-administration of ADCETRIS with rifampin, a potent CYP3A4 inducer, reduced exposure to MMAE by approximately 46%.

Effect of ADCETRIS on other drugsCo-administration of ADCETRIS did not affect exposure to midazolam, a CYP3A4 substrate. MMAE does not inhibit other CYP enzymes at relevant clinical concentrations. ADCETRIS is not expected to alter the exposure to drugs that are metabolized by CYP3A4 enzymes.

Use in specific populationsPregnancyPregnancy Category D. There are no adequate and well-controlled studies with ADCETRIS in pregnant women. However, based on its mechanism of action and findings in animals, ADCETRIS can cause fetal harm when administered to a pregnant woman. Brentuximab vedotin caused embryo-fetal toxicities in animals at maternal exposures that were similar to human exposures at the recommended doses for patients with HL and sALCL. If this drug is used during pregnancy, or if the patient becomes pregnant while receiving this drug, the patient should be apprised of the potential hazard to the fetus.

In an embryo-fetal developmental study, pregnant rats received 2 intravenous doses of 0.3, 1, 3, or 10 mg/kg brentuximab vedotin during the period of organogenesis (once each on Pregnancy Days 6 and 13). Drug-induced embryo-fetal toxicities were seen mainly in animals treated with 3 and 10 mg/kg of the drug and included increased early resorption (≥99%), post-implantation loss (≥99%), decreased numbers of live fetuses, and external malformations (i.e., umbilical hernias and malrotated hindlimbs). Systemic exposure in animals at the brentuximab vedotin dose of 3 mg/kg is approximately the same exposure in patients with HL or sALCL who received the recommended dose of 1.8 mg/kg every three weeks.

Nursing mothersIt is not known whether brentuximab vedotin is excreted in human milk. Because many drugs are excreted in human milk and because of the potential for serious adverse reactions in nursing infants from ADCETRIS a decision should be made whether to discontinue nursing or to discontinue the drug, taking into account the importance of the drug to the mother.

Pediatric useThe safety and effectiveness of ADCETRIS have not been established in the pediatric population. Clinical trials of ADCETRIS included only 9 pediatric patients and this number is not sufficient to determine whether they respond differently than adult patients.

Geriatric useClinical trials of ADCETRIS did not include sufficient numbers of patients aged 65 and over to determine whether they respond differently from younger patients. Safety and efficacy have not been established.

Renal impairmentThe kidney is a route of excretion for MMAE. The influence of renal impairment on the pharmacokinetics of MMAE has not been determined.

Hepatic impairmentThe liver is a route of clearance for MMAE. The influence of hepatic impairment on the pharmacokinetics of MMAE has not been determined.

OverdosageThere is no known antidote for overdosage of ADCETRIS. In case of overdosage, the patient should be closely monitored for adverse reactions, particularly neutropenia, and supportive treatment should be administered.

Dosage and administrationGeneral dosing informationThe recommended dose is 1.8 mg/kg administered only as an intravenous infusion over 30 minutes every 3 weeks. The dose for patients weighing greater than 100 kg should be calculated based on a weight of 100 kg. Do not administer as an intravenous push or bolus. Continue treatment until a maximum of 16 cycles, disease progression or unacceptable toxicity.

Dose modificationPeripheral Neuropathy: Peripheral neuropathy should be managed using a combination of dose delay and reduction to 1.2 mg/kg. For new or worsening Grade 2 or 3 neuropathy, dosing should be held until neuropathy improves to Grade 1 or baseline and then restarted at 1.2 mg/kg. For Grade 4 peripheral neuropathy, ADCETRIS should be discontinued.

Neutropenia: Neutropenia should be managed by dose delays and reductions. The dose of ADCETRIS should be held for Grade 3 or 4 neutropenia until resolution to baseline or Grade 2 or lower. Growth factor support should be considered for subsequent cycles in patients who experience Grade 3 or 4 neutropenia. In patients with recurrent Grade 4 neutropenia despite the use of growth factors, discontinuation or dose reduction of ADCETRIS to 1.2 mg/kg may be considered.

Metastatic Castrate-Resistant Prostate Cancer... Continued from page 27



Prostate Cancer

twice daily. At the preplanned interimanalysis, there was a 35% reduction inthe risk of death. Overall survival was14.8 months for the abiraterone acetateplus prednisone arm in comparison to10.9 months in the placebo plus pred-nisone arm (P <.001).11 Abirateroneacetate has particular appeal to patientssince it is administered orally. It shouldbe taken on an empty stomach, and isgenerally well tolerated. Side effectsthat can be associated with elevatedmineralocorticoid levels, due to CYP17inhibition, include fluid retention/edema, hypokalemia, and hypertension.Liver function tests should be moni-tored routinely.In addition to the aforementioned

antitumor therapies, there are thera-pies available to decrease the risk ofskeletal events, which are prevalent inthis patient population. Zoledronicacid, an intravenous bisphosphonate,is used to reduce and delay bone com-plications due to bone metastases fromsolid tumors, including metastaticCRPC. As it is renally excreted, zole-dronic acid requires dose adjustment inaccordance with renal function.Patients with a normal creatinineclearance receive 4 mg intravenouslyover at least 15 minutes. Side effectscan include flu-like symptoms, includ-ing arthralgias, myalgias, and fever.

Denosumab, a monoclonal antibody,was FDA approved on November 18,2010, for the prevention of skeletal-related events in patients with bonemetastases from solid tumors. A phase3 trial was conducted, in whichpatients with metastatic CRPC wererandomized 1:1 to receive either 120mg subcutaneous denosumab plusintravenous placebo or 4 mg intra-venous zoledronic acid plus subcuta-neous placebo, every 4 weeks. Mediantime to first on-study skeletal-relatedevent was 20.7 months with denosu -mab compared with 17.1 months withzoledronic acid (P = .008).12 The mostcommon adverse reactions for patientsare fatigue/asthenia, hypophos-phatemia, and nausea. In addition,severe hypocalcemia can occur. It is

important that patients who receivethis therapy take a daily calcium supplement.Osteonecrosis of the jaw (ONJ), a

rare complication, can occur witheither zoledronic acid or denosumab.About 94% of published cases of ONJare patients with multiple myeloma ormetastatic carcinoma to the skeletonwho are receiving IV nitrogen-con-taining bisphosphonates. The mostimportant predisposing factors for the

development of bisphosphonate-asso-ciated ONJ are the type and total doseof bisphosphonate and history of trau-ma, dental surgery, or dental infec-tion.13 It is reasonable to requirepatients on these therapies to contacttheir treating practitioner’s office priorto dental appointments.Caring for the patient with metastatic

CRPC can be challenging; however,recent advancements in therapy have notonly broadened the options for patients

in this setting but have, more important-ly, improved survival. Ongoing studies areinvestigating new treatments and includeresearch in the areas of androgen manip-ulation, chemotherapy, and immunother-apy, to mention a few. Early results appearpromising and potentially will not onlyexpand the existing treatment arsenal butmay also show survival benefit forpatients who live with the devastatingdiagnosis of metastatic CRPC. �

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Friday, September 1412:45 – 1:00pm Welcome

Conference Co-Chairs:Sharon Gentry, RN, MSN, AOCN, CBCNLillie D. Shockney, RN, BS, MAS

1:00 – 2:00pm Pre-Conference Workshops& Beginners Track

2:15 – 3:15pm • Core Principles of NavigationNicole Messier, BSN, RN Pamela J. Vlahakis, RN, MSN, CBCN

Members• Grant Writing, Research, and Getting PublishedLinda Fleisher, PhD, MPH Elaine Sein, RN, BSN, OCN, CBCN

• Panel Discussion: Providing Optimal Community Outreach – Lay and Community Jean B. Sellers, RN, MSN, OCN (Moderator)Leah Leilani Beck, BSJessica Denton, MSW

• Implementing a Survivorship Program/ClinicCindy Waddington, RN, MSN, AOCN

3:15 – 3:30pm Break3:30 – 5:00pm Administrators Track

• Administering a Navigation Program Elizabeth Whitley, PhD, RN Bonnie J. Miller, RN, BSN, OCN, FAAMA

Navigators Track• How Do Case Managers and Navigators Interface?

Nancy Skinner, RN-BC, CCM5:00 – 6:00pm FREE TIME6:00 – 8:00pm Welcome Reception/Posters in the Exhibit Hall

Saturday, September 157:30 – 8:30am Breakfast Symposium/Product Theater8:30 – 8:45am Welcome & Introductions

Conference Co-Chairs8:45 – 9:45am General Session 1: Navigation Update: 2012

Current Regulations – Navigation & SurvivorshipCare Plan Linda Ferris, PhD

9:45 – 10:00am Break10:00 – 11:30amDisease-Site–Specific Breakouts

Stand-Alone Sessions• Breast Cancer Navigation

Mary Rooney, RN, BSN, OCN • Lung Cancer Navigation & Smoking

CessationPamela Matten, RN, BSN, OCN

• GI Cancer NavigationCoralyn Martinez, MSN, RN, OCN

www.regonline.com/aonn2012

PRELIMINARY AGENDA*

• Colorectal Cancer Navigation

Maura Kadan, RN, MSN, OCN• GYN Cancer Navigation

Robin Atkinson, RN, BSN, OCN• Prostate Cancer Navigation

Juli Aistars, RN, APNRapid Fire Sessions with Panel• Head, Neck, & Neuro Navigation

Heather Stern, RN, BSN, CNOR, OCNAnd

• Hematology/OncologyTina Scherer, RN, MSN, OCN

Administrators Session • The Role of the Administrator

Lisa Shalkowski, RN, BSN, MSM11:45 – 1:00pm Lunch in the Exhibit Hall1:15 – 2:15pm Advocacy Keynote

Speaker TBD2:15 – 3:15pm General Session 2: Best Practices in

Survivorship Care Rehabilitation(Importance of implementing cancer rehab on day of diagnosis)Julie Silver, MD

3:15 – 4:15pm General Session 3: Plenary SessionFinancial and Legal Issues for Our Cancer PatientsDavid S. Landay, Esq.

4:15 – 6:15pm Poster Award Reception in the Exhibit HallPamela Matten, RN, BSN, OCN

6:15pm Conclusion of Day – Networking FREE TIME

Sunday, September 167:30 – 8:30am Breakfast Symposium/Product Theater8:30 – 9:30am General Session 4: Navigation in the Age of

Personalized Cancer CareSharon Gentry, RN, MSN, AOCN, CBCNLillie D. Shockney, RN, BS, MAS

9:30 – 10:30am General Session 5: Best Practices in AddressingHealth InequitiesLauren Kelley, MSW, MPA Adrienne Lofton, RN

10:30 – 10:45am Break10:45 – 12:15pm Practice Setting – Panel Discussion with

Moderator• Academic

Bonnie J. Miller, RN, BSN, OCN, FAAMA • Community Hospital–Based

Karyl Blaseg, RN, MSN, OCN• Office-Based

Roxanne Parker, MSN 12:15 – 1:15pm Lunch in the Exhibit Hall1:30 – 2:30pm Clinical Survivorship Guidance

Mandi Pratt-Chapman, MA2:30 – 2:45pm Conclusion/Final Remarks

Conference Co-Chairs*Preliminary agenda, subject to change.

*

s c

Third Annual Navigation andSurvivorship Conference

� � � � �� TON_May2012_v7_TON 5/22/12 9:50 AM Page 30

Medical Learning Institute, Inc.Provider approved by the California Board of Registered Nursing,Provider Number 15106, for up to 12.25 contact hours.

REGISTERED NURSE DESIGNATION

This activity is pending approval from the National Association of SocialWorkers. Contact hours for this continuing social worker education activ-ity have been submitted to the National Association of Social Workers.

SOCIAL WORK DESIGNATION

Juli Aistars, RN, APN

Robin Atkinson, RN, BSN, OCN

Leah Leilani Beck, BS

Karyl Blaseg, RN, MSN, OCN

Jessica Denton, MSW

Linda Ferris, PhD

Linda Fleisher, PhD, MPH

Maura Kadan, RN, MSN, OCN

Lauren Kelley, MSW, MPA

David S. Landay, Esq.

Adrienne Lofton, RN

Coralyn Martinez, MSN, RN, OCN

Pamela Matten, RN, BSN, OCN

Nicole Messier, BSN, RN

Bonnie J. Miller, RN, BSN, OCN,FAAMA

Roxanne Parker, MSN

Mary Rooney, RN, BSN, OCN

Tina Scherer, RN, MSN, OCN

Elaine Sein, RN, BSN, OCN, CBCN

Jean B. Sellers, RN, MSN, OCN

Lisa Shalkowski, RN, BSN, MSM

Julie Silver, MD

Nancy Skinner, RN-BC, CCM

Heather Stern, RN, BSN, CNOR, OCN

Pamela J. Vlahakis, RN, MSN, CBCN

Cindy Waddington, RN, MSN, AOCN

Elizabeth Whitley, PhD, RN

F

www.regonline.com/aonn2012w

FACULTY*

Breast Health NavigatorDerrick L. Davis ForsythRegional Cancer CenterWinston-Salem, NC

University Distinguished Service Associate Professor of Breast Cancer Depts of Surgery and OncologyAdministrative Director, Johns Hopkins Breast Clinical ProgramsAdministrative Director, Johns Hopkins Cancer Survivorship ProgramsAssociate Professor, JHU School of Medicine, Depts of Surgery & Gynecology and ObstetricsAssociate Professor, JHU School of NursingBaltimore, MD

Sharon Gentry, RN, MSN, AOCN, CBCN

Lillie D. Shockney, RN, BS, MAS

CONFERENCE CO-CHAIRS

��

*For full information visit www.aonnonline.org

AONN’s Third Annual Conference will continue to advance the nav-igation profession by expanding the scope of educational sessions, net-working opportunities, and poster presentations. In addition, this year’sconference will address the evolving challenges of program improve-ment, the role of personalized medicine, and implementing best prac-tices in navigation, survivorship, and psychosocial care.

CONFERENCE OVERVIEW

GoalAONN’s Third Annual Navigation and Survivorship Conferencewill advance the role of navigation and survivorship in cancer careto ultimately improve the quality of patient care.

Objectives• Discuss the evolution of the role of navigation in healthcare• Assess strategies for navigating diverse patient populations by cancer type and environmental factors

• Define methods for providing patient support and guidance inthe age of personalized cancer care

• Evaluate best practices regarding survivorship and psychosocial care

CONTINUING EDUCATION INFORMATION

This is an opportunity to share research, programs, and results withyour colleagues. Submit your abstract via e-mail to [email protected] Deadline: August 1, 2012

CALL FOR ABSTRACTS

AONN’s Third Annual Conference is the only meeting that gives youaccess to decision-makers and key practitioners involved in oncologynavigation and survivorship. If your company provides any of the follow-ing services/products for the oncology healthcare community, this is themeeting for you.

• Pharmaceutical/Biotech• Genetic Laboratory Services• Navigation Software• Patient Advocacy• Training

TARGET AUDIENCE

• Patient Access• Reimbursement• Publishers• Education• Certification

This educational initiative is directed toward oncology nurse naviga-tors, patient navigators, and social workers.

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

SPONSORS

Register online: www.regonline.com/aonn2012CONFERENCE REGISTRATION

Current Members $295New Members $345Nonmembers $425*

*Register by July 15 and save $100 off full registration of $525.

September 14-16, 2012Phoenix, Arizona Arizona Grand

� � � � �� TON_May2012_v7_TON 5/22/12 9:51 AM Page 31


Multiple Myeloma

Multiple myeloma (MM) is a B-cell neoplasm originatingfrom the plasma cell. The

American Cancer Society estimates thatin 2012 there will be 21,700 new casesand 10,710 deaths in the United Statesdue to MM, making it the third mostcommon hematologic malignancy.1 Themedian age at diagnosis is 69, and it ismore prevalent in men versus womenand in blacks versus whites.2 Using datagenerated between 2002 and 2008, the5-year overall survival rate in myeloma isapproximately 41%, a number that issteadily increasing, due primarily to thenewer treatment regimens currentlybeing used.2 Although highly treatable,there is still no cure for MM and almostall patients become chemotherapy resist-ant at some point during treatment. The former gold standard treatment

for MM, melphalan and prednisone, wasintroduced more than 30 years ago.Since then, newer immunomodulatoryagents (IMiDs) and a proteasomeinhibitor have been studied in numerousclinical trials and approved by the USFood and Drug Administration (FDA)in an attempt to offer patients newer,more effective treatment options and toovercome the multidrug resistance that iscommon among MM patients.3 Otheragents for treating MM, including newproteasome inhibitors and IMiDs, arecurrently in clinical trials. The treatment landscape in MM is

changing rapidly. Helping patients man-age the side effects of these therapies andsupporting their adherence to therapycan potentially increase survival ratesand promote a better quality of life.

BortezomibVelcade (bortezomib) for injection(Millennium, The Takeda OncologyCompany) is a proteasome inhibitorindicated for the treatment of patientswith MM and for patients with mantlecell lymphoma who have received atleast 1 prior therapy.4The recommended starting dose of

bortezomib is 1.3 mg/m2, administeredintravenously (IV) over 3 to 5 secondsat a concentration of 1 mg/mL, or sub-cutaneously (SC) at a concentration of2.5 mg/mL.4 Additional details aboutthe new SC indication will be discussedin a later section of this article. Consultthe full prescribing information at www.velcade.com for detailed dosage andadministration guidelines.

The most commonly reported sideeffects (incidence ≥30%) in clinical tri-als include asthenic conditions (fatigue,malaise, weakness), diarrhea, nausea,constipation, peripheral neuropathy(PN), vomiting, pyrexia, thrombocy-topenia, psychiatric disorders, anorexiaand decreased appetite, neutropenia,neuralgia, leukopenia, and anemia.4 Wediscuss selected side effects in this arti-cle, as well as some of the newer dataregarding administration and the impli-cations for nursing practice.

Peripheral NeuropathyPN can be either disease or treatmentrelated, and bortezomib-inducedperipheral neuropathy (BIPN) is a fre-quent cause of either dose reduction orchanges in the treatment plan.5 In thepivotal trial of previously untreatedMM patients using bortezomib in com-bination with melphalan and pred-nisone, 47% developed some degree ofsensory PN (13% grade 3, 1% grade 4).4However, severe sensory and motor PNshave also been reported. Sensory nervesaffected by neuropathy include smallfibers, which manifest as altered pain,temperature, and sensation, and largefibers that can result in loss of positionsense (proprioception), and ability tofeel vibrations, touch, or pressure.6The underlying mechanism for devel-

opment of BIPN is not known, but accu-mulation of bortezomib in the dorsal rootganglia cells, mitochondrial-mediateddysregulation of Ca2+ homeo stasis, and

dysregulation of neuro trophins havebeen implicated.5A recent article in the Journal of the

Peripheral Nervous System, the officialjournal of the Peripheral NerveSociety, notes that preexisting neu-ropathy is not an uncommon finding inoncology patients.7 For patients withnewly diagnosed MM, the incidence ofpreexisting PN at diagnosis has beenestimated from less than 1% to a highof 13%.8 Bruna and colleagues evaluat-ed the role of preexisting neuropathyinduced by vincristine or bortezomib asa risk factor for development of moresevere bortez omib-induced neuropathyin a mouse model. They reported thatthe presence of a severe neuropathyprior to treatment with bortezomibresulted in a more marked involvementof peripheral nerves.7Richardson and colleagues assessed

PN in two phase 2 studies (256 patientstotal) with relapsed and/or refractoryMM treated with IV bortezomib 1.0 or1.3 mg/m2.9 Patients were evaluated forPN at baseline, during, and after thestudy using both the FunctionalAssessment of Cancer TherapyScale/Gynecologic Oncology Group-Neurotoxicity (FACT/GOG-Ntx) ques-tionnaire and neurologic examination.They found that at baseline, 81% of 239patients had PN by questionnaire and203 of 244 patients (83%) had PN byneurologic exam. Not surprisingly, theincidence of grade ≥3 PN during thestudy was higher among patients with

baseline neuropathy compared withthose patients without (14% vs 4%,respectively). The BIPN seen in this trialappeared to be a cumulative, dose-relat-ed effect with increased incidence duringthe first 5 treatment cycles. For 71% ofthe patients with clinically significantneuropathy, there was resolution orimprovement of symptoms after dosemodification or completion of therapy.9

Managing PNBecause of the increased incidence ofPN in MM patients treated with bortez -omib, they should be carefully assessedfor preexisting neuropathies prior tobeginning therapy and periodically dur-ing treatment. Patients who are diag-nosed with PN prior to starting bortez -omib therapy should receive a carefulrisk-benefit evaluation. In addition,starting bortezomib SC may be an optionfor patients with preexisting or at highrisk for developing PN.4 When assessingpatients, pay particular attention tothose patients with conditions such asdiabetes or autoimmune disorders(rheumatoid arthritis or lupus), chronickidney disease, infections, low levels ofvitamin B12, poor circulation, heavyalcohol use, exposure to environmentalworkplace toxins, or hypothyroidism,which can place patients at higher riskfor developing neuropathies.10Patients receiving bortezomib may

complain of feeling cold, a burning sen-sation, and/or tingling/numbness intheir extremities, the classic stocking

Managing Bortezomib Therapy in Patients WithMultiple MyelomaBy Linda Caldwell, RN, MS, AEP New York, LLC, Millbrook, New York;

Cass Hammond, RN, MSN, CRNP, ATD Partners, LLC, Millbrook, New York;

Kathleen Colson, RN, BSN, BS, Dana-Farber Cancer Institute, Boston, Massachusetts

Table 1 Recommended Dose Modification for Bortezomib-Related Neuropathic Pain and/or Peripheral Sensory or MotorNeuropathy4

Severity of Peripheral Neuropathy Signs and Symptoms* Modification of Dose and Regimen

Grade 1 (asymptomatic; loss of deep tendon reflexes orparesthesia) without pain or loss of function

No action

Grade 1 with pain or grade 2 (moderate symptoms; limitinginstrumental ADL)†

Reduce bortezomib dose to 1 mg/m2

Grade 2 with pain or grade 3 (severe symptoms; limitingself-care ADL)‡

Withhold bortezomib therapy until toxicity resolves; whentoxicity resolves, reinitiate with a reduced dose of bortezomib at 0.7 mg/m2 once per week

Grade 4 (life-threatening consequences; urgent interventionindicated)

Discontinue bortezomib

*Grading based on National Cancer Institute Common Terminology Criteria for Adverse Events; v 4.0.†Instrumental ADL: refers to preparing meals, shopping for groceries or clothes, using telephone, managing money, etc.‡Self-care ADL: refers to bathing, dressing and undressing, feeding self, using the toilet, taking medications, and notbedridden.

Abbreviation: ADL, activities of daily living.



Multiple Myeloma

and glove distribution.11 Dose modifica-tion guidelines found in the prescribinginformation should be followed whenpatients report or are found to havegrade 2 neuropathy or grade 1 associat-ed with pain, as listed in Table 1.Many different grading scales are

available to diagnose PN, but no stan-dard method for administration orinterpretation of the scales has beendeveloped.12 One example of testinguses Semmes-Weinstein monofila-ments. With the patient’s eyes closed,a fine filament is applied to each handand foot, and the patient is instructed tonote when the filament is felt. In theRomberg test, the patient stands stillwith his/her heels together and eyesclosed. If the patient loses his/her bal-ance, the test is positive for loss of pro-prioception. Another simple test canalso be performed using a sharp safety pinor similar object, alternating between thesharp and dull ends, asking the patient toreport the sensation.There is no standard treatment for

BIPN, and patients should be assessedindividually for appropriate potentialtherapy. In addition to bortezomib dosereduction or schedule modification,BIPN can be treated with antidepres-sants, anticonvulsants, amino acids, lido-caine patches, and narcotics, albeit withlimited response and potential sideeffects such as sedation, dry mouth, andconstipation.12 Non pharmacologic ap -proaches include massage, physical andoccupational therapy, and more recently,acupuncture. A recent case report in theliterature describes a 48-year-old AfricanAmerican man with MM who was suc-cessfully treated with bortezomib andstem cell transplantation but developeddebilitating PN during his third cycle ofbortezomib and was resistant to bothgabapentin and morphine sulfate treat-ment. He was successfully treated with14 acupuncture sessions, was able toreturn to work, and remained pain freeand asymptomatic 1 year later.13Nurses have a unique opportunity to

assess, educate, and follow up withpatients regarding PN. Patient educationsafety checklists should include review-ing items such as ensuring the waterheater temperature is adjusted accordingto their ability to feel hot and cold; use ofrubber gloves for dishwashing and heavy-duty pot holders for handling pans; wear-

ing cotton socks and gloves in cold tem-peratures; and avoiding clutter in theirhomes, including slippery area rugs andbath mats.14-16 Ongoing assessment forPN should be done on a regular basis andinclude such items as asking patientsabout stocking and glove numbness, tin-gling, burning, sensitivity to touch, pain,and interference with their activities ofdaily living. Nurses should observe thepatient’s gait to note any difficulty relat-ed to altered proprioception or numbnessin the feet and check his or her ability tobutton, zipper, or tie. If PN is confirmed,nurses should counsel the patient abouthis or her ability to drive or operatemachinery safely and take action withfamily members as appropriate.

ThrombocytopeniaThrombocytopenia (platelet count<100 × 109/L) associated with bortez -omib therapy is thought to be due to areversible effect on megakaryocyticfunction rather than a direct cytotoxiceffect on megakaryocytes or their pro-genitors.17 Platelet budding frommegakaryocytes is regulated in part bythe activity of nuclear factor κB (NF-κB), and the proteasome inhibi-tion seen with bortezomib preventsactivation of NF-κB. Further, thecyclic, transient thrombocytopeniaseen with bortezomib administration ispredictable when compared with cyto-

toxic chemotherapies such as alkylat-ing agents. Lonial and colleaguesassessed patients from 2 studies usingbortez omib: the Study of UncontrolledMultiple Myeloma Managed WithProteasome Inhibition Therapy(SUMMIT) and Clinical Responseand Efficacy Study of Bortezomib inthe Treatment of Relapsing MultipleMyeloma (CREST). They found thatsignificant predictors of grade 3/4 throm-bocytopenia included low baselineplatelet count, high baseline M-proteinconcentration, and the number of previ-ous treatments. Further analysis revealedthat the thrombocytopenia seen withbortezomib is transient; lower plateletcounts are seen during the first 10 days oftreatment, with recovery during the 10-day rest period. Most importantly, overallresponse rates to bortez omib did notappear to be impacted by the baselineplatelet count.17

Managing ThrombocytopeniaThe pretreatment nursing assessment ofMM patients should include a thoroughpatient history for any previous bleedingfrom mucosal or other sites (eg, gas-trointestinal [GI]), history of bruising,or prolonged bleeding following injuryor surgery. A neurologic assessmentshould also be performed to monitor forsymptoms of intracranial bleeding.18Nurses should discuss with their

patients that the thrombocytopeniaassociated with bortezomib therapy isan expected, cyclical, transient, andmanageable side effect of therapy.Reviewing thrombocytopenic precau-tions is essential, and if your institutionor practice does not have a specificteaching sheet on this topic, an excel-lent version is available free from theNational Institutes of Health: PatientEducation: Understanding Your CompleteBlood Count.19 Some important pointsto stress when teaching thrombocyto -penic precautions include using a softtoothbrush and electric shavers; avoidenemas, rectal thermometers, supposi-tories, and tampons; blow the nose gen-tly; avoid eating irritating foods such aspopcorn or apple peels; avoid usingknives or other sharp instruments; and areview of aspirin-containing medica-tions such as pain relievers and certainprescription medications. (The patientguide referenced above contains a list ofcommon aspirin-containing products.)The manufacturer’s recommended

dose-modification guidelines for bortez -omib-associated hematologic toxicitiesare listed in Table 2.

GI Events and ManagementThe incidence of grade 3/4 selected GIside effects among previously untreatedMM patients receiving bortezomib-mel-

Table 2 Dose Modifications During Cycles of Combination Bortezomib, Melphalan, and Prednisone Therapy4

Toxicity Dose Modification or Delay

Hematologic toxicity during a cycle: If prolonged grade 4neutropenia or thrombocytopenia, or thrombocytopeniawith bleeding is observed in the previous cycle

Consider reduction of the melphalan dose by 25% in thenext cycle

If platelet count is not above 30 × 109/L or ANC is notabove 0.75 × 109/L on a bortezomib dosing day (other than day 1)

Bortezomib dose should be withheld

If several bortezomib doses in consecutive cycles are withheld due to toxicity

Bortezomib dose should be reduced by 1 dose level (from1.3 mg/m2 to 1 mg/m2, or from 1 mg/m2 to 0.7 mg/m2)

Grade 3 or higher nonhematologic toxicities Bortezomib therapy should be withheld until symptoms ofthe toxicity have resolved to grade 1 or baseline; thenbortezomib may be reinitiated with 1 dose-level reduction(from 1.3 mg/m2 to 1 mg/m2, or from 1 mg/m2 to 0.7 mg/m2)

Abbreviation: ANC, absolute neutrophil count.For information concerning melphalan and prednisone, see manufacturers’ prescribing information.







Multiple Myeloma

phalan-dexamethasone in a prospectiverandomized trial was 33% to 48%.4Nausea (48%), diarrhea (46%), consti-pation (37%), and vomiting (33%) werethe most common side effects observedin this group of patients.4 Since themedian age of newly diagnosed MMpatients is 62 years, they may have pre-existing GI conditions that could beexacerbated by the combination ofbortezomib-melphalan-prednisone.20Patients should be educated about thepotential GI side effects prior to begin-ning bortezomib therapy and appropri-ate interventions reviewed with them(eg, use of antiemetics, laxatives,antidiarrheals, fluid intake, and dietaryrestrictions).

Herpes Virus Infection (Shingles)and ManagementBecause patients with MM are moresusceptible to infections, it is impor-tant to note that in the randomizedtrials of patients with previouslyuntreated and relapsed MM, the reac-tivation of herpes simplex virus wasmore common in patients treated with

bortez omib (13%) than in the controlgroups (4%-5%).4 Patients whoreceived prophylactic antiviral thera-py were less likely to experience reac-tivation of the herpes virus (3%) thanthose who did not receive the antiviraltreatment (17%).4 It is therefore rec-ommended that MM patients receiv-ing bortez omib should also receiveprophylactic antiviral therapy to avoidvirus reactivation and/or other moreserious complications.4,21

SC Route of Administration NowApprovedOn January 23, 2012, the FDAapproved bortezomib for SC administra-tion in patients with MM and relapsedmantle cell lymphoma.22 This approvalwas based on a pivotal study by Moreauand colleagues,23 who conducted a ran-domized, phase 3, noninferiority studyof 222 (221 evaluable) patients in 53sites across 10 countries in Europe, Asia,and South America. Patients withrelapsed MM who had received 1 to 3previous therapies were randomlyassigned to receive up to eight 21-daycycles of bortezomib 1.3 mg/m2 on days1, 4, 8, and 11 by either SC injection (n= 147) or IV infusion (n = 74). The pri-mary objective was to show noninferior-ity of SC versus IV bortezomib in termsof overall response rate (completeresponse + partial response; ORR) after4 cycles in all patients with measurabledisease who received 1 or more doses ofdrug. Noninferiority was defined asretaining 60% of the IV treatmenteffect. SC injections of 2.5 mg/mL (3.5mg bortezomib reconstituted with 1.4mL normal [0.9%] saline to limit theinjection volume) were given on arotating basis in the thighs orabdomen. Alternating sites betweenright and left abdomen, upper andlower quadrant, or right and left thigh(proximal and distal) was the protocolrecommendation (Figure). IV injectionswere given at a concentration of 1 mg/mL(3.5 mg in 3.5 mL normal saline) as a 3-5second IV push. Patients received a medi-an of 8 cycles, and the ORR after 4 cycleswas 42% in both treatment arms (P =.002), thus demonstrating the noninferi-ority hypothesis in ORR. There were nosignificant differences in the time to pro-gression (10.4 vs 9.4 months) and 1-yearoverall survival (72.6 % vs 76.7%) withSC versus IV bortezomib, respectively.Grade 3 or worse adverse events werenoted in 84 patients (57%) in the SCgroup versus 52 (70%) in the IV group,with the most common being thrombo-cytopenia (13% vs 19%), neutropenia(18% vs 18%), and anemia (12% vs 8%),respectively. Most significantly, the inci-dence of PN of any grade was less com-mon with SC versus IV administration

(38% vs 53%; P = .044). Injection sitereactions consisted mainly of reversibleredness and rarely resulted in reporting ofan adverse event. In addition, in the SCgroup there were fewer dose reductionsand discontinuations due to adverseevents. The investigators suggested thatin addition to reducing bortezomib-relat-ed PN, the increased patient conven-ience and similar efficacy of SC dosingmay be a consideration for future studiesof bortez omib maintenance therapy.23

Reconstitution of Bortezomib for SCand IV UseIt is important to remember that thereconstitution of bortezomib for SC useis different from that for IV use, and cau-tion should be used when calculating thevolume to be administered.• The reconstituted concentration ofbortezomib for SC administration (2.5mg/mL) is greater than that for IVadministration (1 mg/mL)

• For SC dosing, add 1.4 mL 0.9% sodi-um chloride to make a final concentra-tion of 2.5 mg/mL

• For IV dosing, add 3.5 mL 0.9% sodi-um chloride to make a final concentra-tion of 1 mg/mL

• The recommended starting dose is 1.3 mg/m2 for both routes of adminis-tration4,24

• To calculate the total volume of recon-stituted bortezomib to use, determinethe patient’s body surface area (BSA)in square meters (m2) and use the fol-lowing equations:

ConclusionThrough numerous trials and thousandsof patient experiences, bortez omib hasbeen shown to be a safe, effective treat-ment for patients with MM. Sincepatient adherence to treatment can sig-nificantly impact re sponse rates, oncolo-gy nurses can have a positive effect onthis important aspect of treatment byeffectively and appropriately educatingpatients about managing the expectedside effects of bortezomib therapy. As waseffectively demonstrated by Moreau andcolleagues,23 the use of SC bortez omib isa potential alternative to IV administra-tion, especially for patients at risk of

developing side effects and/or those withpoor venous access. �

References1.American Cancer Society. Cancer Facts & Figures 2012.Atlanta, GA: American Cancer Society; 2012.http://www.cancer.org/Research/CancerFactsFigures/CancerFactsFigures/cancer-facts-figures-2012. Accessed May16, 2012.2. Surveillance, Epidemiology, and End Results (SEER).SEER stat fact sheets: myeloma. http://seer.cancer.gov/statfacts/html/mulmy.html#incidence-mortality.Accessed May 16, 2012.3. Rajkumar SV. Multiple myeloma. Curr Probl Cancer.2009;33:7-64.4. Velcade (bortezomib) for Injection [package insert].Cambridge, MA: Millennium: The Takeda OncologyCompany; 2012.5. Argyriou AA, Iconomou G, Kalofonos HP.Bortezomib-induced peripheral neuropathy in multiplemyeloma: a comprehensive review of the literature. Blood.2008;112:1593-1599.6. Wolfe GI, Trivedi JR. Painful peripheral neuropathyand its nonsurgical treatment. Muscle Nerve. 2004;30:3-19.7. Bruna J, Alé A, Velasco R, et al. Evaluation of pre-existing neuropathy and bortezomib retreatment as riskfactors to develop severe neuropathy in a mouse model. JPeripher Nerv Syst. 2011;16:199-212.8. Tariman JD, Love G, McCullagh E, et al; IMF NurseLeadership Board. Peripheral neuropathy associated withnovel therapies in patients with multiple myeloma: con-sensus statement of the IMF Nurse Leadership Board. ClinJ Oncol Nurs. 2008;12(suppl 3):29-36.9. Richardson PG, Briemberg H, Jagannath S, et al.Frequency, characteristics, and reversibility of peripheralneuropathy during treatment of advanced multiple myelo-ma with bortezomib. J Clin Oncol. 2006;24:3113-3120.10. National Institute of Neurological Disorders andStroke. Peripheral Neuropathy Fact Sheet. www.ninds.nih.gov/disorders/peripheralneuropathy. UpdatedAugust 10, 2011. Accessed November 14, 2011.11.Richards T. Managing the side effects of lenalidomideand bortezomib. Community Oncol. 2009:56-57. www.communityoncology.net/co/journal/0602.html. AccessedOctober 28, 2011.12. Wickham R. Chemotherapy-induced peripheral neu-ropathy: a review and implications for oncology nursingpractice. Clin J Oncol Nurs. 2007;11:361-376.13. Bao T, Zhang R, Badros A, et al. Acupuncture treat-ment for bortezomib-induced peripheral neuropathy: acase report. Pain Res Treat. 2011. www.ncbi.nlm.nih.gov/pmc/articles/PMC3199913/ ?tool=pubmed. AccessedNovember 28, 2011.14. Almadrones LA, Arcot R. Patient guide to peripher-al neuropathy. Oncol Nurs Forum. 1999;26:1359-1360.15. Sorich J, Taubes B, Wagner A, et al. Oxaliplatin:practical guidelines for administration. Clin J Oncol Nurs.2004;8:251-256.16. Sweeney CW. Understanding peripheral neuropathyin patients with cancer: background and patient assess-ment. Clin J Oncol Nurs. 2002;6:163-166.17. Lonial S, Waller EK, Richardson PG, et al; SUM-MIT/CREST Investigators. Risk factors and kinetics ofthrombocytopenia associated with bortezomib forrelapsed, refractory multiple myeloma. Blood. 2005;106:3777-3784.18. Miceli T, Colson K, Gavino M, et al.Myelosuppression associated with novel therapies inpatients with multiple myeloma: a consensus statement ofthe IMF Nurse Leadership Board. Clin J Onc Nurs.2008;12(3 suppl):13-20.19. National Institutes of Health Clinical Center. PatientEducation: Understanding Your Complete Blood Count.www.cc.nih.gov/ccc/patient_education/pepubs/cbc97.pdf. Published November 2008. Accessed November21, 2011.20. Multiple Myeloma Research Foundation. Newlydiagnosed patients: what is multiple myeloma.www.themmrf.org/living-with-multiple-myeloma/newly-diagnosed-patients/what-is-multiple-myeloma/. AccessedNovember 21, 2011.21. Taniguchi D, Takahara O, Takasaki Y, et al. Fatalcytomegalovirus pneumonia and associated herpes virusinfection in a relapsed/refractory multiple myelomapatient treated with bortezomib plus dexamethasone.Case Rep Oncol. 2009;2:140-143.22. FDA Approves Subcutaneous Administration ofVELCADE® In All Approved Indications.Businesswire; January 23, 2012. www.bioportfolio.com/news/article/926407/Fda-Approves-Subcutaneous-Administration-Of-Velcade-In-All-Approved-Indications.html. Accessed January 25, 2012.23. Moreau P, Pylypenko H, Grosicki S, et al.Subcutaneous versus intravenous administration ofbortezomib in patients with relapsed multiple myelo-ma: a randomised, phase 3, non-inferiority study.Lancet Oncol. 2011;12:431-440.24. Dear Healthcare Professional letter. Velcade Website. http://www.velcade.com/Files/PDFs/V-12-0047_SC_Patient_Announcement_Letter_FINAL.pdf.Accessed January 30, 2012.

Figure. SC Injections Site Rotation.

Managing Bortezomib Therapy in Patients... Continued from page 33

IV Administration (1 mg/mL concentration)

Bortezomib dose (mg/m2) × BSA

1 mg/mL

SC Administration (2.5 mg/mL concentration)

Bortezomib dose (mg/m2) × BSA

2.5 mg/mL



Multiple Myeloma

Lymphomas

The best strategy for managementof low-tumor-burden follicularlymphoma (FL) following re -

sponse to induction therapy is contro-versial. The phase 3 RESORT studycompared maintenance rituximab ther-apy versus rituximab retreatment at dis-ease progression, and results suggest thatretreatment is the preferred approach.The study was presented at the 53rdAnnual Meeting of the AmericanSociety of Hematology. The strategies achieved a similar time

to treatment failure (TTTF) in this FLpatient population, with no differencein quality of life or anxiety at 12months. Both strategies appear to delaytime to chemotherapy compared withhistorical controls. Although mainte-nance therapy prolonged the time untilcytotoxic therapy was needed, almost 4times more rituximab was used, makingmaintenance therapy by far the morecostly approach.“Given the excellent outcome with

retreatment, the toxicity profile, the lackof quality of life difference [between the

2 approaches], and the required doses ofrituximab, retreatment is our recom-mended strategy if electing to use ritux-imab,” stated lead investigator BradKahl, MD, University of Wisconsin,Madison. “The retreatment strategy isless costly, and we believe it is the pre-ferred option to help patients with low-tumor-burden FL manage their disease.”Kahl said that the study did not deter-

mine which strategy is best for improvingoverall survival. Such a study would haveto compare watch and wait versusretreatment versus maintenance therapy.RESORT enrolled 384 patients with

FL histology; of these, 274 (71%)responded to induction therapy withrituximab and were randomized to

retreatment (n = 134) or maintenancerituximab (n = 140).Median TTTF (primary end point)

was 3.6 years with retreatment versus3.9 years with maintenance rituximab.At 3 years of follow-up, only 5% ofpatients in the maintenance armrequired cytotoxic chemotherapy ver-sus 14% of patients in the retreatmentarm. However, patients assigned toretreatment used a mean of 4.5 doses ofrituximab over that time, while thoseassigned to maintenance rituximabused a mean of about 16 doses.Fewer than 5% of patients in the

trial experienced severe hematologicor nonhematologic toxicities. No dif-ference between the arms was observed

in deaths and second cancers. Therewas 1 adverse event leading to discon-tinuation in the retreatment arm and 7in the maintenance arm.At 12 months’ follow-up after ran-

domization, no difference was found inhealth-related quality of life or burdenof stress.Kahl said that the investigators were

concerned that patients assigned toretreatment might experience moreanxiety than those in the maintenancearm because they knew they had can-cer and weren’t being treated, but thisconcern was not borne out.Commenting on this study, Jane

Winter, MD, moderator of the pressconference where RESORT was dis-cussed, and Professor at NorthwesternUni versity Feinberg School ofMedicine, Chicago, said: “If we canlimit the frequency of treatment, orreduce the need for chemotherapyand still maintain good outcomes, wecan reduce some of the burdens onboth the patients and the healthcarecommunity.” � —AG

Retreatment With Rituximab as Effective asMaintenance Rituximab but Less Costly inIndolent Follicular Lymphoma

At 5 years of follow-up of theVISTA trial, the combinationof bortezomib plus melphalan

and prednisone (VMP) demonstrated asurvival advantage over MP alone asup-front treatment of patients withmultiple myeloma who were not trans-plant candidates. At a median follow-up of 60.1 months, the absolute differ-ence in overall survival (OS) betweenthe treatment arms was 13 months,according to final results presented atthe 53rd Annual Meeting of theAmerican Society of Hematology.Patients assigned to the MP arm whotook bortezomib at disease progressionfailed to achieve the survival advantageof those who received bortezomib as partof up-front treatment.“The 5-year results of VISTA con-

firm the significant survival benefit of

VMP versus MP…. These data demon-strate that it is important to providethe best induction therapy—VMP—up front,” stated Jesús San Miguel,MD, Universitario de Salamanca,Salamanca, Spain.

The study population included 682patients, with a median age of 71years; 30% were aged 75 and older, andone-third had advanced disease. Lessthan 5% of patients in each arm werelost to follow-up.

Median OS was 56 months with VMPversus 43 months with MP (P = .0004).The benefit of up-front VMP was main-tained across all prespecified subgroups,including patients with high-risk cytoge-netics. Time to next treatment was sig-nificantly longer in VMP-treated versusMP-treated patients (median of 27months vs 19.2 months, respectively; P <.0001), and treatment-free intervalwas also longer (16.6 months vs 8.3months, respectively; P <.0001).A similar percentage of patients in

each group received subsequent thera-pies at relapse, with the exception ofbortezomib: 22% in the VMP group ver-sus 43% of patients in the MP groupwere treated with bortezomib at relapse.Among patients who required subse-quent anticancer therapies, OS was sig-nificantly longer in patients treated

with VMP up front: median 55.7months versus 46.4 months, respective-ly (P = .0162).Regarding the safety of VMP, San

Miguel said, “We saw no emerging safe-ty signal for an increase in secondary pri-mary malignancies [SPMs]. I think thesedata on SPMs are solid, with the rate asexpected in the general population oreven lower. VMP is completely safe.”Hematologic SPMs were reported in

3 patients (1%) in each group over the5-year follow-up; nonhematologicSPMs were found in 16 patients in theVMP group and 10 in the MP group.The expected rate of SPMs in the gen-eral population is 1.9 per 100 patient-years; the rate in the VMP arm waslower than expected at 1.6 per 100patient-years, and the rate in the MParm was 1.3. �

Five-Year Follow-up of VISTA Trial Confirms Long-term Survival Benefit for Bortezomib-Containing Regimen Up FrontBy Alice Goodman

“The retreatment strategy is less costly, and we

believe it is the preferred option to help patients

with low-tumor-burden FL manage their disease.”

—Brad Kahl, MD

The benefit of up-front

VMP was maintained

across all prespecified

subgroups.



Conference News:

The need to optimize the treat-ment of patients with cancerwhile using healthcare resources

wisely—in other words, providing“value-based cancer care”—is not atopic of debate, but how to achieve thispressing goal is far from clear. In a paneldiscussion during the Association forValue-Based Cancer Care’s SecondAnnual Conference, held in Houston,Texas, strategists from the payer side ofthe issue discussed the current trendsand the challenges they are facing.Burt Zweigenhaft, BS, President and

Chief Executive Officer of OncoMed,Great Neck, New York, who led the dis-cussion, noted that the rising cost ofcancer care is clearly the trigger pointfor change. “The cost curve is unsus-tainable. Who will win and who willlose? Clearly, there are realignments.”Ira M. Klein, MD, MBA, Chief of

Staff to the Chief Medical Officer atAetna Oncology Strategy, New York,added, “We get feedback from our dif-ferent customers as to what they want,from the self-insured employers to thesmall businesses down to the individ-ual in the market. And the unifyingtheme is that they cannot sustain anymore cost.”

Employers Are ConfusedEmployers may be steadily downsizingtheir benefits, but this does not meanthey do so without pain, participantsnoted. “Employers are more paternalis-tic than one would think. They areconcerned about the care theiremployees are getting,” said Klein.“They want benefit designs that do notdeny patients access to essential servic-es, but they want these to be acquiredat the most favorable unit price. Cost isa very big factor to them.”Maria Lopes, MD, MS, Chief Med -

ical Officer for AMC Health, Cresskill,New Jersey, agreed. “Employers are con-cerned about cost and about what ishappening in the marketplace, and theyare looking to payers for solutions.”Employers clearly do not understand

why costs are so high, added WinstonWong, PharmD, Associate VicePresident of Pharmacy Managementwith CareFirst BlueCross BlueShieldin Maryland. “The employers ask theirconsultants. The consultants come tous because they think pharmacy is thesilver bullet. When you look at it fromthe employer and consultant stand-points, you see there is not much

understanding about what is driving thenumbers,” he said.

Drug Costs: The Big BugabooThe exorbitant cost of new treatmentsclearly contributes to the crisis in pay-ing for cancer care, and payers’ handsare relatively tied to do much aboutthis, the panelists said.“We know drugs are the biggest

part of the escalation,” observedZweigenhaft, and John Fox, MD,MHA, Associate Vice President ofMedical Affairs for Priority Health,Grand Rapids, Michigan, proposed 2main reasons for this.

“Number one, we do not have thewherewithal or interest in the publicdomain to say that society will not payfor a cancer drug because it is too expen-sive,” Fox offered. “Number two, thereare state mandates to cover expensivedrugs, and the drug companies have thepower to set the price of the drug. Wecannot control these prices, yet that iswhere the greatest cost is.”Fox contrasted the system in the

United States with that of the UnitedKingdom, which does consider the costof a drug when deciding its fate. “In theUnited Kingdom, they take the 2 inde-pendent variables, which are outcomesestablished through clinical trials andwillingness to pay, and that defines thedependent variable, which is the cost ofthe drug,” he said. “In this country, themanufacturer sets the cost of thedrug…. The conundrum is that thepharmaceutical industry has a responsi-bility to its investors and the innovatorshave to recoup their investments, yetthe people who pay for that are increas-ingly unable to do so.”Although discussions about reducing

emergency department visits and hospi-

talizations as a cost-savings approachhave merit, they stem merely from thefact that these are “things we can con-trol,” Fox said. “The reality is that untilwe find a way to provide more rational-ity around our drug reimbursements, Ido not know that there is a solution.”

Keeping Oncology Community-BasedPayers indicated and studies haveshown that cancer care is more afford-able when delivered in the communityrather than the hospital setting; howev-er, economic factors are steadily threat-ening the viability of this site of care,because community practices are beingsold or absorbed by hospitals, or aremerely closing.This trend worries Jeffrey A. Scott,

MD, Senior Vice President and GeneralManager for P4 Healthcare CardinalHealth Specialty Solutions. “What willit take for this to stop?” he questioned.“When will health plans incentivizedoctors to stay out of the hospital? Weknow the lowest cost comes from treat-ing patients in the community, but howdo we drive this?”Zweigenhaft noted that the “shift to a

hospital base” is a universal concern inthe payer community, because thisessentially doubles the cost of deliveringcancer care, with little or no improve-ment in outcomes. Panelists agreed thatsite of service is an important issue.Part of the lure of hospital-based care,

as Zweigenhaft put it, is the 340B DrugPricing Program, which limits the cost ofcovered outpatient drugs to certain fed-eral grantees, federally qualified healthcenter look-alikes, and qualified hospi-tals. Participation in the program resultsin savings estimated to be 20% to 50% ofthe cost of pharmaceuticals, which natu-rally appeals to providers. According toZweigenhaft, the pitch made by hospitalrepresentatives to physician groups is theopportunity to share in the substantialadditional revenue afforded through340B drug pricing.Scott agreed that 340B pricing is

“clearly a driver for getting new doctorsinto the hospital,” and part of the rea-son why struggling community practicesview the hospital system as “the savior.”What it will take to strengthen com-

munity oncology practices is not com-pletely clear, but Mona M. Chitre,PharmD, CGP, Director of ClinicalServices, Strategy and Policy forExcellus BlueCross Blue Shield, FLRx

Pharmacy Management, Rochester,New York, said helping them maintain“cost neutrality” is important. Her com-pany’s goals are to create innovativeprograms to pay for patient manage-ment, help patients avoid emergencydepartment visits, and aid clinicians inreducing other unnecessary services.

Guiding Physicians to BestPracticesValue in cancer care, however, is notonly about cost but also about quality,and the 2 components are necessary foroptimizing value while maintaininggood outcomes, the panel agreed. Lopessuggested that the concept of valuemust be aligned with an appropriateoutcome, and this can be difficult todetermine.Scott added that better measures are

needed to define quality outcomes, andthat there is increasing recognition thatit is “total cost of care” that mattersmost—which includes reductions indownstream costs and returningpatients to work.Klein agreed that benefits programs

cannot be designed simply on the basisof cost. “We want quality first, then wedeliver on cost,” he said. Scott added,“There is no question that good, qualitycare is already being provided, but itcomes down to how to maintain thatquality at a lower cost. That is the bigdiscussion we have with providers.”Standardization is an important part

of this strategy, typically via guidelinesand clinical pathways. “We found thatby more or less standardizing treatmentsin the program we have with communi-ty oncologists, we take out variabilityand have a gross savings of about 13%,”Wong reported. “These savings will beshared with the community oncologistsas an effort to maintain their marginsand to be an incentive to sustain theircommunity practices.”Moving from branded to generic

products has also been a big cost-saver,and reducing emergency departmentvisits and hospitalization rates by 4%has produced additional savings. “Weknow the savings are there,” he said.According to Klein, this works best

when providers are in the driver’s seat.“We delegate decision-making to physi-cian groups and allow them to choosetheir pathways. You get higher qualityand lower costs because you give controland power to the providers to use whatthey are comfortable with,” he said.

Payer Trends in Oncology: Challenges andSolutionsPutting Patients First Remains a Key ComponentBy Caroline Helwick

“Employers are

concerned about cost

and about what is

happening in the

marketplace, and they

are looking to payers

for solutions.”

—Maria Lopes, MD, MS



Conference News:

Scott suggested that pathways work bestwhen they are “narrow,” which is whatP4 attempts to do with providers. “Wetry to neutralize the name of the drugsso physicians are free to choose a regi-men based on what is best for thepatient and separate from the econom-ics of it. We have demonstrated in 10different markets that you can use con-sensus to drive a narrow set of pathways,and it works, although it may not be thelong-term answer.”Lopes added that there is a need to do

more to aid physicians in decision-mak-ing. “We want to align incentives,” shesaid, emphasizing that healthy collabo-ration is critical to success. “We will notwin without good partnerships with ourtreating providers.”

Need to Involve the PatientCentral to any conversation about can-cer care should be the patient. Theyshould also become more active partici-pants in the quest for value, and there isroom for improvement in this area, thepanel pointed out.“The ‘value proposition’ has to be

considered at the patient level,” saidChitre. New York State now haschemotherapy parity. “Patients will notpay any differential for generic versusbranded drugs, so the ‘value discussion’with the patient is actually absent,” shenoted. “If a drug is indicated or listed as2A or 2B in the Compendia, it is cov-ered and at a high level. There is verylittle patient out-of-pocket expense,and therefore very little driving our

members to ask ‘value questions’ of theirproviders.”She observed, however, that the

trend toward high-deductible premiumsis beginning to alter how patients talkabout value to their providers.Wong reported that CareFirst pro-

grams are beginning to integrate oncol-ogy with primary care through thepatient-centered medical home model,and this is helping to steer care in thedirection of value. “These 2 specialtiesare collaborating. Primary care is direct-ing patients to oncology practices theyperceive will provide the best qualityand value,” he said (see an interviewwith Wong below).Ultimately, what emerges as the pic-

ture of value-based cancer care must be

patient-centered, the panel agreed. A“fully engaged” patient is one whounderstands the treatment scenario anddetermines what is most important tohim or her, said Fox.This is only done when physicians

have time for it, added Klein. “If wecould get physicians to spend more timetalking to patients, all our costs wouldgo down, because the patient would feelmore empowered to do the right thing,”he maintained. “Comparatively speak-ing, physician labor time is cheap. Thecost-over-quality balance must hierar-chically satisfy all stakeholders as equi-tably as possible. We have to manageexpectations. We cannot move cancercare forward until we change society’sperceptions.” �

At the Association for Value-Based Cancer Care (AVBCC)second annual meeting,

Winston Wong, PharmD, expressed con-cerns that the site of delivery of cancercare affects efforts to rein in costs andprovide value in cancer care. Wongexpanded on this issue in the followinginterview.

Why do you believe that the site ofdelivery of cancer care can impactthe attempt to rein in costs of cancer care and provide value?Wong: Here is why. When chemother-apy is delivered to a patient in thephysician’s office, there are the cost ofthe drug, administrative costs, and thecost of ancillary services. Let’s say thetotal office visit, including the cost ofchemotherapy, is $4000. You can takethat exact same service and drug anddeliver it at a large center, such as, in ourarea, Johns Hopkins, and the cost couldbe $6000 or even up to $8000.Essentially, it may double or even triplein cost, depending on the procedure, theservice, and the drug that is prescribed.

Why is there such a large differential in cost?Wong: It is basically because thehealthcare system cannot functionwithout the large hospitals. They havemarket power and can negotiate betterdeals. At the end of the day, hospitalbilling will be at least twice that of acommunity practice, across the board.

Do large hospitals and cancer centers acknowledge this?Wong: Their comment to payers wouldbe that they are tertiary care hospitals,

and that their patient population is sick-er, and to some degree that is true. Largehospitals may get more difficult cases,administer more expensive third-linetherapies, and so forth. But comparingapples to apples, their costs are muchhigher than in community practices.

What can be done to bring moreequity?Wong: On the oncology side, we havenot been able to achieve more equity yet.The strategy that we at CareFirst are try-ing to employ initially with our PathwaysProgram is to reimburse at a higher rateto community practices. We may notnecessarily be directing patients awayfrom hospitals, but we are doing some-thing to help maintain communityoncology practices so that they are avail-able to treat these patients. If there arefewer community practices, patients withcancer have less choices.The site-of-care issue will be driven by

the viability of community practices. Ifwe cannot help community oncologistsstay in business, the site of care will notbe an issue.

You have talked about the need tointegrate primary care and to bringmore value to oncology. Could youelaborate on this?Wong: Here is an example of the cur-rent state of things. My mother passedaway in 2007. When she was diagnosedwith cancer and was being treated withchemotherapy, she became neutropenicand ended up in the emergency depart-ment. The hospital contacted the pri-mary care physician (PCP) on record,but he had no clue about her condition.Once an oncologist was taking care of

her, there had been no communicationwith the PCP. And let’s look at sur-vivorship. She may have to go back tothe oncologist for some routine tests,but she may have an annual check-upthe following week with her PCP, andhe may order the same laboratory tests.This kind of overlap and duplicationshould be eliminated from the system.

How is CareFirst BlueCrossBlueShield advancing this conceptof more integrated care?Wong: With the primary care patient-centered medical home, we are trying toinvolve the PCP as the “quarterback ofcare,” as we say. Currently, when anindividual is diagnosed with cancer andreferred by his or her PCP to a special-ist, the PCP usually severs ties with thepatient. We are asking our PCPs to bemore accountable and to follow thesepatients while they are under the care ofspecialists—oncologists or others—andmaintain primary care as the patient’shome, but within an integrated process.Maybe 5 of 10 patients with cancer

will ask their PCP to refer them to anoncologist, but the other 50% willchoose an oncologist on the basis offavorable word of mouth. Or, they maywant to go, for example, to MDAnderson, because of its reputation andnot because they have seen scientificevidence that their care will be better orthat community care is worse. We allpay more for that patient, with very littledifference in quality of care or in out-comes compared with care in the com-munity setting. We believe that the PCPcan direct the patient more towardvalue-based cancer care. PCPs can helpguide these referrals, and they can take

care of the non–cancer-related condi-tions that patients with cancer will have.We want this care to be under the PCP,not the oncologist.

How are PCPs and oncologistsaccepting this model?Wong: We do not know yet—our pro-gram just started—but this is somethingwe are interested in learning. Webelieve that it is in everyone’s bestinterest for patients to have a coordina-tor of care, and we think that the mostimportant provider in this regard is thePCP. We think that PCPs and oncolo-gists working together will becomeinevitable with the changing time. Asthe PCP becomes more involved, therewill have to be more communicationbetween them.

What progress is being made tobring this concept to fruition?Wong: There are many groups withtheir own small projects like ours, andnone is known to be the best way to dothis. I think that these will eventuallymerge into something that we will alluse; however, we are still trying to getsome accountability around these pro-grams, and we are still very early inthat game. �

Site of Care Influences Value in Cancer CareInterview With Winston Wong, PharmDAssociate Vice President, Pharmacy Management, CareFirst BlueCross BlueShield of Maryland

Winston Wong, PharmD


The inaugural annual conferenceof the Global BiomarkersConsortium brought together an

international panel of oncology expertsto explore the rapidly evolving field ofbiomarker research. Cochairs of theevent were Hope S. Rugo, MD, directorof Breast Oncology and Clinical TrialsEducation at the University of CaliforniaSan Francisco, and Rüdiger Hehlmann,MD, PhD, professor of medicine at theUniversity of Heidelberg. MichaelKattan, PhD, Vincent Miller, MD, EdithPerez, MD, and Charles Bennett, MD,PhD, served as session chairs.At the conference, held March 9-11,

2012, in Orlando, Florida, a diverse fieldof experts addressed oncologists, hema-tologists, oncology nurses, pharmacists,and other healthcare professionals on awide range of topics related to the clini-cal application of biomarkers in thetreatment of solid tumors and hemato-logic malignancies. Conference attend -ees had numerous opportunities to askquestions. In addition, an audienceresponse system provided opportunitiesfor interactive learning experiences.

Hehlmann opened the conferencewith a valuable historical overview ofgenetic profiling and oncologic biomark-ers. In discussing development of newtechnologies, Miller reported, “There arean unprecedented number of targetedtherapies in clinical trials—about 500targeted therapies looking at about 140genomic alterations.” In looking forwardto next-generation sequencing, Millerconcluded, “So I’m really excited aboutthese broader technologies that mayallow us to help more patients and morerationally approach treating patients inthe near future.” Case studies of several types of cancer

were presented by panel members. Perezpresented “Evidence-Based Medicine toTranslational Medicine to PersonalizedMedicine: A Natural Evolution,” andBeth Faiman, PhD(c), MSN, APRN-

BC, AOCN, discussed “Roles andResponsibilities of the InterprofessionalTeam.” Perez and Faiman led a groupcomposed of several doctors who hadpresented case studies in a panel ques-

tion-and-answer session on “In -corporating Personalized Medicine IntoPractice.”Personalized medicine based on an

understanding of predictive molecular

biomarkers holds great promise.Conferences such as this one help clini-cians and other healthcare professionalskeep up to date on developments in thischallenging field. �

Global Biomarkers Consortium—Implementing thePromise of Personalized Cancer Care


Conference News:

PROVENGE® (sipuleucel-T)Suspension for Intravenous Infusion Rx Only

BRIEF SUMMARY — See full Prescribing Information for complete product information

INDICATIONS AND USAGE: PROVENGE® (sipuleucel-T) is an autologous cellular immunotherapy indicated for the treatment of asymptomatic or minimally symptomatic metastatic castrate resistant (hormone refractory) prostate cancer.

DOSAGE AND ADMINISTRATION For Autologous Use Only.

diphenhydramine.

the infusion bag.Do Not Initiate Infusion of Expired Product.

Do Not Use a Cell Filter.

(See Dosage and Administration [2] of full Prescribing Information.)

CONTRAINDICATIONS: None.

WARNINGS AND PRECAUTIONS

PROVENGE is intended solely for autologous use.

Acute infusion reactions

following the third infusion. Some (1.2%) patients in the PROVENGE group were

PROVENGE group.

administered as needed.

Handling Precautions for Control of Infectious Disease. PROVENGE is notleukapheresis material and PROVENGE may carry the risk of transmitting infectious

should be followed.

Concomitant Chemotherapy or Immunosuppressive Therapy. Use of either

with PROVENGE.

Product Safety Testing. PROVENGE is released for infusion based on the microbial

Dendreon will notify the treating physician. Dendreon will attempt to identify the

and communicate the results to the treating physician. Dendreon may request additional information from the physician in order to determine the source of contamination.

(See Warnings and Precautions [5] of full Prescribing Information.)

ADVERSE REACTIONS

mononuclear cells.

included acute infusion reactions (see Warnings and Precautions)

tumor flare.

number of these patients discontinued treatment as a result. Monitoring for infectious

were Caucasian.

Table 1 Incidence of Adverse Events Occurring in ≥5% of Patients Randomized to PROVENGE

Any Adverse EventChillsFatigue

NauseaJoint acheHeadacheCitrate toxicityParesthesiaVomiting

ConstipationPainParesthesia oralPain in extremity

Muscle ache

Diarrhea

Musculoskeletal painDyspneaEdema peripheralHot flushHematuriaMuscle spasms

591 (98.3)

247 (41.1)

186 (30.9)

7 (1.2)

291 (96.0) 97 (32.0)

All Gradesn (%)

All Gradesn (%)

Grade 3-5n (%)

Grade 3-5n (%)

PROVENGE (N = 601) Control* (N = 303)

(Table 1 continued on next page.)

Personalized medicine

based on an

understanding of

predictive molecular

biomarkers holds

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Prostate Cancer

Cerebrovascular Events.

(See Adverse Reactions [6] of full Prescribing Information.)

To report SUSPECTED ADVERSE REACTIONS, contact Dendreon Corporation at 1-877-336-3736 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch.

Table 1 Incidence of Adverse Events Occurring in ≥5% of Patients Randomized to PROVENGE

Hypertension

Upper respiratory tract infection

Musculoskeletal chest painCoughNeck painWeight decreasedUrinary tract infectionRashSweatingTremor

All Gradesn (%)

All Gradesn (%)

Grade 3-5n (%)

Grade 3-5n (%)

PROVENGE (N = 601) Control* (N = 303)

Dendreon Corporation Seattle, Washington 98101

PROVENGE are registered trademarks of Dendreon Corporation.P-A-11.10-073.02(b)

References: 1. Kantoff PW, Higano CS, Shore ND, et al; for the IMPACT Study Investigators. Sipuleucel-T immunotherapy for castration-resistant prostate cancer. N Engl J Med. 2010;363:411-422. 2. PROVENGE [package insert]. Dendreon Corporation; June 2011. 3. NCCN Clinical Practice Guidelines in Oncology: Prostate Cancer. V.4.2011. National Comprehensive Cancer Network Web site. www.nccn.org. Accessed October 24, 2011.

References1. Ferlay J, Bray F, Pisani P, et al. GLOBOCAN 2000:cancer incidence, mortality and prevalence worldwide.Version 1.0. IARC Cancer Base No. 5. Lyon, France:IARC Press; 2001.2. US Cancer Statistics Working Group. United StatesCancer Statistics: 1999-2007 Incidence and Mortality Web-based Report. Atlanta, GA: Department of Health andHuman Services, Centers for Disease Control andPrevention, and National Cancer Institute; 2010.3.Hoffman RM, Gilliland FD, Eley JW, et al. Racial andethnic differences in advanced-stage prostate cancer: the

Prostate Cancer Outcomes Study. J Natl Cancer Inst.2001;93:388-395.4. Woods VD, Montgomery SB, Belliard JC, et al.Culture, black men, and prostate cancer: what is reality?Cancer Control. 2004;11:388-396.5. Pashayan N, Pharoah P, Neal DE, et al. Stage shift inPSA-detected prostate cancers - effect modification byGleason score. J Med Screen. 2009;16:98-101.6. Seruga B, Ocana A, Tannock IF. Drug resistance inmetastatic castration-resistant prostate cancer. Nat RevClin Oncol. 2011;8:12-23.7. Tannock IF, de Wit R, Berry WR, et al. Docetaxel plus

prednisone or mitoxantrone plus prednisone for advancedprostate cancer. N Engl J Med. 2004;351:1502-1512.8. Berthold DR, Pond GR, Soban F, et al. Docetaxel plusprednisone or mitoxantrone plus prednisone foradvanced prostate cancer: updated survival in the TAX327 study. J Clin Oncol. 2008;26(2):242-245.9. de Bono JS, Oudard S, Ozguroglu M. Prednisone pluscabazitaxel or mitoxantrone for metastatic castration-resistant prostate cancer progressing after docetaxeltreatment: a randomised open-label trial. Lancet.2010;376:1147-1154.10. Kantoff PW, Higano CS, Shore ND, et al.

Sipuleucel-T immunotherapy for castration-resistantprostate cancer. N Engl J Med. 2010;363:411-422.11. de Bono JS, Logethetis CJ, Molina A, et al.Abiraterone and increased survival in metastaticprostate cancer. N Engl J Med. 2011;364:1995-2005.12. Fizazi K, Carducci M, Smith M, et al. Denosumabversus zoledronic acid for treatment of bone metastasesin men with castration-resistant prostate cancer: a ran-domised, double-blind study. Lancet. 2011;377:813-822.13. Woo SB, Hellstein JW, Kalmar JR. Narrative [cor-rected] review: bisphosphonates and osteonecrosis of thejaws. Ann Intern Med. 2006;144:753-761.

Metastatic Castrate-Resistant Prostate Cancer... Continued from page 29


Prostate cancer cell

Resting T cell PROVENGE

Activated T cell attacks prostate cancer

PROVENGE-activated T cell

ACTIVATE THE POWER OF THE IMMUNE SYSTEM. EXTEND SURVIVAL.

PROVENGEIN ADVANCED PROSTATE CANCER...

www.PROVENGE.com©2012 Dendreon Corporation. All rights reserved. February 2012. P-A-02.12-025.00

PROVENGE extends median survival beyond 2 years1

Only 1.5% of patients treated with PROVENGE in the pivotal trial discontinued treatment due to adverse events2

— The most common adverse events in PROVENGE trials were chills, fatigue, fever, back pain, nausea, joint ache, and headache2

PROVENGE is the first and only FDA-approved immunotherapy for advanced prostate cancer The NCCN recommends PROVENGE as a first-line treatment for men with asymptomatic or minimally symptomatic metastatic castrate resistant prostate cancer (NCCN Category 1 recommendation)3

INDICATION: PROVENGE® (sipuleucel-T) is an autologous cellular immunotherapy indicated for the treatment of asymptomatic or minimally symptomatic metastatic castrate resistant (hormone refractory) prostate cancer. IMPORTANT SAFETY INFORMATION: PROVENGE is intended solely for autologous use and is not routinely tested for transmissible infectious diseases. In controlled clinical trials, serious adverse events reported in the PROVENGE group include acute infusion reactions (occurring within 1 day of infusion) and cerebrovascular events. Severe (Grade 3) acute infusion reactions were reported in 3.5% of patients in the PROVENGE group. Reactions included chills, fever, fatigue, asthenia, dyspnea, hypoxia, bronchospasm, dizziness, headache, hypertension, muscle ache, nausea, and vomiting. No Grade 4 or 5 acute infusion reactions were reported in patients in the PROVENGE group.The most common adverse events (incidence ≥15%) reported in the PROVENGE group were chills, fatigue, fever, back pain, nausea, joint ache, and headache.For more information on PROVENGE, please see Brief Summary of Prescribing Information on adjacent page.


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Special Issue May 2012, VOL 5, NO 4