Register

Today for Your

Second annual Considerations in

Multiple M

yeloma

newsletter series.

ww

w.coexm.com

SAN ANTONIO—Breast cancer patients and theironcologists and oncology nurses sometimes disagreeon the goals of chemotherapy, according to resultsreleased at the 2008 San Antonio Breast CancerSymposium by a group from the University of VirginiaHealth System in Charlottesville.

Heather West, MD, and her associates comparedtreatment objectives of 53 breast cancer patients under-going chemotherapy and their providers (11 oncologists

Anthracycline-based regi-mens have improved thelives of patients with hu-

man epidermal growth factor-2(HER2)-overexpressing breast can-cers, but because of their toxicities,many practitioners would like to beable to move away from these drugs.

Many oncologists at the 2008annual meeting of the AmericanSociety of Clinical Oncology(ASCO) felt that a paclitaxel, car-

boplatin, trastuzumab (TCH) com-bination is a reasonable alternativeto an anthracycline-based regimenfor patients with HER2-overexpress-ing recurrent or metastatic breastcancers. Although the acute sideeffects may be as severe as with ananthracycline regimen, they felt theywere manageable. Long term, TCHmay present less risk for cardiotoxic-ity even though the trastuzumab inthe regimen has this potential.

“I think a lot of people use it. But Iworry that there’s more opinion herethan decision making that’s 100%based on the totality of the evi-dence,” said Eric Winer, MD, in aninterview with The Oncology Nurse.Winer is director of the BreastOncology Center at Dana FarberCancer Institute in Boston. He andothers offered that a real advancewould be to be able to predict

JANUARY/FEBRUARY 2009 • VOL. 2, NO. 1 www.theoncologynurse.com

© 2009 Green Hill Healthcare Communications, LLC

MEDICAL MINUTESAcupuncture may reduce vasomotor symptoms in breast cancer patients

page 8

BREAST CANCER

Continued on page 20

Decision Aids as a Guide forCancer Patients Making

Clinical Decisions

Continued on page 20

BREAST CANCER

Nonanthracycline Regimens Provide Alternatives for HER2-positive Breast Cancers

HEMATOLOGIC CANCERS

SAN FRANCISCO—Prophylactic use of the low-molecular-weight heparin (LMWH) nadroparin cuts therisk of thromboembolic events by 50% in cancer patientsreceiving chemotherapy. The rate of thromboembolismranges from 4% to 10% in ambulatory cancer patients,and blood thinners are rarely used for prophylaxis,explained Giancarlo Agnelli, MD, of the University

Nadroparin Halves the Risk of Thromboembolic Events

in Cancer Patients Receiving Chemotherapy

Continued on page 9

Breast Cancer Patients andProviders May Dispute

Treatment Goals

COMPLIMENTARY CE CREDIT

AT WWW.COEXM.COM

PROGRAM #09CE 035

College of NursingContinuing Nursing Education

PAGE 27

www.coexm.comREAREACH US ONLINE ACH US ONLINE ATT

• View current and past issues

• Register to receive your free subscription

• Access CE activities

COMPLIMENTARY CE CREDIT

AT WWW.COEXM.COM

Nearly 2000 people attended the Oncology Nursing

Society’s (ONS) 9th Annual Institutes of Learning and

2008 Advanced Practice Nursing Conference in Seattle.

page 15

HEMATOLOGICCANCERSStrategies for determining theextent of non-Hodgkin’s lymphoma

page 12

ONS CONGRESS

®®The Leader

in News and

Meeting

Coverage

Taxotere®* (docetaxel) and carboplatin plus Herceptinprovided benefit consistent with AC→TH1

•In BCIRG 006, conducted by the Breast Cancer International Research Group (BCIRG), patients were randomized (1:1:1) to receiveone of the following regimens:

– TCH– AC→TH: doxorubicin plus cyclophosphamide followed by Taxotere and Herceptin– AC→T: doxorubicin plus cyclophosphamide followed by Taxotere

•Both Herceptin-containing regimens significantly reduced the risk of disease recurrence, compared with AC→T

TCH provided disease-free survivalIn the adjuvant treatment of HER2+ breast cancer,

Disease-free survival (DFS)1,2

†HR = hazard ratio; CI =95% confidence interval.

Number at risk

AC→T

AC→TH

TCH

1073

1074

1075

971

1023

1018

802

885

877

417

457

447

103

126

126

0 1 2 3 4

1.0

0.0

0.2

0.4

0.6

0.8

DFS (years)

Pro

po

rtio

neve

nt-

free

AC→T (n=1073)AC→TH (n=1074)TCH (n=1075)

in relative risk of recurrence

vs AC→T

(HR=0.60, CI: 0.48-0.76; P< 0.0001)†

AC→TH:40% reduction

in relative risk of recurrence

vs AC→T

(HR=0.67, CI: 0.54-0.84; P=0.0006)†

TCH:33% reduction

Absolute DFSat 3 years86.3% (TCH)88.0% (AC→TH)82.3% (AC→T)

Boxed WARNINGS and Additional Important Safety InformationHerceptin administration can result in sub-clinical and clinical cardiac failure manifesting as congestive heart failure(CHF) and decreased left ventricular ejection fraction (LVEF). The incidence and severity of left ventricular cardiac dysfunction washighest in patients who received Herceptin concurrently with anthracycline-containing chemotherapy regimens. Discontinue Herceptintreatment in patients receiving adjuvant therapy and strongly consider discontinuation of Herceptin in patients with metastatic breastcancer who develop a clinically significant decrease in left ventricular function.

Patients should undergo monitoring for decreased left ventricular function before Herceptin treatment, and frequently during and afterHerceptin treatment. More frequent monitoring should be employed if Herceptin is withheld in patients who develop significant left ventricularcardiac dysfunction. In one adjuvant clinical trial, cardiac ischemia or infarction occurred in the Herceptin-containing regimens.

*Taxotere is a registered trademark of sanofi-aventis U.S. LLC.‡High-risk features for patients with ER/PR+ breast cancer include: tumor size >2 cm, age <35 years, and histologic and/or nuclear grade 2/3.

Adjuvant indicationsHerceptin is indicated for adjuvant treatment of HER2-overexpressing node-positive or node-negative (ER/PR-negative or with onehigh-risk feature‡) breast cancer:

•As part of a treatment regimen containing doxorubicin, cyclophosphamide, and either paclitaxel or docetaxel

•With docetaxel and carboplatin

•As a single agent following multi-modality anthracycline-based therapy

References: 1. Herceptin Prescribing Information. Genentech, Inc. May 2008. 2. Data on file. Genentech, Inc.

Please see brief summary of full Prescribing Information, including Boxed WARNINGSand additional important safety information, on the following pages.

www.herceptin.com

©2008 Genentech USA So. San Francisco, CA All rights reserved. 9488200 11/08

The TCH regimen enabled a highercompletion rate with shorter durationof IV therapy

•The TCH regimen enables immediate initiation of Herceptinwith chemotherapy1

•The TCH regimen reduces the overall duration of infused therapy to12 months, compared with 15 months with the AC→TH regimen1

•On average, for every 100 patients receiving each regimen inBCIRG 006, 13 more were able to complete therapy with TCHthan AC→TH2

– 86.3% of patients in the TCH arm were able to completeplanned adjuvant therapy vs 73.5% of patients in theAC→TH arm

benefit with reduced cardiac risk1

Non-anthracycline regimen reducedcardiac risk1

•In BCIRG 006, a lower rate of congestive heart failure (CHF)was seen with the TCH regimen vs the AC→TH regimen

– 0.4% with TCH– 2% with AC→TH– 0.3% with AC→T

Boxed WARNINGS and Additional Important Safety Information (continued)Serious infusion reactions and pulmonary toxicity have occurred; fatal infusion reactions have been reported. In most cases,symptoms occurred during or within 24 hours of administration of Herceptin. Herceptin infusion should be interrupted for patients experiencingdyspnea or clinically significant hypotension. Patients should be monitored until signs and symptoms completely resolve. Discontinue Herceptinfor infusion reactions manifesting as anaphylaxis, angioedema, interstitial pneumonitis, or acute respiratory distress syndrome.

Exacerbation of chemotherapy-induced neutropenia has also occurred.

Herceptin can cause oligohydramnios and fetal harm when administered to a pregnant woman. The most common adverse reactionsassociated with Herceptin use were fever, nausea, vomiting, infusion reactions, diarrhea, infections, increased cough, headache, fatigue,dyspnea, rash, neutropenia, anemia, and myalgia.

The first approvednon-anthracycline

Herceptin-containing regimen

HERCEPTIN® (trastuzumab)Brief Summary For full Prescribing Information, see package insert.

WARNING: CARDIOMYOPATHY, INFUSION REACTIONS,and PULMONARY TOXICITYCardiomyopathy

Herceptin can result in sub-clinical and clinicalcardiac failure manifesting as CHF and decreased LVEF.The incidence and severity of left ventricular cardiacdysfunction was highest in patients who received Herceptin concurrently with anthracycline-containingchemotherapy regimens.

Evaluate left ventricular function in all patients priorto and during treatment with Herceptin. DiscontinueHerceptin treatment in patients receiving adjuvant therapyand strongly consider discontinuation of Herceptin treatment in patients with metastatic breast cancerfor clinically significant decrease in left ventricularfunction. [see Warnings and Precautions and Dosage andAdministration]Infusion Reactions; Pulmonary Toxicity

Herceptin administration can result in serious infusion reactions and pulmonary toxicity. Fatal infusionreactions have been reported. In most cases, symptomsoccurred during or within 24 hours of administration ofHerceptin. Herceptin infusion should be interrupted forpatients experiencing dyspnea or clinically significanthypotension. Patients should be monitored until signsand symptoms completely resolve. Discontinue Herceptinfor infusion reactions manifesting as anaphylaxis, angioedema, interstitial pneumonitis, or acute respiratorydistress syndrome. [see Warnings and Precautions]

INDICATIONS AND USAGE Adjuvant Breast Cancer Herceptin is indicated for adjuvant treatment of HER2 overexpressing node positive or node negative (ER/PR negative or with one high risk feature [see Clinical Studies]) breast cancer • As part of a treatment regimen consisting of doxorubicin, Cyclophosphamide, and either paclitaxel or docetaxel • With docetaxel and carboplatin • As a single agent following multi-modality anthracyclinebased therapy. Metastatic Breast Cancer Herceptinis indicated: • In combination with paclitaxel for first-line treatment of HER2-overexpressing metastaticbreast cancer • As a single agent for treatment ofHER2-overexpressing breast cancer in patients whohave received one or more chemotherapy regimensfor metastatic disease. CONTRAINDICATIONS None.WARNINGS AND PRECAUTIONS CardiomyopathyHerceptin can cause left ventricular cardiac dysfunction, arrhythmias, hypertension, disabling cardiac failure,cardiomyopathy, and cardiac death [see BoxedWarning: Cardiomyopathy] . Herceptin can also cause asymptomatic decline in left ventricular ejection fraction(LVEF). There is a 4–6 fold increase in the incidence of symptomatic myocardial dysfunction among patientsreceiving Herceptin as a single agent or in combination therapy compared with those not receiving Herceptin. The highest absolute incidence occurs when Herceptin isadministered with an anthracycline. Withhold Herceptinfor ≥16% absolute decrease in LVEF from pre-treatment values or an LVEF value below institutional limits ofnormal and ≥10% absolute decrease in LVEF from pre-treatment values. [see Dosage and Administration] Thesafety of continuation or resumption of Herceptin inpatients with Herceptin-induced left ventricular cardiacdysfunction has not been studied. Cardiac MonitoringConduct thorough cardiac assessment, includinghistory, physical examination, and determinationof LVEF by echocardiogram or MUGA scan. Thefollowing schedule is recommended: • Baseline LVEFmeasurement immediately prior to initiation of Herceptin• LVEF measurements every 3 months during and upon completion of Herceptin • Repeat LVEF measurement at 4 week intervals if Herceptin is withheld for significant left ventricular cardiac dysfunction [see Dosage and Administration] • LVEF measurements every 6 months for at least 2 years following completion of Herceptin as a component of adjuvant therapy. In Study 1, 16% (136/844) of patients discontinued Herceptin due toclinical evidence of myocardial dysfunction or significant decline in LVEF. In Study 3, the number of patients who discontinued Herceptin due to cardiac toxicity was2.6% (44/1678). In Study 4, a total of 2.9% (31/1056) patients in the TCH arm (1.5% during the chemotherapy phase and 1.4% during the monotherapy phase) and 5.7% (61/1068) patients in the AC-TH arm (1.5% during the chemotherapy phase and 4.2% during the monotherapy phase) discontinued Herceptin due to cardiac toxicity. Among 32 patients receiving adjuvant chemotherapy(Studies 1 and 2) who developed congestive heart failure, one patient died of cardiomyopathy and all other patientswere receiving cardiac medication at last follow-up. Approximately half of the surviving patients had recovery to a normal LVEF (defined as ≥ 50%) on continuing medicalmanagement at the time of last follow-up. Incidence of congestive heart failure is presented in Table 1. The safety of continuation or resumption of Herceptin inpatients with Herceptin-induced left ventricular cardiacdysfunction has not been studied.

Table 1 Incidence of Congestive Heart Failure in Adjuvant Breast Cancer Studies

Incidence of CHF

Study Regimen Herceptin Control

1 & 2a ACb Paclitaxel+Herceptin 2% (32/1677) 0.4% (7/1600)

3 Chemo Herceptinmonotherapy 2% (30/1678) 0.3% (5/1708)

4 ACb Docetaxel+Herceptin 2% (20/1068) 0.3% (3/1050)

4 Docetaxel+Carbo+Herceptin 0.4% (4/1056) 0.3% (3/1050))

a Includes 1 patient with fatal cardiomyopathy.b Anthracycline (doxorubicin) and cyclophosphamide.

Table 2 Incidence of Cardiac Dysfunctiona in MetastaticBreast Cancer Studies

Incidence

NYHA I-IV NYHA III-IV

Study Event Herceptin Control Herceptin Control

5 Cardiac(AC)b Dysfunction 28% 7% 19% 3%

5 Cardiac(paclitaxel) Dysfunction 11% 1% 4% 1%

6 Cardiac Dysfunctionc 7% N/A 5% N/A

aCongestive heart failure or significant asymptomaticdecrease in LVEF. bAnthracycline (doxorubicin or epirubicin)and cyclophosphamide. cIncludes 1 patient with fatalcardiomyopathy.

Infusion Reactions Infusion reactions consist of asymptom complex characterized by fever and chills,and on occasion included nausea, vomiting, pain (in some cases at tumor sites) , headache, dizziness,dyspnea, hypotension, rash, and asthenia. [see AdverseReactions ] . In postmarketing reports, serious and fatalinfusion reactions have been reported. Severe reactionswhich include bronchospasm, anaphylaxis, angioedema, hypoxia, and severe hypotension, were usually reportedduring or immediately following the initial infusion.However, the onset and clinical course were variable including progressive worsening, initial improvementfollowed by clinical deterioration, or delayed post-infusion events with rapid clinical deterioration. Forfatal events, death occurred within hours to daysfollowing a serious infusion reaction. Interrupt Herceptin infusion in all patients experiencing dyspnea, clinicallysignificant hypotension, and intervention of medicaltherapy administered, which may include: epinephrine,corticosteroids, diphenhydramine, bronchodilators, andoxygen. Patients should be evaluated and carefullymonitored until complete resolution of signs andsymptoms. Permanent discontinuation should be stronglyconsidered in all patients with severe infusion reactions.There are no data regarding the most appropriate method of identification of patients who may safely be retreated with Herceptin after experiencing a severe infusionreaction. Prior to resumption of Herceptin infusion, themajority of patients who experienced a severe infusionreaction were pre-medicated with antihistamines and/or corticosteroids. While some patients tolerated Herceptininfusions, others had recurrent severe infusion reactionsdespite pre-medications. Exacerbation of Chemotherapy-Induced Neutropenia In randomized, controlled clinicaltrials in women with metastatic breast cancer, the per-patient incidences of NCI CTC Grade 3-4 neutropenia and of febrile neutropenia were higher in patients receivingHerceptin in combination with myelosuppressivechemotherapy as compared to those who receivedchemotherapy alone. The incidence of septic death was not significantly increased. [see Adverse Reactions ] .Pulmonary Toxicity Herceptin use can result in serious and fatal pulmonary toxicity. Pulmonary toxicity includes dyspnea, interstitial pneumonitis, pulmonary infiltrates,pleural effusions, non-cardiogenic pulmonary edema,pulmonary insufficiency and hypoxia, acute respiratorydistress syndrome, and pulmonary fibrosis. Such events can occur as sequelae of infusion reactions [see Warnings and Precautions ] . Patients with symptomatic intrinsic lung disease or with extensive tumor involvement of the lungs, resulting in dyspnea at rest, appear to have more severe toxicity. HER2 Testing Detection of HER2 proteinoverexpression is necessary for selection of patientsappropriate for Herceptin therapy because these arethe only patients studied and for whom benefit has beenshown. Assessment for HER2 overexpression and of HER2gene amplification should be performed by laboratorieswith demonstrated proficiency in the specific technologybeing utilized. Improper assay performance, including use of suboptimally fixed tissue, failure to utilize specifiedreagents, deviation from specific assay instructions, andfailure to include appropriate controls for assay validation,can lead to unreliable results. Several FDA-approvedcommercial assays are available to aid in the selection ofpatients for Herceptin therapy. These include HercepTestTM

and Pathway® HER-2/neu (IHC assays) and PathVysion®

and HER2 FISH pharmDxTM (FISH assays). Users shouldrefer to the package inserts of specific assay kits forinformation on the validation and performance of eachassay. Limitations in assay precision (particularly for theIHC method) and in the direct linkage between assayresult and overexpression of the Herceptin target (forthe FISH method) make it inadvisable to rely on a singlemethod to rule out potential Herceptin benefit. A negativeFISH result does not rule out HER2 overexpression andpotential benefit from Herceptin. Treatment outcomesfor metastatic breast cancer (Study 5) as a function ofIHC and FISH testing are provided in Table 9. Treatmentoutcomes for adjuvant breast cancer (Studies 2 and 3) asa function of IHC and FISH testing are provided in Table 7.HER2 Protein Overexpression Detection Methods HER2protein overexpression can be established by measuringHER2 protein using an IHC method. HercepTest®, one testapproved for this use, was assessed for concordance withthe Clinical Trial Assay (CTA), using tumor specimenscollected and stored independently from those obtainedin Herceptin clinical studies in women with metastaticbreast cancer. Data are provided in the package insert forHercepTest®. HER2 Gene Amplification Detection MethodThe presence of HER2 protein overexpression and geneamplification are highly correlated, therefore the useof FISH to detect gene amplification may be employedfor selection of patients appropriate for Herceptintherapy. PathVysion®, one test approved for this use, wasevaluated in an exploratory, retrospective assessmentof available CTA 2+ or 3+ tumor specimens collected aspart of patient screening for clinical studies in metastaticbreast cancer (Studies 5 and 6). Data are provided in thepackage insert for PathVysion®. Embryo-Fetal Toxicity(Pregnancy Category D) Herceptin can cause fetal harmwhen administered to a pregnant woman. Post-marketingcase reports suggest that Herceptin use during pregnancyincreases the risk of oligohydramnios during the second and third trimesters. If Herceptin is used during pregnancy

or if a woman becomes pregnant while taking Herceptin, she should be apprised of the potential hazard to a fetus. [see Use in Specific Populations ] . ADVERSE REACTIONSThe following adverse reactions are discussed in greaterdetail in other sections of the label: • Cardiomyopathy [see Warnings and Precautions ] • Infusion reactions[see Warnings and Precautions ] • Exacerbation ofchemotherapy-induced neutropenia [see Warnings and Precautions ] • Pulmonary toxicity [see Warnings and Precautions ] The most common adverse reactions inpatients receiving Herceptin are fever, nausea, vomiting, infusion reactions, diarrhea, infections, increased cough,headache, fatigue, dyspnea, rash, neutropenia, anemia,and myalgia. Adverse reactions requiring interruptionor discontinuation of Herceptin treatment include CHF, significant decline in left ventricular cardiac function, severe infusion reactions, and pulmonary toxicity [seeDosage and Administration ] . Clinical Trials ExperienceBecause clinical trials are conducted under widelyvarying conditions, adverse reaction rates observed inthe 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. Adjuvant BreastCancer Studies The data below reflect exposure toHerceptin across three randomized, open-label studies,Studies 1, 2, and 3, with (n= 3355) or without (n= 3308) trastuzumab in the adjuvant treatment of breast cancer. The data summarized in Table 3 below, from Study 3, reflect exposure to Herceptin in 1678 patients; themedian treatment duration was 51 weeks and median number of infusions was 18. Among the 3386 patientsenrolled in Study 3, the median age was 49 years (range: 21 to 80 years), 83% of patients were Caucasian, and 13% were Asian.

Table 3 Adverse Reactions for Study 3, All Gradesa:

MedDRA (v. 7.1) 1 Year Herceptin ObservationAdverse Event Preferred Term (n= 1678) (n= 1708)

Cardiac

Hypertension 64 (4%) 35 (2%)

Dizziness 60 (4%) 29 (2%)

Ejection Fraction Decreased 58 (3.5%) 11 (0.6%)

Palpitations 48 (3%) 12 (0.7%)

Cardiac Arrhythmiasb 40 (3%) 17 (1%)

Cardiac Failure Congestive 30 (2%) 5 (0.3%)

Cardiac Failure 9 (0.5%) 4 (0.2%)

Cardiac Disorder 5 (0.3%) 0 (0%)

Ventricular Dysfunction 4 (0.2%) 0 (0%)

Respiratory Thoracic Mediastinal Disorders

Nasopharyngitis 135 (8%) 43 (3%)

Cough 81 (5%) 34 (2%)

Influenza 70 (4%) 9 (0.5%)

Dyspnea 57 (3%) 26 (2%)

URI 46 (3%) 20 (1%)

Rhinitis 36 (2%) 6 (0.4%)

Pharyngolaryngeal Pain 32 (2%) 8 (0.5%)

Sinusitis 26 (2%) 5 (0.3%)

Epistaxis 25 (2%) 1 (0.06%)

Pulmonary Hypertension 4 (0.2%) 0 (0%)

Interstitial Pneumonitis 4 (0.2%) 0 (0%)

Gastrointestinal Disorders

Diarrhea 123 (7%) 16 (1%)

Nausea 108 (6%) 19 (1%)

Vomiting 58 (3.5%) 10 (0.6%)

Constipation 33 (2%) 17 (1%)

Dyspepsia 30 (2%) 9 (0.5%)

Upper Abdominal Pain 29 (2%) 15 (1%)

Musculoskeletal & Connective Tissue Disorders

Arthralgia 137 (8%) 98 (6%)

Back Pain 91 (5%) 58 (3%)

Myalgia 63 (4%) 17 (1%)

Bone Pain 49 (3%) 26 (2%)

Muscle Spasm 46 (3%) 3 (0.2%)

Nervous System Disorders

Headache 162 (10%) 49 (3%)

Paraesthesia 29 (2%) 11 (0.6%)

Skin & Subcutaneous Tissue Disorders

Rash 70 (4%) 10 (0.6%)

Nail Disorders 43 (2%) 0 (0%)

Pruritus 40 (2%) 10 (0.6%)

General Disorders

Pyrexia 100 (6%) 6 (0.4%)

Edema Peripheral 79 (5%) 37 (2%)

Chills 85 (5%) 0 (0%)

Asthenia 75 (4.5%) 30 (2%)

Influenza-like Illness 40 (2%) 3 (0.2%)

Sudden Death 1 (0.06%) 0 (0%)

Infections

Nasopharyngitis 135 (8%) 43 (3%)

UTI 39 (3%) 13 (0.8%)

Immune System Disorders

Hypersensitivity 10 (0.6%) 1 (0.06%)

Autoimmune Thyroiditis 4 (0.3%) 0 (0%)

a The incidence of Grade 3/4 adverse reactions was <1% inboth arms for each listed term. b Higher level grouping term.

The data from Studies 1 and 2 were obtained from 3206 patients enrolled, of which 1635 patients received Herceptin; the median treatment duration was 50 weeks. The median age was 49.0 years (range: 24-80); 84% of patients were White, and 7% were Black, 4% were Hispanic, and 4% were Asian. In Study 1, only Grade 3–5 adverse events, treatment-related Grade 2 events, and Grade 2–5 dyspnea were collected during and for up to 3 months following protocol-specified treatment. The following non-cardiac adverse reactions of Grade 2-5 occurred at an incidence of at least 2% greater among patients randomized to Herceptin plus chemotherapy ascompared to chemotherapy alone: arthralgia (31% vs. 28%), fatigue (28% vs. 22%), infection (22% vs. 14%), hot flashes (17% vs. 15%), anemia (13% vs. 7%), dyspnea (12% vs. 4%), rash/desquamation (11% vs. 7%), neutropenia (7% vs. 5%), headache (6% vs. 4%), and insomnia (3.7%vs. 1.5%). The majority of these events were Grade 2 in severity. In Study 2, data collection was limited to

the following investigator-attributed treatment-related adverse reactions: NCI-CTC Grade 4 and 5 hematologic toxicities, Grade 3–5 non-hematologic toxicities, selected Grade 2–5 toxicities associated with taxanes (myalgia, arthralgias, nail changes, motor neuropathy, sensory neuropathy) and Grade 1–5 cardiac toxicities occurringduring chemotherapy and/or Herceptin treatment. Thefollowing non-cardiac adverse reactions of Grade 2–5occurred at an incidence of at least 2% greater among patients randomized to Herceptin plus chemotherapy ascompared to chemotherapy alone: arthralgia (11% vs. 8.4%), myalgia (10% vs. 8%), nail changes (9% vs. 7%), and dyspnea (2.5% vs. 0.1%). The majority of these events were Grade 2 in severity. Safety data from Study 4 reflect exposure to Herceptin as part of an adjuvant treatment regimen from 2124 patients receiving at least one dose of study treatment [AC-TH: n = 1068; TCH: n = 1056]. The overall median treatment duration was 54 weeks in both the AC-TH and TCH arms. The median numberof infusions was 26 in the AC-TH arm and 30 in the TCH arm, including weekly infusions during the chemotherapyphase and every three week dosing in the monotherapy period. Among these patients, the median age was 49 years (range 22 to 74 years). In Study 4, the toxicityprofile was similar to that reported in Studies 1, 2, and 3 with the exception of a low incidence of CHF in the TCH arm. Metastatic Breast Cancer Studies The data below reflect exposure to Herceptin in one randomized, open-label study, Study 5, of chemotherapy with (n=235) or without (n=234) trastuzumab in patients with metastatic breast cancer, and one single-arm study (Study 6;n=222) in patients with metastatic breast cancer. Data in Table 5 are based on Studies 5 and 6. Among the 464 patients treated in Study 5, the median age was 52 years (range: 25–77 years). Eighty-nine percent were White,5% Black, 1% Asian and 5% other racial/ethnic groups. All patients received 4 mg/kg initial dose of Herceptin followed by 2 mg/kg weekly. The percentages of patientswho received Herceptin treatment for ≥ 6 months and≥ 12 months were 58% and 9%, respectively. Among the 352 patients treated in single agent studies (213 patients from Study 6), the median age was 50 years (range 28–86 years), 100% had breast cancer, 86%were White, 3% were Black, 3% were Asian, and 8% in other racial/ethnic groups. Most of the patientsreceived 4 mg/kg initial dose of Herceptin followedby 2 mg/kg weekly. The percentages of patients who received Herceptin treatment for ≥ 6 months and≥ 12 months were 31% and 16%, respectively.

Table 4 Per-Patient Incidence of Adverse ReactionsOccurring in ≥ 5% of Patients in Uncontrolled Studies or at Increased Incidence in the Herceptin Arm (Studies 5 and 6) (Percent of Patients)

Herceptin Single + Paclitaxel Herceptin ACb

Agenta Paclitaxel Alone + ACb Alonen = 352 n = 91 n = 95 n = 143 n = 135

Body as a WholePain 47 61 62 57 42Asthenia 42 62 57 54 55Fever 36 49 23 56 34Chills 32 41 4 35 11Headache 26 36 28 44 31Abdominal pain 22 34 22 23 18Back pain 22 34 30 27 15Infection 20 47 27 47 31Flu syndrome 10 12 5 12 6Accidental

injury 6 13 3 9 4Allergic

reaction 3 8 2 4 2

Cardiovascular Tachycardia 5 12 4 10 5Congestive heart failure 7 11 1 28 7

DigestiveNausea 33 51 9 76 77Diarrhea 25 45 29 45 26Vomiting 23 37 28 53 49Nausea and 8 14 11 18 9vomitingAnorexia 14 24 16 31 26

Heme & Lymphatic

Anemia 4 14 9 36 26Leukopenia 3 24 17 52 34

Metabolic Peripheral

edema 10 22 20 20 17Edema 8 10 8 11 5

Musculoskeletal Bone pain 7 24 18 7 7Arthralgia 6 37 21 8 9

Nervous Insomnia 14 25 13 29 15Dizziness 13 22 24 24 18Paresthesia 9 48 39 17 11Depression 6 12 13 20 12Peripheral

neuritis 2 23 16 2 2Neuropathy 1 13 5 4 4

Respiratory Cough

increased 26 41 22 43 29Dyspnea 22 27 26 42 25Rhinitis 14 22 5 22 16Pharyngitis 12 22 14 30 18Sinusitis 9 21 7 13 6

Skin Rash 18 38 18 27 17Herpes simplex 2 12 3 7 9Acne 2 11 3 3 < 1

Urogenital Urinary tractinfection 5 18 14 13 7

aData for Herceptin single agent were from 4 studies,including 213 patients from Study 6. bAnthracycline(doxorubicin or epirubicin) and cyclophosphamide.

The following subsections provide additional detailregarding adverse reactions observed in clinical

January/February 2009 GREEN HILL HEALTHCARE COMMUNICATIONS 3

NE

WS

NO

TE

SN

EW

S N

OT

ES

trials of adjuvant breast, metastatic breast cancer,or post-marketing experience. Cardiomyopathy Serialmeasurement of cardiac function (LVEF) was obtained in clinical trials in the adjuvant treatment of breastcancer. In Study 3, the median duration of follow-up was 12.6 months (12.4 months in the observation arm;12.6 months in the 1-year Herceptin arm); and in Studies 1 and 2, 23 months in the AC-T arm, 24 months in the AC-TH arm. In Studies 1 and 2, 6% of patients were not permitted to initiate Herceptin following completion of AC chemotherapy due to cardiac dysfunction (LVEF < 50% or ≥15 point decline in LVEF from baseline to end of AC). Following initiation of Herceptin therapy, the incidence of new-onset dose-limiting myocardial dysfunction washigher among patients receiving Herceptin and paclitaxelas compared to those receiving paclitaxel alone inStudies 1 and 2, and in patients receiving Herceptin monotherapy compared to observation in Study 3 (see Table 5, Figures 1 and 2).

Table 5a Per-patient Incidence of New Onset Myocardial Dysfunction (by LVEF) Studies 1, 2, 3 and 4

LVEF <50% and Absolute Absolute LVEFDecrease from Baseline Decrease

LVEF ≥ 10% ≥ 16% <20% and<50% decrease decrease ≥ 10% ≥ 20%

Studies 1 & 2b

AC TH 22.8% 18.3% 11.7% 33.4% 9.2%(n=1606) (366) (294) (188) (536) (148)

AC T 9.1% 5.4% 2.2% 18.3% 2.4%(n=1488) (136) (81) (33) (272) (36)

Study 3Herceptin 8.6% 7.0% 3.8% 22.4% 3.5%(n=1678) (144) (118) (64) (376) (59)

Observation 2.7% 2.0% 1.2% 11.9% 1.2%(n=1708) (46) (35) (20) (204) (21)

Study 4c

TCH 8.5% 5.9% 3.3% 34.5% 6.3%(n=1056) (90) (62) (35) (364) (67)

AC TH 17% 13.3% 9.8% 44.3% 13.2%(n=1068) (182) (142) (105) (473) (141)

AC T 9.5% 6.6% 3.3% 34% 5.5%(n=1050) (100) (69) (35) (357) (58)

aFor Studies 1, 2 and 3, events are counted from the beginning of Herceptin treatment. For Study 4, events are counted from the date of randomization. bStudies 1 and 2 regimens: doxorubicin and cyclophosphamide followed bypaclitaxel (AC T) or paclitaxel plus Herceptin (AC TH).cStudy 4 regimens: doxorubicin and cyclophosphamidefollowed by docetaxel (AC T) or docetaxel plus Herceptin(AC TH); docetaxel and carboplatin plus Herceptin(TCH).

Figure 1 Studies 1 and 2: Cumulative Incidence of Time to First LVEF Decline of ≥ 10 Percentage Points from Baselineand to Below 50% with Death as a Competing Risk Event

Time 0 is initiation of paclitaxel or Herceptin + paclitaxel therapy.

Figure 2 Study 3: Cumulative Incidence of Time to First LVEF Decline of ≥ 10 Percentage Points from Baseline andto Below 50% with Death as a Competing Risk Event

Time 0 is the date of randomization.

Figure 3 Study 4: Cumulative Incidence of Time to First LVEF Decline of ≥ 10 Percentage Points from Baseline andto Below 50% with Death as a Competing Risk Event

Time 0 is the date of randomization.

The incidence of treatment emergent congestive heart failure among patients in the metastatic breast cancer trials was classified for severity using the New York Heart Association classification system (I–IV, where IV is the most severe level of cardiac failure) (see Table 2). In the metastatic breast cancer trials the probability of cardiac dysfunction was highest in patients who receivedHerceptin concurrently with anthracyclines. InfusionReactions During the first infusion with Herceptin, the symptoms most commonly reported were chills and fever, occurring in approximately 40% of patients in clinicaltrials. Symptoms were treated with acetaminophen,diphenhydramine, and meperidine (with or withoutreduction in the rate of Herceptin infusion); permanentdiscontinuation of Herceptin for infusional toxicity wasrequired in <1% of patients. Other signs and/or symptoms may include nausea, vomiting, pain (in some cases at tumor sites), rigors, headache, dizziness, dyspnea, hypotension, elevated blood pressure, rash, and asthenia. Infusional toxicity occurred in 21% and 35% of patients, and was

severe in 1.4% and 9% of patients, on second or subsequent Herceptin infusions administered as monotherapy or incombination with chemotherapy, respectively. In the post-marketing setting, severe infusion reactions, includinghypersensitivity, anaphylaxis, and angioedema have beenreported. Anemia In randomized controlled clinical trials,the overall incidence of anemia (30% vs. 21% [Study 5]), of selected NCI-CTC Grade 2–5 anemia (12.5% vs. 6.6%[Study 1]), and of anemia requiring transfusions (0.1% vs. 0patients [Study 2]) were increased in patients receivingHerceptin and chemotherapy compared with thosereceiving chemotherapy alone. Following the administrationof Herceptin as a single agent (Study 6), the incidence of NCI-CTC Grade 3 anemia was <1%. Neutropenia Inrandomized controlled clinical trials in the adjuvant setting,the incidence of selected NCI-CTC Grade 4–5 neutropenia (2% vs. 0.7% [Study 2]) and of selected Grade 2–5neutropenia (7.1% vs. 4.5 % [Study 1]) were increased in patients receiving Herceptin and chemotherapy compared with those receiving chemotherapy alone. In a randomized, controlled trial in patients with metastatic breast cancer, the incidences of NCI-CTC Grade 3/4 neutropenia (32% vs. 22%) and of febrile neutropenia (23% vs. 17%) were also increased in patients randomized to Herceptin incombination with myelosuppressive chemotherapy ascompared to chemotherapy alone. Infection The overallincidences of infection (46% vs. 30% [Study 5]), of selected NCI-CTC Grade 2–5 infection/febrile neutropenia (22% vs. 14% [Study 1]) and of selected Grade 3–5 infection/febrile neutropenia (3.3% vs. 1.4%) [Study 2]), were higher in patients receiving Herceptin and chemotherapy comparedwith those receiving chemotherapy alone. The mostcommon site of infections in the adjuvant setting involvedthe upper respiratory tract, skin, and urinary tract. In Study 4, the overall incidence of infection was higher with the addition of Herceptin to AC-T but not to TCH [44% (AC-TH),37% (TCH), 38% (AC-T)] . The incidences of NCI-CTC grade 3-4 infection were similar [25% (AC-TH), 21% (TCH), 23% (AC-T)] across the three arms. In a randomized, controlled trial in treatment of metastatic breast cancer, the reported incidence of febrile neutropenia was higher (23% vs. 17%) in patients receiving Herceptin in combination withmyelosuppressive chemotherapy as compared tochemotherapy alone. Pulmonary Toxicity Adjuvant BreastCancer: Among women receiving adjuvant therapy forbreast cancer, the incidence of selected NCI-CTC Grade 2–5 pulmonary toxicity (14% vs. 5% [Study 1]) and of selected NCI-CTC Grade 3–5 pulmonary toxicity andspontaneous reported Grade 2 dyspnea (3.4% vs. 1%[Study 2]) was higher in patients receiving Herceptin and chemotherapy compared with chemotherapy alone. Themost common pulmonary toxicity was dyspnea (NCI CTC Grade 2–5: 12% vs. 4% [Study 1]; NCI-CTC Grade 2–5: 2.5% vs. 0.1% [Study 2]). Pneumonitis/pulmonary infiltratesoccurred in 0.7% of patients receiving Herceptin comparedwith 0.3% of those receiving chemotherapy alone. Fatal respiratory failure occurred in 3 patients receivingHerceptin, one as a component of multi-organ system failure, as compared to 1 patient receiving chemotherapy alone. In Study 3, there were 4 cases of interstitialpneumonitis in Herceptin-treated patients compared tonone in the control arm. Metastatic Breast Cancer: Among women receiving Herceptin for treatment of metastatic breast cancer, the incidence of pulmonary toxicity was also increased. Pulmonary adverse events have beenreported in the post-marketing experience as part of the symptom complex of infusion reactions. Pulmonary eventsinclude bronchospasm, hypoxia, dyspnea, pulmonaryinfiltrates, pleural effusions, non-cardiogenic pulmonaryedema, and acute respiratory distress syndrome. For a detailed description, see Warnings and Precautions .Thrombosis/Embolism In 4 randomized, controlled clinicaltrials, the incidence of thrombotic adverse events was higher in patients receiving Herceptin and chemotherapycompared to chemotherapy alone in three studies (3.0% vs. 1.3% [Study 1] , 2.5% and 3.7% vs. 2.2% [Study 4] and 2.1% vs. 0% [Study 5]). Diarrhea Among women receivingadjuvant therapy for breast cancer, the incidence of NCI-CTC Grade 2–5 diarrhea (6.2% vs. 4.8% [Study 1]) and of NCI-CTC Grade 3–5 diarrhea (1.6% vs. 0% [Study 2]), and of Grade 1–4 diarrhea (7% vs. 1% [Study 3]) were higher in patients receiving Herceptin as compared to controls. In Study 4, the incidence of Grade 3–4 diarrhea was higher [5.7% AC-TH, 5.5% TCH vs. 3.0% AC-T] and of Grade 1–4 was higher [51% AC-TH, 63% TCH vs. 43% AC-T] among women receiving Herceptin. Of patients receivingHerceptin as a single agent for the treatment of metastatic breast cancer, 25% experienced diarrhea. An increased incidence of diarrhea was observed in patients receivingHerceptin in combination with chemotherapy for treatment of metastatic breast cancer. Glomerulopathy In the post-marketing setting, rare cases of nephrotic syndrome with pathologic evidence of glomerulopathy have been reported.The time to onset ranged from 4 months to approximately 18 months from initiation of Herceptin therapy. Pathologicfindings included membranous glomerulonephritis, focalglomerulosclerosis, and fibrillary glomerulonephritis.Complications included volume overload and congestiveheart failure. Immunogenicity As with all therapeuticproteins, there is a potential for immunogenicity. Among 903 women with metastatic breast cancer, human anti-human antibody (HAHA) to Herceptin was detected in one patient using an enzyme-linked immunosorbent assay(ELISA). This patient did not experience an allergicreaction. Samples for assessment of HAHA were not collected in studies of adjuvant breast cancer. Theincidence of antibody formation is highly dependent on the sensitivity and the specificity of the assay. Additionally, the observed incidence of antibody (including neutralizing antibody) positivity in an assay may be influenced by several factors including assay methodology, samplehandling, timing of sample collection, concomitantmedications, and underlying disease. For these reasons,comparison of the incidence of antibodies to Herceptin with the incidence of antibodies to other products may be misleading. USE IN SPECIFIC POPULATIONS PregnancyTeratogenic Effects: Category D [see Warnings andPrecautions] Herceptin can cause fetal harm whenadministered to a pregnant woman. Post-marketing case reports suggest that Herceptin use during pregnancyincreases the risk for oligohydramnios during the secondand third trimester. If Herceptin is used during pregnancy or if a woman becomes pregnant while taking Herceptin,

she should be apprised of the potential hazard to a fetus. In the post-marketing setting, oligohydramnios was reported in women who received Herceptin during pregnancy, either alone or in combination with chemotherapy. In half of these women, amniotic fluid index increased after Herceptin wasstopped. In one case, Herceptin was resumed after the amniotic fluid index improved, and oligohydramniosrecurred. Women using Herceptin during pregnancy shouldbe monitored for oligohydramnios. If oligohydramniosoccurs, fetal testing should be done that is appropriate forgestational age and consistent with community standards of care. Additional intravenous (IV) hydration has beenhelpful when oligohydramnios has occurred followingadministration of other chemotherapy agents; however, the effects of additional IV hydration with Herceptintreatment are not known. Reproduction studies incynomolgus monkeys at doses up to 25 times therecommended weekly human dose of 2 mg/kg trastuzumab have revealed no evidence of harm to the fetus. However, HER2 protein expression is high in many embryonic tissuesincluding cardiac and neural tissues; in mutant micelacking HER2, embryos died in early gestation. Placentaltransfer of trastuzumab during the early (Days 20-50 of gestation) and late (Days 120-150 of gestation) fetaldevelopment period was observed in monkeys. [SeeNonclinical Toxicology ] Because animal reproductionstudies are not always predictive of human response, Herceptin should be used during pregnancy only if the potential benefit to the mother justifies the potential risk to the fetus. Nursing Mothers It is not known whetherHerceptin is excreted in human milk, but human IgG is excreted in human milk. Published data suggest that breastmilk antibodies do not enter the neonatal and infantcirculation in substantial amounts. Trastuzumab waspresent in the breast milk of lactating cynomolgus monkeys given 12.5 times the recommended weekly human dose of2 mg/kg of Herceptin. Infant monkeys with detectable serum levels of trastuzumab did not have any adverse effects on growth or development from birth to 3 months of age; however, trastuzumab levels in animal breast milk may not accurately reflect human breast milk levels. Because many drugs are secreted in human milk and because of thepotential for serious adverse reactions in nursing infantsfrom Herceptin, a decision should be made whether to discontinue nursing, or discontinue drug, taking intoaccount the elimination half-life of trastuzumab and theimportance of the drug to the mother. Pediatric Use Thesafety and effectiveness of Herceptin in pediatric patientshas not been established. Geriatric Use Herceptin hasbeen administered to 386 patients who were 65 years of age or over (253 in the adjuvant treatment and 133 in metastatic breast cancer treatment settings). The risk of cardiac dysfunction was increased in geriatric patients ascompared to younger patients in both those receiving treatment for metastatic disease in Studies 5 and 6, or adjuvant therapy in Studies 1 and 2. Limitations in datacollection and differences in study design of the 4 studies of Herceptin in adjuvant treatment of breast cancerpreclude a determination of whether the toxicity profile of Herceptin in older patients is different from youngerpatients. The reported clinical experience is not adequateto determine whether the efficacy improvements (ORR,TTP, OS, DFS) of Herceptin treatment in older patients isdifferent from that observed in patients <65 years of age for metastatic disease and adjuvant treatment.OVERDOSAGE There is no experience with overdosage in human clinical trials. Single doses higher than 8 mg/kg have not been tested. PATIENT COUNSELINGINFORMATION • Advise patients to contact a health care professional immediately for any of the following: new onset or worsening shortness of breath, cough, swelling of the ankles/legs, swelling of the face, palpitations, weightgain of more than 5 pounds in 24 hours, dizziness or loss ofconsciousness [see Boxed Warning: Cardiomyopathy ] .• Advise women with reproductive potential to useeffective contraceptive methods during treatment and for a minimum of six months following Herceptin [seePregnancy ] . • Encourage pregnant women who are using Herceptin to enroll in the Cancer and Childbirth Registry [see Pregnancy ] .

HERCEPTIN® [trastuzumab]Manufactured by: 4839802Genentech, Inc. Initial US Approval: Sept. 19981 DNA Way Revision Date: May 2008South San Francisco, CA LK0726 717291094080-4990 9317800

©2008 Genentech USA

NewsNotes■ ONS Launches Survivorship,

Gero-oncology InitiativesThe Oncology Nursing Society (ONS)

in December 2008 announced two newinitiatives, one on survivorship and oneon gero-oncology. The Survivorship In-itiative will focus on providing resourcesfor all nurses caring for patients who aresurvivors of adult cancers. The number ofcancer survivors in the United States isestimated to be about 12 million and isgrowing. “One goal of the initiative is toraise awareness that survivorship care isevery nurse’s responsibility,” said ONSpresident Brenda Nevidjon, RN, MSN,FAAN (www.ons.org). The Gero-oncolo-gy Advocacy Initiative is one of the strate-gic efforts planned by the ONS GeriatricsTask Force to address the education needsof nurses caring for older patients withcancer. More than 60% of new cancerdiagnoses and 70% of cancer deathsoccur in patients 65 years of age or older.“As the population continues to age, alloncology nurses caring for adults mustbecome knowledgeable about the specialneeds of older people with cancer,” saidNevidjon. In a related development, theAmerican Academy of Nursing has re-ceived a $9.3-million grant from theJohn A. Hartford Foundation to preparegeriatric nursing faculty to teach the nextgeneration of nurses about the specialneeds of older patients.

■ Improved Stool DNA TestA simplified, noninvasive colorectal can-

cer screening test that detects tumor DNAin stool is an improvement over an earliergeneration assay, according to a report in the American Journal of Gastroenterology.Itzkowitz and colleagues found that the new-generation test, which uses only two mark-ers, demonstrated high sensitivity (83%)and specificity (82%) for colorectal cancer.The investigators noted that the majority ofcancers were detected regardless of tumorstage, tumor location, or patient age. Thenew version, they say, will make the test eas-ier to perform, reduce the cost, and facilitatedistribution to local laboratories.

■ Air Travel Presents Little Risk ofLymphedema for Breast CancerSurvivorsPressure changes in airplane cabins hold

little risk for lymphedema for breast cancersurvivors. A recent study by Kilbreath andcolleagues, presented at the San AntonioBreast Cancer Symposium, found that only5% of 63 women who had been treated forbreast cancer developed a clinically signifi-cant increase in intracellular fluid in their“at-risk” arm during a long-distance flight.Mastectomy with full axillary node dissec-tion and long-haul travel were associatedwith greater risk. Extracellular fluid fluctuat-ed somewhat but without a significant effecton impedance ratio. The impedance ratioincreased by 2% or less in 48 women and 2%to 5% in 12. The researchers hope thesefindings will help dispel myths that havekept some breast cancer survivors from fly-ing. (www.sabcs.org)

4 GREEN HILL HEALTHCARE COMMUNICATIONS January/February 2009

CO

NT

EN

TS

CO

NTE

NTS

OncologyNurse

TheOncologyNurse

The

The Official Newspaperof Record for

the Hem/Onc Nurse

™

PUBLISHING STAFF

PublisherPhilip Pawelkophil@greenhillhc.com

Editorial DirectorKaren Rosenbergkaren@greenhillhc.com

Managing EditorLara J. Reiman

Associate EditorDawn Lagrosa

Production ManagerStephanie Laudien

Directors, Client ServicesJohn W. Hennessyjohn@greenhillhc.com

Russell Hennessyrussell@greenhillhc.com

Business ManagerBlanche Marchittoblanche@greenhillhc.com

Executive AdministratorsThiel HennessyLisa Russo

241 Forsgate Drive, Suite 205C

Monroe Twp, NJ 08831

Vol. 2, No. 1 January/February 2009

Green Hill Healthcare Communications LLCGreen Hill Healthcare Communications, LLCHGYour Innovative Partners in Medical Media™

™

Departments

3 News Notes

6 Editor’s Letter

8 Medical Minutes

33 Meetings

Isabell Castellano, RN

Bristol-Myers Squibb Children’s Hospital

Robert Wood Johnson University Hospital

New Brunswick, NJ

Deena Damsky Dell, RN, MSN, AOCN, BC

Fox Chase Cancer Center

Philadelphia, PA

Wendy DiSalvo, BSN, MSN, FNP, AOCN

Dartmouth Hitchcock Medical Center

Norris Cotton Cancer Center

Lebanon, NH

Denice Economou, RN, MN, AOCN

City of Hope National Medical Center

Duarte, CA

Constance Engelking, RN, MS, OCN

The CHE Consulting Group, Inc.

Mt. Kisco, NY

Amy Ford, RN, BSN, OCN

Creative Cancer Concepts, Inc.

Rockwall, TX

Lyssa Friedman, RN, MPA, OCN

Veracyte, Inc

South San Francisco, CA

Sharon S. Gentry, RN, MSN, AOCN

Derrick L. Davis Forsyth Regional Cancer Center

Winston-Salem, NC

Marilyn L. Haas, PhD, RN, CNS, ANP-C

Mountain Radiation Oncology

Asheville, NC

Cassandra J. Hammond, RN, MSN, CRNP

Avid Education Partners, LLC

Sharpsburg, MD

Taline Khoukaz, NP, MSN, ACNP-C

University of Southern California

Norris Cancer Center & Hospital

Los Angeles, CA

Sandra E. Kurtin, RN, MS, AOCN, ANP-C

Arizona Cancer Center

Tucson, AZ

Ann McNeill, MSN, RN, NP-C, OCN

The Cancer Center at Hackensack University

Medical Center

Hackensack, NJ

Kena C. Miller, RN, MSN, FNP

Roswell Park Cancer Institute

Buffalo, NY

Dolores “Jeff” Nordquist, RN, MS, CS, FNP

Mayo Clinic

Rochester, MN

Melinda Oberleitner, RN, DNS, APRN, CNS

College of Nursing and Allied Health Professions

University of Louisiana

Lafayette, LA

Gary Shelton, MSN, ARNP, AOCNNYU Cancer InstituteNew York, NY

Lori Stover, RN, BSNWestern Pennsylvania Cancer Institute Pittsburgh, PA

Joseph D. Tariman, RN, MN, ARNP-BC, OCNUniversity of Washington School of Nursing Seattle, WA

Pamela Hallquist Viale, RN, MS, CS, ANP, AOCNSaratoga, CA

Connie Visovsky, RN, PhD, APRNUniversity of Nebraska, College of NursingOmaha, NE

Jeanne Westphal, RNMeeker County Memorial HospitalLitchfield, MN

Rita Wickham, OCN, PhD, RNRush University College of NursingRush-Presbyterian-St. Luke’s Medical CenterChicago, IL

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

OTHER SPECIALTIES

Susan Goodin, PharmD, FCCP, BCOPCancer Institute of New JerseyNew Brunswick, NJ

Amanda Saldivar, MS, RD, LD Cleveland Clinic Taussig Cancer InstituteCleveland, OH

Barbara Savage, LISWCleveland Clinic Taussig Cancer InstituteCleveland, OH

OncologyNurse

TheOncologyNurse

The

The Official Newspaperof Record for

the Hem/Onc Nurse

™

EDITORIAL BOARD

EDITOR-IN-CHIEF

Beth Faiman, RN, MSN, APRN, BC,

AOCN

Cleveland Clinic Taussig

Cancer Institute

Cleveland, OH

Feature Articles10 Hematologic Cancers

FCR improves progression-free survival

12 Hematologic CancersNon-Hodgkin’s lymphomas, Part 3: Diagnostic strategies

19 Breast CancerSkin moisturizers may expose patients to estrogen

19 Breast CancerObesity increases risk for contralateral breast cancer

27 Continuing EducationDecision aids as guide for cancer patients making clinical

decisions

32 Oncology NutritionUse of alternative diets

www.coexm.comREAREACH US ONLINE ACH US ONLINE ATT

• View current and past issues

• Register to receive your free subscription

• Access CE activities

• Find answers to questionsabout mTOR

www.TargetmTORTargetmTOR.com

Novartis Oncology knows you have questions about mTOR.Introducing the answers.

The mammalian target of rapamycin, mTOR, is an important new target for cancer therapy in multipletumor types. Visit www.TargetmTOR.com and register online to stay informed on the latest news aboutmTOR in renal cell carcinoma, neuroendocrine tumors, and other tumor types.

Charged with information about mTOR, www.TargetmTOR.com furthers Novartis’s dedication

to providing you with the latest information on mTOR.

©2009 Novartis 3/09 C-ONC-100081

ED

ITO

R’S

LE

TT

ER

ED

ITO

R’S

LE

TT

ER

February is National Cancer PreventionMonth, and in recognition of thisevent, the American Society of Clinical

Oncology has issued a policy statement high-lighting oncologists’ role in cancer preven-tion (www.asco.org). “Oncologists areuniquely poised to guide patients and familymembers through the complicated issues ofassessing and reducing their cancer risk,”writes ASCO president Richard L. Schilsky,MD. That is true, but oncology nurses andother members of the healthcare team alsohave a responsibility to counsel patientsabout prevention and treatment of cancer.

Choices are not always clear cut, however,as the article about anthracycline-based ver-sus nonanthracycline-based regimens forbreast cancer illustrates. As new therapiesbecome available, healthcare providers haveto weigh the alternatives and decide how bestto apply them in their own practices. Forpatients, the vast amount of information can

be overwhelming. As reported at the SanAntonio Breast Cancer Symposium, goodcommunication between patients andproviders about available treatments andtheir risks and benefits is needed to ensuremutual agreement about the goals of therapy.

It is also important to discuss diet andother lifestyle choices with our patients. AsAmanda Saldivar explains in her articleabout alternative diets, patients with canceroften view dietary changes as a way to takecontrol of their health. Certain changes,such as lowering consumption of fat andcalories or increasing intake of fruits andvegetables, can be beneficial, but more ex-treme changes, as recommended in severalpopular alternative diets, can have harmfuleffects. As nurses, we are often the first onespatients turn to for advice, and we must beprepared to help our patients find reliablesources of information and make goodchoices about these and other matters.

In the continuing education article,Stacey and colleagues explain that manyfactors, including the patient’s values andbeliefs, must be taken into consideration inchoosing the best strategy for an individualpatient, and simply providing patients withfacts may not be sufficient. They explainthe concept of shared decision making andreview different strategies that have beenused with varying degrees of success inhelping patients make high-quality deci-sions about their care. Their case reportprovides an illustration of how a carefullythought-out decision aid can be used in theclinical setting.

We are always interested in innovativeapproaches to patient education and coun-seling. If there are certain methods or inter-ventions that you have found effective inyour own practice and you would like toshare them with your colleagues, pleasewrite to us at Karen@greenhillhc.com.

A Letter from the Editor

BETH FAIMAN, RN, MSN,APRN, BC, AOCN

EDITOR-IN-CHIEF

EDITORIAL CORRESPONDENCE should be addressed toEDITORIAL DIRECTOR, The Oncology Nurse™, 241 ForsgateDrive, Suite 205C, Monroe Twp, NJ 08831. E-mail: karen@greenhillhc.com. YEARLY SUBSCRIPTION RATES: United States andpossessions: individuals, $105.00; institutions, $135.00; single issues$17.00. Orders will be billed at individual rate until proof of status isconfirmed. Prices are subject to change without notice.Correspondence regarding permission to reprint all or part of anyarticle published in this journal should be addressed to REPRINTPERMISSIONS DEPARTMENT, Green Hill HealthcareCommunications, LLC, 241 Forsgate Drive, Suite 205C, MonroeTwp, NJ 08831. The ideas and opinions expressed in The Oncology

Nurse™ do not necessarily reflect those of the Editorial Board, theEditorial Director, or the Publisher. Publication of an advertisementor other product mention in The Oncology Nurse™ should not be con-strued as an endorsement of the product or the manufacturer’s claims.Readers are encouraged to contact the manufacturer with questionsabout the features or limitations of the products mentioned. Neitherthe Editorial Board nor the Publisher assumes any responsibility forany injury and/or damage to persons or property arising out of orrelated to any use of the material contained in this periodical. Thereader is advised to check the appropriate medical literature and theproduct information currently provided by the manufacturer of eachdrug to be administered to verify the dosage, the method and durationof administration, or contraindications. It is the responsibility of thetreating physician or other healthcare professional, relying on inde-pendent experience and knowledge of the patient, to determine drugdosages and the best treatment for the patient. Every effort has beenmade to check generic and trade names, and to verify dosages. Theultimate responsibility, however, lies with the prescribing physician.Please convey any errors to the Editorial Director. ISSN #1944-9798.

The Oncology Nurse™ is published 7 times a year by Green HillHealthcare Communications, LLC, 241 Forsgate Drive, Suite 205C,Monroe Twp, NJ 08831. Telephone: 732.656.7935. Fax:732.656.7938. Copyright ©2009 by Green Hill HealthcareCommunications, LLC. All rights reserved. The Oncology Nurse™ logois a trademark of Green Hill Healthcare Communications, LLC. Nopart of this publication may be reproduced or transmitted in any formor by any means now or hereafter known, electronic or mechanical,including photocopy, recording, or any informational storage andretrieval system, without written permission from the Publisher.Printed in the United States of America.

ComingSoon

CE article:

Reimbursement for Cancer Therapies:

The Role of Cost-effectiveness Analysis

New Technologies in HER2 Testing

Cancer treatment–Related Bone Loss and Osteoporosis

Coriell Personalized Medicine Collaborative

Increasing Oncology Patient Participation inClinical Trials: The Coalition of Cancer

Cooperative Groups

Reports from ASCO Gastrointestinal CancersSymposium, Genitourinary Cancers Symposium,

ONS 10th National Conference on Cancer Nursing Research

For a free subscription go to www.theoncologynurse.com

6 GREEN HILL HEALTHCARE COMMUNICATIONS January/February 2009

References: 1. Asbury AK. Approach to the patient with peripheral neuropathy. In: Kasper DL, Braunwald E, Hauser SL, Longo DL, Jameson JL,

Fauci AS, eds. Harrison’s Principles of Internal Medicine. 16th ed. New York, NY: McGraw-Hill Medical Publishing Division; 2004:2500-2510.

2. Armstrong T, Almadrones L, Gilbert MR. Chemotherapy-induced peripheral neuropathy. Oncol Nurs Forum. 2005;32(23):305-311. 3. Ghobrial

IM, Rajkumar SV. Management of thalidomide toxicity. J Support Oncol. 2003;1(3):194-205. 4. Richardson PG, Briemberg H, Jagannath S, et al.

Frequency, characteristics, and reversibility of peripheral neuropathy during treatment of advanced multiple myeloma with bortezomib.

J Clin Oncol. 2006;24(19):3113-3120. 5. Hausheer FH, Schilsky RL, Bain S, Berghorn EJ, Lieberman F. Diagnosis, management, and evaluation of

chemotherapy-induced peripheral neuropathy. Semin Oncol. 2006;33(1):15-49. 6. Stillman M, Cata JP. Management of chemotherapy-induced

peripheral neuropathy. Curr Pain Headache Rep. 2006;10(4):279-287. 7. Lavoie Smith EM, Beck SL. The total neuropathy score: a tool for

measuring chemotherapy-induced peripheral neuropathy. Oncol Nurs Forum. 2008;35(1):96-102. 8. Markman M. Chemotherapy-induced

peripheral neuropathy: underreported and underappreciated. Curr Pain Headache Rep. 2006;10(9):275-278.

Is peripheral neuropathyholding them back?

Intervene early to preserve quality of life

Peripheral neuropathy (PN) can have a devastating effect on patients with multiple myeloma

(MM). These patients have an increased risk since both MM and some of its treatments

can cause PN.1-4 Even though PN symptoms are mild at the outset, eventually they can

have an impact on patients’ lives, limiting their ability to do the activities they enjoy. And

these effects may cause permanent damage.5,6 That is why it is so important to identify

symptoms early.2

Assessing PN is critical to optimizing myeloma management

A baseline assessment is the first step in preventing or controlling the symptoms of PN.2

Patients with MM may have pre-existing conditions, such as diabetes, that can lead to

PN.7 By identifying pre-existing PN early on, you can better monitor patients throughout

treatment.

Identifying and assessing symptoms can be challenging. The sensations caused by

PN are subjective, and patients may be hesitant to share these symptoms since it may

lead to changes in their treatment plan.5,8 Therefore, it is important to encourage your

patients to report any symptoms they may be experiencing.7 Here are some questions

to start the dialogue:

• “Do you have any unusual sensations (pins and needles, shooting pain like electric

current) in your feet, legs, or hands?”

• “Would you describe these sensations as tingling, numbness, burning, or pain?”

• “Do any of these sensations or feelings keep you from doing things like buttoning your

shirt or using a fork and knife?”

• “Have your legs or arms been weak? Does this weakness keep you from taking part in

the activities you enjoy, like needlework or golfing?”

Discuss PN with your patients early and often

Multiple myeloma treatments may cause PN symptoms and the damage may be

permanent.3,4 By identifying patients at risk and assessing their symptoms, you can:

• Help them overcome their fears: assure your patients that a change in treatment plan in

response to PN does not have to compromise efficacy

• Assess PN at baseline and throughout treatment to help guide treatment decisions2

Your intervention can help ensure your patients’ treatment

allows them to pursue the things they love

©2008 Celgene Corporation 10/08 CELG08083T

8 GREEN HILL HEALTHCARE COMMUNICATIONS January/February 2009

ME

DIC

AL

MIN

UT

ES

ME

DIC

AL

MIN

UT

ES

Breast cancer patients who receive breast-conserving therapy andradiation do not need a follow-up mammogram until 12 months afterradiation, according to California researchers. Current AmericanSociety of Clinical Oncology (ASCO) and National ComprehensiveCancer Network (NCCN) guidelines recommend follow-up mammo-grams between 6 and 12 months after radiation.

Researchers at University of California campuses in LosAngeles and San Diego studied 408 women who were treated withbreast-conserving therapy and radia-tion between 1995 and 2005 and hadfollow-up mammograms within 1 yearafter completing radiation. The medi-an interval between radiation and theinitial mammogram was 3.1 months.They found that only 10 women hadsuspicious findings on their mammo-grams and, of those, only two werefound to have recurrent cancer. Bothof these cases were noninvasive ductalcarcinomas.

The cost of a mammogram is about$115, and many women experience mod-erate to severe pain during the procedureand high levels of anxiety during a needlebiopsy. The authors of this new studydetermined that because only 0.49 recur-rences were detected per 100 mammo-grams and only noninvasive ductal carci-noma was found, mammograms shouldnot be performed until at least 1 year afterradiation to avoid the medical and psy-chological costs associated with mam-mography.

“Omitting the initial postradiotherapyexamination may improve the psycholog-ical well-being of patients, especially forwomen who already have been shown tohave breast cancer,” said lead studyauthor Kevin Lin, MD, a radiation oncol-ogist at Advanced Oncology Center,West Covina, California.

The most recent NCCN guidelines

propose a follow-up mammogram 6 to 12 months after radiation.ASCO guidelines recommend a follow-up mammogram 1 yearafter the initial mammogram that led to diagnosis, but no earlierthan 6 months after radiation. Accounting for the time after theinitial diagnostic mammogram to have a biopsy, surgery, and radi-ation therapy, following the ASCO guidelines would likely resultin mammograms being done 6 to 9 months after the completion ofradiation, according to Lin.

A minimally invasive approach to treating high-risk patientswith stage I non–small-cell lung cancer (NSCLC) may signifi-cantly reduce the risk of local disease reccurrence, according toresearchers at Allegheny General Hospital in Pittsburgh,Pennsylvania. The procedure, which was developed at the hos-pital over the past 10 years, involves removing only the cancer-ous section of the lung and enveloping the surgical site in a meshmaterial that is embedded with radioactive seeds. The seeds emita low dose of radiation over a prolonged period of time in aneffort to eradicate any remaining cancer cells.

“The standard of care for patients with this particular diseaseis a lobectomy, or surgical removal of the entire lobe of the lung.Many patients, however, are considered high-risk for this proce-dure because of cardiopulmonary complications or other comor-bidities. In these cases, sublobar wedge resection is a more toler-able approach, but one that carries a much higher chance oflocal cancer recurrence,” said principal study investigatorAthanasios Colonias, MD, a radiation oncologist at AlleghenyGeneral Hospital. “Our study suggests that when intraoperative125l Vicryl mesh brachytherapy is added to sublobar resection,the local treatment failure rate is substantially reduced.”

Colonias and his colleagues examined the outcomes of 145high-risk patients with stage I NSCLC who underwent sublobarresection with adjuvant intraoperative mesh brachytherapybetween January 1996 and February 2008. Local treatment fail-

ure was defined as a cancer recurrence within the involved lobe.At a median follow-up of 38 months, the researchers found six

local recurrences (4.1%) in the treated group compared with anexpected cancer recurrence rate of 20% with sublobar resectiononly, based on previously published data. No patient- or tumor-specific factors (age, histology, sex, stage, location of tumor, andtumor size) or surgical or dosimetric factors (margin status, openversus video-assisted approach, total activity, number of seeds,dose prescribed, and targeted area) were predictive of localrecurrence. All the procedures were well tolerated by patientswith regard to pulmonary function and morbidity.

“Of the more than 150,000 people diagnosed each year withlung cancer, fewer than 20% are identified with disease in itsearliest and more curable stage. For high-risk patients, however,even a stage I diagnosis poses significant therapeutic challengesand generally poor odds of a long-term recovery. It would appearthat those odds may be improved considerably by combiningsublobar resection with intraoperative mesh brachytherapy,”said Robert Keenan, MD, director of thoracic surgery atAllegheny General Hospital.

He said a large, randomized, multicenter clinical trial withthis approach is currently under way, which should establish theefficacy of the procedure more definitively. The study is beingcoordinated by the American College of Surgeons OncologyGroup and involves more than a dozen major US hospitals.

Medical MinutesBY JOHN SCHIESZER

John Schieszer is an

award-winning national

journalist and radio

broadcaster of The

Medical Minute.

He can be reached at

medminutes@aol.com.

New Approach to Reducing Lung Cancer Recurrence Showing Promise

New Study Suggests Mammograms Most Effective 12 Months after Radiation Treatment

Acupuncture appears to be as effective andlonger lasting in managing common debilitat-ing vasomotor symptoms associated withbreast cancer treatment—hot flashes, nightsweats, and excessive sweating—than conven-tional drug therapy, and has no side effects.Additional benefits of acupuncture treatmentfor breast cancer patients include an increasedsense of well-being, more energy and, in somecases, a higher sex drive, which were not expe-rienced in patients who underwent drug treat-ment for their hot flashes.

The investigators conducted a randomizedclinical trial that compared acupuncture treat-ment with the selective serotonin-norepi-nephrine reuptake inhibitor venlafaxine for 12weeks to determine whether acupuncturereduced vasomotor symptoms in breast cancerpatients receiving hormonal therapy and pro-duced fewer side effects than venlafaxine. Thestudy involved 47 breast cancer patients whoreceived either tamoxifen or anastrozole andhad at least 14 hot flashes per week. Theresults showed that acupuncture reduced hotflashes as effectively as venlafaxine, with noside effects. In addition, acupuncture providedseveral additional health benefits.

“Our study shows thatphysicians and patientshave an additional ther-apy for something thataffects the majority ofbreast cancer survivorsand actually has bene-fits, as opposed to moreside effects. The effectsare more durable than adrug commonly used to treat these vasomotorsymptoms and, ultimately, [the treatment] ismore cost-effective for insurance companies,”said lead study author Eleanor Walker, MD, aradiation oncologist at Henry Ford Hospital,Detroit, Michigan.

She said the reduction in hot flashes lastedlonger after acupuncture treatment than afterdrug therapy. She noted that 80% of womentreated for breast cancer suffer from hot flashesafter being treated with chemotherapy and/orantiestrogen hormones, such as tamoxifen oranastrozole. Most clinicians now treat thesymptoms with steroids and/or antidepressantmedications. However, these drugs have addi-tional side effects, such as weight gain, nausea,constipation, and fatigue.

Acupuncture May Help Reduce Side Effects of Breast Cancer Treatment

and 8.8% of those in the placebo group),1.9% in the gastrointestinal tract(1.5% vs 2.7%, respectively), 7.5% inthe pancreas (8.3% vs 5.8%, respec-tively), and 1% in “other” sites (0.4%vs 2.2%, respectively).

Nadroparin was particularly effectivein patients with lung cancer, reducingthe risk of thromboembolic events by40%, Agnelli said. The number neededto treat to prevent one thromboembolicevent in lung cancer patients was 18.9.

Prophylactic treatment with nadro-parin in this population did notincrease the risk of adverse events. No

significant differences were observedbetween treatment groups in secondaryend points, including major bleeds,minor bleeds, deaths at the end oftreatment, and death at 12 months.

Even with such encouraging results,Agnelli said he was not hopeful thatone study would change clinical prac-tice. He suggested that future studiesshould focus on cancer patients at highrisk for thromboembolic events, suchas those with cancers of the lung andpancreas.

Commenting on Agnelli’s presen-tation, Agnes Lee, MD, associate pro-

fessor of medicine at McMasterUniversity in Hamilton, Ontario,Canada, noted that cancer-associatedthromboembolic events have morethan doubled in the past 20 years, and“we need to reduce this burden.” Shenoted that “the current guidelines donot recommend routine prophylaxisin outpatients requiring chemothera-py, but now with four randomized tri-als [including PROTECHT] showinga benefit, perhaps these guidelineswill be changed.”

—Alice Goodman

of Perugia, Italy, during a presentationat the 2008 meeting of the AmericanSociety of Hematology (ASH).

Prophylactic blood thinners are usedin cancer patients mainly for standardindications, such as a central venouscatheter, but rarely in ambulatorypatients receiving chemotherapy. Thelarge, double-blind, multicenter PRO-phylaxis of ThromboEmbolism duringChemoTherapy (PROTECHT) studysought to shed some light on this issue byenrolling 1166 patients at 62 Italian cen-ters and randomizing them in a 2:1 ratioto receive LMWH nadroparin 3800 IU

or placebo for the duration of chemo-therapy to a maximum of 4 months.Treatment was initiated on day 1 of thefirst cycle or a new course of chemother-apy. At ASH, Agnelli presented primaryefficacy and safety data for 769nadroparin-treated patients versus 381patients in the placebo group. Patientsenrolled in the trial had a variety ofmetastatic or locally advanced cancers,including lung, gastrointestinal, pancre-atic, breast, ovarian, and head and neckcancers.

The overall rate of thromboembolicevents was 16 (2.1%) in the nadroparingroup versus 15 (3.9%) in the placebogroup. The difference was statisticallysignificant (P = .024), for a relative riskreduction of 49.6%. The absolute rate of deep vein thrombosis was 1% innadroparin-treated patients versus 2.1%among placebo patients. Similar reduc-tions were achieved for pulmonaryembolism, stroke, and visceral venousthrombosis. Analysis of thromboembolicevents by treatment and cancer siteshowed that 5.4% occurred in the lung(3.5% of those in the nadroparin group

Nadroparin Halves the RiskContinued from cover

January/February 2009 GREEN HILL HEALTHCARE COMMUNICATIONS 9

HE

MA

TO

LO

GIC

CA

NC

ER

SH

EM

AT

OL

OG

IC C

AN

CE

RS

Neulasta® (pegfilgrastim) is indicated to decrease the incidence of infection, as manifested by febrile neutropenia, in patients with nonmyeloid malignancies receiving myelosuppressive anti-cancer drugs associated with a clinically significant incidence of febrile neutropenia.

Important Safety InformationSplenic rupture (including fatal cases), acute respiratory distresssyndrome, and sickle cell crises have been reported. Allergic reactions, including anaphylaxis, have also been reported. The majority of these reactions occurred upon initial exposure.However, in rare cases, allergic reactions, including anaphylaxis, recurred within days after discontinuing anti-allergic treatment.

In a placebo-controlled trial, bone pain occurred at a higher incidence in Neulasta®-treated patients as compared to placebo-treated patients (31% vs. 26%). The most common adverse eventsreported in either placebo- or active-controlled trials wereconsistent with the underlying cancer diagnosis and its treatmentwith chemotherapy, with the exception of bone pain.

Please refer to brief summary of Neulasta® Prescribing Information.

Consequences of febrile neutropenia,

such as hospitalization, may impact patient care

First- and subsequent-cycle Neulasta® achieved significant

results in patients receiving a moderate-risk* regimen:

■ 94% reduction in febrile neutropenia vs. placebo (17% vs. 1%).1,2

■ 93% reduction in febrile neutropenia–related hospitalization

vs. placebo (14% vs. 1%).1,2

Start with support*Regimens associated with ≥ 17% risk of febrile neutropenia.

© 2009 Amgen. All rights reserved. MC41456-C 12-08 Class I www.neulasta.com

In moderate-risk* regimens

Approach chemotherapy with confidence by reducing the risk of febrile neutropenia

Neulasta® is given once per chemotherapycycle and should not be administered in the period between 14 days beforeand 24 hours after administration of cytotoxic chemotherapy.

The overall rate ofthromboembolicevents was 16(2.1%) in thenadroparin groupversus 15 (3.9%) inthe placebo group.

Did you

Know?Skin cancer is the most common

form of cancer in the United

States; more cases of skin cancer

are diagnosed each year than

cancers of the breast, prostate,

lung, and colon combined.

Source: www.skincancer.org.

SAN FRANCISCO—Treatment withfludarabine, cyclophosphamide, and rit-uximab (FCR) improved progression-free survival (PFS) compared with stan-dard fludarabine and cyclophosphamide(FC) in patients with chronic lympho-cytic leukemia (CLL) in two separatepivotal phase 3 studies presented at the2008 Annual Meeting of the AmericanSociety of Hematology (ASH).

Each study, one of previously untreat-ed patients and one of patients with

relapsed or refractory CLL, is reputedlythe largest randomized clinical trial everreported of its respective patient group.Results of these two trials are potential-ly practice-changing, with FCR poisedto replace FC as the new standard ofcare, according to investigators.

The FCR regimen was first shown tobe superior to FC alone in CLL byMichael Keating’s group at M.D.Anderson Cancer Center. CLL8 (pre-viously untreated patients) and the

REACH study (relapsed or refractorypatients), presented at ASH, provideconfirmatory evidence for a survivalbenefit for FCR in CLL.

CLL8CLL8, an international study con-

ducted at 191 sites across 11 countries,included 817 previously untreatedpatients who received either FCR orFC. The primary end point was PFS. At2 years, 76.6% of patients were alive

with no disease progression in the FCRgroup versus 63% in the FC group.

“The management of CLL is set tochange markedly, as physicians havemore options and greater treatmentexpectations for their patients. Thedata from CLL8 suggest that rituximabcombined with chemotherapy has thepotential to become the new standardof care for CLL patients,” statedMichael Hallek, MD, UniversityHospital of Cologne, Germany, onbehalf of the German CLL StudyGroup.

Complete response (CR) rate was44.5% for FCR and 22.9% for FC (P =.01). Partial response (PR) was lowerin the FCR group (3.3% vs 8.1%, P =.01), which Hallek attributed to thehigh rates of CR in the rituximab-con-taining arm. At a median follow-up of25.5 months, median PFS was 42.8months for FCR versus 32.3 months forFC (P = .000007).

No new safety concerns were report-ed with the addition of rituximab tostandard chemotherapy. The rituximab-containing regimen was associated withmore neutropenia, but the rates ofinfection and other severe adverseevents were not higher than with stan-dard chemotherapy alone.

REACH trialREACH, a randomized, internation-

al trial conducted at 88 sites across 17countries, randomized 552 patientswith relapsed or refractory CLL toreceive either FCR or FC. The primaryend point, as in the CLL8 trial, wasPFS. The lead investigator was TadeuszRobak, MD, of the Medical Universityof Lodz, Poland.

Robak said, “Rituximab has alreadyrevolutionized the treatment of non-Hodgkin’s lymphoma. The results inCLL underscore an important role ofrituximab in the management of CLL,which is currently a life-threateningincurable disease.”

CR was 24.3% for FCR versus 13% forFC (P = .0007). PR rates were similar inthe two groups. Overall response rateswere 69.9% versus 58%, respectively (P= .0034). At a median follow-up time of25.3 months, median PFS was 30.6months for FCR versus 20.6 months forFC (P = .0002).

Adverse events were similar to whathas been reported previously with theseregimens. The rituximab-containingregimen was associated with a slightincrease in febrile neutropenia, infusionreactions, benign and malignant neo-plasms, and hepatitis B.

A trend was observed toward im-proved overall survival for FCR versusFC but longer follow-up is needed todetermine an overall survival benefit.

Both studies were supported by Roche.

—AG

Hematologic CancersRituximab Added to Fludarabine and Cyclophosphamide

Improves Progression-free Survival

10 GREEN HILL HEALTHCARE COMMUNICATIONS January/February 2009

HE

MA

TO

LO

GIC

CA

NC

ER

SH

EM

AT

OL

OG

IC C

AN

CE

RS

BRIEF SUMMARY OF PRESCRIBING INFORMATION

INDICATIONS AND USAGE

Neulasta® is indicated to decrease the incidence of infection, as manifested by febrile neutropenia, in patients with nonmyeloid malignancies receivingmyelosuppressive anticancer drugs associated with a clinically significantincidence of febrile neutropenia.

CONTRAINDICATIONS

Neulasta® is contraindicated in patients with known hypersensitivity to E coli-derived proteins‚ pegfilgrastim‚ Filgrastim, or any other component of the product.

WARNINGS

General

The safety and efficacy of Neulasta® for peripheral blood progenitor cell (PBPC)mobilization has not been evaluated in adequate and well-controlled studies.Neulasta® should not be used for PBPC mobilization.

Splenic Rupture

SPLENIC RUPTURE, INCLUDING FATAL CASES, HAS BEEN REPORTEDFOLLOWING THE ADMINISTRATION OF NEULASTA® AND ITS PARENTCOMPOUND, FILGRASTIM. PATIENTS RECEIVING NEULASTA®

WHO REPORT LEFT UPPER ABDOMINAL AND/OR SHOULDER TIPPAIN SHOULD BE EVALUATED FOR AN ENLARGED SPLEEN ORSPLENIC RUPTURE.

Acute Respiratory Distress Syndrome (ARDS)

Acute respiratory distress syndrome (ARDS) has been reported in patients receivingNeulasta®, and is postulated to be secondary to an influx of neutrophils to sitesof inflammation in the lungs. Patients receiving Neulasta® who develop fever, lunginfiltrates, or respiratory distress should be evaluated for the possibility of ARDS.In the event that ARDS occurs, Neulasta® should be discontinued and/or withhelduntil resolution of ARDS and patients should receive appropriate medicalmanagement for this condition.

Allergic Reactions

Allergic reactions to Neulasta®, including anaphylaxis, skin rash, urticaria, anderythema/flushing have been reported in postmarketing experience. Themajority of reported events occurred upon initial exposure. In some cases,symptoms recurred with rechallenge, suggesting a causal relationship. In rarecases, allergic reactions including anaphylaxis, recurred within days after initialanti-allergic treatment was discontinued. If a serious allergic reaction occurs,appropriate therapy should be administered, with close patient follow-up overseveral days. Neulasta® should be permanently discontinued in patients withserious allergic reactions.

Sickle Cell Disorders

Severe sickle cell crises have been associated with the use of Neulasta® in patientswith sickle cell disorders. Severe sickle cell crises, in some cases resulting indeath, have also been associated with Filgrastim, the parent compound ofpegfilgrastim. Only physicians qualified by specialized training or experience in thetreatment of patients with sickle cell disorders should prescribe Neulasta® for suchpatients, and only after careful consideration of the potential risks and benefits.

PRECAUTIONS

General

Use With Chemotherapy and/or Radiation Therapy

Neulasta® should not be administered in the period between 14 days before and24 hours after administration of cytotoxic chemotherapy (see DOSAGE ANDADMINISTRATION) because of the potential for an increase in sensitivity ofrapidly dividing myeloid cells to cytotoxic chemotherapy.

The use of Neulasta® has not been studied in patients receiving chemotherapyassociated with delayed myelosuppression (eg, nitrosoureas, mitomycin C).

The administration of Neulasta® concomitantly with 5-fluorouracil or otherantimetabolites has not been evaluated in patients. Administration ofpegfilgrastim at 0, 1, and 3 days before 5-fluorouracil resulted in increasedmortality in mice; administration of pegfilgrastim 24 hours after 5-fluorouracildid not adversely affect survival.

The use of Neulasta® has not been studied in patients receiving radiation therapy.

Potential Effect on Malignant Cells

Pegfilgrastim is a growth factor that primarily stimulates neutrophils andneutrophil precursors; however, the G-CSF receptor through which pegfilgrastimand Filgrastim act has been found on tumor cell lines, including some myeloid,T-lymphoid, lung, head and neck, and bladder tumor cell lines. The possibilitythat pegfilgrastim can act as a growth factor for any tumor type cannot beexcluded. Use of Neulasta® in myeloid malignancies and myelodysplasia (MDS)has not been studied. In a randomized study comparing the effects of the parentcompound of Neulasta®, Filgrastim, to placebo in patients undergoing remissioninduction and consolidation chemotherapy for acute myeloid leukemia, importantdifferences in remission rate between the two arms were excluded. Disease-freesurvival and overall survival were comparable; however, the study was notdesigned to detect important differences in these endpoints.*

Information for Patients

Patients should be informed of the possible side effects of Neulasta® and beinstructed to report them to the prescribing physician. Patients should be informedof the signs and symptoms of allergic drug reactions and be advised of appropriateactions. Patients should be counseled on the importance of compliance withtheir Neulasta® treatment, including regular monitoring of blood counts.

If it is determined that a patient or caregiver can safely and effectively administerNeulasta® (pegfilgrastim) at home, appropriate instruction on the proper use ofNeulasta® (pegfilgrastim) should be provided for patients and their caregivers,including careful review of the “Information for Patients and Caregivers” insert.Patients and caregivers should be cautioned against the reuse of needles,syringes, or drug product, and be thoroughly instructed in their proper disposal.A puncture-resistant container for the disposal of used syringes and needlesshould be available.

Laboratory Monitoring

To assess a patient’s hematologic status and ability to tolerate myelosuppressivechemotherapy, a complete blood count and platelet count should be obtainedbefore chemotherapy is administered. Regular monitoring of hematocrit valueand platelet count is recommended.

Drug Interaction

No formal drug interaction studies between Neulasta® and other drugs have been performed. Drugs such as lithium may potentiate the release of neutrophils;patients receiving lithium and Neulasta® should have more frequent monitoringof neutrophil counts.

Increased hematopoietic activity of the bone marrow in response to growth factortherapy has been associated with transient positive bone imaging changes. Thisshould be considered when interpreting bone-imaging results.

Carcinogenesis, Mutagenesis, and Impairment of Fertility

No mutagenesis studies were conducted with pegfilgrastim. The carcinogenicpotential of pegfilgrastim has not been evaluated in long-term animal studies. In a toxicity study of 6 months duration in rats given once weekly subcutaneousinjections of up to 1000 mcg/kg of pegfilgrastim (approximately 23-fold higherthan the recommended human dose), no precancerous or cancerous lesionswere noted.

When administered once weekly via subcutaneous injections to male and femalerats at doses up to 1000 mcg/kg prior to, and during mating, reproductiveperformance, fertility, and sperm assessment parameters were not affected.

Pregnancy Category C

Pegfilgrastim has been shown to have adverse effects in pregnant rabbits whenadministered subcutaneously every other day during gestation at doses as low as 50 mcg/kg/dose (approximately 4-fold higher than the recommended humandose). Decreased maternal food consumption, accompanied by a decreasedmaternal body weight gain and decreased fetal body weights were observed at 50 to 1000 mcg/kg/dose. Pegfilgrastim doses of 200 and 250 mcg/kg/doseresulted in an increased incidence of abortions. Increased post-implantation lossdue to early resorptions was observed at doses of 200 to 1000 mcg/kg/dose, anddecreased numbers of live rabbit fetuses were observed at pegfilgrastim doses of200 to 1000 mcg/kg/dose, given every other day.

Subcutaneous injections of pegfilgrastim of up to 1000 mcg/kg/dose every other day during the period of organogenesis in rats were not associated with an embryotoxic or fetotoxic outcome. However, an increased incidence(compared to historical controls) of wavy ribs was observed in rat fetuses at1000 mcg/kg/dose every other day. Very low levels (< 0.5%) of pegfilgrastimcrossed the placenta when administered subcutaneously to pregnant rats everyother day during gestation.

Once weekly subcutaneous injections of pegfilgrastim to female rats from day 6 of gestation through day 18 of lactation at doses up to 1000 mcg/kg/dose didnot result in any adverse maternal effects. There were no deleterious effects onthe growth and development of the offspring and no adverse effects were foundupon assessment of fertility indices.

There are no adequate and well-controlled studies in pregnant women. Neulasta®

should be used during pregnancy only if the potential benefit to the motherjustifies the potential risk to the fetus.

Nursing Mothers

It is not known whether pegfilgrastim is excreted in human milk. Because manydrugs are excreted in human milk‚ caution should be exercised when Neulasta®

is administered to a nursing woman.

Pediatric Use

The safety and effectiveness of Neulasta® in pediatric patients have not beenestablished. The 6 mg fixed dose single-use syringe formulation should not be used in infants, children, and smaller adolescents weighing less than 45 kg.

Geriatric Use

Of the 932 patients with cancer who received Neulasta® in clinical studies, 139 (15%) were age 65 and over, and 18 (2%) were age 75 and over. No overalldifferences in safety or effectiveness were observed between patients age 65 andolder and younger patients.

ADVERSE REACTIONS

(See WARNINGS, Splenic Rupture, Acute Respiratory DistressSyndrome (ARDS), Allergic Reactions, and Sickle Cell Disorders.)

Clinical Trial Experience

Because clinical trials are conducted under widely varying conditions, adversereaction rates observed in the clinical trials of Neulasta® cannot be directlycompared to rates in the clinical trials of other drugs and may not reflect the ratesobserved in practice. The adverse reaction information from clinical trials does,however, provide a basis for identifying the adverse events that appear to berelated to Neulasta® use and for approximating rates.

The data described below reflect exposure to Neulasta® in 932 patients.Neulasta® was studied in placebo- and active-controlled trials (n = 467, and n = 465, respectively). The population encompassed an age range of 21 to 88 years. Ninety-two percent of patients were female. The ethnicity of the patientswas as follows: 75% Caucasian, 18% Hispanic, 5% Black, and 1% Asian.Patients with solid tumors (breast [n = 823], lung and thoracic tumors [n = 53])or lymphoma (n = 56) received Neulasta® after nonmyeloablative cytotoxicchemotherapy. Most patients received a single 100 mcg/kg (n = 259) or a single 6 mg (n = 546) dose per chemotherapy cycle over 4 cycles.

In the placebo-controlled trial, bone pain occurred at a higher incidence in Neulasta®-treated patients as compared to placebo-treated patients. Theincidence of other commonly reported adverse events were similar in theNeulasta®- and placebo-treated patients, and were consistent with the underlyingcancer diagnosis and its treatment with chemotherapy. The data in Table 1 reflectthose adverse events occurring in at least 10% of patients treated with Neulasta®

in the placebo-controlled study.

Table 1. Adverse Events Occurring in ≥10%a of Patients in the Placebo-Controlled Study

aEvents occurring in ≥10% of Neulasta®-treated patients and at a higher incidence

as compared to placebo-treated patientsbBone pain is limited to the specified adverse event term “bone pain”

EventNeulasta®

(n = 467)Placebo (n = 461)

Alopecia 48% 47%

Bone Painb 31% 26%

Diarrhea 29% 28%

Pyrexia (not includingfebrile neutropenia)

23% 22%

Myalgia 21% 18%

Headache 16% 14%

Arthralgia 16% 13%

Vomiting 13% 11%

Asthenia 13% 11%

Peripheral Edema 12% 10%

Constipation 10% 6%

In the active controlled studies, common adverse events occurred at similar ratesand severities in both treatment arms (Neulasta®, n = 465; Filgrastim, n = 331).These adverse experiences occurred at rates between 72% and 15% andincluded: nausea, fatigue, alopecia, diarrhea, vomiting, constipation, fever,anorexia, skeletal pain, headache, taste perversion, dyspepsia, myalgia,insomnia, abdominal pain, arthralgia, generalized weakness, peripheral edema,dizziness, granulocytopenia, stomatitis, mucositis, and neutropenic fever.

Bone Pain

The analysis of bone pain described below is based on a composite analysisusing multiple, related, adverse event terms.

In the placebo-controlled study, the incidence of bone pain was 57% inNeulasta®-treated patients compared to 50% in placebo-treated patients. Bone pain was generally reported to be of mild-to-moderate severity.

Among patients experiencing bone pain, approximately 37% of Neulasta®-and31% of placebo-treated patients utilized non-narcotic analgesics and 10% ofNeulasta®- and 9% of placebo-treated patients utilized narcotic analgesics.

In the active-controlled studies, the use of non-narcotic and narcotic analgesicsin association with bone pain was similar between Neulasta®-and Filgrastim-treated patients. No patient withdrew from study due to bone pain.

Laboratory Abnormalities

In clinical studies, leukocytosis (WBC counts > 100 x 109/L) was observed in less than 1% of 932 patients with nonmyeloid malignancies receivingNeulasta®. Leukocytosis was not associated with any adverse effects.

Immunogenicity

As with all therapeutic proteins, there is a potential for immunogenicity. Bindingantibodies to pegfilgrastim were detected using a BIAcore assay. The approximatelimit of detection for this assay is 500 ng/mL. Pre-existing binding antibodieswere detected in approximately 6% (51/849) of patients with metastatic breastcancer. Four of 521 pegfilgrastim-treated subjects who were negative at baselinedeveloped binding antibodies to pegfilgrastim following treatment. None of these 4patients had evidence of neutralizing antibodies detected using a cell-based bioassay.

The detection of antibody formation is highly dependent on the sensitivity andspecificity of the assay, and the observed incidence of antibody positivity in anassay may be influenced by several factors, including sample handling,concomitant medications, and underlying disease. Therefore, comparison of theincidence of antibodies to Neulasta® with the incidence of antibodies to otherproducts may be misleading.

Cytopenias resulting from a neutralizing antibody response to exogenous growthfactors have been reported on rare occasions in patients treated with otherrecombinant growth factors. There is a theoretical possibility that an antibodydirected against pegfilgrastim may cross-react with endogenous G-CSF, resultingin immune-mediated neutropenia. This has not been observed in clinical studiesof Neulasta®.

Postmarketing Experience

The following adverse reactions have been identified during postapproval ofNeulasta®. Because these reactions are reported voluntarily from a population ofuncertain size, it is not always possible to reliably estimate their frequency orestablish a causal relationship to drug exposure.

• splenic rupture (see WARNINGS: Splenic Rupture)

• acute respiratory distress syndrome (ARDS) (see WARNINGS: AcuteRespiratory Distress Syndrome)

• allergic reactions (including anaphylaxis, skin rash, urticaria,erythema/flushing) (see WARNINGS: Allergic Reactions)

• sickle cell crisis (see WARNINGS: Sickle Cell Disorders)

• injection site pain

• Sweet’s syndrome (acute febrile dermatosis)

OVERDOSAGE

The maximum amount of Neulasta® that can be safely administered in single or multiple doses has not been determined. Single subcutaneous doses of 300 mcg/kg have been administered to 8 healthy volunteers and 3 patients with non-small cell lung cancer without serious adverse effects. These patientsexperienced a mean maximum ANC of 55 x 109/L, with a corresponding meanmaximum WBC of 67 x 109/L. The absolute maximum ANC observed was 96 x109/L with a corresponding absolute maximum WBC observed of 120 x 109/L.The duration of leukocytosis ranged from 6 to 13 days. Leukapheresis should be considered in the management of symptomatic individuals.

DOSAGE AND ADMINISTRATION

The recommended dosage of Neulasta® is a single subcutaneous injection of 6 mg administered once per chemotherapy cycle. Neulasta® should not be administered in the period between 14 days before and 24 hours afteradministration of cytotoxic chemotherapy (see PRECAUTIONS).

The 6 mg fixed-dose formulation should not be used in infants, children, andsmaller adolescents weighing less than 45 kg.

No dosing adjustment is necessary for renal dysfunction.

Neulasta® should be visually inspected for discoloration and particulate matterbefore administration. Neulasta® should not be administered if discoloration orparticulates are observed.

Rx Only

This product, its production, and/or its use may be covered by one or more USPatents, including US Patent Nos. 5,824,784; 4,810,643; 4,999,291; 5,582,823;5,580,755, as well as other patents or patents pending.

REFERENCE

v.8 Issue Date: 10/2007

Manufactured by:Amgen Manufacturing, Limited, a subsidiary of Amgen Inc. One Amgen Center DriveThousand Oaks, CA 91320-1799©2002–2007 Amgen Inc. All rights reserved. MC40421

Start with support

*Heil G, Hoelzer D, Sanz MA, et al. A randomized, double-blind, placebo-controlled, phase III study of Filgrastim in remission induction and consolidationtherapy for adults with de novo Acute Myeloid Leukemia. Blood. 1997;90:4710-4718.

References: 1. Vogel C, et al. J Clin Oncol. 2005;23:1178-1184. 2. Neulasta® (pegfilgrastim) Prescribing Information. Thousand Oaks, Calif: Amgen.

Other drug transfer devices claim to be closed, but they lack the independent, clinical evidence to prove it. They claim to offer affordability,but their incompatibility with all drugs and vial sizes means you’ll pay more with inadequate coverage and drug waste. They claim familiar ease of use, but their wet connections guarantee exposure, even with perfect user form.

Strip away the claims and see for yourself what others have already confirmed. Ordinary lemon juice and litmus strips(or sodium bicarbonate and urine dipsticks) are all you need to conduct a simple pH test to determine the leakproof integrity of today’s available transfer devices. So take the test—and then demand the facts.

Backed by 14+ years of experience devoted solely to the development of our closed-system drug transfer device (CSTD) and supported by more than 10 independent, peer-reviewed, published clinical studies, we can factually state that our product offers clinically-proven,full spectrum protection. Can they?

Know You’re Safe With

Strip away the claims

See for yourself what othershave already confirmed

Spiros™ & Clave® by ICU Medical Inc. (Same connections also found on Genie™) B. Braun OnGuard™ Vial Adaptor & Syringe Adaptor by Teva Medical Ltd.

Alaris SmartSite® Vented Vial Access Device & Texium™ Male Luer by Cardinal Health PhaSeal® Protector & Injector Luer Lock by Carmel Pharma

Leakproof Connection Integrity TestAuthor: James Jorgenson, RPh, MS, FASHP, Executive Director, Pharmacy Services, Clarian Health Partners, Methodist Hospital, Indianapolis, IN

RESULTS: No leakage was observed after 10 manipulations with the PhaSeal System.Visible leakage occurred outside of the ICU Medical System, the B. Braun OnGuard™ System and the Cardinal Health/Alaris System during all manipulations.

Carmel Pharma, Inc. | 7029 Huntley Road | Suite O | Columbus, OH 43229Phone: 614-841-0504 | Toll Free: 866-487-9250 | Fax: 614-841-0525

E-mail: info@carmelpharmaUSA.com | www.carmelpharma.com

Find more information and evidence-based research at www.PhaSeal.com or call 866-487-9250

HE

MA

TO

LO

GIC

CA

NC

ER

SH

EM

AT

OL

OG

IC C

AN

CE

RS

12 GREEN HILL HEALTHCARE COMMUNICATIONS January/February 2009

Hematologic CancersUnraveling the Complexities of

Non-Hodgkin’s Lymphomas. Part 3Diagnostic Strategies for Determining the Extent of Disease

BY SANDRA E. KURTIN, RN, MS, AOCN, ANP-C

ARIZONA CANCER CENTER, UNIVERSITY OF ARIZONA, TUCSON

Successful treatment of non-Hodgkin’s lymphoma (NHL) isbased on a complete evaluation of

the disease, including location andextent of organ involvement, and anadequate tissue diagnosis. Prognosis forpatients with NHL varies widely, basedon the information obtained during the

diagnostic process. In addition, responsecriteria widely used for malignant lym-phomas include specific parameters forchanges in the measurable disease frombaseline following treatment.1 Accuratestaging of lymphoma presents a uniquechallenge as the disease may be localizedor diffuse and may involve any organ in

the body, making it difficult to differen-tiate it from other malignancies, infec-tions, or benign etiologies.2 Therefore, asystematic diagnostic process is criticalto making an accurate diagnosis.

Initial evaluationThe initial evaluation of a patient

suspected of having NHL includes acomplete history and physical examina-tion with particular attention to nodalsites, organomegaly, abdominal masses,and skin infiltrates. Complete laborato-ry analysis and selected imaging studies

Table. Imaging Strategies for Non-Hodgkin’s Lymphoma

Imaging method Advantages Disadvantages/Limitations Patient considerations

CT scan • Most commonly used • Decreased specificity for normal sized • Requires fasting 4 hours before

• Widespread availability and structures, slow-growing tumors, and lesions imaging of the abdomen or pelvis

reproducibility across scanners with poor contrast to surrounding structures • Oral contrast (taken 1 hour before

• Open scanner with short scanning • Not useful in detecting bone marrow scan) allows differentiation of the

times—patient friendly involvement bowel from surrounding structures

• Relatively low cost • Exposure to ionizing radiation—up to 25 mSv • IV contrast is used to define soft-

• Current standard of care for initial with neck, chest, abdomen, and pelvis tissue changes with some risk of

staging of NHL hypersensitivity and renal impairment

Patient requires screening for both

before use of IV contrast

PET scan • Ability to detect metabolic changes in • Role in initial diagnosis is not clear • Imaging obtained within 3 weeks of

areas involved with lymphoma that are • Limited value in indolent subtypes of NHL administration of granulocyte colony-

below CT criteria (< 1 cm) • Exposure to ionizing radiation— stimulating proteins will be difficult

• May be helpful in detecting a preferred 3.3 mSv to 7.6 mSv to interpret owing to diffuse uptake

site for tissue biopsy • CT component is used for localization in marrow-producing regions

• Persistently positive FDG-PET scans of FDG activity • Requires fasting 4 to 6 hours before

reported to correlate with an increased • Limited value in areas with high procedure

risk of relapse in DLBCL physiologic activity: brain, • Procedure starts 60 minutes after

• Provides useful information in myocardium, gastrointestinal tract, the injection of the FDG dose

treatment planning for local urinary tract, muscles, salivary glands • Hyperglycemia, intense physical

radiotherapy • Scanning time 30 to 40 minutes activity, active infection may interfere

with accuracy

PET/CT fusion • Provides higher resolution CT on the • Expensive • Preparation is similar to that for PET

same machine as the FDG-PET, • Radiation exposure is similar to that • Requires patient to lie still through-

allowing more exact anatomic and with CT scan (25 mSv) out procedure to reduce artifact

functional imaging • IV contrast is required for higher

resolution CT with similar risks

MRI • No radiation exposure • Not available to patients with • Requires long scanning time (up to

• Best method for soft-tissue contrast, implanted pacemakers, defibrillators, 60 minutes for total spine) in a

particularly for bone or muscle imaging pumps, or older Port-A-Caths narrow space with loud clicking

• Reduced risk of hypersensitivity • Not patient friendly—time and confinement noise difficult for patients with

• More limited availability and less uniformity claustrophobia, tremors, bowel or

in technique bladder control problems, or severe

• Higher cost pain

CT indicates computed tomography; DLBCL, diffuse large B-cell lymphoma; FDG, 18F-fluoro-2-deoxyglucose; IV, intravenous; MRI, magnetic resonance imaging; NHL, non-Hodgkin’s lymphoma; PET, positron emission tomography.

Sources: References 1 and 6 through 8.

Continued on page 30

Patient Support Coordinator ProgramA dedicated, central point of contact helping

providers and patients who rely on Celgene products

Trained professionals providing personal assistance concerning:

• Reimbursement assistance, insurance claims, and appeals

• Medicare Issues

• Locating co-pay assistance programs and services

• Identifying pharmacies that are registered to dispense Celgene products

• Determining the status of a prescription

• Inquiries regarding Celgene’s patient assistance program

• Providing information regarding Celgene products and their restricted distribution programs (RevAssist® or S.T.E.P.S.®) or appropriate contacts for other questions

© 2008 Celgene Corporation 07/08 CELG07002R7T

To contact a PSC:Call 1-800-931-8691Email patientsupport@celgene.comFax 1-800-822-2496www.CelgenePSC.com

Available to answer questions Monday – Friday from 8:00 AM to 7:00 PM ET

RevAssist® S.T.E.P.S.®, Patient Support Coordinator®, and PSC® are registered trademarks of Celgene Corporation.

JOIN the Academy of OncologyNurse Navigators and receive morethan $200 off future Annual Meeting registration for Full Members.

AONNAcademy of Oncology Nurse Navigators

AONN membership is for Oncology Nurses—AND all

Oncology Caregivers, including Nurse Navigators, Practice

Managers, and Nursing Administrators, devoted to the

complexities of the cancer care treatment continuum.

Information on patient care and treatment strategies, side

effect management, patient outreach and navigation programs,

and much more is thoroughly covered in AONN’s vast

resources of benefits.

AONN membership provides you with:

• A subscription to the journal,

The Oncology Nurse (TON)

(a $150 value), and the bimonthly

journal, Multidisciplinary

Cancer Care.

• Discounts on all AONN

educational programs, including

free continuing education

supplements, and more than $200

off future Annual Meeting registration

for Full Members.

• Discounts on all AONN education

materials, such as the Peer-Spectives web portal and all

educational supplements.

• Free patient brochures on a range of issues impacting

cancer patients (eg, Treatment Guidelines, CINV, Pain

Management, DVT, Chemotherapy Toxicities, Skin

Reactions, Reimbursement Information, Coding Updates)

will soon be available.

• A new website (to be launched in 2009) with enhanced

members-only sections with clinical resources, a special

section for educators, and continuing updates on grant

opportunities for researchers, in addition to AONN’s

searchable membership directory.

• Advocacy for initiatives to increase the number of

professionals entering the field of oncology; to provide fair

and adequate reimbursement for clinical services; and to

increase funding for research.

To become an AONN member, visitwww.theoncologynurse.com or www.coexm.com

and join while persuing the latest free CE offerings.

Not a member of the Academy of Oncology Nurse Navigators...AONN?

Join a network of individuals dedicated to enhancing the lives of Cancer Patients. Join AONN.

®$39.95

First Year

Membership

Free educational materials at www.COEXM.com

Ability to interact with your peers across the country

Free patient brochures covering

a variety of disease states

January/February 2009 GREEN HILL HEALTHCARE COMMUNICATIONS 15

CO

NF

ER

EN

CE

NE

WS

CO

NF

ER

EN

CE

NE

WS

SEATTLE—A program that involvescollaboration between advanced prac-tice nurses (APNs) and genetic coun-selors provides a model for providingeducation, genetic counseling and test-ing, and medical management for indi-gent patients with a suspected heredi-tary predisposition for breast cancer.

Oncology nurse practitioner WendyVogel set up the Breast CancerAwareness, Risk Assessment andEvaluation (Breast CARE) Programwith genetic counselor DeborahPencarinha in Tennessee that now ischanging breast care significantly intheir region of the country.

“It could be adopted at other cen-ters. There are few programs like oursin the country right now. Other nursepractitioners could partner with genet-ic counselors in their own communi-ties. We want people to know howthey can get funding and how success-ful you can be when you work collabo-ratively,” said Vogel, who presenteddata from this program at the 2008Oncology Nursing Society (ONS)Advanced Practice Nursing Con-ference and Institutes of Learning.

From 2006 until the present the pro-gram has provided education aboutbreast and ovarian cancer for morethan 10,340 healthcare providers,

high-risk individuals, indigent women,relatives, and community members inthe Kingsport, Tennessee, metropoli-tan area. Thirty-five patients havebeen seen in the Breast CARE clinic,and 18 have received free BRCAanalysis. A total of four BRCA carriershave so far been identified and fol-lowed. In addition, two patients haveenrolled in clinical trials, and threepatients received financial assistancefor treatments, such as tamoxifen.

“Preventative care is an area whereAPNs can partner with other clinicians,combining their individual areas ofexpertise, thus increasing their potentialimpact on health outcomes. Ultimately,it is our goal to help prevent breast can-cer deaths,” said Vogel in an interviewwith The Oncology Nurse. “When weidentify a genetic mutation, we aresearching for services, such as free or low-cost mammography or breast [magneticresonance] screening, even prophylacticsurgical services. We get them hooked upto the appropriate healthcare services forthe close follow-up and care they need.”

For this program, funding and supportwas secured from the Susan G. KomenFoundation for a Cure local affiliate, thelocal hospital system, and the countyhealth department. The Breast CAREClinic is held six times a year, and the

oncology APN provides risk assessment,physical examinations (including clini-cal breast examination), and educationabout self-breast examinations. Rec-ommendations are made for screeningand preventive care. In addition, refer-rals for free or low-cost screening exami-nations are given as well as help forobtaining free or low-cost tamoxifen asindicated. In some cases, help is given forobtaining free or low-cost prophylacticsurgery for breast and ovarian cancer.The genetic counselor examines a three-generation family history and makes arisk assessment, provides genetic coun-seling, and assists with genetic testing.The genetic testing is paid for by theBreast CARE program. When a muta-tion is found, the genetic counselorassists the patient with disclosing theresults to family members.

Much of the program is geared towardwomen who have been neglected in thepast. The Breast CARE Program pro-vides outreach to healthcare providers aswell as public education for rural com-munities, less educated patients, andhigh-risk ethnic populations. It also pro-vides a support group for patients andfamily members identified as high-riskbased on family history and geneticmutations.

“Genetic testing is very expensive.Many women can’t get it because theyare underinsured,” said Vogel, who is anoncology nurse practitioner at KingsportHematology/Oncology, Kingsport, Ten-nessee. “We need to raise communityawareness about this issue, and [APNs]are well suited to do this.”

—John Schieszer

Model Program Provides Breast Cancer Education, Counseling, and Treatment for High-risk, Indigent Patients

SEATTLE—Cancer patients with neu-ropathic symptoms appear to havehigher pain levels, suffer from painlonger, and have more difficulty per-forming their usual activities of dailyliving than do patients without neuro-pathic symptoms, according to re-searchers at the University of SouthFlorida.

“I have spent most of my career as achemotherapy nurse, and I have seenthis as a growing problem. I had a suspi-cion that neuropathic pain was more dif-ficult to control, and it is becoming morecommon as we use chemotherapy drugsthat are likely to cause peripheral neu-ropathy,” said study investigator CindyTofthagen, MSN, ARNP, who is aninstructor of nursing at the University ofSouth Florida, Tampa. “This is the firststudy to look at this specific patient pop-ulation in this way. It is an understudiedarea, and the more we find out about thedifferences between patients who haveneuropathic pain compared with othertypes of pain, it will help us to treatpatients more appropriately.”

Tofthagen, who presented the studyfindings at the 2008 Oncology NursingSociety (ONS) Advanced PracticeNursing Conference and Institutes ofLearning, said surgery, radiation, andchemotherapy are known to cause neu-

ropathic pain in cancer patients. It hasbeen thought that neuropathic pain ismore difficult to manage, but few stud-ies have investigated this issue thor-oughly in cancer patients.

The researchers used the Theory ofUnpleasant Symptoms as the theoreti-cal framework for this study. Tofthagensaid etiology is a physiological factor,and it directly influences the painexperience. In addition, it is well estab-lished that painful neuropathic symp-toms negatively influence physical per-formance and emotional well-being.To help better examine this issue incancer patients, the Florida researchersasked 170 outpatients with cancer painto complete the Brief Pain Inventory.

The patients were divided into twogroups: patients who described theirpain using at least one neuropathicdescriptor (burning, numbness, tin-gling, or electric-like) and patientswho did not use any neuropathicdescriptors. There were 75 patients inthe neuropathic group and 95 patientsin the other group.

The investigators found that pa-tients who used at least one neuropath-ic descriptor had significantly higherlevels of current pain, worst pain, andleast pain compared with thosepatients in the second group. In addi-

tion, pain interference with generalactivity, mood, walking ability, nor-mal work, relationships, and sleepwas significantly worse in the patientswith neuropathic symptoms. Thesepatients also were more likely todescribe their pain as continuous asopposed to intermittent. In addition,these patients had been in pain anaverage of 2.5 times longer than thosecancer patients who did not use neu-ropathic descriptors.

“Nurses should care about thisbecause we don’t have good treat-ments for neuropathic pain, and sowe need to look for better ways oftreating it and managing thesepatients,” said Tofthagen in aninterview with The Oncology Nurse.“Nurses should ask their patientsabout it…in order to know how it isimpacting their quality of life. Thatcan be the first step.”

She said an aggressive approachto neuropathic pain in cancer

patients can include medical manage-ment, a neurology referral, physicaltherapy, and occupational therapy.Tofthagen said more efforts are neededto better understand which interven-tions may be most effective in cancerpatients with neuropathic pain.

—John Schieszer

ONS CongressContinued from cover

Continued on page 16

Cancer Patients with Neuropathic Symptoms May Experience More Severe Pain than Patients without Neuropathic Symptoms

Pain interference with general activity,

mood, walking ability, normal work, rela-

tionships, and sleep was significantly worse

in the patients with neuropathic symptoms.

SEATTLE—Advanced practice nurses(APNs) working either independently orcollaboratively with psychiatrists may pro-vide cost-effective, timely access to psychi-atric/mental health services for oncologypatients, according to Texas researchers.

Depression and anxiety are commonamong oncology patients and can nega-tively affect drug efficacy and treatment

compliance and result in adverse metabol-ic changes. To address these issues, a psy-chiatry section was created in 1990 at theM. D. Anderson Cancer Center, whichprovides consultation/liaison services,without a dedicated psychiatry unit.

Mary K. Hughes, BS, MS, RN, CNS, ofthe University of Texas M. D. AndersonCancer Center, Houston, Texas, presented

an overview of the program’s success at the2008 Oncology Nursing Society (ONS)Advanced Practice Nursing Conferenceand Institutes of Learning. She said that attheir facility psychiatry is now a depart-ment made up of five APNs (three clinicalnurse specialists [CNSs] and two nursepractitioners [NPs]) and four psychiatrists.The APNs function both as independent

16 GREEN HILL HEALTHCARE COMMUNICATIONS January/February 2009

CO

NF

ER

EN

CE

NE

WS

CO

NF

ER

EN

CE

NE

WS

ONS CongressContinued from page 15

Advanced Practice Nurses Facilitate Mental Health Care for Oncology Patientstherapists and/or collaboratorswith the staff psychiatrists. Thegroup provides multimodal thera-py to both inpatients and outpa-tients. The five APNs evaluatepatients independently; however,they request medical psychiatricassessment and intervention whenwarranted. Because CNSs do nothave authority to prescribe med-ications, they mainly see outpa-tients. Conversely, the NPs main-ly see inpatients because theyhave the authority to prescribemedications.

“We found that the patients dobetter. The patients tend to beless anxious and more focusedand not so worried. We helpthem with their anxiety and theissues they are facing with theircancer. Sexual dysfunction is anissue, and substance abuse issuesmay also be involved. We havethree subspecialists who can tai-lor treatment for these issues,”said Hughes.

“By utilizing [APNs] in psychi-atry, it is possible to provide morepatients with access to psychi-atric care. Nurses are holistic,and we see patients as a wholeand are not focused on a specificcancer. We see how their canceraffects them emotionally, spiritu-ally, physically, and socially, andwe try to help the patients livebetter. Most patients are grievingbecause they have lost theirhealth, and this is different fromdepression. We help the patientidentify their losses and grieve,”said Hughes in an interview withThe Oncology Nurse.

Since 2003, each APN hasbeen able to bill for services in thehospital and in the outpatientclinic. Currently, the APNs seeapproximately 50% of all thepatients in the psychiatry depart-ment. She noted that outpatientconsults to psychiatry are nowseen within 7 days and inpatientsare seen within 24 hours, thanksto the availability of APNs.Hughes said the program hasworked so well that it may be anapproach that other centers acrossthe country want to adopt.

“The attending physicians maybe uncomfortable with patientswho cry a lot or are calling on thephone a lot. Then, they will refer[those patients] to the APNs whocan coordinate their psychiatriccare and treat them. We are thepoint people,” Hughes explained.“This program works very, verywell. Other hospitals may havedifferent models, but this modelis working quite well and it mayoffer some benefits that are notachieved with other programs.”

—John Schieszer

Which CSF is proven to help prevent early death*

by fighting fungal infections?

LEUKINEGoes beyond neutrophil recovery to reduce the incidence of fatal infections1,2

▲ Reduces the incidence of early death associated with fungal infections, including deaths

due to Aspergillus and Candida*1-3

▲ Reduces the incidence of life-threatening, severe, and fatal infections1,2

▲ Shortens time to neutrophil recovery1,2

▲ Adverse event profile similar to placebo1

*During and within 30 days of study completion.2

LEUKINE is indicated for use following induction chemotherapy in older adults with AML to shorten time to neutrophil recovery and to reduce the incidence of severe

and life-threatening infections and infections resulting in death.

Important Information

In controlled clinical trials across all indications, no significant differences were

observed between LEUKINE- and placebo-treated patients in the type or frequency

of adverse events with the exception of an increase in skin-associated events

in the LEUKINE group in the pivotal AML trial. There were occasional reports

of fluid retention, dyspnea, supraventricular tachycardia, and laboratory

abnormalities (increases in creatinine, bilirubin, and liver enzymes).

Other adverse events have been reported; please see full Prescribing

Information, which contains a more complete listing of indications,

contraindications, warnings, precautions, adverse events, and

dosage and administration guidelines.

Please see adjacent brief summary of full Prescribing Information.

LEUKINE

References: 1. LEUKINE® (sargramostim) [package insert]. Seattle, Wash: Bayer HealthCare Pharmaceuticals Inc.; 2007.2. Rowe JM, Rubin A, Mazza JJ, et al. Incidence of infections in adult patients (> 55 years) with acute myeloid leukemia treatedwith yeast-derived GM-CSF (sargramostim): results of a double-blind prospective study by the Eastern Cooperative Oncology Group. In: Hiddemann W, et al, eds. Acute Leukemias V: Experimental Approaches and Management of Refractory Diseases.Berlin, Germany: Springer-Verlag; 1996:178-184. 3. Rowe JM. Treatment of acute myeloid leukemia with cytokines: effect onduration of neutropenia and response to infections. Clin Infect Dis. 1998;26:1290-1294.

© 2007 Bayer HealthCare Pharmaceuticals Inc., Wayne, NJ 07470

All rights reserved. 561-10-0001-07B Printed in USA December 2007

For patients 55 years and

older with AML following

induction chemotherapy...

6701801BS (11981)Revision date 4/08US License 1791

Rx only

BRIEF SUMMARY

CONSULT PACKAGE INSERT FOR FULL PRESCRIBING INFORMATION

INDICATIONS AND USAGEUse Following Induction Chemotherapy in Acute Myelogenous Leukemia LEUKINE isindicated for use following induction chemotherapy in older adult patients with acute myelogenous leukemia(AML) to shorten time to neutrophil recovery and to reduce the incidence of severe and life-threateninginfections and infections resulting in death. The safety and efficacy of LEUKINE have not been assessed inpatients with AML under 55 years of age.

The term acute myelogenous leukemia, also referred to as acute non-lymphocytic leukemia (ANLL),encompasses a heterogeneous group of leukemias arising from various non-lymphoid cell lines which havebeen defined morphologically by the French-American-British (FAB) system of classification.Use in Mobilization and Following Transplantation of Autologous Peripheral BloodProgenitor Cells LEUKINE is indicated for the mobilization of hematopoietic progenitor cells intoperipheral blood for collection by leukapheresis. Mobilization allows for the collection of increased numbersof progenitor cells capable of engraftment as compared with collection without mobilization. Aftermyeloablative chemotherapy, the transplantation of an increased number of progenitor cells can lead to morerapid engraftment, which may result in a decreased need for supportive care. Myeloid reconstitution is furtheraccelerated by administration of LEUKINE following peripheral blood progenitor cell transplantation.Use in Myeloid Reconstitution After Autologous Bone Marrow Transplantation LEUKINE isindicated for acceleration of myeloid recovery in patients with non-Hodgkin’s lymphoma (NHL), acutelymphoblastic leukemia (ALL) and Hodgkin’s disease undergoing autologous bone marrow transplantation(BMT). After autologous BMT in patients with NHL, ALL, or Hodgkin’s disease, LEUKINE has been found tobe safe and effective in accelerating myeloid engraftment, decreasing median duration of antibioticadministration, reducing the median duration of infectious episodes and shortening the median duration ofhospitalization. Hematologic response to LEUKINE can be detected by complete blood count (CBC) withdifferential cell counts performed twice per week.Use in Myeloid Reconstitution After Allogeneic Bone Marrow Transplantation LEUKINE isindicated for acceleration of myeloid recovery in patients undergoing allogeneic BMT from HLA-matchedrelated donors. LEUKINE has been found to be safe and effective in accelerating myeloid engraftment,reducing the incidence of bacteremia and other culture positive infections, and shortening the medianduration of hospitalization.

Use in Bone Marrow Transplantation Failure or Engraftment Delay LEUKINE is indicated inpatients who have undergone allogeneic or autologous bone marrow transplantation (BMT) in whomengraftment is delayed or has failed. LEUKINE has been found to be safe and effective in prolonging survivalof patients who are experiencing graft failure or engraftment delay, in the presence or absence of infection,following autologous or allogeneic BMT. Survival benefit may be relatively greater in those patients whodemonstrate one or more of the following characteristics: autologous BMT failure or engraftment delay,no previous total body irradiation, malignancy other than leukemia or a multiple organ failure (MOF)score ≤ two (see CLINICAL EXPERIENCE). Hematologic response to LEUKINE can be detected bycomplete blood count (CBC) with differential performed twice per week.

CONTRAINDICATIONSLEUKINE is contraindicated:1) in patients with excessive leukemic myeloid blasts in the bone marrow or peripheral blood (≥ 10%);2) in patients with known hypersensitivity to GM-CSF, yeast-derived products or any component of the

product;3) for concomitant use with chemotherapy and radiotherapy.

Due to the potential sensitivity of rapidly dividing hematopoietic progenitor cells, LEUKINE should notbe administered simultaneously with cytotoxic chemotherapy or radiotherapy or within 24 hours precedingor following chemotherapy or radiotherapy. In one controlled study, patients with small cell lung cancerreceived LEUKINE and concurrent thoracic radiotherapy and chemotherapy or the identical radiotherapy andchemotherapy without LEUKINE. The patients randomized to LEUKINE had significantly higher incidence ofadverse events, including higher mortality and a higher incidence of grade 3 and 4 infections and grade 3and 4 thrombocytopenia.11

WARNINGSPediatric Use Benzyl alcohol is a constituent of liquid LEUKINE and Bacteriostatic Water for Injectiondiluent. Benzyl alcohol has been reported to be associated with a fatal “Gasping Syndrome” in prematureinfants. Liquid solutions containing benzyl alcohol (including liquid LEUKINE ) or lyophilizedLEUKINE reconstituted with Bacteriostatic Water for Injection, USP (0.9% benzyl alcohol)should not be administered to neonates (see PRECAUTIONS and DOSAGE ANDADMINISTRATION).Fluid Retention Edema, capillary leak syndrome, pleural and/or pericardial effusion have been reportedin patients after LEUKINE administration. In 156 patients enrolled in placebo-controlled studies usingLEUKINE at a dose of 250 mcg/m2/day by 2-hour IV infusion, the reported incidences of fluid retention(LEUKINE vs. placebo) were as follows: peripheral edema, 11% vs. 7%; pleural effusion, 1% vs. 0%; andpericardial effusion, 4% vs. 1%. Capillary leak syndrome was not observed in this limited number of studies;based on other uncontrolled studies and reports from users of marketed LEUKINE, the incidence is estimatedto be less than 1%. In patients with preexisting pleural and pericardial effusions, administration of LEUKINEmay aggravate fluid retention; however, fluid retention associated with or worsened by LEUKINE has beenreversible after interruption or dose reduction of LEUKINE with or without diuretic therapy. LEUKINE should beused with caution in patients with preexisting fluid retention, pulmonary infiltrates or congestive heart failure.

Respiratory Symptoms Sequestration of granulocytes in the pulmonary circulation has beendocumented following LEUKINE infusion12 and dyspnea has been reported occasionally in patients treatedwith LEUKINE. Special attention should be given to respiratory symptoms during or immediately followingLEUKINE infusion, especially in patients with preexisting lung disease. In patients displaying dyspnea duringLEUKINE administration, the rate of infusion should be reduced by half. If respiratory symptoms worsendespite infusion rate reduction, the infusion should be discontinued. Subsequent IV infusions may beadministered following the standard dose schedule with careful monitoring. LEUKINE should beadministered with caution in patients with hypoxia.

Cardiovascular Symptoms Occasional transient supraventricular arrhythmia has been reported inuncontrolled studies during LEUKINE administration, particularly in patients with a previous history ofcardiac arrhythmia. However, these arrhythmias have been reversible after discontinuation of LEUKINE.LEUKINE should be used with caution in patients with preexisting cardiac disease.

Renal and Hepatic Dysfunction In some patients with preexisting renal or hepatic dysfunction enrolledin uncontrolled clinical trials, administration of LEUKINE has induced elevation of serum creatinine orbilirubin and hepatic enzymes. Dose reduction or interruption of LEUKINE administration has resulted in adecrease to pretreatment values. However, in controlled clinical trials the incidences of renal and hepaticdysfunction were comparable between LEUKINE (250 mcg/m2/day by 2-hour IV infusion) and placebo-treated patients. Monitoring of renal and hepatic function in patients displaying renal or hepatic dysfunctionprior to initiation of treatment is recommended at least every other week during LEUKINE administration.

PRECAUTIONSGeneral Parenteral administration of recombinant proteins should be attended by appropriate precautionsin case an allergic or untoward reaction occurs. Serious allergic or anaphylactic reactions have beenreported. If any serious allergic or anaphylactic reaction occurs, LEUKINE therapy should immediately bediscontinued and appropriate therapy initiated.

A syndrome characterized by respiratory distress, hypoxia, flushing, hypotension, syncope, and/ortachycardia has been reported following the first administration of LEUKINE in a particular cycle. These signshave resolved with symptomatic treatment and usually do not recur with subsequent doses in the same cycleof treatment.

Stimulation of marrow precursors with LEUKINE may result in a rapid rise in white blood cell (WBC)count. If the ANC exceeds 20,000 cells/mm3 or if the platelet count exceeds 500,000/mm3, LEUKINEadministration should be interrupted or the dose reduced by half. The decision to reduce the dose or interrupttreatment should be based on the clinical condition of the patient. Excessive blood counts have returned tonormal or baseline levels within three to seven days following cessation of LEUKINE therapy. Twice weeklymonitoring of CBC with differential (including examination for the presence of blast cells) should beperformed to preclude development of excessive counts.

Growth Factor Potential LEUKINE is a growth factor that primarily stimulates normal myeloidprecursors. However, the possibility that LEUKINE can act as a growth factor for any tumor type, particularlymyeloid malignancies, cannot be excluded. Because of the possibility of tumor growth potentiation,precaution should be exercised when using this drug in any malignancy with myeloid characteristics.

Should disease progression be detected during LEUKINE treatment, LEUKINE therapy should bediscontinued.

LEUKINE has been administered to patients with myelodysplastic syndromes (MDS) in uncontrolledstudies without evidence of increased relapse rates.13, 14, 15 Controlled studies have not been performed inpatients with MDS.

Use in Patients Receiving Purged Bone Marrow LEUKINE is effective in accelerating myeloidrecovery in patients receiving bone marrow purged by anti-B lymphocyte monoclonal antibodies. Dataobtained from uncontrolled studies suggest that if in vitro marrow purging with chemical agents causes asignificant decrease in the number of responsive hematopoietic progenitors, the patient may not respond toLEUKINE. When the bone marrow purging process preserves a sufficient number of progenitors (>1.2 x104/kg), a beneficial effect of LEUKINE on myeloid engraftment has been reported.16

Use in Patients Previously Exposed to Intensive Chemotherapy/Radiotherapy In patients whobefore autologous BMT, have received extensive radiotherapy to hematopoietic sites for the treatment ofprimary disease in the abdomen or chest, or have been exposed to multiple myelotoxic agents (alkylatingagents, anthracycline antibiotics and antimetabolites), the effect of LEUKINE on myeloid reconstitution maybe limited.

Use in Patients with Malignancy Undergoing LEUKINE-Mobilized PBPC Collection Whenusing LEUKINE to mobilize PBPC, the limited in vitro data suggest that tumor cells may be released andreinfused into the patient in the leukapheresis product. The effect of reinfusion of tumor cells has not beenwell studied and the data are inconclusive.

Information for Patients LEUKINE should be used under the guidance and supervision of a health careprofessional. However, when the physician determines that LEUKINE may be used outside of the hospital oroffice setting, persons who will be administering LEUKINE should be instructed as to the proper dose, and themethod of reconstituting and administering LEUKINE (see DOSAGE AND ADMINISTRATION). If homeuse is prescribed, patients should be instructed in the importance of proper disposal and cautioned againstthe reuse of needles, syringes, drug product, and diluent. A puncture resistant container should be used bythe patient for the disposal of used needles.

Patients should be informed of the serious and most common adverse reactions associated withLEUKINE administration (see ADVERSE REACTIONS). Female patients of childbearing potentialshould be advised of the possible risks to the fetus of LEUKINE (see PRECAUTIONS, PregnancyCategory C).

Laboratory Monitoring LEUKINE can induce variable increases in WBC and/or platelet counts. In orderto avoid potential complications of excessive leukocytosis (WBC >50,000 cells/mm3; ANC >20,000cells/mm3), a CBC is recommended twice per week during LEUKINE therapy. Monitoring of renal and hepaticfunction in patients displaying renal or hepatic dysfunction prior to initiation of treatment is recommended atleast biweekly during LEUKINE administration. Body weight and hydration status should be carefullymonitored during LEUKINE administration.

Drug Interaction Interactions between LEUKINE and other drugs have not been fully evaluated. Drugswhich may potentiate the myeloproliferative effects of LEUKINE, such as lithium and corticosteroids, shouldbe used with caution.

Carcinogenesis, Mutagenesis, Impairment of Fertility Animal studies have not been conductedwith LEUKINE to evaluate the carcinogenic potential or the effect on fertility.

Pregnancy (Category C) Animal reproduction studies have not been conducted with LEUKINE. It is notknown whether LEUKINE can cause fetal harm when administered to a pregnant woman or can affectreproductive capability. LEUKINE should be given to a pregnant woman only if clearly needed.

Nursing Mothers It is not known whether LEUKINE is excreted in human milk. Because many drugs areexcreted in human milk, LEUKINE should be administered to a nursing woman only if clearly needed.

Pediatric Use Safety and effectiveness in pediatric patients have not been established; however, availablesafety data indicate that LEUKINE does not exhibit any greater toxicity in pediatric patients than in adults. Atotal of 124 pediatric subjects between the ages of 4 months and 18 years have been treated with LEUKINEin clinical trials at doses ranging from 60-1,000 mcg/m2/day intravenously and 4-1,500 mcg/m2/daysubcutaneously. In 53 pediatric patients enrolled in controlled studies at a dose of 250 mcg/m2/day by 2-hour IV infusion, the type and frequency of adverse events were comparable to those reported for the adultpopulation. Liquid solutions containing benzyl alcohol (including liquid LEUKINE ) orlyophilized LEUKINE reconstituted with Bacteriostatic Water for Injection, USP (0.9% benzylalcohol) should not be administered to neonates (see WARNINGS).

Geriatric Use In the clinical trials, experience in older patients (age ≥65 years), was limited to the acutemyelogenous leukemia (AML) study. Of the 52 patients treated with LEUKINE in this randomized study, 22patients were age 65-70 years and 30 patients were age 55-64 years. The number of placebo patients in eachage group were 13 and 33 patients respectively. This was not an adequate database from which determinationof differences in efficacy endpoints or safety assessments could be reliably made and this clinical study wasnot designed to evaluate difference between these two age groups. Analyses of general trends in safety andefficacy were undertaken and demonstrate similar patterns for older (65-70 yrs) vs younger patients (55-64yrs). Greater sensitivity of some older individuals cannot be ruled out.

ADVERSE REACTIONSAutologous and Allogeneic Bone Marrow Transplantation LEUKINE is generally well tolerated.In three placebo-controlled studies enrolling a total of 156 patients after autologous BMT or peripheral bloodprogenitor cell transplantation, events reported in at least 10% of patients who received IV LEUKINE orplacebo were as reported in Table 6.

No significant differences were observed between LEUKINE and placebo-treated patients in the type orfrequency of laboratory abnormalities, including renal and hepatic parameters. In some patients withpreexisting renal or hepatic dysfunction enrolled in uncontrolled clinical trials, administration of LEUKINEhas induced elevation of serum creatinine or bilirubin and hepatic enzymes (see WARNINGS). In addition,there was no significant difference in relapse rate and 24 month survival between the LEUKINE and placebo-treated patients.

In the placebo-controlled trial of 109 patients after allogeneic BMT, events reported in at least 10% ofpatients who received IV LEUKINE or placebo were as reported in Table 7.

There were no significant differences in the incidence or severity of GVHD, relapse rates and survivalbetween the LEUKINE and placebo-treated patients.

Adverse events observed for the patients treated with LEUKINE in the historically-controlled BMT failurestudy were similar to those reported in the placebo-controlled studies. In addition, headache (26%),pericardial effusion (25%), arthralgia (21%) and myalgia (18%) were also reported in patients treated withLEUKINE in the graft failure study.

In uncontrolled Phase I/II studies with LEUKINE in 215 patients, the most frequent adverse events werefever, asthenia, headache, bone pain, chills and myalgia. These systemic events were generally mild ormoderate and were usually prevented or reversed by the administration of analgesics and antipyretics suchas acetaminophen. In these uncontrolled trials, other infrequent events reported were dyspnea, peripheraledema, and rash.

Reports of events occurring with marketed LEUKINE include arrhythmia, fainting, eosinophilia, dizziness,hypotension, injection site reactions, pain (including abdominal, back, chest, and joint pain), tachycardia,thrombosis, and transient liver function abnormalities.

In patients with preexisting edema, capillary leak syndrome, pleural and/or pericardial effusion,administration of LEUKINE may aggravate fluid retention (see WARNINGS). Body weight and hydrationstatus should be carefully monitored during LEUKINE administration.

Adverse events observed in pediatric patients in controlled studies were comparable to those observed inadult patients.

Acute Myelogenous Leukemia Adverse events reported in at least 10% of patients who receivedLEUKINE or placebo were as reported in Table 8.

Nearly all patients reported leukopenia, thrombocytopenia and anemia. The frequency and type ofadverse events observed following induction were similar between LEUKINE and placebo groups. Theonly significant difference in the rates of these adverse events was an increase in skin associated eventsin the LEUKINE group (p=0.002). No significant differences were observed in laboratory results, renalor hepatic toxicity. No significant differences were observed between the LEUKINE and placebo-treatedpatients for adverse events following consolidation. There was no significant difference in response rateor relapse rate.

In a historically-controlled study of 86 patients with acute myelogenous leukemia (AML), theLEUKINE treated group exhibited an increased incidence of weight gain (p=0.007), low serum proteinsand prolonged prothrombin time (p=0.02) when compared to the control group. Two LEUKINE treatedpatients had progressive increase in circulating monocytes and promonocytes and blasts in the marrowwhich reversed when LEUKINE was discontinued. The historical control group exhibited an increasedincidence of cardiac events (p=0.018), liver function abnormalities (p=0.008), and neurocorticalhemorrhagic events (p=0.025).15

Antibody Formation Serum samples collected before and after LEUKINE treatment from 214 patientswith a variety of underlying diseases have been examined for immunogenicity based on the presence ofantibodies. Neutralizing antibodies were detected in five of 214 patients (2.3%) after receiving LEUKINE bycontinuous IV infusion (three patients) or subcutaneous injection (SC)(two patients) for 28 to 84 days inmultiple courses. All five patients had impaired hematopoiesis before the administration of LEUKINE andconsequently the effect of the development of anti-GM-CSF antibodies on normal hematopoiesis could notbe assessed. Antibody studies of 75 patients with Crohn’s disease receiving LEUKINE by subcutaneousinjection with normal hematopoiesis and no other immunosuppressive drugs showed one patient (1.3%)with detectable neutralizing antibodies. The clinical relevance of the presence of these antibodies areunknown. Drug-induced neutropenia, neutralization of endogenous GM-CSF activity and diminution of thetherapeutic effect of LEUKINE secondary to formation of neutralizing antibody remain a theoretical possibility.Serious allergic and anaphylactoid reactions have been reported with LEUKINE but the rate of occurrence ofantibodies in such patients has not been assessed.

Overdosage The maximum amount of LEUKINE that can be safely administered in single or multipledoses has not been determined. Doses up to 100 mcg/kg/day (4,000 mcg/m2/day or 16 times therecommended dose) were administered to four patients in a Phase I uncontrolled clinical study bycontinuous IV infusion for 7 to 18 days. Increases in WBC up to 200,000 cells/mm3 were observed. Adverseevents reported were dyspnea, malaise, nausea, fever, rash, sinus tachycardia, headache and chills. All theseevents were reversible after discontinuation of LEUKINE.

In case of overdosage, LEUKINE therapy should be discontinued and the patient carefully monitored forWBC increase and respiratory symptoms.

REFERENCES11. Bunn P, Crowley J, Kelly K, et al. Chemoradiotherapy with or without granulocyte-macrophage colony-

stimulating factor in the treatment of limited-stage small-cell lung cancer: a prospective phase IIIrandomized study of the southwest oncology group. JCO 1995; 13(7):1632-1641.

12. Herrmann F, Schulz G, Lindemann A, et al. Yeast-expressed granulocyte-macrophage colony-stimulating factor in cancer patients: A phase Ib clinical study. In Behring Institute ResearchCommunications, Colony Stimulating Factors-CSF. International Symposium, Garmisch-Partenkirchen,West Germany. 1988; 83:107-118.

13. Estey EH, Dixon D, Kantarjian H, et al. Treatment of poor-prognosis, newly diagnosed acute myeloidleukemia with Ara-C and recombinant human granulocyte-macrophage colony-stimulating factor. Blood1990; 75(9):1766-1769.

14. Vadhan-Raj S, Keating M, LeMaistre A, et al. Effects of recombinant human granulocyte-macrophagecolony-stimulating factor in patients with myelodysplastic syndromes. NEJM 1987; 317:1545-1552.

15. Buchner T, Hiddemann W, Koenigsmann M, et al. Recombinant human granulocyte-macrophage colonystimulating factor after chemotherapy in patients with acute myeloid leukemia at higher age or afterrelapse. Blood 1991; 78(5):1190-1197.

16. Blazar BR, Kersey JH, McGlave PB, et al. In vivo administration of recombinant humangranulocyte/macrophage colony-stimulating factor in acute lymphoblastic leukemia patients receivingpurged autografts. Blood 1989; 73(3):849-857.

© 2008, Bayer HealthCare Pharmaceuticals Inc. All rights reserved.

U.S. Patent Nos. 5,391,485; 5,393,870; and 5,229,496. Licensed under Research Corporation TechnologiesU.S. Patent No. 5,602,007, and under Novartis Corporation U.S. Patent Nos. 5,942,221; 5,908,763;5,895,646; 5,891,429; and 5,720,952.

Manufactured by:

Bayer HealthCare Pharmaceuticals, LLC.Seattle, WA 98101

US License No. 1791 6701801BS (11981) Revised April 2008

Percent of AuBMT Patients Reporting Events

LEUKINE PlaceboEvents by Body System (n=79) (n=77)

Body, GeneralFever 95 96Mucous membrane disorder 75 78Asthenia 66 51Malaise 57 51Sepsis 11 14Digestive SystemNausea 90 96Diarrhea 89 82Vomiting 85 90Anorexia 54 58GI disorder 37 47GI hemorrhage 27 33Stomatitis 24 29Liver damage 13 14Skin and AppendagesAlopecia 73 74Rash 44 38

LEUKINE PlaceboEvents by Body System (n=79) (n=77)

Metabolic, Nutritional DisorderEdema 34 35Peripheral edema 11 7Respiratory SystemDyspnea 28 31Lung disorder 20 23Hemic and Lymphatic SystemBlood dyscrasia 25 27Cardiovascular SystemHemorrhage 23 30Urogenital SystemUrinary tract disorder 14 13Kidney function abnormal 8 10Nervous SystemCNS disorder 11 16

Table 6

Percent of Allogeneic BMT Patients Reporting Events

LEUKINE PlaceboEvents by Body System (n=53) (n=56)

Body, GeneralFever 77 80Abdominal pain 38 23Headache 36 36Chills 25 20Pain 17 36Asthenia 17 20Chest pain 15 9Back pain 9 18Digestive SystemDiarrhea 81 66Nausea 70 66Vomiting 70 57Stomatitis 62 63Anorexia 51 57Dyspepsia 17 20Hematemesis 13 7Dysphagia 11 7GI hemorrhage 11 5Constipation 8 11Skin and AppendagesRash 70 73Alopecia 45 45Pruritis 23 13Musculo-skeletal SystemBone pain 21 5Arthralgia 11 4Special SensesEye hemorrhage 11 0Cardiovascular SystemHypertension 34 32Tachycardia 11 9

LEUKINE PlaceboEvents by Body System (n=53) (n=56)

Metabolic/Nutritional DisordersBilirubinemia 30 27Hyperglycemia 25 23Peripheral edema 15 21Increased creatinine 15 14Hypomagnesemia 15 9Increased SGPT 13 16Edema 13 11Increased alk. phosphatase 8 14Respiratory SystemPharyngitis 23 13Epistaxis 17 16Dyspnea 15 14Rhinitis 11 14Hemic and Lymphatic SystemThrombocytopenia 19 34Leukopenia 17 29Petechia 6 11Agranulocytosis 6 11Urogenital SystemHematuria 9 21Nervous SystemParesthesia 11 13Insomnia 11 9Anxiety 11 2Laboratory Abnormalities*High glucose 41 49Low albumin 27 36High BUN 23 17Low calcium 2 7High cholesterol 17 8

*Grade 3 and 4 laboratory abnormalities only. Denominators may vary due to missing laboratorymeasurements.

Table 7

Percent of AML Patients Reporting Events

LEUKINE PlaceboEvents by Body System (n=52) (n=47)

Body, GeneralFever (no infection) 81 74Infection 65 68Weight loss 37 28Weight gain 8 21Chills 19 26Allergy 12 15Sweats 6 13Digestive SystemNausea 58 55Liver 77 83Diarrhea 52 53Vomiting 46 34Stomatitis 42 43Anorexia 13 11Abdominal distention 4 13Skin and AppendagesSkin 77 45Alopecia 37 51

LEUKINE PlaceboEvents by Body System (n=52) (n=47)

Metabolic/Nutritional DisorderMetabolic 58 49Edema 25 23Respiratory SystemPulmonary 48 64Hemic and Lymphatic SystemCoagulation 19 21Cardiovascular SystemHemorrhage 29 43Hypertension 25 32Cardiac 23 32Hypotension 13 26Urogenital SystemGU 50 57Nervous SystemNeuro-clinical 42 53Neuro-motor 25 26Neuro-psych 15 26Neuro-sensory 6 11

Table 8

SAN ANTONIO—Breast cancer pa-tients who use topical moisturizers maybe exposing themselves to estrogenwithout knowing it, investigatorsreported at the 2008 San AntonioBreast Cancer Symposium.

Adrienne Olson, PharmD, withBreastlink in Long Beach, California,and her colleagues used high-perform-ance liquid chromatography to determinethe estrogen content of 16 popular over-the-counter (OTC) skin moisturizers.

“My research was prompted by myexperience during treatment for estro-gen receptor–positive breast cancer,”Olson explained in an interview. “I wasundergoing very heavy chemotherapy,and my skin had become very drybecause of menopause brought on bychemotherapy,” she said. “I startedapplying a rejuvenating cream to myface, which began to look like the faceof a 16-year-old. I strongly suspectedthat the product contained estrogenbecause only estrogen could restore theskin to such a youthful appearance.”

When she tested the OTC productsfor their estrogen content, she found thatfour samples contained > 0.40% estriol,one contained 0.17% estriol, and onecontained 0.05% estrone. However,none of the creams tested had listedestrogen among its ingredients.

“Until the late 1970s, intact epidermiswas generally considered to be a barrierto topically applied medications con-tained in creams and ointments,” Olson,

a 7-year breast cancer survivor, wrote inher poster presentation. The Food, Drug,and Cosmetic Act of 1938 “embraced”this concept, and, as a result, cosmeticlaw today is “largely enforced using thisoutdated idea as its basis.”

She was quick to add, however, thatthe skin is now known to be a porous,absorbing organ. “This is especially truewhen women have just taken a showeror bath, and the skin is hot and steamy,”she said. “This is the time when womenare likely to apply a moisturizer.”

Olson observed that topically ap-plied estrogens are more efficientlyabsorbed into the body than estrogensadministered orally because of thefirst-pass effect by the liver and addedthat estrogen receptor–positive breastcancer patients should avoid exoge-nously administered estrogen to mini-mize the risk of a recurrence. This isespecially important in women takingaromatase inhibitors because topicalestrogen may blunt the therapeuticeffect of these agents.

“Just as patients can make informedchoices regarding the use of hormonereplacement therapy, they should havethe right to make an informed choiceregarding the use of a moisturizer,”Olson said. “In order to make thatchoice, they need to know what themoisturizer contains. And for estrogenreceptor–positive patients, that meansa moisturizer free of estrogen and otherestrogen-active molecules.”

—Jill Stein

January/February 2009 GREEN HILL HEALTHCARE COMMUNICATIONS 19

BR

EA

ST

CA

NC

ER

BR

EA

ST

CA

NC

ER

Melanoma, the most deadly form ofskin cancer, arises from melano-

cytes, the pigment-producing cells of theskin. Melanoma is expected to be diag-nosed in approximately 62,480 individu-als (34,950 men and 27,530 women) andcause an estimated 8420 deaths in theUnited States in 2008.1,2 The incidence ofmelanoma is increasing faster than anyother malignancy. In 1935, an individ-ual’s lifetime risk for developing invasivemelanoma in this country was 1 in 1500;in 2010, this risk is projected to be 1 in 50.According to the World Health Organi-zation, approximately 132,000 melanomaskin cancers occur globally each year,and the incidence of melanoma isincreasing faster than any other malig-nancy worldwide.3-5

Approximately 80% of melanomas are

diagnosed at a localized stage and the 5-year survival rate associated with this formof the disease is about 99%.1 In contrast, the5-year survival rates for regional and dis-tant stages of the disease are much lower(65% and 15%, respectively).1 Patients diag-nosed with stage IV melanoma have verypoor prognoses and relatively few treat-ment options. These patients continue topose a significant challenge to clinicians.

Over the past decade, several novelagents have been developed for the treat-ment of metastatic melanoma. Encour-aging safety and efficacy results fromrecent clinical trials evaluating many ofthese therapies were presented at the 44thannual meeting of the American Society ofClinical Oncology (ASCO), held May 30-June 3, 2008, in Chicago, Illinois, and arehighlighted in this publication.

New Therapeutic Approachesto Metastatic Melanoma

September 2008 • Vol. 1 • No. 2

INTRODUCTION

© 2008 Center of Excellence Media, LLCCECre

dits

Offer

ed

PublisherPhilip Pawelko

phil@coexm.com

Editorial DirectorSusan Berry

susan@coexm.com

Copy EditorBonnie Nickel

Senior Production ManagerAlaina Pede

Directors of Client ServicesJohn W. Hennessyjohn@coexm.com

Russell Hennessyrussell@coexm.com

Circulation Departmentcirculation@coexm.com

Director of HumanResources

Blanche Marchitto

IN THIS ISSUE:

• Updates from the 44th Annual Meeting of the American

Society of Clinical Oncology

• Multidisciplinary Perspectives on Melanoma Treatment

LeAnn B. Norris, PharmD, BCPS

Sandra Beam, RN, BS, OCN, CCRC

Jointly sponsored by Medical Learning Institute, Inc. and Center of Excellence Media, LLC

Visit us at:

www.coexm.com

A Supplement to

Supported by

an educational grant from

Pfizer, Inc.

© 2008 Center of Excellence Media, LLC

MULTIDISCIPLINARY TEAM PRESENTATIONS BY

Dear Colleague:

It is my distinct pleasure to offer this newsletter entitled “Considerations in MultipleMyeloma: Hard-to-Treat Patients,” the third issue in a series of newsletters featuring top-ics relevant to your multidisciplinary team approach to caring for patients with multiplemyeloma (MM).

Together with a faculty of hematologists/oncologists, oncology nurses, and oncologypharmacists, we focus our discussion on one topic for each newsletter. While the previousissues focused on patients with renal dysfunction (another hard-to-treat population of MMpatients) and on treatment-naive patients, this issue discusses treatment of patients withrelapsed/refractory disease, as well as those with high-risk factors, including elderly patients,patients with abnormal cytogenetics, and those with elevated β2-microglobulin levels.Topics in upcoming issues will include health economics and side effect management.

It is our sincere hope that the information presented here is of value to you in your careof patients with MM.

Sincerely,

Sagar Lonial, MDAssociate Professor of Hematology and OncologyEmory University

Supported by aneducational grant from

Millennium

Pharmaceuticals, Inc.

LETTER TO OUR READERS

August 2008 • Volume 1 • Number 3

Editor in Chief

Sagar Lonial, MDEmory University

Jointly sponsored by CME Consultants and Center of Excellence Media.

CME/

CECr

edits

Offer

ed

Considerations inMultiple Myeloma:

Hard-to-Treat Patients

Shaji Kumar, MDMayo Clinic

Elizabeth Bilotti,MSN,APRN, BC,OCN®St Vincent’s Comprehensive Cancer Center

Kamakshi Rao, PharmD, BCOPUniversity of North Carolina Hospitals

www.coexm.com

FREE CE newslettersat www.COEXM.com

Interactive online presentations withpolling questions at www.COEXM.com

FREE CE newslettersat www.COEXM.com

Emerging Therapies forMyelodysplastic Syndromes

August 2008 • Vol. 1 • No. 1

A Supplement to

Myelodysplastic syndromes (MDS)are a group of blood disorders in

which the bone marrow does not func-tion properly and produces defectiveblood cells. These abnormal blood cellsusually die before they leave the bonemarrow or shortly after entering thebloodstream. As a result, patients withMDS have low blood cell counts, orcytopenias. Approximately 30% of pa-tients with MDS will progress to acutemyeloid leukemia (AML),1 a rapidly grow-ing cancer of bone marrow cells that is dif-ficult to treat and has a poor prognosis.

According to the American CancerSociety, an estimated 10,000 to 15,000new cases of MDS occur annually.1 Thenumber of new cases diagnosed eachyear is likely to increase in prevalence asthe elderly population continues to grow.About 80% to 90% of all patients with

MDS are older than 60 years; the condi-tion is rare in young adults.1

MDS can cause many different signsand symptoms. Most patients experiencecomplications of blood cell deficienciesthat cause a wide array of highly debilitat-ing symptoms. Many patients with MDSexperience severe, chronic anemia, requir-ing red blood cell (RBC) transfusions asfrequently as every 2 weeks. In addition todisrupting and diminishing quality of life,frequent transfusions are associated withan increased risk of iron overload, transfu-sion reactions, and infection from agentstransmitted through the transfusedblood.1,2 Leukopenia (especially neutrope-nia or granulocytopenia) can cause seri-ous infections with high fevers. Thrombo-cytopenia can cause excessive bruisingand bleeding, which can become life-threatening as the disease progresses.1,2

INTRODUCTION

Supported by

an educational grant from

Celgene Corporation

© 2008 Center of Excellence Media, LLCCECre

dits

Offer

ed

PublisherPhilip Pawelko

phil@coexm.com

Editorial DirectorSusan Berry

susan@coexm.com

Copy EditorBonnie Nickel

Senior Production ManagerAlaina Pede

Directors of Client ServicesJohn W. Hennessyjohn@coexm.com

Russell Hennessyrussell@coexm.com

Circulation Departmentcirculation@coexm.com

Director of HumanResources

Blanche Marchitto

IN THIS ISSUE:

• Updates from the 44th Annual Meeting of the American Society

of Clinical Oncology

• Nursing Strategies and Interventions for Managing Patients

with Myelodysplastic Syndromes

by Erin P. Demakos, RN, CCRC

Mount Sinai School of Medicine, New York, NY

Jointly sponsored by Medical Learning Institute, Inc. and Center of Excellence Media, LLC

Visit us at:

www.coexm.com

www.COEXM.com strives to provide the most up-to-date clinical information thatwill improve cancer care and outcomes for patients through specialty products,

across multimedia platforms, reaching multiple stakeholders and customers.

Current activities at www.COEXM.com include:• Considerations in Multiple Myeloma •Emerging Therapies for Myelodysplastic Syndromes

• New Therapeutic Approaches to Metastatic Melanoma • Skin Toxicities Associated with EGFR-

Inhibitor Therapy • Current and Future Perspectives on the Treatment of Colorectal Cancer

ON DEMANDFREE CONTINUING EDUCATION CREDITS

FREE • ACCREDITED • EVIDENCE-BASED • CLINICALLY RELEVANT • INSTANT CERTIFICATION

Registered participants will receive email announcementsas new educational activities become available.

The development of epidermal growthfactor receptor inhibitors (EGFRIs) has

expanded treatment options for patientswith cancer. Although these agents are gen-erally well tolerated, skin toxicities, includ-ing papulopustular rash, xerosis, pruritus,fissures, and hair and nail alterations, areoften associated with their use. Theseadverse events can affect patients bothphysically and psychosocially and may leadto dose reduction, interruption of therapy,or discontinuation of therapy. Therefore, thetimely and effective management of skin

toxicities related to treatment is imperativeto ensure consistent EGFRI administrationand maintenance of patient quality of life.

Oncology nurses who care for patientsreceiving EGFRI therapy must beequipped with practical strategies forassessing and managing toxicities relatedto treatment. This newsletter provides anoverview of the pathophysiology andclinical presentation of skin reactionsassociated with EGFRI therapy, as well ascurrent recommendations for gradingand treating these toxicities.

Effective Management Strategiesfor Skin Toxicities Associated WithEpidermal Growth Factor Receptor(EGFR)-Inhibitor Therapy

September 2008 • Vol. 1 • No. 3A Supplement to

INTRODUCTION

Supported by

an educational grant from

ImClone Systems

Incorporated

© 2008 Center of Excellence Media, LLCCECre

dits

Offer

ed

PublisherPhilip Pawelko

phil@coexm.com

Editorial DirectorSusan Berry

susan@coexm.com

Copy EditorBonnie Nickel

Senior Production ManagerAlaina Pede

Directors of Client ServicesJohn W. Hennessyjohn@coexm.com

Russell Hennessyrussell@coexm.com

Circulation Departmentcirculation@coexm.com

Director of HumanResources

Blanche Marchitto

IN THIS ISSUE:

• Updates from the 44th Annual Meeting of the American

Society of Clinical Oncology

• Management Strategies for Skin and Nail Toxicities

Pamela Hallquist Viale, RN, MS, CS, ANP, AOCNP

University of California, San Francisco

Laura Zitella, RN, MS, NP, AOCN®

Stanford University Medical Center

Jointly sponsored by Medical Learning Institute, Inc. and Center of Excellence Media, LLC

Visit us at:

www.coexm.com

REGISTER TODAY AT www.COEXM.com

Use of Skin Moisturizers May Expose Breast Cancer Patients to Estrogen

Breast Cancer

ObesityIncreases Risk

for ContralateralBreast Cancer

SAN ANTONIO—Obesity seems tobe a significant risk factor for the devel-opment of contralateral breast cancer,investigators from the Louisiana StateUniversity Health Sciences Center,Shreveport, announced at the 2008 SanAntonio Breast Cancer Symposium.

Marco Quispe, MD, and his col-leagues reviewed the electronic med-ical charts of patients with invasivebreast cancer over a recent 25-yearperiod. The analysis excluded patientswith stage IV disease at the time ofdiagnosis.

Of the 647 patients who were diag-nosed with invasive breast cancer, 72(11%) had recurrent intramammarybreast cancer, which was defined as anew diagnosis of invasive or in-situbreast cancer at least 6 months afterthe diagnosis of primary invasive

Continued on page 20

20 GREEN HILL HEALTHCARE COMMUNICATIONS January/February 2009

BR

EA

ST

CA

NC

ER

BR

EA

ST

CA

NC

ER

which patients would do better with ananthracycline or who may do well withan alternative regimen. One determin-ing factor may be a history or the pres-ence of heart disease, diminished car-diac function, or other risks for cardiacproblems.

William Gradishar, MD, professor ofmedicine at Northwestern Universityin Chicago, considers TCH an alterna-tive to a doxorubicin, cyclophos-phamide, docetaxel, trastuzumab com-bination (ACTH) for HER2-positivebreast cancer. “I don’t know that[TCH] is better, but it’s a perfectlyacceptable regimen,” he said, butnoted that clinicians have long experi-ence with anthracyclines, and the datafor TCH are more limited. “I thinkpeople feel comfortable with the toxic-ity profile of ACTH,” he noted, andtherefore continue to use it.

Mark Pegram, MD, professor ofmedical oncology in the BramanFamily Breast Cancer Institute at theUniversity of Miami in Florida, was adeveloper of the taxotere, carbo-platin, trastuzumab regimen for theadjuvant treatment of HER2-positiveearly breast cancer, which the USFood and Drug Administrationapproved on May 22, 2008, as thefirst taxane-based, nonanthracycline-containing chemotherapy regimen forthis indication.

“It’s a very, very active regimen inlocally advanced breast cancer,”Pegram told The Oncology Nurse. “Andbased on the BCIRG 006 adjuvantstudy, we know that it’s a very robustregimen and safer than an anthracy-cline-based regimen with trastuzumablong term in the adjuvant setting.” Thestudy showed that taxotere, carbo-platin, and trastuzumab withoutanthracycline was as efficacious as ananthracycline followed by trastuzumab.“So I think off-study [the taxotere, car-boplatin, trastuzumab combination] is

a perfectly acceptable standard regi-men at this point....The community atlarge in North America is using theregimen with increasing frequencysince probably the last year, year and ahalf,” Pegram estimated.

He said that a US Oncology trialshowed that docetaxel/cyclophos-phamide had superior efficacy to ananthracycline-based regimen. “So I feelcomfortable prescribing nonanthracy-cline regimens. Not everybody does.”

Pegram noted that topoisomerase IIalpha is the target of anthracyclines,and its expression is amplified onlywhen HER2 is overexpressed. “It’s real-ly the HER2-positive and ergo, TopoII-positive patient subset, that benefitsfrom anthracyclines [in adjuvant tri-als], and all others probably don’t,” hesaid. “And HER2-positive patients, aslong as they’re treated with trastuzu-mab, then you don’t need to give theman anthracycline.”

When TCH may be most useful

Although everyone takes the acutetoxicity of TCH seriously, the regimenmay be particularly useful in the treat-ment of bulky disease or when a fastresponse is desired. “I’ve used TCH inthe first-line setting for that group ofpatients—that is, high volume, organ-threatening metastatic breast cancerpreviously untreated,” said MarlonKleinman, MD, of Hematology/Oncology of the North Shore, a pri-vate group practice in Skokie, Illinois.In this setting, Dana Zakalik, MD, of

William Beaumont Hospital in RoyalOak, Michigan, said TCH did show asurvival advantage, “one of the fewregimens that showed that.”

Kleinman said TCH is also a reason-able regimen when there are cardiacrisks, “so I’m not invoking the risk ofan anthracycline by using TCH,although [trastuzumab] is not totallyinnocent regarding cardiac risk. So, Istill go through the routine of evaluat-ing [patients] from a cardiac perspec-tive with MUGA [multiple-gatedacquisition] scans, echo [cardiograms],[and] cardiology consults if necessary.”

Tatiana Prowell, MD, of the AvonFoundation Breast Cancer Center atJohns Hopkins University in Balti-more concurred. “We know that thebest predictors for anthracycline-induced cardiotoxicity are advancingage and pre-existing heart disease.Certainly for older patients in whomcardiac toxicity is a particular con-cern, TCH is an especially promisingregimen,” she said.

Development of less toxic regimensis definitely needed, Winer said. USOncology is conducting the TC-TACtrial, comparing regimens of docetaxeland cyclophosphamide with or withoutdoxorubicin for early-stage HER2-neg-ative breast cancer patients. And theNSABP B38 trial compares standarddoxorubicin doses with dose-densedoxorubicin in node-positive patients.A secondary end point of the trial istoxicity of the different regimens.

—Daniel M. Keller

Nonanthracycline RegimensContinued from cover

and three oncology nurses). Surveyparticipants were women aged 18 yearsor older with breast cancer who wereundergoing any chemotherapy or bio-logic therapy during a recent 12-month period at university- or commu-nity-based cancer clinics.

“Research has shown that duringtheir visit with oncologists, patientsconsistently identify prognosis andtreatment as important topics theywish to address,” West and her col-leagues wrote in their poster presenta-tion. “Despite a recent emphasis onproviding patients with more detailedinformation about their proposedtreatments, the literature suggests that20% to 50% of patients harbor miscon-

ceptions related to the therapeuticgoal.” Evidence also suggests thatproviders are largely unaware of thesemisunderstandings, they added.

In the present study, patients wereasked to predict the physician’s goal,physicians were asked to predict thepatient’s goal, and nurses were asked topredict the patient’s and physician’sgoals.

The results revealed that 36% ofpatients and physicians agreed on thegoal of chemotherapy. The physician’sperception of the patient’s goal wascorrect only 33% of the time, whereasthe nurse’s perception was correct 41%of the time.

When response categories were “col-

lapsed” into groups with similar broadtreatment intent (palliative vs cura-tive/ adjuvant), the level of agreementrose from 81% to 94%.

“Breast cancer patients actually havea very high uptake of informationthrough friends, the Internet, andother sources,” said West, who is nowwith Baylor College of Medicine inHouston, Texas. “In fact, when physi-cians initiate a discussion ofchemotherapy, patients are alreadyhighly knowledgeable. However, whilethey appear to be well informed as towhich side effects they might experi-ence and when they might experiencesuch effects, they seem to be ‘missingthe forest for the trees.’ In other words,

they don’t understand the broad goalsof chemotherapy.”

West added that the most importantgoal for providers is “not to cover them-selves by describing every possible sideeffect with patients” but instead toexplain specifically the goal the therapyaims to achieve. “After a discussion oftherapeutic goals, providers can thenexplain the risks and benefits of havingto experience such side effects in order toobtain treatment benefits,” she added.

She noted that future research inlarger, more diverse populations willhelp determine whether the findingsfrom this study are generalizable.

—Jill Stein

Providers/Patients Dispute Treatment GoalsContinued from cover

“Certainly for older patients in whomcardiac toxicity is a particular concern,TCH is an especially promising regimen.”

breast cancer. Of these cases, 28were ipsilateral and 44 were con-tralateral.

Patients with contralateral breastcancer were more likely to be obese(ie, body mass index > 30 kg/m2) atdiagnosis than patients with ipsilat-eral breast cancer (64% vs 25%; P =.001), to have a higher mean age atdiagnosis (51 vs 46 years; P = .04),and to have primary breast cancerwith estrogen receptor–positive sta-tus (67% vs 39%; P = .05).

The results showed that obesity atthe time primary invasive breast can-cer is diagnosed correlated with anincreased risk for contralateral breastcancer in both univariate and multi-variate analyses. The investigatorsalso found that for intramammaryoccurrence, obese women wereapproximately five times as likely todevelop contralateral breast cancercompared with nonobese women.

Several factors contribute to a poorprognosis in obese women with breastcancer, Quispe pointed out. For exam-ple, an obese patient is more likely tobe diagnosed at a later stage due to thedifficulty in identifying a palpablelesion in a larger breast. In addition,the treatment of breast cancer may beparticularly challenging because obesepatients have a higher rate of compli-cations from surgery and radiotherapy.Also, chemotherapy may be less effec-tive in obese women because of sys-temic undertreatment and alteredpharmacokinetics.

Finally, he said that additional stud-ies are needed to further define theimpact of obesity on breast canceroutcomes. The ability to define whichpatients are at increased risk for de-veloping contralateral breast cancerwill help better determine appropriateprevention strategies.

—Jill Stein

ObesityContinued from page 19

Finally in the treatment

of higher-risk MDS*…

* MDS, myelodysplastic syndromes; higher-risk MDS,

Intermediate-2- and High-risk MDS

per International Prognostic Scoring System (IPSS).

Please see Important Safety Information and Brief Summary of full Prescribing Information on following pages.

... A Breakthrough in

azacitidine for injection

Proven Results. Extended Survival.

Study 4, the Survival Study (AZA-001), was a phase 3, prospective, international, multicenter, randomized, controlled, parallel-group, non-crossover study of 358 adult (≥18 years) patients with

higher-risk MDS (IPSS Intermediate-2 or High), and FAB*-defined refractory anemia with excess blasts (RAEB), or RAEB in transformation (RAEB-T†), or dysplastic-type chronic myelomonocytic

leukemia (CMMoL), using modified FAB criteria. Patients were randomized to receive either VIDAZA (75 mg/m2 SC daily for 7 days each 28-day cycle) + best supportive care (BSC; transfusions,

antibiotics, G-CSF for neutropenic infection), or 1 of 3 conventional care regimens (CCR). CCR treatments included BSC alone; low-dose cytarabine (L-DAC; 20 mg/m2 SC daily for 14 days every 28 to 42

days); or 7+3 chemotherapy (induction with cytarabine 100-200 mg/m2/d by continuous IV infusion over 7 days plus an anthracycline days 1-3 [plus a maximum of 2 consolidation cycles]). CCR were

pre-selected by study investigators. The primary end point of the study was overall survival.1

VIDAZA® is indicated for treatment of patients with the following French-American-British (FAB) myelodysplastic syndrome subtypes: refractory anemia (RA) or refractory anemia with ringed sideroblasts (RARS) (if accompanied by neutropenia or thrombocytopenia or requiring transfusions), refractory anemia with excess blasts (RAEB), refractory anemia with excess blasts in transformation (RAEB-T), and chronic myelomonocytic leukemia (CMMoL).

Please see Important Safety Information and Brief Summary of full Prescribing Information on following pages.

* French-American-British classification for MDS.† Bone marrow blast count ≥20% is classified by the WHO as AML. The investigators in the Survival Study (AZA-001) classified RAEB-T as blasts 21%-29%.1

S U R V I V A L

VIDAZA nearly doubled the 2-year overall survival rate1

VIDAZA is the first and only agent proven to extend overall survival vsconventional care regimens (CCR) in patients with higher-risk MDS

Pro

po

rtio

nS

urv

ivin

g

Time (Months) From Randomization

15.0 months

24.5 months

CCR

VIDAZA

1.0

0.9

0.1

0.2

0.3

0.4

0.5

0.6

0.7

0.8

0.00 5 10 15 20 25 30 35 40

Log–Rank P=.0001

HR=0.58 (95% CI, 0.43–0.77)

Important Safety Information

s�6)$!:!�IS�CONTRAINDICATED�IN�PATIENTS�WITH�A�KNOWN�HYPERSENSITIVITY�TO�AZACITIDINE�OR�MANNITOL�AND�IN�PATIENTS�WITHADVANCED�MALIGNANT�HEPATIC�TUMORS

s�)N�3TUDIES���AND����THE�MOST�COMMONLY�OCCURRING�ADVERSE�REACTIONS�BY�3#�ROUTE�WERE�NAUSEA���������ANEMIA���������THROMBOCYTOPENIA���������VOMITING���������PYREXIA���������LEUKOPENIA���������DIARRHEA��������INJECTION�SITE�ERYTHEMA���������CONSTIPATION���������NEUTROPENIA���������AND�ECCHYMOSIS���������/THER�ADVERSE�REACTIONS�INCLUDED�DIZZINESS���������CHEST�PAIN���������FEBRILE�NEUTROPENIA���������MYALGIA���������INJECTION�SITE�REACTION���������AND�MALAISE���������)N�3TUDY����THE�MOST�COMMON�ADVERSE�REACTIONS�BY�)6�ROUTE�ALSO�INCLUDED�PETECHIAE���������WEAKNESS���������RIGORS���������AND�HYPOKALEMIA�������

s�)N�3TUDY����THE�MOST�COMMONLY�OCCURRING�ADVERSE�REACTIONS�WERE�THROMBOCYTOPENIA���������NEUTROPENIA��������ANEMIA���������CONSTIPATION���������NAUSEA���������INJECTION�SITE�ERYTHEMA���������AND�PYREXIA��������4HE�MOST�COMMONLY�OCCURRING�'RADE�����ADVERSE�REACTIONS�WERE�NEUTROPENIA���������THROMBOCYTOPENIA��������LEUKOPENIA���������ANEMIA���������AND�FEBRILE�NEUTROPENIA�������

s "ECAUSE�TREATMENT�WITH�6)$!:!�IS�ASSOCIATED�WITH�ANEMIA��NEUTROPENIA��AND�THROMBOCYTOPENIA��COMPLETE�BLOOD�COUNTSSHOULD�BE�PERFORMED�AS�NEEDED�TO�MONITOR�RESPONSE�AND�TOXICITY��BUT�AT�A�MINIMUM��PRIOR�TO�EACH�DOSING�CYCLE

s�"ECAUSE�AZACITIDINE�IS�POTENTIALLY�HEPATOTOXIC�IN�PATIENTS�WITH�SEVERE�PREEXISTING�HEPATIC�IMPAIRMENT��CAUTION�IS�NEEDED�IN�PATIENTS�WITH�LIVER�DISEASE��)N�ADDITION��AZACITIDINE�AND�ITS�METABOLITES�ARE�SUBSTANTIALLY�EXCRETED�BY�THE�KIDNEYS�AND�THE�RISK�OF�TOXIC�REACTIONS�TO�THIS�DRUG�MAY�BE�GREATER�IN�PATIENTS�WITH�IMPAIRED�RENAL�FUNCTION��"ECAUSE�ELDERLY�PATIENTS�ARE�MORE�LIKELY�TO�HAVE�DECREASED�RENAL�FUNCTION��IT�MAY�BE�USEFUL�TO�MONITOR�RENAL�FUNCTION

s�6)$!:!�MAY�CAUSE�FETAL�HARM�WHEN�ADMINISTERED�TO�A�PREGNANT�WOMAN��7OMEN�OF�CHILDBEARING�POTENTIAL�SHOULD�BE�APPRISED�OF�THE�POTENTIAL�HAZARD�TO�THE�FETUS��-EN�SHOULD�BE�ADVISED�NOT�TO�FATHER�A�CHILD�WHILE�RECEIVING�6)$!:!

s�.URSING�MOTHERS�SHOULD�BE�ADVISED�TO�DISCONTINUE�NURSING�OR�THE�DRUG��TAKING�INTO�CONSIDERATION�THE�IMPORTANCE�OF�THE�DRUG�TO�THE�MOTHER

0LEASE�SEE�"RIEF�3UMMARY�OF�FULL�0RESCRIBING)NFORMATION�ON�FOLLOWING�PAGES�

Reference: 1. $ATA�ON�FILE��#ELGENE�#ORPORATION�

6)$!:!® IS�A�REGISTERED�TRADEMARK�OF�#ELGENE�#ORPORATION�

©�����#ELGENE�#ORPORATION����������������������������6)$�����

There’s only VIDAZA®

VIDAZA significantly extended median overall survival vs CCR

s �����MONTHS�FOR�PATIENTS�ON�6)$!:!�VS����MONTHS�FOR�PATIENTS�ON�##2��P��������(2������;����#)������ ����=

VIDAZA nearly doubled the 2-year overall survival rate vs CCR

s ����SURVIVAL�FOR�6)$!:!�VS�����SURVIVAL�FOR�##2�;������DIFFERENCE������#)������ ����=�

Patients continued treatment until disease progression,

relapse after response, or unacceptable toxicity

s 4O�OPTIMIZE�PATIENT�BENEFIT��INVESTIGATORS�AIMED�TO�TREAT�PATIENTS�WITH�6)$!:!�FOR�AT�LEAST���CYCLES�

s 0ATIENTS�RECEIVING�6)$!:!�WERE�TREATED�FOR�A�MEDIAN�OF���CYCLES��RANGE�� ��

For proven survival in higher-risk MDS

azacitidine for injection

Proven Results. Extended Survival.T

������� ��� ����� ��� ����� ������� ������� � ���� ������ ����� �� ���� ��� ����� ��������� ��� �������� ������� ����������

� ����������� ��� �������� �������� ���� ������� ������������ ������� ��� ��������� �� ������ �� ��� ������� ��������������!�� � " �!#������� ��� �� ������� ������ $ ���������� ����� "%�# �� ���������� ����� �� ����� �������� � "� ���������� �� ���������� �� ��������������� �� ��&���� ���� �� �� #' ���������� ������ �� �(�� ��� � "%�)!#' ���������� ����� �� �(�� ��� � � ���� �������� "%�)!��#' ��������� ������������� ���*��� "+,,�-#�

����!������������ "� ��#���� $%�&�� '�( �� �)*��+������ ������������� � ������ �� ��.����� �������� ������ ����� ���� ����� �� �������� �������

", '-(��+��+� �#� - � ��� ����� �� $��� �%������ ������������� � ������ �� � *��� ����� �� �.�� �� �/������ �� ��������

. /�!����� ��� 0!���������."� ���*�1 ��) ��(��� �� �2��*3��- �(������������ �� ������ � ������ �� �����' ���������� ��� ���������������� +������������ ����� ����� �� ��������� � ������ �� ������ �� ��� � ��� ��(���' ��� �� � �����'���� �� ���� �� �� ������ ����� ���� ������ �� ��� ����������� �� ��� ��� ��� �� � �����' �� ������ �� �&���� ����� ����� �� ������� �� ������� �� �� �� ���� ����� ��� ���������� �� ��� ����� ������ �� ��������� ����� ���� �������� ���������

.", ��#��� 0���4�+ ��& '�( �� �*(��*�� !���� � �/������ ���������� ��������(� � ������ �� �.��� ����( ��� ������ ��������'������ ������ � ������ �� �.�� � �� �� 0����� �� �(��� .� ����� ������ ��� �� ���� ����� �� � ��.� ���� ������ �������� �� �(������� ������ .� ������ ���� ��� ����� ����� �/���������������' � ������� � ��� ������ �� �� ���� ������ 123 �4-� �/������ ������������� ������� �� ��.����� �������� ������ ����� ���� ���������� �!�"��� 5����� ��� ������.��� �� ������ � ������ �� ,�5 ��� ������ �������� ��.� ��� ���� ����� � ��� � ������ ����(������ ���� ��� ������ ���� �

."5 !��% �3���*%� ��+%���� ���������� ������ ���� ���.���� ���� �������� �� ����� ������ ��� ����� ��.� ������������ ������ � ������ ������� �� ����.���� �/������ � ��������� �� ����� ���������������� ����� ��� ���,�5 ������� � �� ������' ����� ������� ���� ' ������ � � ���� � �������������� �� 163 �)&4- � � ������ �� �� ��*���� ���� ��� ����*����� " ���� ���� ��12 �)&4-# ��.������ � 7 ������ �� +,- ������� �� �/������ ��� ����� ��� �� ���(�������������� � ���� ���������� 163 �)&4- �� ���.���� �� !89 �� ���� �������� �����' ����� ��� ����� �� ������� �� ���� ���� ������ �� ��������� ���!� ���� �������� ���������� 0����� �� ����� �������� ����� �� ��� ��� �������� ��� ��(��� ��� �/������ ��� � ��������� ��� ������� �(������ �� ��� *���� ���� ������ �� ��������� ���!# ���� ������������ ��������� 5����� ��� ������.��� �� ������ � ������ �� ,�5 ��� ����� ��������� ��.� ��� ���� ����� � ��� � ������ ��� �(������ ���� ��� ������ ���� �

." $��� ����& 63�� ��- ��+ ++������� ����� ����� ����� �� ��������� � ������ �� ������ �� ��� � ��� ��(���' ��� �� � ������' ���� �� ���� ������ -.�� ���� ��� ��� ���� �������� ����� �� ������� ���� �� �������� ��������

.". 0��&���-0��&���- � �&��- ������� ��� ��� � ����� ���� ��� ���� ����� �� � �������� ����� �/������ ��� �� �������������������� � ����� � :���� �� ���������� �������� ����� �� ��. �� �� �.�� �������������� ��������� �� ������� ����� ��� �� ���&���� ��� �������������� ���� � �������� ����� �� ������� �� �� ���� � �� ����� ��������� �� � � ������ ������ �������� ��� ��*�� �� ����' ��� ������ ����� �� ���� �� �� ��� �������� ��/��� �� ��� ���� ���� $�� %����� ��������� �&�"���

."7 �+� �� $%�+,�� ����� �� ��. �� �� ��� ������ � ���� ��� ����.�� ��������� �� ������� �� ����� ���� '������������� ��������� �� ���� ��� ��� ��� �� ����� � ����� �� ����������� �� � ����������� ���� '������ (�)�����* �"����

7 ����!�� !��������7"� �#��#��8��#��+� !�� ���+ ��+���3�� �� � 2�� 63�%��& ��� ���+9 �����' ����������' ���������������'���.���� ���� ��������' ����� ������' ����� ������� ���� ' ����*�����' ������ ���� ���� ������ �� �������� ���"# ���# ������

$�+ ��**��%- ���)����& ��#��+� !�� ���+ ��� �� �� !�) ��9 ��� ��' �����' ���������������'.�����' ����(�' ���*�����' �������' �;����� �� ��������' ��� ������' ����������' �������� � ��� �� � ������ ��.�� � ������� �� �� ����� �� � ������� ��������' ���� ' ��*�� �������*������

��#��+� !�� ���+ $�+ :��;)�� %- �<,=� !�+)% ��& �� �%����% �� ��#�� ��� ��� �� �� !�) ��9� ����������$ ���*�����' ���������������' ������������� � <���$ ���*�����' ����������' ���������������' ����(�' ��������' ������ ������������� � %������$ ���*�����' ����������' ����������������

7", ��#��+� !�� ���+ �� �%����% ���%+!���� � ������ ���� ��� ��������� ����� ���� .����� ������� ' ��.�� � ������� ���� �� ��.�� ���� ������ ���� �� � ���� ������ �� ������� �������� �� ���� � ��� ������ ���� �� ������� ���� ������ ��� ������� ��� ���� �� ��.�� � �������� ��� ���� �� ����� ���� ������� �(�� ��� �� ������ �==2 ,�5 ������ ���� = ������ ���� � 5���� > � � ������.������ ���������� ���� "5+ ���� �������#' 5���� 6 ��� 2 ��� ���� ��� ���� "��� �� 5+ ���� ������ ��� ��� �� �� ���� �������#' ��� 5���� = � �� ����������� ������/�� ���� "5+ ���� ������# ���� ���� %����� �"!��� ��5���� >' 6 ��� 2' � ����� �� 6?@ ������ ��� �(�� �� �� ������' ������� >>? �(�� �� ��� ? ����� "�����(������ ? ����� # �� ���� ��� ?3 �(�� �� ��� ������� ���� >6 ����� "�����(������ ��� ����#������� � ����� ������� � ������.������ ���������� ��� ������������ ���� "�A>73 ��� �A>>@'�� ����.���#� ��� ��������� � ��� ���������� ���� "�A663# � 62 �� B6 ���� ��� "���� ??�=���� #' ?@C ����' ��� B=C ���' ��� ��� ,�5 �� �,-� ��� ��������� � ��� �� ���� "�A=@# � 27 ��@> ���� ��� "���� ?2�> ���� #' ?7C����' ��� >33C���� ,� � ������ ����.�� �.����� ���� �� � ������ 73 ��� >33 ��4�6� �� 5���� =' � ����� �� >D7 ������ �� ������� * ,�5 "������� %�)! ���%�)!�� ������ # ��� �(�� �� �� ������� E� ��� � ������ ' >>B ��� �(�� �� ��� ? �� ���� ����� '��� ?2 ��� �� ��� � >6 ����� � ��� ���� ��� �� �� ��������� � ?@�> ���� "������ ���� =6 �� @2���� #' D=C ��� ����' ��� BBC ��� ���� ,� � ������ ����.�� ���� ������ �� � �� D7 ��4�6�

����� > ��� ��� ��.�� � ������� �������� � �� ��� � 7C �� ������ ������� �� ������ "5+# �5���� > ��� 6� �� �������� �� ���� ���� ������� �� �(�� ��� � ������ ��� ��� ������������������� ���� ��� ��� �� ��.���� �����$ ������ ����.�� ������ ��� � ���� �� >>�= ����� ������� ��� � ��� �� ��.���� ��� � ?�> ����� �

�3%� �9 $�+ :��;)�� %- �3+��#�� ��#��+� !�� ���+ ��.">= �� �%% �� ��������� �� 0 ��� +? � )���+ � �� ,�

�)*3�� �=� �� 0 ��� +

�-+ �* ��&� �%++ �%% ������3 �3+��# ����

0�������� ���* ��@,,>� ��@A,�

B%��� �� %-*(2 �� +-+ �* ��+�����+

����� >72 "?B�7# 7B "?=�>#

����� �����.���� >6 "7�7# 7 "7�=#

����� ���������� 2? ">?�=# = "=�2#

-��*����� >3? "=@�6# 6D "6B�2#

9��������� D> "26�2# >3 ">3�B#

��������������� >== "?7�7# =6 "=7�D#

�+ ���� �+ ��% ��+�����+

�������� �������� 6? ">>�@# > ">�>#

+�� ������ D= "22�?# ? "?�7#

������� @3 "2?�=# >2 ">=�>#

F��.�� ������� 6> "B�7# = "=�2#

-�� � ���� >6 "7�7# 3

,���� ���������� >> "7�3# > ">�>#

9�� �� >77 "D3�7# >? ">D�=#

5������ >D "D�D# 3

������ >>B "7=�># 7 "7�=#

�����% ��+�����+ �� �*���+ � ���+� � ����� ���+

+�� � ��� 2? ">?�=# 7 "7�=#

��;����� �� ��� �� 2> ">=�># 3

��;����� �� �������� DD "27�3# 3

��;����� �� ��������� >> "7�3# 3

��;����� �� ��� 73 "66�D# 3

��;����� �� ���������� ������ >> "7�3# 3

��;����� �� ������ >7 "?�@# 3

��;����� �� ������� 23 ">2�?# 3

��;����� �� ����� >> "7�3# 3

-������� >D "D�D# 6 "6�6#

,��� � 6= ">3�B# > ">�>#

0���(� >>= "7>�@# 6@ "23�=#

����� ���+ �� ����+ ���+

9� ��������� 26 ">=�7# 2 "2�2#

0������� 6= ">3�B# 7 "7�=#

8���� �� ������� ����� ������� 6@ ">6�D# = "=�2#

���)�-1 (��+����&1 �� (�����)�%��*(%�� ���+

0� � ���������� ���������� >2 "7�B# > ">�>#

$� 3�%�+* �� �) �� ��� ��+�����+

�����(� =7 "63�7# ? "?�7#

$)+�)%�+C�%� % �� ������ �#� �++)���+�����+

��������� =B "66�2# 2 "2�2#

+�� � ��� ��� >> "7�3# 3

,����� 27 ">7�B# 6 "6�6#

���#�)+ +-+ �* ��+�����+

�//�� => ">@�?# 7 "7�=#

<������� =@ "6>�@# >3 ">3�B#

0+-�2� ��� ��+�����+

��(��� 6B ">2�6# 2 "2�2#

�� ���� 6= ">3�B# = "=�2#

!�+(�� ��-1 2����� �� *���+ ��%��+�����+

�� ���� ?= "6B�># >> ">6�3#

�C�� �� +)3�) ���)+ �++)� ��+�����+

��� *� >> "7�3# > ">�>#

)������ ?D "23�7# >= ">7�6#

)������� 2D ">?�@# = "=�2#

%� � 2> ">=�># B "B�@#

5*� ������ >> "7�3# > ">�>#

8������ >2 "7�B# > ">�>#

�+�)%� ��+�����+

<������� >B "@�?# 3

<������ �� >7 "?�@# 6 "6�6#

0������� 76 "62�?# @ "@�D#

� ,������ ���� �� ��� ��� ��������� ���� ��� � ������ ��� ���� ������� ���� ��� ���� ���������������

� ������� ��.�� � ������� ���� ��� ������ �(�� �� �� ������' ������� ������ ����� ��� �� �.������ �� ��.���� �

� ������� ��.�� � ������� ���� �� ��.���� ����� ����� �(����� ��� ��.�� � �.��� ����� ��� �.���� �������

����� 6 ��� ��� ��.�� � ������� �������� � �� ��� � 7C �� ������ ������� �� ������ �5���� =� 5���� �� 5���� > ��� 6 �� ����� ���.�' ������� �� �(�� ��� �� ��������� �� ������� ������ "���� >6�6 ����� # �������� �� �� � ������.� ���� "���� D�7 ����� #�

�3%� ,9 $�+ :��;)�� %- �3+��#�� ��#��+� !�� ���+ ��.">= �� 2� ������

��� �� 0 ��� + �� 2� 0����� &� 8� 2 ��� ��� ���� 5D !�� ���+? � )�- �

�)*3�� �=� �� 0 ��� +

��- ���� ���� 5D

B�+ B�+ �)((�� �#� �)((�� �#�

�-+ �* ��&� �%++ ������ ��� ��%- ������ ��� ��%-0�������� ���* ��@�E.� ��@�>,� ��@�E.� ��@�>,�

B%��� �� %-*(2 �� +-+ �*��+�����+

����� B3 "7>�=# =7 "==�># 6= ">2�D# B "@�@#

����� ���������� 6= ">2�D# >3 "B�@# 66 ">6�?# D "?�B#

-��*����� 26 ">@�2# 6 "6�3# 6? ">=�B# > ">�3#

9��������� >>7 "?7�D# 6B "6@�=# >3D "?>�># 66 "6>�?#

��������������� >66 "?B�D# 27 "2=�2# >36 "7@�2# 6B "6@�=#

�+ ���� �+ ��% ��+�����+

�������� ��� 66 ">6�?# D "?�B# D "=�3# 3

+�� ������ @@ "73�2# @ "D�@# 6 ">�># 3

�� ��� � >3 "7�D# 6 "6�3# 3 3

9�� �� @= "=@�3# >6 ">>�@# 2 ">�D# 3

������ =D "6?�B# D "?�B# 3 3

�����% ��+�����+ ���*���+ � ��� +� � ����� ���+

����� =6 "6=�3# >6 ">>�@# ? "2�=# 6 "6�3#

��;����� �� ��� �� B "7�># 3 3 3

��;����� �� �������� D7 "=6�B# 3 3 3

��;����� �� �������� >> "?�2# 3 3 3

��;����� �� �������� B "7�># 3 3 3

��;����� �� ��� 22 ">@�B# 3 3 3

��;����� �� �� � >3 "7�D# 3 3 3

��;����� �� ������� 7> "6B�># 3 > "3�?# 3

0���(� 72 "23�2# >@ ">D�?# @ "=�?# > ">�3#

����� ���+ �� ����+ ���+

%��� >3 "7�D# > ">�3# 3 3

8���� �� ������� �����

������� >? "B�># = "2�B# 2 ">�D# 3

8����� ����� ������� >7 "@�?# 2 "6�B# 2 ">�D# 3

��#�+ �& ���+

:���� ������ �� >= "@�3# 3 > "3�?# 3

$� 3�%�+* �� �) �� �����+�����+

<���*����� >> "?�2# 2 "6�B# 2 ">�D# 2 "6�B#

���#�)+ +-+ �* ��+�����+

-������� >2 "D�=# 6 "6�3# 3 > ">�3#

0+-�2� ��� ��+�����+

��(��� B "7�># > ">�3# 3 3

�� ���� >7 "@�?# 2 "6�B# 3 3

!��% �� )����- ��+�����+

<������� >> "?�2# 6 "6�3# = "6�2# > ">�3#

!�+(�� ��-1 2����� ��*���+ ��% ��+�����+

�� ���� 6? ">=�B# 7 "=�B# ? "2�=# 6 "6�3#

�� ���� �(������� B "7�># > ">�3# 3 3

0���������������� ��� >> "?�2# 2 "6�B# 3 3

�C�� �� +)3�) ���)+ �++)���+�����+

)������� >2 "D�=# 2 "6�B# 3 3

0������� 63 ">>�=# = "2�B# 6 ">�># 3

0����� 6> ">6�3# 6 "6�3# 3 3

%� � >@ ">3�2# > ">�3# 3 3

�+�)%� ��+�����+

<������� �� >7 "@�?# = "2�B# 6 ">�># 6 "6�3#

� ,������ ������ �� ��� ��� ��������� ���� ���� � ������ ��� ���� ������� ���� ��� ���� ����������

�� 5���� >' 6 ��� = �� 5+ ���� ������ �� ������' ��.�� � ������� �� ����������' ������������

����' �����' ��� ��' .�����' �������' ��� ������' ��� �;����� �� ��������4������� ������ ��

����� � � ������� �� ����� �� � �� ������� ��.�� � ������� ���� ������ �� �� ���� ����

������� ����� ��� �� � > �� 6 ����� �� 5+ ��������� �������� �� ����� ����� ������� ������������

����' ����������' �����' ��� ��' .�����' �;����� �� ��������4���4��� ��4�������' ��� ������'

��������' �//�� ' ��(���' ����*�����' ��� � ����� ����� �� ��� ������ �� �� ��� ��.�� �

������� ���� ����� �� � ���&����� �.�� ��� ���� � �� ����������

E.�����' ��.�� � ������� ��� &������.��� ���� ������ ��� �� ��� 5+ ���� � ��.�� � �������

���� �������� �� �� ��������� � ������ �� ��� �� ����� �� ���� ������ ������� ��� �� ��

������� "����' �������� �� ���# ��� �������� �� ������� "����' �������' ��������' �� ����������#�

�� ������ ���� �� ����� 5+ �� �� ������' ��� ������� ���� ��.�� � ������� �������� �� �

���� �� 1 7C "��� ��� �� ����� � ����� > �� 6# ��� ��������$

B%��� �� %-*(2 �� +-+ �* ��+�����+9 ������������ ' ���� ����� ������' �����������'

������������ ����� ��+�����+9 ����� ���������' ������ ������' ������ ������ ����� �.�' ������

�� ������� ���� �' ����� �.� �������������� �-� ��+�����+9 ��� ����������� �+ ���� �+ ��% ��+������+9 �.������� ' �� ������ ���� ����������' ������' ��������� �� �� � �����% ��+�����+ ���*���+ � ��� +� � ����� ���+9 �������� �� ����������' ������� ��� ��� ������ �����������' � �

���� ����������� �� ��� � �������� '�( �3�%��- ��+�����+9 ������� �� � �**)�� +-+ �* ��+������+9 ����������� ���*' ����� �� �.��� ����� ���+ �� ����+ ���+9 �� �� ���' �������� �������'

������� ' ��� ������ ' �;����� �� �������' G��� ���� �� ' ���������� �� ' ��������

������������' �������� G��� ����' �� ' ���� ���*' 5������������� ���������' 5�������������

�������' ��(���� �� � $� 3�%�+* �� �) �� ��� ��+�����+9 �����������$)+�)%�+C�%� % �������� �#� �++)� ��+�����+9 ���� ��� �����.����' �� ��� ��*�� ' ���* ���� ���(%+*+ 3���&�1*%�&�� �� )�+(�������9 ���*��� ��� � ���#�)+ +-+ �* ��+�����+9 �������� ����������' ����

.�� �� ' ���������� ����������� !��% �� )����- ��+�����+9 ��� ���' ����� ������� !�+(�� ��-1 2����� �� *���+ ��% ��+�����+9 ������� ' ���� ���������' �������� ' �� ������� � ��� �

�C�� �� +)3�) ���)+ �++)� ��+�����+9 �������� �������� ��' �� � ������' *� ���������

�)�&��% �� *����% (�����)��+9 ������� �������� �+�)%� ��+�����+9 ����� ���� ������� ���

7"5 0�+ *�C� ��& �4(���������.�� � ������� ������� ���� ��������� ������ ��.� ���� ���� �� ��� � �������� �����

������ ���� �� �������

E �!�� ����!�������9� ������ � � ���� �� ��������� ��������� ������ ������ ��� ����� ����� ��.� ���� ����

������ ���� ���� +���������* �"���� �+� ���� �������� ���������

F ��� �� �0���:�� 0�0�6������F"� 0��&���-0��&���- � �&��- ������� ��� ��� � ����� ���� ��� ���� ����� �� � �������� ����� �/������ � ���������� �

����� � :���� �� ���������� �������� ����� �� ��. �� �� �.�� ��������� ����� ���������

�� ������� �� �� ���� � �� ����� ��������� �� � � ������ ������ �������� ��� ��*�� ��

����' ��� ������ ����� �� ���� �� �� ��� �������� ��/��� �� ��� ���� � ����� ������� �� ����

������ ����.�� ������ ����� ��� ������ �������� ���� '������ (�)�����* �"����

)���� ��������(��� ���� � ��� ��.����� � ==C ���&����� �� ���������� ��������� �����

"����� �� �� ������# ����� � ���� �0 "�������������# �;����� �� ? ��4�6 "�����(������ @C ��

��� ����������� ����� ���� �� � �� � ��4�6 �� # �/������ �� �� ����� ��� >3� ��.��������

��� ���������� � ��� ���� ��.� ���� �������� � ��� �.�� �/������ �� �� ������ �� �����

��� >7 �� �� � �� H2�>6 ��4�6 "�����(������ =C�>?C ��� ����������� ����� ���� �� � �� �

��4�6 �� #� �� ��� ' �/������ � ������� ��������(� ��� �.�� �0 �� �� ����� ��� =�@

"�� �����������# �� � �� � �� ? ��4�6 "�����(������ @C �� ��� ����������� ����� ���� �� �

�� � ��4�6 �� #' �������� ��������� � ��� ������������� ����� "�� �� ����� ��� >�2# ��� ��

��.�� � ������ �� ��� ������ � �/������ ��� �� ������� ����� ���������� � ��� ����� � ���� �0

�� � �� 2 �� >6 ��4�6 "�����(������ @C ��� ����������� ����� ���� �� � �� � ��4�6 �� #

�.�� �� �� ����� ��� B' >3' >> �� >6� �� �� ���� �/������ ��� �� ����� ����� ��� ���� �����

�� 2�>6 ��4�6 �� �� ����� ��� B ��� >3� �.����� �.� ����� ��� ����� � ������� �� BC �� �������

�� ��� ���� � �� � �� �� ����� ��� B� ���� ������� �������$ +95 ������� "�(���������4

�������������#' ��� ������� "��������' ���� ����' ���������' �����������#' ��� ����� "�����

������' �� ��� �� ' �����' ��� �� ���������� #�

F"5 �)�+��& $� 2��+�� ��� *��� ������ �/������ �� � ��������� ��� �(������ � ����� ��*� !���� � �� ���

�������� ��� ����������� ��� ��� �/������ � ����� ���� ��� ��� �������� ��� ����

��.�� � ������� � ��� �� ����� ' � ��� �� ����� �� ���� ������ �� � ������� ��� �� �� ��

� ������� ��� ����' ��*�� ��� ��� ������� ��� ��������� �� ��� ���� �� ��� �������

F" 0��� ��� �+�5����� ��� ������.��� � ������� ������ ��.� ��� ���� � ���� ����

F". ���� ��� �+�E� ��� ����� ������ �� ������ � 5���� >' 6 ��� 2' ?6C ��� ?7 ���� ��� ����� ��� 6>C ��� D7

���� ��� ������ 9� �.����� ��������� � ������.��� ��� �� ��.�� ������ ��� � ������ ���

������� ������ � �� ������ ����� ��� �� ����.��� ��������� � ��� ���&����� �� ��.�� � �������

�� ��.�� � ������ ?7 ���� ��� ����� �������� �� ������� ������ � E� ��� >DB ������ ������/��

�� �/������ � 5���� =' ?@C ��� ?7 ���� ��� ����� ��� 6>C ��� D7 ���� ��� ������ 5��..�� ����

��� ������ ?7 ���� ��� ����� ��� ��� ���� �� �.����� ��..�� �� ��� � ��� ��;���� �� ��.�� �

������� �������� �� ���� ���&����� � ������ 1 ?7 ���� �� ��� ��� ������ ?7 ���� �� ��� ���

������ �/������ ��� � ��������� ��� *��� �� �� �� �������� �(������ �� ��� *����' ��� ��� � *

�� ��.�� � ������� �� �� ���� ��� �� ������� � ������ �� ������ ����� �������� !���� � �������

������ ��� ���� �*��� �� ��.� ������ �� ����� �������' � ��� �� � ���� �� ������ ����� ������� ���������� �� ��������� ����� ���� �������� ������� �������� �� �������� �������

F"7 ������ ����������+����� ��� �� �������� ����.��� ��������� � ����� ��� ������� �� �� �� �������

F"E !��F������ ���� B3C �� ��� ������ � ��� ���� ��� +���� ��� ���������' �� ������ �� ������ +���

�� �� ��� ����+���� �� ��� �� ����

�5 ����6�����6 ��G���6��H������&���+�+1 $) &���+�+1 �*(��*�� �� :�� �%� -��� �������� ������������ �� �/������ � �.������� � ��� ��� ��� � �/������ ������ �����

�� ��� ����������� � ��� � ������ ��� �� 6�6 ��4*� "?�? ��4�6' �����(������ @C ��� ������

������ ����� ���� �� � �� � ��4�6 �� # ���� ����� �0 ����� ��� ��� ��* ��� 76 ��* � ��

����� �� ������� �� ����� � ��� �������������� � ���' ����' ������� �����' ��� *� �

��� � ��� ������� �� �/������ �0 �� 6�3 ��4*� "?�3 ��4�6' �����(������ @C ��� ������

������ ����� ���� �� � �� � ��4�6 �� # ���� � ��* ��� 73 ��* � � ����������� ���� �

��� �� �� ��� ��*�� �� >7 �� ?3 ��4�6 "�����(������ 63�@3C ��� ����������� ����� ����

�� � �� � ��4�6 �� # ��.����� �� ����� �� ������� �� �� ������ ����� �������� �� ������� �

��� �������� ��� ��� ������ �������� �� �/������ � �� ��� � � .��� �������� � ��� 5�����

����� ��������� ���� ��>33 ��� �.���� ���� �� ���)@' ) ������� ��� ���� :0>= 0��'

:02>320' :02>3=0' ��� ++>32� � � .��� ������ ���� ������� � �� � ��� � �������� ����

��� ����� ��������� � ���� � ��� � �� � .��� ���������� � �� � ��� � -7>D@I �������� ����

��� 5���� ��� ��� ������ ���� � �/������ � �������� � �������� ��� �������� ���� � �

��� � ��� ��� ������ ������ �� �/������ � ��� �� ��� ������� �� ��������� � -7>D@I

��� � ���� ��� 5���� ��� ��� ������ ���� �

���� ������ �� �/������ �� ���� ��� �� B�B ��4�6 "�����(������ BC ��� ����������� �����

���� �� � �� � ��4�6 �� # ���� ��� 2 ��� ���� �� ����� �� ��������� ������ ��� �� ����� �

������ �� ������� ��� �� �� ��� ���� ����� �� �&���� �������� ��� �� ������ ��.���������

��������� �� ���� ��� 2 ��� ��� ��* ��� >> �� >? ��* �� �� � �� >7�23 ��4�6 "�����(�

������ 63�=3C' ��� ����������� ����� ���� �� � �� � ��4�6 �� # �� ����� � ������ ��

���� �� ��� �� �� ��� �������� ' ��� ������ �� ���� ����� ���������� �� ������ ��

��������� ���� ��� ����� �� �� �� ������ � ����� ������ � �� � ������� ����' ���� ���

������� ��� >? ��* �� 6= ��4�6 �� ����� � �� ����� � � �������� ������ � ����� ������

��� �(����� �� ��� 6 �� �� ������

�E 0������ ������6��� ��:�!$������� ����� ������ �� ����� ���� ��� ��� ����� ��� ��������� �.�� �� ����� � �� ��

��. � ���� �� ���������� �������� �� �.�� ������� �������� ��� ����.�� ��������� ��

������� �� ��� �� ������ ' � ��� �� ����� �� ���� ������ �� � ������� ��� �� �� �� � �

������� ��� ����' ��*�� ��� ��� ������� ��� ��������� �� ��� ���� �� ��� ������� ��. � ��� ���

�� ������ � ���� ��� ����.�� ��������� �� �������

,����������� ���$ +������ +���������

5����' 9J 3DB3>

,����������� ��$ !�� ����� -��������� ' ���� E� !�(��� E������� F��<

!������' E< ==>=? 22DB3 <����4:� ������ F������

��0��0��33> !5 3@43@

Clinical decision making by cancer patients is a complexprocess. While it is widely accepted that impressive advancesover the past decade have led to disease-specific guidelines and

clinical pathways for some cancers, which makes decision making fair-ly straightforward, many decisions are preference-sensitive and there-fore more difficult. Some examples of preference-sensitive decisionsfor patients with cancer are:

• Use of tamoxifen for prevention of breast cancer• Genetic testing• Prostate-specific antigen screening• Treatment for early-stage breast and prostate cancer• When to stop active treatment• Location of end-of-life care.To make preference-sensitive cancer decisions, oncology care

providers need to assess patients’ values for benefits and harms acrosscancer screening and/or treatment options. Because there is no suchthing as a “best choice” for everyone, decisions are defined as being ofsuperior quality when they are based on current scientific evidenceand take into account patients’ informed values and preferences.1-3

Unfortunately, there are multiple obstacles to high-quality decisionmaking. For example, evidence seems to suggest that standard coun-seling in clinical practice does not produce high-quality decisions.4-7 In

addition, although patients have a variety of means for accessing multi-ple sources of medical information, they often lack the breadth ofknowledge or the confidence needed to be able to assess screening andtreatment options effectively. They also may have unrealistic expecta-tions as well as decisional conflict that thwart effective decision making.

Patients exposed to decision aids are more likely to be involved indecision making. Patient involvement in decision-making processes,in turn, can boost patient satisfaction, understanding, and confidencein the decisions that are made, and ultimately contribute to better-quality decisions.

Shared decision makingUntil recently, physicians and their “designates” were the sole

providers of medical information and therefore the sole decision mak-ers; a practice referred to as a “paternalistic model.” Over the pastdecade, however, with improved access to medical information,patients have become increasingly involved in clinical decision mak-ing. A shared decision-making approach in which patients discusswith their clinicians current evidence on treatment options and makea mutually agreed-on choice offers several benefits:

• It provides individualized patient-centered care• It complies with legal and ethical patient rights

Complimentary

January/February 2009 GREEN HILL HEALTHCARE COMMUNICATIONS 27

Decision Aids as a Guide for CancerPatients Making Clinical Decisions

HOW TO RECEIVE NURSING CREDIT

To receive continuing education credit, learners must:

• Read the article in its entirety

• Take the CE self-assessment test and complete the evaluation test:

1. Log on to www.coexm.com.

2. Click on The Oncology Nurse.

3. Click on UNMC logo on homepage.

4. Register to participate.

5. Enter program number #09CE 035.

• Complete and submit the evaluation form online (enter program number #09CE 035).

Nurses must answer at least 70% of the questions on the post-test correctly. If Internet

access is not available, please fax a request for an evaluation form to 402-559-6379,

Attn: Anji Wittman (please include return fax number) or e-mail concne@unmc.edu

• The estimated time to complete this activity is 1 hour. Your continuing education

certificate can be printed by following the directions online after successful com-

pletion of the post-test.

DISCLAIMERS

The opinions or views expressed in this continuing education activity are those of the fac-

ulty and do not necessarily reflect the opinions or recommendations of the University of

Nebraska Medical Center College of Nursing Continuing Nursing Education.

While the University of Nebraska Medical Center College of Nursing Continuing

Nursing Education is an ANCC accredited organization, this does not imply endorse-

ment by the UNMC or ANCC of any commercial products affiliated with this activity.

LEARNING OBJECTIVES

After completing this activity, the reader should be better able to:

• Cite examples of preference-sensitive decisions patients with cancer may face.

• Explain the benefits of a shared decision-making approach.

• Describe interventions that have been used to promote patient involvement in clinical

decision making.

TARGET AUDIENCE

Advanced practice nurses, registered nurses, and other interested healthcare profes-

sionals, especially those caring for cancer patients.

COST

This program is complimentary for all learners.

EDITORIAL BOARDCarol Bennett, MSc

Ottawa Health Research Institute

Clinical Epidemiology Program

Ottawa, ON K1Y 4E9

Sharon Gentry, RN, MSN, AOCN

Derrick L. Davis Forsyth Regional

Cancer Center

Winston-Salem, NC 27103

Patrick Medina, PharmD, BCOP

University of Oklahoma College of

Pharmacy

Oklahoma City, OK 73126

Rajiv Samant, MD

Faculty of Medicine

University of Ottawa

Ottawa, ON K1H 8M5

The Ottawa Hospital Cancer Center

Ottawa, ON K1H 8L6

Dawn Stacey, RN, MScN, PhD,

CON(C)

School of Nursing

University of Ottawa

Ottawa, ON K1H 8M5

PLANNING COMMITTEE

Lisa Anzai, RN, MA

Nurse Planner

University of Nebraska Medical Center

College of Nursing

985330 Nebraska Medical Center

Omaha, NE 68198-5330

Catherine Bevil, RN, EdD

Director, Continuing Nursing Education

and Evaluation

University of Nebraska Medical Center

College of Nursing

985330 Nebraska Medical Center

Omaha, NE 68198-5330

Dawn Lagrosa

Associate Editor

Green Hill Healthcare

Communications, LLC

241 Forsgate Drive

Monroe Twp, NJ 08831

Emily Lauritzen

University of Nebraska Medical Center

College of Nursing

985330 Nebraska Medical Center

Omaha, NE 68198-5330

Lara J. Reiman

Managing Editor

Green Hill Healthcare

Communications, LLC

241 Forsgate Drive

Monroe Twp, NJ 08831

Karen Rosenberg

Editorial Director

Green Hill Healthcare

Communications, LLC

241 Forsgate Drive

Monroe Twp, NJ 08831

FACULTY/PLANNER DISCLOSURES

All planners and faculty participating in continuing educa-

tion activities provided by the University of Nebraska

Medical Center, College of Nursing Continuing Nursing

Education are expected to disclose to the audience any sig-

nificant support or substantial relationship(s) with providers

of commercial products and/or devices discussed in this

activity and/or with any commercial supporters of the activ-

ity. In addition, all faculty are expected to openly disclose

any off-label, experimental, or investigational use of drugs

or devices discussed in their presentation. The planners

and faculty have been advised that this activity must be

free from commercial bias and based upon all the available

scientifically rigorous data from research that conforms to

accepted standards of experimental design, data collection,

and analysis.

The authors, reviewers, and planning committee members

listed below have stated they have no significant or substan-

tial relationship with providers of commercial products

and/or devices discussed in this activity and/or with any

commercial supporter of this activity.

• Lisa Anzai, RN, MA

• Carol Bennett, MSc

• Catherine Bevil, RN, EdD

• Sharon Gentry, RN, MSN, AOCN

• Dawn Lagrosa

• Patrick Medina, PharmD, BCOP

• Lara J. Reiman

• Karen Rosenberg

• Rajiv Samant, MD

• Jill Stein

• Gary C. Yee, PharmD, FCCP, BCOP

The following author has stated that she has the following

financial relationships:

• Dawn Stacey, RN, MScN, PhD, CON(C), is a consultant for

Ortho Biotech Canada involved in patient decision aid

development for patients with psoriasis, and receives

grant/research support from the Foundation for Informed

Medical Decision Making.

CONTINUING NURSING EDUCATION ACCREDITATION AND

CONTACT HOURS STATEMENT

The University of Nebraska Medical Center

College of Nursing Continuing Nursing

Education is accredited as a provider of con-

tinuing nursing education by the American Nurses Credentialing

Center’s Commission on Accreditation.

This activity is provided for 1.0 contact hour under ANCC criteria.

Provided for 1.2 contact hours under Iowa Provider #78. Provider

Approved by the California Board of Registered Nursing, Provider

#13699 for 1.2 contact hours.

BY DAWN STACEY, RN, MSCN, PhD, CON(C)1; RAJIV SAMANT, MD2; CAROL BENNETT, MSC

3

1School of Nursing; 2University of Ottawa and Ottawa Hospital Regional Cancer Centre; and 3Ottawa Health Research Institute, Clinical Epidemiology Program, Ontario, Canada

CONTINUING EDUCATIONAT WWW.COEXM.COM

CONTINUING EDUCATIONAT WWW.COEXM.COM

Program #09CE 035 • RELEASE DATE: February 15, 2009 • EXPIRATION DATE: February 14, 2010

28 GREEN HILL HEALTHCARE COMMUNICATIONS January/February 2009

• It addresses the patient’s desire to be involved• It is accountable for screening and treatments used• It improves patient satisfaction with the decision-

making process• It can potentially improve patient health out-

comes.Despite these benefits, many clinicians have not

adopted the practice of shared decision making.8

Oncologists, in particular, often do not encouragepatient involvement to the extent that patients wouldlike.9-11 It may be that oncologists underestimate theextent to which their patients want to be involved inthe decision-making process.5,6 Patient preferences arehard to predict, given that there do not seem to be anyfactors proven to correlate with patient preferences orpreferred role in decision making. Thus, clinicians needto use an individualized approach when determiningwhether a patient seeks to participate in decision mak-ing, and, if so, to what extent.12,13

Interventions to promote patient involvementin decision making

An array of interventions is available that aim toboost patient involvement in the decision-makingprocess. The best interventions are those that helppatients recognize that a decision needs to be made,understand the scientific evidence currently available,and clarify their values associated with the outcomesof screening and treatment options—all of whichshould help produce a top-quality decision.1 Con-ventional patient education materials have notproved to be sufficient. The following options have alldemonstrated benefit.

Patient decision aids. These are tools that translateevidence into patient-friendly form by providing, at aminimum, information on the options, risks and bene-fits of screening and treatment options, and implicitmethods to clarify personal values.14 Values can be clar-ified implicitly by providing details on what it is like toundergo the procedures and to live with the physical,social, and emotional consequences in a way thatmakes it possible for patients to formulate personalvalue judgments. Decision aids also may include infor-mation on the medical condition and the likelihood ofthe benefits and risk of the various options. Patientdecision aids are usually self-administered and areavailable in several patient-friendly formats, for exam-ple, as paper handouts, videos or DVDs, or computersoftware. Some decision aids are administered by thepractitioner and may involve more complex approach-es. Given the relative ease of updating information andminimal dissemination costs, the Internet has becomethe primary resource for patient decision aids.

We reviewed 23 randomized controlled trials thatfocused on cancer-related decisions such as prostateand colon cancer screening, breast cancer genetic test-ing, and breast and prostate cancer treatment.15 The23 trials were drawn from the 55 randomized con-trolled trials included in the Cochrane systematicreview of patient decision aids.

Overall, patient decision aids were shown to consis-tently improve knowledge, decrease decisional con-flict, and lead to choices that were compatible withpatients’ values.15 When we compared cancer-specificdecision aids with usual care, we found that individu-

als who received patient decision aids were more like-ly to participate in decision making and were betterinformed than persons not receiving such aids.Patients exposed to cancer-specific decision aids thatincluded descriptions of outcomes and probabilitiesmore often had accurate risk perceptions than thosewho did not receive this information. Cancer-specificdecision aids also can prevent overuse of some aggres-sive interventions as well as underuse of other inter-ventions.

Although patient decision aids have been shown tobe useful in oncology, they have not been routinelyincorporated into oncology practices. Common obsta-cles to the use of these aids include a lack of skillsamong healthcare professionals in shared decisionmaking, a lack of awareness of patient decision aids,and availability of patient decision aids on a limitednumber of decisions.16

Question prompt sheets. These are standardized setsof questions that guide patients on how to obtaininformation during the consultation.17

Consultation planning. This is a process wherebytrained facilitators coach patients on how to devel-op their own list of questions to ask during their

consultation. Trained facilitators are usually nurses,patient navigators, or individuals who work at theresource center.18

Decision coaching. Decision coaching facilitatespatient involvement in decision making.19 Decisioncoaches are health professionals who assess patients’decisional conflict and related needs, guide patientsthrough the decision-making process using decisionaids and/or evidence-based information, and monitorfor factors that can influence the patient’s implementa-tion of the shared decision.

Future researchAlthough cancer patients are seeking increased par-

ticipation in clinical decision making with the ultimategoal of achieving better clinical decisions, moreresearch is needed to help achieve these goals. Futurestudies are needed to:

• assess the impact of patient decision aids onpatient–clinician communication

• identify ways to overcome barriers to the adoption ofpatient decision aids by routine oncology practices

• determine effective ways to make patient decisionaids easily accessible to patients

• explore the implications of legally requiring thatthese interventions be included in the informedconsent process

• establish effective approaches to help oncologistsand patients transition from the standard paternal-istic doctor–patient model to a shared decision-making model.

Decision Aids as a Guide for CancerPatients Making Clinical Decisions: A Nurse’s PerspectiveBY SHARON GENTRY, RN, MSN, AOCN

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

The article by Stacey and colleagues remindshealthcare professionals of the transition frompaternalistic patient non-decision making that

our oldest patients may have experienced to the currentactive participation in medical decision making that ourpatients currently face in many healthcare settings.

Teamwork is essential for a satisfactory and high-qual-ity medical journey for the patient. The patient brings tothe shared decision-making process his or her knowl-edge, whether it is basic understanding of their disease orextensive understanding of treatment choices. Thisknowledge is colored with the patient’s values and cul-ture. Healthcare professionals bring the current scientif-ic evidence to best treat the specific disease, which thepatient needs to understand to make a high-quality deci-sion about his or her care.

Patient decision aids are the common link and solutionto merge the team together. Although, as Stacey and col-leagues discuss, studies have shown that decision aids canimprove patients’ knowledge and help them makeinformed decisions about their care, they are not widelyused in oncology practices. It takes a commitment from

the healthcare staff to make patients aware of appropriatedecision aids, become skilled in using them, and maketime for a shared decision consultation. The patient mustinvest time to complete the aids prior to consultation.

It is important to point out that a decision tool is notsimply a patient education sheet or other teaching mate-rial that is intended solely to increase a patient’s knowl-edge base. For example, a chemotherapy teaching sheetis not a decision aid. A question prompt sheet is notmeant to be used alone but instead as a guide to addresswhat information the patient needs. An example of adecision aid available on the Internet is CancerNexProfiler (www.oncolink.upenn.edu). This is a free,interactive tool that allows a patient to get informationabout treatment options and outcomes that can be dis-cussed with the healthcare team.

As healthcare professionals, we need to stay on thelearning curve and increase our personal awareness ofcurrent decision aids that may be beneficial for patients.To ensure quality decision making by our patients, thedecision aids should be used early during the patient’smedical journey.

Program #09CE 035 • RELEASE DATE: February 15, 2009 • EXPIRATION DATE: February 14, 2010

Complimentary

COMMENTARYCOMMENTARY

CONTINUING EDUCATIONAT WWW.COEXM.COM

CONTINUING EDUCATIONAT WWW.COEXM.COM

Clinicians need to use an individualized approach whendetermining whether a patient seeks to participate indecision making, and, if so, to what extent.

January/February 2009 GREEN HILL HEALTHCARE COMMUNICATIONS 29

ConclusionPublic surveys consistently indicate that people want

to be involved in health decisions. However, whenfaced with values-sensitive decisions related to cancerscreening and treatment, current clinical counseling isinadequate and patients need guidance to gain theirdesired role in decision making. Interventions to sup-port patients’ involvement in decision making includepatient decision aids, question prompt sheets, consul-tation planning, and decision coaching. Healthcareprofessionals have an important role in assessing fac-tors influencing patients’ decision-making needs, pro-viding support to address their needs by using effectiveinterventions, and monitoring patients’ progress inmaking and implementing decisions.

Case Report

Decision Coaching for Man with Early-stageProstate Cancer

A 51-year-old patient, recently diagnosed withearly-stage prostate cancer by his urologist, wasgiven educational material regarding treatmentoptions and booked for a follow-up visit. When theoncology nurse did an initial assessment, she foundthat although Mr Smith felt that he had enoughinformation about his options, he was not surewhich option was best for him, primarily because hefelt unclear about which risks and benefits ofoptions were most important. The dialogue that

ensued clarified that, for Mr Smith, the benefit oftreatment—increased chance of survival for menunder age 65—outweighed the side effects of treat-ment and that he wanted to seek active treatment ver-sus watchful waiting. He was still undecided regardingthe best treatment option (radiation or surgery). Thefollowing dialogue provides an overview of the deci-sion support that was provided in preparation for dis-cussion with the urologist.

Clarify the options and their benefits“You are correct that the chance of cure is about the

same for both radiation and surgery, and you seem tohave a good sense of what is involved with these treat-ments. At this point, it would help if you could thinkabout the side effects of these treatments and deter-mine which ones are more important for you to avoid.Would it help if I reviewed these side effects and thechance that they will occur?”

Side effects of options“There are three main side effects of prostate cancer

treatments. Bladder problems are more likely to occurwith surgery; bowel irritation is more likely to occurwith radiation; and impotence can occur to differingdegrees with both options. For bladder problems,research shows that if 100 men like you had surgery,about 10 to 20 men would have bladder problems,such as dribbling or leaking of urine. For bowel irrita-tion, if 100 men like you had radiation, about 30 men

would have bowel irritation, such as diarrhea duringtreatment, but only five to 10 men will have longer-term diarrhea and need to be more careful about whatthey eat. Impotence can occur in at least half of thepatients regardless of the treatment. The difference isthat you will know if you are impotent within daysafter surgery and, if you are, it is usually permanent; forradiation therapy, the impotence has a more gradualonset and may not be permanent.”

Clarify patient values“Have you thought about what it means to live with

possible side effects of treatment such as urinary drib-ling, impotence, or diarrhea from bowel irritation? Isthere one that is more important for you to avoid?”

Screen for decisional difficulties“Now that we have discussed the different options,

are you leaning toward one treatment more thananother, or is there anything else that you would liketo discuss?”

Given his active lifestyle and the possible impact onsexual relations, Mr Smith clearly preferred to livewith the potential complications of radiation andavoid the chance of urinary dribbling and impotenceassociated with surgery.

References1. Elwyn G, O’Connor A, Stacey D, et al. Developing a quality criteria framework

for patient decision aids: online international Delphi consensus process. BMJ.

2006;333:417.

2. Sepucha KR, Fowler FJ Jr, Mulley AG Jr. Policy support for patient-centered

care: the need for measurable improvements in decision quality. Health Aff

(Millwood). 2004;Suppl Web Exclusives:VAR54-VAR62.

3. Ratliff A, Angell M, Dow RW, et al. What is a good decision? Eff Clin Pract.

1999;2:185-197.

4. Guimond P, Bunn H, O’Connor AM, et al. Validation of a tool to assess health

practitioners’ decision support and communication skills. Patient Educ Couns.

2003;50:235-245.

5. Elwyn G, Hutchings H, Edwards A, et al. The OPTION scale: measuring the

extent that clinicians involve patients in decision-making tasks. Health Expect.

2005;8:34-42.

6. Loh A, Simon D, Hennig K, et al. The assessment of depressive patients’

involvement in decision making in audio-taped primary care consultations.

Patient Educ Couns. 2006;63:314-318.

7. Stevenson FA, Cox K, Britten N, Dundar Y. A systematic review of the research

on communication between patients and health care professionals about medi-

cines: the consequences for concordance. Health Expect. 2004;7:235-245.

8. Gravel K, Légaré F, Graham ID. Barriers and facilitators to implementing shared

decision-making in clinical practice: a systematic review of health professionals’

perceptions. Implement Sci. 2006;1:16.

9. Butow P, Harrison JD, Choy, ET, et al. Health professional and consumer views

on involving breast cancer patients in the multidisciplinary discussion of their

disease and treatment plan. Cancer. 2007;110:1937-1944.

10. Elkin E, Kim SH, Casper ES, et al. Desire for information and involvement in

treatment decisions: elderly cancer patients’ preferences and their physicians’

perceptions. J Clin Oncol. 2007;25:5275-5280.

11. Kleeberg UR, Feyer P, Günther W, Behrens M. Patient satisfaction in outpatient

cancer care: a prospective survey using The PASQOC questionnaire. Support

Care Cancer. 2008;16:947-954.

12. Bruera E, Willey JS, Palmer JL, Rosales M. Treatment decisions for breast carci-

noma: patient preferences and physician perceptions. Cancer. 2002;94:2076-2080.

13. Bruera E, Sweeney C, Calder K, et al. Patient preferences versus physician per-

ceptions of treatment decisions in cancer care. J Clin Oncol. 2001;19:2883-2885.

14. O’Connor AM, Rostom A, Fiset V, et al. Decision aids for patients facing health

treatment or screening decisions: systematic review. BMJ. 1999;319:731-734.

15. Stacey D, Samant R, Bennett C. Decision making in oncology: a review of

patient decision aids to support patient participation. CA Cancer J Clin.

2008;58:293-304.

16. Gravel K, Légaré F, Graham ID. Barriers and facilitators to implementing shared

decision-making in clinical practice: a systematic review of health professionals’

perceptions. Implement Sci. 2006;1:16.

17. Kinnersley P, Edwards A, Hood K, et al. Interventions before consultations for

helping patients address their information needs. Cochrane Database Syst Rev.

2007;(3):CD004565.

18. Belkora J, Katapodi M, Moore D, et al. Evaluation of a visit preparation inter-

vention implemented in two rural, underserved counties of Northern

California. Patient Educ Couns. 2006;64:350-359.

19. Stacey D, Murray MA, Légaré F, et al. Decision coaching to support shared deci-

sion making: a framework, evidence, and implications for nursing practice, edu-

cation, and policy. Worldviews Evid Based Nurs. 2008;5:25-35.

Jill Stein contributed to the preparation of this manuscript.

Program #09CE 035 • RELEASE DATE: February 15, 2009 • EXPIRATION DATE: February 14, 2010

Complimentary

CONTINUING EDUCATIONAT WWW.COEXM.COM

CONTINUING EDUCATIONAT WWW.COEXM.COM

Decision Aids as a Guide for CancerPatients Making Clinical Decisions: A Pharmacist’s PerspectiveBY PATRICK MEDINA, PHARMD, BCOP

University of Oklahoma College of Pharmacy, Oklahoma City

Pharmacists tend to be data driven, often forgettingthe importance of including patients in the deci-sion-making process. It is often assumed that

patients will want the treatment dictated by the literatureusing “evidence-based medicine.” However, the “data”often contradict this perception. Several surveys note thatpatients’ willingness to undergo treatment as well as theirtolerability of certain cancer-related adverse effects is dif-ferent from healthcare professionals’ perceptions.

The article by Stacey and colleagues remindshealthcare professionals that the medical informationboom largely found on the Internet requires health-care professionals to transition from paternalisticpatient non-decision making to a shared decision-making approach.

Stacey and colleagues point out that current oncol-ogy practices have not routinely adopted thisapproach, despite several benefits cited in the article.Patients who use these aids were better informed andmore involved in their decision making—a goal thatmost practices should welcome. One reason is thatconventional patient education materials may not besufficient to do the job. This is an area where pharma-

cists should use their expertise and improve theresources available.

Because most patient decision aids are self-adminis-tered and available on the Internet, healthcare profes-sionals, including pharmacists, can assist patients infinding well-validated decision aids that will be usefulfor their particular disease state. For instance, patientscan use www.collaborativecare.net to assist them inmaking decisions about their breast cancer treatment.

In summary, the article by Stacey and colleagues high-lights the importance of clinical practices incorporating ashared decision-making approach to improve theirpatients’ care. Although current tools have limitations,several have shown benefit in assisting patients who aremaking difficult decisions, and often the results contra-dict conventional wisdom. Pharmacists can assist thisprocess by guiding patients to appropriate tools as well asimproving the decision-making tools currently available.

As individualized care increases with genetic testingand pharmacogenomic profiling, use of decision-makingtools will increase. These tools will need to be incorpo-rated into clinical practice by healthcare professionals,including pharmacists.

COMMENTARYCOMMENTARY

30 GREEN HILL HEALTHCARE COMMUNICATIONS January/February 2009

HE

MA

TO

LO

GIC

CA

NC

ER

SH

EM

AT

OL

OG

IC C

AN

CE

RS

complete the diagnostic process. Thepatient history will help to identify thebehavior of lymphadenopathy, small- tomedium-sized nodes that wax and wanein indolent subtypes or lymph nodesrapidly increasing in size in aggressivesubtypes. The history also will establishthe presence or absence of B symptoms(fever, night sweats, or weight loss).The tissue diagnosis is best achieved byexcisional lymph node biopsy, bonemarrow biopsy, and aspirate, the detailsof which have been reviewed in Part 2of this series (December 2008). Carefuland systematic physical examinationwith use of a consistent measurementtool and documentation of each nodalsite is critical for effective evaluation. Inaddition, the physical examination pro-vides an excellent method to estimatedisease response between imaging stud-ies, with no risk to the patient. Inpatients with no palpable adenopathyor organomegaly, evaluation will rely onselected imaging studies or changes inlaboratory parameters.

Classification systemsThe Ann Arbor Staging classifica-

tion system, originally designed forHodgkin’s lymphoma, is most common-ly used to describe the distribution andnumber of nodal sites and the presenceor absence of extranodal disease or con-stitutional symptoms.3 The Cotswold-modified Ann Arbor classification sys-tem provides a staging framework more

consistent with the characteristics ofNHL, including a designation of bulkydisease and specific parameters fordescription of extranodal involvement.1

Bulky disease is defined as a single nodalmass exceeding 10 cm in maximumdiameter or a mediastinal mass exceed-ing one third of the maximum transtho-racic diameter. Bulky disease is consid-ered an adverse prognostic indicator.Extranodal involvement most ofteninvolves the spleen or bone marrow.Hepatic involvement is most common infollicular lymphoma (FL) and diffuselarge B-cell lymphoma (DLBCL). Gas-trointestinal involvement is common inmantle cell lymphoma, mucosa-associat-ed lymphoid tissue (MALT), and gastriclymphomas and will require specific diag-nostic testing.

Prognostic indicatorsThe two most common subtypes of

NHL are FL and DLBCL. Both diseaseshave established prognostic grading sys-tems that require accurate characteriza-tion of nodal areas, including the loca-tion and number of nodal sites. Thepresence of more than four nodal sites isconsidered an adverse prognostic vari-able in the Follicular Lymphoma In-ternational Prognostic Index.3 Nodalsites above and below the diaphragm ordisseminated disease indicates advanceddisease in the Ann Arbor classification.3

Two or more extranodal sites of diseaseare adverse prognostic findings in the

International Prognostic Index usedfor DLBCL.4 Although individuallymph node size is not a part of theprognostic systems, parameters are sug-gested for the initiation of therapybased on the size, number, and second-ary effects of nodal sites. High tumorburden (ie, nodal masses > 7 cm, threenodes in three distinct areas each > 3cm, symptomatic splenic enlargement,organ compression, malignant ascitesor pleural effusion, rapid generalizedprogression of nodal sites, or life-threatening organ involvement) isgenerally indicative of more advanced,aggressive disease and the need to ini-tiate immediate therapy.5,6

Imaging studiesImaging studies are critical for the

initial staging, prognostication, andevaluation of response to treatment forNHL. Radiologic assessment of treat-ment response has been the gold stan-dard for estimating the risk of relapse.1

Historically, a patient with NHLrequired a number of invasive proce-dures to estimate the extent of disease.Scientific and technologic advanceshave revolutionized the diagnosticprocess. The introduction of computedtomography (CT) in the 1970s provid-ed a means for evaluating abnormallymph nodes (> 1 cm) or extranodalsites. CT scans remain the standardimaging strategy for estimating theanatomic extent of disease.6,7 More re-cently, 18F-fluoro-2-deoxyglucose (FDG)positron emission tomography (PET),whole-body magnetic resonance imag-ing, and FDG-PET/CT fusion imaginghave provided complimentary strate-gies for characterization of NHL. Eachof these technologies has advantagesand disadvantages in terms of sensitiv-ity, specificity, risk to the patient, andcost (Table).

The risk of radiation exposure overtime is of particular concern in a patientwith potentially curable disease or whois expected to be treated over an extend-ed period. Estimated risks for cancer as aresult of radiation exposure during diag-nostic imaging vary by modality but arebased on the radiation burden (mSv)over time, children being at greatest risk.The US Food and Drug Administrationestimates a dose of 10 mSv may be asso-ciated with a 1:2000 risk of developingfatal cancer.7 The risk is reduced consid-erably after the age of 50. Patients ofchildbearing age will need particularattention, with careful screening andeducation to avoid exposure duringpregnancy.

Recent analyses of PET and PET/CTin particular, which evaluate glycolyticactivity as a surrogate for increasedmetabolic activity, have changed therecommendations for staging andrestaging for NHL.6-8 These technolo-

gies provide functional imaging tech-niques and an advantage in certain cir-cumstances, particularly the evaluationof patients for autologous stem celltransplant and local radiotherapy.9,10

Kwee and colleagues provide a com-prehensive analysis of imaging tech-nologies used in the staging of malig-nant lymphoma.7 The majority ofpublished studies specific to imagingstrategies for NHL have been based onretrospective analysis with no cleardelineation of histiologic subtype.Most trials included all types of lym-phoma, including Hodgkin’s lym-phoma, which has very specific recom-mendations for imaging. Invasivediagnostic technologies are still requiredfor selected subtypes of NHL, includingendoscopic evaluation for gastric orMALT lymphoma involving the stom-ach or small bowel, lumbar puncture forcentral nervous system lymphoma, andcolonoscopy for mantle-cell or MALTlymphoma. Prospective trials analyzingimaging strategies concurrently withactive therapies are under way and willprovide data critical to refinement ofstandard imaging guidelines for NHL.Many questions remain, including theutility of each method in terms of theaffect on prognosis, changes in thera-peutic intervention, cost, and risks tothe patient.

References1. Cheson B, Pfistner B, Juweid M, et al. Revised

response criteria for malignant lymphoma. J Clin

Oncol. 2007;25:579-586.

2. Podoloff D, Advani R, Allred C, et al. NCCN task

force report: positron emission tomography

(PET)/computed tomography (CT) scanning in

cancer. J Natl Compr Canc Netw. 2007;5(Suppl

1):S1-S22.

3. Solai-Celigny P, Roy P, Colombat P, et al.

Follicular lymphoma international prognostic

index. Blood. 2004;104:1258-1265.

4. The International Non-Hodgkin’s Lymphoma

Prognostic Factors Project. A predictive model for

aggressive non-Hodgkin’s lymphoma. N Engl J

Med. 1993;329:987-994.

5. Salles G. Clinical features, prognosis and treat-

ment of follicular lymphoma. Hematology Am Soc

Hematol Educ Program. 2007;216-225.

6. National Comprehensive Cancer Network.

NCCN Clinical Practice Guidelines in Oncology:

Non-Hodgkin’s Lymphoma, V.3.2008. www.

nccn.org/professionals/physician_gls/PDF/nhl.pdf.

Accessed January 22, 2009.

7. Kwee TC, Kwee RM, Nievelstein RA. Imaging in

staging of malignant lymphoma: a systematic

review. Blood. 2008;111:504-516.

8. Barentsz J, Takahashi S, Oyen W, et al. Commonly

used imaging techniques for diagnosis and staging.

J Clin Oncol. 2006;24:3234-3244.

9. Hoppe BS, Moskowitz CH, Zang Z, et al. The role

of FDG-PET imaging and involved field radiother-

apy in relapsed or refractory large B-cell lym-

phoma. Bone Marrow Transplant. January 12, 2009.

e-Pub ahead of print.

10. Svoboda J, Andreadis C, Elstrom R, et al.

Prognostic value of FDG-PET scan imaging in

lymphoma patients undergoing autologous stem

cell transplantation. Bone Marrow Transplant.

2006;38:211-216.

Diagnostic StrategiesContinued from page 12

Imaging studies are critical for the initial

staging, prognostication, and evaluation

of response to treatment for NHL.

• Postsurgical Treatment for GIST PatientsThe US Food and Drug Administration has approved imatinib mesylate (Gleevec, Novartis) for

the postsurgical treatment of adult patients after complete removal of Kit (CD117)-positive

gastrointestinal stromal tumors (GIST). The drug is the only postsurgical treatment indicated

to delay the return of this cancer.

• Degarelix for Prostate CancerThe FDA has approved degarelix (Ferring), an injectable gonadotropin-releasing hormone

receptor inhibitor, for treatment of advanced prostate cancer. The agent is the first drug

approved for the treatment of prostate cancer in several years.

• Oral Formulation of FludarabineThe FDA has approved a tablet formulation of fludarabine phosphate (oral fludarabine,

Antisoma) as a second-line treatment for adults with B-cell chronic lymphocytic leukemia.

Marketing authorization also has been granted under the FDA’s accelerated approval pro-

visions. Under these provisions, the company is required to perform an additional clinical trial.

• Drug Helps Mobilize Hematopoietic Stem CellsThe FDA has granted marketing approval for plerixafor injection (Mozobil, Genzyme), which is

intended to be used in combination with granulocyte colony-stimulating factor to mobilize

hematopoietic stem cells to the bloodstream for collection and subsequent antilogous trans-

plantation in patients with non-Hodgkin’s lymphoma and multiple myeloma.The product also

has been granted orphan drug designation.

Recent FDAApprovals

Nerve

Submucosa

Mucosa

GELCLAIR® CoatingPrescribe 6 boxes of GELCLAIR®

for a 30 day supply

GELCLAIR® provides soothing, long-lasting pain relief1 at the first sign of oral mucositis.

Contains no alcohol and no lidocaine, so patients won’t experience drying, stinging or numbing.

For additional information, visit www.gelclair.com or call 1-877-GELCLAIR.

GELCLAIR® is available at your

local pharmacy and at:

Ingredients: Water, Maltodextrin, Propylene Glycol, Polyvinylpyrrolidone (PVP), Sodium Hyaluronate, Potassium Sorbate, Sodium Benzoate, Hydroxyethylcellulose, PEG-40 Hydrogenated Castor Oil, Disodium Edetate,

Benzalkonium Chloride, Flavoring, Saccharin Sodium, Glycyrrhetinic Acid. Contents: 15 mL per single-use packet. Commercial boxes contain 15 single-use packets. (NDC 24477-010-15) Indications: GELCLAIR® has a

mechanical action indicated for the management of pain and relief of pain by adhering to the mucosal surface of the mouth, soothing oral lesions of various etiologies, including oral mucositis/stomatitis (may be caused

by chemotherapy or radiation therapy), irritation due to oral surgery, traumatic ulcers caused by braces or ill-fitting dentures, or disease. Also indicated for diffuse aphthous ulcers. Contraindications: The administration

of GELCLAIR® is contraindicated in any patient with a known or suspected hypersensitivity to any of its ingredients. Side effects: At the time of producing this leaflet, no adverse effects have been reported in clinical

trials with the use of GELCLAIR®. Postmarketing reports have included infrequent complaints of burning sensation in the mouth.

Reference: 1. Innocenti M, Moscatelli G, Lopez S. Efficacy of Gelclair® in reducing pain in patients with oral lesions: preliminary findings from an open pilot study. J Pain Symptom Manage. 2002;24:455-457.

GELCLAIR® is a registered trademark of Helsinn Healthcare SA, Lugano, Switzerland. Manufactured for Helsinn Healthcare SA, Lugano, Switzerland. Marketed and distributed by

EKR Therapeutics, Inc., Cedar Knolls, NJ 07927.

©2008 EKR Therapeutics, Inc. All rights reserved. GEL070

Gelclair® can bring a smile

to the face of patients with

oral mucositis

Soothing the way to relief

Now serving patients nationwideToll Free: 877-977-9118

Patients often question their dietsafter learning about their cancerdiagnosis, wondering what they

should or should not eat. Manypatients feel that by controlling theirdiets they have some sense of controlover their health. Changes in diet canhave several benefits to the patientwith cancer, including helping to alle-viate side effects from treatment (forexample, following a low-fat, low-fiber diet to help manage nausea ordiarrhea), increasing nutrient con-sumption (by following a plant-baseddiet), or maintaining a healthy weightto help lower recurrence (by limitingfat and calories).

Although these changes, with theguidance of a registered dietitian, canhave a positive impact on the patient’squality of life and disease management,when taken to the extreme, they canhave the opposite effect.

Many alternative diets promote anincrease in fruit, vegetable, and com-

plex carbohydrate consumption and,to a degree, lower intake of animalprotein. However, they traditionallyinvolve severe calorie and proteinrestriction and advocate use of sup-plementation with herbs and vita-mins to help “detoxify” the body. Onealternative diet is thought to be thebasis for all other alternative diets.1

The Gerson regimen, developed byMax Gerson, a German physicianwho practiced in the United Statesfrom the late 1930s to 1950s, consistsof a strict organic vegetarian diet com-bined with coffee enemas, herbal andnutrient supplementation, and pancre-atic enzymes. The diet is purposely highin potassium and low in sodium, withno added fat and no animal protein forthe first 4 weeks.2 Patients are requiredto consume a glass of juice made ofspecified fruits and vegetables that arepressed every hour for 13 hours to helpthe patient incorporate nutrients “frommore than 20 pounds of fruits and veg-etables” daily.3

Those following the diet may notuse aluminum (they must cook in castiron and may not have any cannedfruits or vegetables) or consumedrinking water, and all food must befresh.3 Studies analyzing this methodhave been retrospective, and noprospective controlled studies havebeen able to duplicate the effects.1

There have been reports of electrolyteimbalance and infection from coffeeenemas given four times per day.4,5

The cost to visit Gerson’s health

restoration center in California for a6-day introductory course in the regi-men is $2900 per person.3

The Gonzalez regimen is based onsimilar theories as the Gerson regi-men, but there are more than 90 vari-ations of the diet, ranging from strictvegetarian to a high-fat, high-meatdiet.6 This difference is a result of thetheory that disease is individualizedbased on a person’s metabolic profileand the chosen diet is designed torestore balance.6

The diet is combined with con-sumption of 130 to 160 capsules ofporcine pancreatic enzymes and othertypes of supplements. This regimen hasbeen shown to be beneficial in smallsample sizes of patients with pancreaticcancer and is currently being studied ina trial sponsored by the NationalCenter for Complimentary and Alter-native Medicine.6

The macrobiotic diet was originallydeveloped by George Osawha and pop-ularized in the United States byMischio Kushi.7 Kushi’s guidelines arebased on eating foods grown in a per-son’s “climate”; as a result, this oftenlimits options for foods from the groupsthat are a basis of the diet. Organicallygrown whole grains constitute 40% to60% of food intake and vegetables(other than potatoes, tomatoes, egg-plant, peppers, spinach, beets, and zuc-chini) 20% to 30%.7 The diet doesinclude some protein sources; however,the 5% to 10% of volume from legumesand dried beans and limited amounts offish (avoidance of all other sources ofanimal protein is recommended) doesnot allow for adequate protein intake,especially for a patient with cancer.Specific fruit is allowed only two orthree times per week, and water isallowed only in small amounts.7 Asthese are only guidelines, Kushi recom-mends an individualized consultationwith a specialist at the Kushi Institute,which is available at $325 per session;however, patients are encouraged toparticipate in a week-long session tohelp understand how to implement therecommendations, costing $1950 with a$400 service fee for shuttling from theairport (this does not include lodging).7

Because of the emphasis on choosingonly locally grown, in-season foods,there is a great risk for micronutrientand overall calorie deficiency for mostAmericans pursuing this regimen.

These three programs are the onesthat patients most often ask about,

but there are several more variationsand new diets promising outcomesthat have not been proved undermedical practitioners’ guidelines ofevidence-based practice.

Counseling patientsWhen educating patients regarding

alternative diets, I encourage them toreview guidelines of the AmericanDietetic Association for spotting“junk science.” These include evalu-ating a program’s claim to a quick fix,listing warnings or disclaimers, listinggood or bad foods, basing recommen-dations on small studies, and sound-ing too good to be true.8

It is important to redirect patients tosources that will encourage healthychanges, such as the American CancerSociety’s Nutrition and PhysicalActivity Guidelines,9 the AmericanInstitute of Cancer Research (www.aicr.org) guidelines, and MyPyramid(www.mypyramid.gov). Trying to em-phasize the risk versus the benefit ofthese programs can be challengingwhen working with patients who feelthat these programs are going to betheir “magic bullet.” To help themcontinue to feel in control, it is impor-tant to understand their desire to makechanges. At the same time, patientsneed to understand the potential risksof alternative diets and they need edu-cation on what is needed to help themtolerate treatment.

References1. National Cancer Institute. Gerson therapy

PDQ. http://www.cancer.gov/cancertopics/pdq/cam/gerson/HealthProfessional. AccessedOctober 15, 2008.

2. Questionable methods of cancer manage-ment: “nutritional” therapies. CA Cancer JClin. 1993;43:309-319.

3. The Gerson Institute. Healing your body withthe Gerson therapy. http://www.gerson.org/g_therapy/default.asp. Accessed October 13,2008.

4. Margolin KA, Green MR. Polymicrobialenteric septicemia from coffee enemas. West JMed. 1984;140:460.

5. Eisele JW, Reay DT. Deaths related to coffeeenemas. JAMA. 1980;244:1608-1609.

6. National Cancer Institute. Gonzalez PDQ.http://www.cancer.gov/cancertopics/pdq/cam/gonzalez/HealthProfessional. Accessed October15, 2008.

7. The Kushi Institute. http://www.kushiinstitute.org/. Accessed October 10, 2008.

8. American Dietetic Association. Red flags ofjunk science. http://www.eatright.org/cps/rde/xchg/ada/hs.xsl/home_17982_ENU_HTML.htm. Accessed October 15, 2008.

9. American Cancer Society. The CompleteGuide—Nutrition and Physical Activity.http://www.cancer.org/docroot/PED/content/PED_3_2X_Diet_and_Activity_Factors_That_Affect_Risks .asp?s itearea=PED.Accessed October 15, 2008.

32 GREEN HILL HEALTHCARE COMMUNICATIONS January/February 2009

ON

CO

LO

GY

NU

TR

ITIO

NO

NC

OL

OG

Y N

UT

RIT

ION

Oncology NutritionUse of Alternative Diets

BY AMANDA SALDIVAR,MS, RD, LD

TAUSSIG CANCER INSTITUTE,

CLEVELAND, OHIO

When educating patients regarding alter-native diets, I encourage them to reviewguidelines of the American DieteticAssociation for spotting “junk science.”

©iStockphoto.com/David H Lewis

26-28 ORLANDO, FL

2009 Genitourinary Cancers

Symposium

www.asco.org

26-28 BARCELONA, SPAIN

2nd International Conference on

Innovative Approaches in Head and

Neck Oncology (ICHNO)

www.estro-events.org

27-28 NEW YORK, NY

Seventh International Symposium on

Supportive Care in Oncology:

Cancer Management in the Era of

Targeted Agents

www.cancerlearning.com

4-7 MIAMI, FL

Miami Breast Cancer

Conference 2009

www.cancerlearning.com

5-7 FT. LAUDERDALE, FL

Palliative Medicine & Supportive

Oncology 2009—The 13th Annual

International Symposium

www.clevelandclinicmeded.com

MARCH 2009FEBRUARY 2009

Meetings

MARCH 2009

January/February 2009 GREEN HILL HEALTHCARE COMMUNICATIONS 33

ME

ETIN

GS

RITUXAN® (Rituximab) Brief summary—Please consult full prescribing information.

INDICATIONS AND USAGE Non-Hodgkin’s Lymphoma (NHL) Rituxan®

(rituximab) is indicated for the treatment of patients with: Relapsed or refractory,low-grade or follicular, CD20-positive, B-cell NHL as a single agent; Previouslyuntreated follicular, CD20-positive, B-cell NHL in combination with CVPchemotherapy; Non-progressing (including stable disease), low-grade, CD20-positive B-cell NHL, as a single agent, after first-line CVP chemotherapy;Previously untreated diffuse large B-cell, CD20-positive NHL in combination withCHOP or other anthracycline-based chemotherapy regimens. WARNINGS ANDPRECAUTIONS Infusion Reactions Rituxan can cause severe, including fatal,infusion reactions. Severe reactions typically occurred during the first infusion withtime to onset of 30–120 minutes. Rituxan-induced infusion reactions andsequelae include urticaria, hypotension, angioedema, hypoxia, bronchospasm,pulmonary infiltrates, acute respiratory distress syndrome, myocardial infarction,ventricular fibrillation, cardiogenic shock, or anaphylactoid events. Premedicatepatients with an antihistamine and acetaminophen prior to dosing. Institutemedical management (e.g., glucocorticoids, epinephrine, bronchodilators, oroxygen) for infusion reactions as needed. Depending on the severity of theinfusion reaction and the required interventions, consider resumption of theinfusion at a minimum 50% reduction in rate after symptoms have resolved.Closely monitor the following patients: those with preexisting cardiac orpulmonary conditions, those who experienced prior cardiopulmonary adversereactions, and those with high numbers of circulating malignant cells(≥25,000/mm3). [See Boxed Warning, Warnings and Precautions, AdverseReactions.] Tumor Lysis Syndrome (TLS) Rapid reduction in tumor volumefollowed by acute renal failure, hyperkalemia, hypocalcemia, hyperuricemia, orhyperphosphatemia, can occur within 12–24 hours after the first infusion. FatalTLS cases have occurred after administration of Rituxan. A high number ofcirculating malignant cells (≥25,000/mm3) or high tumor burden confers a greaterrisk of TLS after rituximab. Consider prophylaxis for TLS in patients at high risk.Correct electrolyte abnormalities, monitor renal function and fluid balance, andadminister supportive care, including dialysis as indicated. [See Boxed Warning.]Severe Mucocutaneous Reactions Mucocutaneous reactions, some with fataloutcome, can occur in patients treated with Rituxan. These reactions includeparaneoplastic pemphigus, Stevens-Johnson syndrome, lichenoid dermatitis,vesiculobullous dermatitis, and toxic epidermal necrolysis. The onset of thesereactions has varied from 1–13 weeks following Rituxan exposure. DiscontinueRituxan in patients who experience a severe mucocutaneous reaction. The safetyof readministration of Rituxan to patients with severe mucocutaneous reactionshas not been determined. [See Boxed Warning, Adverse Reactions.] ProgressiveMultifocal Leukoencephalopathy (PML) JC virus infection resulting in PMLand death can occur in Rituxan-treated patients with hematologic malignancies or with autoimmune diseases. The majority of patients with hematologicmalignancies diagnosed with PML received Rituxan in combination withchemotherapy or as part of a hematopoietic stem cell transplant. The patients withautoimmune diseases had prior or concurrent immunosuppressive therapy. Mostcases of PML were diagnosed within 12 months of their last infusion of Rituxan.Consider the diagnosis of PML in any patient presenting with new-onsetneurologic manifestations. Discontinue Rituxan and consider discontinuation orreduction of any concomitant chemotherapy or immunosuppressive therapy inpatients who develop PML. [See Boxed Warning, Adverse Reactions.] Hepatitis BVirus (HBV) Reactivation Hepatitis B Virus (HBV) reactivation with fulminanthepatitis, hepatic failure, and death can occur in patients with hematologicmalignancies treated with Rituxan. The median time to the diagnosis of hepatitiswas approximately 4 months after the initiation of Rituxan and approximately onemonth after the last dose. Screen patients at high risk of HBV infection beforeinitiation of Rituxan. Closely monitor carriers of hepatitis B for clinical andlaboratory signs of active HBV infection for several months following Rituxantherapy. Discontinue Rituxan and any concomitant chemotherapy in patients whodevelop viral hepatitis, and institute appropriate treatment including antiviraltherapy. Insufficient data exist regarding the safety of resuming Rituxan in patientswho develop hepatitis subsequent to HBV reactivation. [See Adverse Reactions.]Other Viral Infections The following additional serious viral infections, eithernew, reactivated, or exacerbated, have been identified in clinical studies orpostmarketing reports. The majority of patients received Rituxan in combinationwith chemotherapy or as part of a hematopoietic stem cell transplant. These viralinfections included cytomegalovirus, herpes simplex virus, parvovirus B19,varicella zoster virus, West Nile virus, and hepatitis C. In some cases, the viralinfections occurred as late as one year following discontinuation of Rituxan andhave resulted in death. [See Adverse Reactions.] Cardiovascular Discontinueinfusions for serious or life-threatening cardiac arrhythmias. Perform cardiacmonitoring during and after all infusions of Rituxan for patients who developclinically significant arrhythmias or who have a history of arrhythmia or angina.[See Adverse Reactions.] Renal Severe, including fatal, renal toxicity can occurafter Rituxan administration in patients with hematologic malignancies. Renaltoxicity has occurred in patients with high numbers of circulating malignant cells(≥25,000/mm3) or high tumor burden who experience tumor lysis syndrome andin patients with NHL administered concomitant cisplatin therapy during clinicaltrials. The combination of cisplatin and Rituxan is not an approved treatmentregimen. Use extreme caution if this non-approved combination is used in clinicaltrials and monitor closely for signs of renal failure. Consider discontinuation ofRituxan for patients with a rising serum creatinine or oliguria. Bowel Obstructionand Perforation Abdominal pain, bowel obstruction and perforation, in some

WARNING: FATAL INFUSION REACTIONS, TUMOR LYSIS SYNDROME(TLS), SEVERE MUCOCUTANEOUS REACTIONS, and PROGRESSIVEMULTIFOCAL LEUKOENCEPHALOPATHY (PML)Infusion Reactions: Rituxan administration can result in serious,including fatal infusion reactions. Deaths within 24 hours of Rituxaninfusion have occurred. Approximately 80% of fatal infusion reactionsoccurred in association with the first infusion. Carefully monitorpatients during infusions. Discontinue Rituxan infusion and providemedical treatment for Grade 3 or 4 infusion reactions [see Warningsand Precautions, Adverse Reactions]. Tumor Lysis Syndrome (TLS):Acute renal failure requiring dialysis with instances of fatal outcomecan occur in the setting of TLS following treatment of non-Hodgkin’slymphoma (NHL) patients with Rituxan [see Warnings and Precautions,Adverse Reactions]. Severe Mucocutaneous Reactions: Severe,including fatal, mucocutaneous reactions can occur in patientsreceiving Rituxan [see Warnings and Precautions, Adverse Reactions].Progressive Multifocal Leukoencephalopathy (PML): JC virus infectionresulting in PML and death can occur in patients receiving Rituxan [seeWarnings and Precautions, Adverse Reactions].

cases leading to death, can occur in patients receiving Rituxan in combinationwith chemotherapy. In postmarketing reports, the mean time to documentedgastrointestinal perforation was 6 (range 1–77) days in patients with NHL.Perform a thorough diagnostic evaluation and institute appropriate treatment forcomplaints of abdominal pain, especially early in the course of Rituxan therapy.[See Adverse Reactions.] Immunization The safety of immunization with live viralvaccines following Rituxan therapy has not been studied and vaccination with livevirus vaccines is not recommended. For NHL patients, the benefits of primary orbooster vaccinations should be weighted against the risks of delay in initiation ofRituxan therapy. Laboratory Monitoring Because Rituxan binds to all CD20-positive B lymphocytes (malignant and non-malignant), obtain complete bloodcounts (CBC) and platelet counts at regular intervals during Rituxan therapy andmore frequently in patients who develop cytopenias [see Adverse Reactions]. Theduration of cytopenias caused by Rituxan can extend months beyond thetreatment period. ADVERSE REACTIONS The most common adverse reactions ofRituxan (incidence ≥25%) observed in patients with NHL are infusion reactions,fever, chills, infection, asthenia, and lymphopenia. The most important seriousadverse reactions of Rituxan are infusion reactions, tumor lysis syndrome,mucocutaneous toxicities, hepatitis B reactivation with fulminant hepatitis, PML,other viral infections, cardiac arrhythmias, renal toxicity, and bowel obstructionand perforation. Clinical Trials Experience Non-Hodgkin’s LymphomaBecause clinical trials are conducted under widely varying conditions, adversereaction rates observed in the clinical trials of a drug cannot be directly comparedto rates in the clinical trials of another drug and may not reflect the rates observedin practice. The data described below reflect exposure to Rituxan in 1606patients, with exposures ranging from a single infusion up to 6–8 months. Rituxanwas studied in both single-agent and active-controlled trials (n = 356 and n =1250). These data were obtained in adults with low-grade, follicular, or DLBCLNHL. Most patients received Rituxan as an infusion of 375 mg/m2 per infusion,given as a single agent weekly for up to 8 doses, in combination withchemotherapy for up to 8 doses, or following chemotherapy for up to 16 doses.Infusion Reactions In the majority of patients with NHL, infusion reactionsconsisting of fever, chills/rigors, nausea, pruritus, angioedema, hypotension,headache, bronchospasm, urticaria, rash, vomiting, myalgia, dizziness, orhypertension occurred during the first Rituxan infusion. Infusion reactions typicallyoccurred within 30 to 120 minutes of beginning the first infusion and resolvedwith slowing or interruption of the Rituxan infusion and with supportive care(diphenhydramine, acetaminophen, and intravenous saline). The incidence ofinfusion reactions was highest during the first infusion (77%) and decreased witheach subsequent infusion. [See Boxed Warning, Warnings and Precautions.]Infections Serious infections (NCI CTCAE Grade 3 or 4), including sepsis,occurred in less than 5% of patients with NHL in the single-arm studies. Theoverall incidence of infections was 31% (bacterial 19%, viral 10%, unknown 6%,and fungal 1%). [See Warnings and Precautions.] In randomized, controlledstudies where Rituxan was administered following chemotherapy for thetreatment of follicular or low-grade NHL, the rate of infection was higher amongpatients who received Rituxan. In diffuse large B-cell lymphoma patients, viralinfections occurred more frequently in those who received Rituxan. Cytopeniasand hypogammaglobulinemia In patients with NHL receiving rituximabmonotherapy, NCI-CTC Grade 3 and 4 cytopenias were reported in 48% ofpatients. These included lymphopenia (40%), neutropenia (6%), leukopenia (4%),anemia (3%), and thrombocytopenia (2%). The median duration of lymphopeniawas 14 days (range, 1–588 days) and of neutropenia was 13 days (range, 2–116days). A single occurrence of transient aplastic anemia (pure red cell aplasia) andtwo occurrences of hemolytic anemia following Rituxan therapy occurred duringthe single-arm studies. In studies of monotherapy, Rituxan-induced B-celldepletion occurred in 70% to 80% of patients with NHL. Decreased IgM and IgGserum levels occurred in 14% of these patients. Single-Agent Rituxan Adversereactions in Table 1 occurred in 356 patients with relapsed or refractory, low-grade or follicular, CD20-positive, B-cell NHL treated in single-arm studies ofRituxan administered as a single agent. Most patients received Rituxan 375 mg/m2

weekly for 4 doses.Table 1Incidence of Adverse Events in ≥5% of Patients with Relapsed or Refractory, Low-Grade or Follicular NHL, Receiving Single-agent Rituxan (N = 356)a,b

aAdverse reactions observed up to 12 months following Rituxan.

bAdverse reactions graded for severity by

NCI-CTC criteria.

In these single-arm Rituxan studies, bronchiolitis obliterans occurred during andup to 6 months after Rituxan infusion. Rituxan in Combination WithChemotherapy Adverse reactions information below is based on 1250 patientswho received Rituxan in combination with chemotherapy or followingchemotherapy. Rituxan in Combination With Chemotherapy for Low-GradeNHL In Study 4, patients in the R-CVP arm experienced a higher incidence ofinfusional toxicity and neutropenia compared to patients in the CVP arm. Thefollowing adverse reactions occurred more frequently (≥5%) in patients receivingR-CVP compared to CVP alone: rash (17% vs. 5%), cough (15% vs. 6%), flushing(14% vs. 3%), rigors (10% vs. 2%), pruritus (10% vs. 1%), neutropenia (8% vs.3%), and chest tightness (7% vs. 1%). In Study 5, the following adverse reactionswere reported more frequently (≥5%) in patients receiving Rituxan following CVPcompared to patients who received no further therapy: fatigue (39% vs. 14%),anemia (35% vs. 20%), peripheral sensory neuropathy (30% vs. 18%), infections(19% vs. 9%), pulmonary toxicity (18% vs. 10%), hepato-biliary toxicity (17% vs.7%), rash and/or pruritus (17% vs. 5%), arthralgia (12% vs. 3%), and weight gain(11% vs. 4%). Neutropenia was the only Grade 3 or 4 adverse reaction thatoccurred more frequently (≥2%) in the Rituxan arm compared with those whoreceived no further therapy (4% vs. 1%). Rituxan in Combination With

All Grades (%) Grade 3 and 4 (%)

Any Adverse Events 99 57Body as a Whole 86 10

Fever 53 1Chills 33 3Infection 31 4Asthenia 26 1Headache 19 1Abdominal Pain 14 1Pain 12 1Back Pain 10 1Throat Irritation 9 0Flushing 5 0

Heme and Lymphatic System 67 48Lymphopenia 48 40Leukopenia 14 4Neutropenia 14 6Thrombocytopenia 12 2Anemia 8 3

Skin and Appendages 44 2Night Sweats 15 1Rash 15 1Pruritus 14 1Urticaria 8 1

All Grades (%) Grade 3 and 4 (%)

Respiratory System 38 4Increased Cough 13 1Rhinitis 12 1Bronchospasm 8 1Dyspnea 7 1Sinusitis 6 0

Metabolic and Nutritional Disorders 38 3

Angioedema 11 1Hyperglycemia 9 1Peripheral Edema 8 0LDH Increase 7 0

Digestive System 37 2Nausea 23 1Diarrhea 10 1Vomiting 10 1

Nervous System 32 1Dizziness 10 1Anxiety 5 1

Musculoskeletal System 26 3Myalgia 10 1Arthralgia 10 1

Cardiovascular System 25 3Hypotension 10 1Hypertension 6 1

Chemotherapy for DLBCL In Studies 6 and 7, the following adverse reactions,regardless of severity, were reported more frequently (≥5%) in patients age ≥60years receiving R-CHOP as compared to CHOP alone: pyrexia (56% vs. 46%), lungdisorder (31% vs. 24%), cardiac disorder (29% vs. 21%), and chills (13% vs. 4%).Detailed safety data collection in these studies was primarily limited to Grade 3and 4 adverse reactions and serious adverse reactions. In Study 7, a review ofcardiac toxicity determined that supraventricular arrhythmias or tachycardiaaccounted for most of the difference in cardiac disorders (4.5% for R-CHOP vs.1.0% for CHOP). The following Grade 3 or 4 adverse reactions occurred morefrequently among patients in the R-CHOP arm compared with those in the CHOParm: thrombocytopenia (9% vs. 7%) and lung disorder (6% vs. 3%). Other Grade3 or 4 adverse reactions occurring more frequently among patients receiving R-CHOP were viral infection (Study 7), neutropenia (Studies 7 and 8), and anemia(Study 8). Immunogenicity As with all therapeutic proteins, there is a potentialfor immunogenicity. The observed incidence of antibody (including neutralizingantibody) positivity in an assay is highly dependent on several factors includingassay sensitivity and specificity, assay methodology, sample handling, timing ofsample collection, concomitant medications, and underlying disease. For thesereasons, comparison of the incidence of antibodies to Rituxan with the incidenceof antibodies to other products may be misleading. Using an ELISA assay, anti-human anti-chimeric antibody (HACA) was detected in 4 of 356 (1.1%) patientswith low-grade or follicular NHL receiving single-agent Rituxan. Three of the fourpatients had an objective clinical response. The clinical relevance of HACAformation in rituximab treated patients is unclear. Postmarketing ExperienceThe following adverse reactions have been identified during postapproval use ofRituxan in hematologic malignancies. Because these reactions are reportedvoluntarily from a population of uncertain size, it is not always possible to reliablyestimate their frequency or establish a causal relationship to drug exposure.Decisions to include these reactions in labeling are typically based on one or moreof the following factors: (1) seriousness of the reaction, (2) frequency of reporting,or (3) strength of causal connection to Rituxan. Hematologic: prolongedpancytopenia, marrow hypoplasia, and late-onset neutropenia, hyperviscositysyndrome in Waldenstrom’s macroglobulinemia. Cardiac: fatal cardiac failure.Immune/Autoimmune Events: uveitis, optic neuritis, systemic vasculitis, pleuritis,lupus-like syndrome, serum sickness, polyarticular arthritis, and vasculitis with rash. Infection: viral infections, including progressive multifocalleukoencephalopathy (PML), increase in fatal infections in HIV-associatedlymphoma, and a reported increased incidence of Grade 3 and 4 infections inpatients with previously treated lymphoma without known HIV infection.Neoplasia: disease progression of Kaposi’s sarcoma. Skin: severe mucocutaneousreactions. Gastrointestinal: bowel obstruction and perforation. Pulmonary: fatalbronchiolitis obliterans and pneumonitis (including interstitial pneumonitis). DRUGINTERACTIONS Formal drug interaction studies have not been performed withRituxan. USE IN SPECIFIC POPULATIONS Pregnancy Category C: There areno adequate and well-controlled studies of rituximab in pregnant women.Postmarketing data indicate that B-cell lymphocytopenia generally lasting lessthan six months can occur in infants exposed to rituximab in-utero. Rituximab wasdetected postnatally in the serum of infants exposed in-utero. Non-Hodgkin’slymphoma is a serious condition that requires treatment. Rituximab should beused during pregnancy only if the potential benefit to the mother justifies thepotential risk to the fetus. Reproduction studies in cynomolgus monkeys atmaternal exposures similar to human therapeutic exposures showed no evidenceof teratogenic effects. However, B-cell lymphoid tissue was reduced in theoffspring of treated dams. The B-cell counts returned to normal levels, andimmunologic function was restored within 6 months of birth. Nursing Mothers Itis not known whether Rituxan is secreted into human milk. However, Rituxan issecreted in the milk of lactating cynomolgus monkeys, and IgG is excreted inhuman milk. Published data suggest that antibodies in breast milk do not enterthe neonatal and infant circulations in substantial amounts. The unknown risks tothe infant from oral ingestion of Rituxan should be weighed against the knownbenefits of breastfeeding. Pediatric Use The safety and effectiveness of Rituxanin pediatric patients have not been established. Geriatric Use Diffuse Large B-Cell NHL Among patients with DLBCL evaluated in three randomized, active-controlled trials, 927 patients received Rituxan in combination with chemotherapy.Of these, 396 (43%) were age 65 or greater and 123 (13%) were age 75 orgreater. No overall differences in effectiveness were observed between thesepatients and younger patients. Cardiac adverse reactions, mostly supraventriculararrhythmias, occurred more frequently among elderly patients. Serious pulmonaryadverse reactions were also more common among the elderly, includingpneumonia and pneumonitis. Low-Grade or Follicular Non-Hodgkin’sLymphoma Clinical studies of Rituxan in low-grade or follicular, CD20-positive,B-cell NHL did not include sufficient numbers of patients aged 65 and over todetermine whether they respond differently from younger subjects.OVERDOSAGE There has been no experience with overdosage in human clinicaltrials. Single doses of up to 500 mg/m2 have been given in dose-escalationclinical trials. NONCLINICAL TOXICOLOGY Carcinogenesis, Mutagenesis,Impairment of Fertility No long term animal studies have been performed toestablish the carcinogenic or mutagenic potential of Rituxan or to determinepotential effects on fertility in males or females. PATIENT COUNSELINGINFORMATION Patients should be provided the Rituxan Medication Guide andprovided an opportunity to read prior to each treatment session. Because cautionshould be exercised in administering Rituxan to patients with active infections, it isimportant that the patient’s overall health be assessed at each visit and anyquestions resulting from the patient’s reading of the Medication Guide bediscussed. Rituxan is detectable in serum for up to six months followingcompletion of therapy. Individuals of childbearing potential should use effectivecontraception during treatment and for 12 months after Rituxan therapy.

Revised 9/2008 (4835505)

Jointly Marketed by: Biogen Idec Inc. 5200 Research Place San Diego, CA 92122Genentech USA, Inc. 1 DNA Way South San Francisco, CA 94080-4990

©2008 Biogen Idec Inc. and Genentech, Inc. 7140917 October 2008

ME

ETIN

GS

7-12 SAN DIEGO, CA

2009 Society of Interventional

Radiology Annual Meeting

www.sirweb.org

8-10 TAMPA, FL

American Society of Preventive

Oncology 33nd Annual Meeting

www.aspo.org

11-15 HOLLYWOOD, FL

NCCN 14th Annual Conference:

Clinical Practice Guidelines & Quality

Cancer Care

www.nccn.org

©iS

tockp

ho

to.c

om

/Nic

ole

Mo

rse

©iS

tockp

ho

to.c

om

/Ch

ris P

ritc

ha

rd©

iSto

ckp

ho

to.c

om

/Lo

ren

a M

olin

ari

You help patients reach their treatment goalsRITUXAN is a proven path for many patients battling non-Hodgkin’s lymphoma (NHL),but they can’t complete the journey alone.

Oncology nurses are central members of a cancer care team—working together to achieve improved outcomes. Your guidance and leadership help patients reach their treatment goals. We recognize your commitment and support your continued efforts with innovative patient-education materials and services.

RITUXAN is indicated for the treatment of patients with:

• Relapsed or refractory, low-grade or follicular, CD20-positive, B-cell NHL as a single agent

• Previously untreated follicular, CD20-positive, B-cell NHL in combination with CVP chemotherapy

• Non-progressing (including stable disease), low-grade, CD20-positive,B-cell NHL, as a single agent, after first-line CVP chemotherapy

• Previously untreated diffuse large B-cell, CD20-positive NHL in combination with CHOP or other anthracycline-based chemotherapy regimens

Reference: 1. RITUXAN® (Rituximab) full prescribing information, Genentech, Inc., 2008.

Please see brief summary of prescribing information on adjacent page.

Attention Healthcare Provider: Provide Medication Guide to patient prior to RITUXAN infusion.

BOXED WARNINGS and Additional Important Safety Information

The most important serious adverse reactions of RITUXAN are fatal infusionreactions, tumor lysis syndrome (TLS), severe mucocutaneous reactions,progressive multifocal leukoencephalopathy (PML), hepatitis B reactivation withfulminant hepatitis, other viral infections, cardiovascular events, renal toxicity, andbowel obstruction and perforation. The most common adverse reactions of RITUXAN(incidence ≥25%) observed in patients with NHL are infusion reactions, fever, chills,infection, asthenia, and lymphopenia.1

Leading patients towardimproved outcomes

To learn more, ask a RITUXAN representative or visit

www.rituxan.com/lymphoma

PROVE N. POWE R FU L.

©2008 Genentech, Inc., and Biogen Idec Inc. All rights reserved. 9231900 April 2008