January/February 2009 Vol. 2 No. 1

To R co da eg nd ww annu y f iste w. al or r co new Yo ex sle ur tte m www.theoncologynurse.com .co r ser m ies.

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JANUARY/FEBRUARY 2009 • VOL. 2, NO. 1

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ns io at er id ns Co a m lo ye M

HEMATOLOGIC CANCERS Strategies for determining the extent of non-Hodgkin’s lymphoma

le tip ul M

MEDICAL MINUTES Acupuncture may reduce vasomotor symptoms in breast cancer patients

ader e L e Th and s w in Ne eting Me age r Cove

ONS CONGRESS

BREAST CANCER

Nonanthracycline Regimens Provide Alternatives for HER2positive Breast Cancers

A

nthracycline-based regimens have improved the lives of patients with human epidermal growth factor-2 (HER2)-overexpressing breast cancers, but because of their toxicities, many practitioners would like to be able to move away from these drugs.

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

boplatin, trastuzumab (TCH) combination is a reasonable alternative to an anthracycline-based regimen for patients with HER2-overexpressing recurrent or metastatic breast cancers. Although the acute side effects may be as severe as with an anthracycline regimen, they felt they were manageable. Long term, TCH may present less risk for cardiotoxicity even though the trastuzumab in the regimen has this potential.

HEMATOLOGIC CANCERS

Nadroparin Halves the Risk of Thromboembolic Events in Cancer Patients Receiving Chemotherapy

“I think a lot of people use it. But I worry that there’s more opinion here than decision making that’s 100% based on the totality of the evidence,” said Eric Winer, MD, in an interview with The Oncology Nurse.

Winer is director of the Breast Oncology Center at Dana Farber Cancer Institute in Boston. He and others offered that a real advance would be to be able to predict Continued on page 20

BREAST CANCER

Breast Cancer Patients and Providers May Dispute Treatment Goals

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

SAN ANTONIO—Breast cancer patients and their oncologists and oncology nurses sometimes disagree on the goals of chemotherapy, according to results released at the 2008 San Antonio Breast Cancer Symposium by a group from the University of Virginia Health System in Charlottesville.

Heather West, MD, and her associates compared treatment objectives of 53 breast cancer patients undergoing chemotherapy and their providers (11 oncologists

Continued on page 9

Continued on page 20

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 COMPLIMENTARY CE CREDIT AT WWW.COEXM.COM PROGRAM #09CE 035

Decision Aids as a Guide for Cancer Patients Making Clinical Decisions

College of Nursing Continuing Nursing Education

PAGE 27

REACH US ONLINE AT www.coexm.com • View current and past issues • Register to receive your free subscription • Access CE activities

© 2009 Green Hill Healthcare Communications, LLC

In the adjuvant treatment of HER2+ breast cancer,

TCH provided disease-free survival Taxotere®* (docetaxel) and carboplatin plus Herceptin provided benefit consistent with AC→TH1

•In BCIRG 006, conducted by the Breast Cancer International Research Group (BCIRG), patients were randomized (1:1:1) to receive one 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

•

Disease-free survival (DFS)1,2 1.0

Absolute DFS at 3 years 86.3% (TCH) 88.0% (AC→TH) 82.3% (AC→T)

Proportion event-free

0.8

TCH: 33% reduction

0.6

in relative risk of recurrence vs AC→T (HR=0.67, CI: 0.54 -0.84; P =0.0006)†

0.4

AC→TH: 40% reduction

0.2

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)†

0.0 0

1

2

3

4

417 457 447

103 126 126

DFS (years)

Number at risk

AC→T 1073 AC→TH 1074 1075 TCH

971 1023 1018

802 885 877

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

Adjuvant indications Herceptin is indicated for adjuvant treatment of HER2-overexpressing node-positive or node-negative (ER/PR-negative or with one high-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

• • •

*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.

Boxed WARNINGS and Additional Important Safety Information Herceptin 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 was highest in patients who received Herceptin concurrently with anthracycline-containing chemotherapy regimens. Discontinue Herceptin treatment in patients receiving adjuvant therapy and strongly consider discontinuation of Herceptin in patients with metastatic breast cancer 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 after Herceptin treatment. More frequent monitoring should be employed if Herceptin is withheld in patients who develop significant left ventricular cardiac dysfunction. In one adjuvant clinical trial, cardiac ischemia or infarction occurred in the Herceptin-containing regimens.

The first approved non-anthracycline Herceptin-containing regimen

1

benefit with reduced cardiac risk Non-anthracycline regimen reduced cardiac 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

The TCH regimen enabled a higher completion rate with shorter duration of IV therapy

•The TCH regimen enables immediate initiation of Herceptin with chemotherapy 1

•The TCH regimen reduces the overall duration of infused therapy to 12 months, compared with 15 months with the AC→TH regimen1

•On average, for every 100 patients receiving each regimen in

BCIRG 006, 13 more were able to complete therapy with TCH than AC→TH 2 – 86.3% of patients in the TCH arm were able to complete planned adjuvant therapy vs 73.5% of patients in the AC→TH arm

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 experiencing dyspnea or clinically significant hypotension. Patients should be monitored until signs and symptoms completely resolve. Discontinue Herceptin for 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 reactions associated with Herceptin use were fever, nausea, vomiting, infusion reactions, diarrhea, infections, increased cough, headache, fatigue, dyspnea, rash, neutropenia, anemia, and myalgia.

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

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

www.herceptin.com ©2008 Genentech USA

So. San Francisco, CA

All rights reserved.

9488200

11/08

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

WARNING: CARDIOMYOPATHY, INFUSION REACTIONS, and PULMONARY TOXICITY Cardiomyopathy Herceptin can result in sub-clinical and clinical cardiac failure manifesting as CHF and decreased LVEF. The incidence and severity of left ventricular cardiac dysfunction was highest in patients who received Herceptin concurrently with anthracycline-containing chemotherapy regimens.

Evaluate left ventricular function in all patients prior to and during treatment with Herceptin. Discontinue Herceptin treatment in patients receiving adjuvant therapy and strongly consider discontinuation of Herceptin treatment in patients with metastatic breast cancer for clinically significant decrease in left ventricular function. [see Warnings and Precautions and Dosage and Administration] Infusion Reactions; Pulmonary Toxicity Herceptin administration can result in serious infusion reactions and pulmonary toxicity. 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 experiencing dyspnea or clinically significant hypotension. Patients should be monitored until signs and symptoms completely resolve. Discontinue Herceptin for infusion reactions manifesting as anaphylaxis, angioedema, interstitial pneumonitis, or acute respiratory distress 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 anthracycline based therapy. Metastatic Breast Cancer Herceptin is indicated: • In combination with paclitaxel for firstline treatment of HER2-overexpressing metastatic breast cancer • As a single agent for treatment of HER2-overexpressing breast cancer in patients who have received one or more chemotherapy regimens for metastatic disease. CONTRAINDICATIONS None.

WARNINGS AND PRECAUTIONS Cardiomyopathy Herceptin can cause left ventricular cardiac dysfunction, arrhythmias, hypertension, disabling cardiac failure, cardiomyopathy, and cardiac death [see Boxed Warning: 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 patients receiving Herceptin as a single agent or in combination therapy compared with those not receiving Herceptin.

The highest absolute incidence occurs when Herceptin is administered with an anthracycline. Withhold Herceptin for ≥16% absolute decrease in LVEF from pre-treatment values or an LVEF value below institutional limits of normal and ≥10% absolute decrease in LVEF from pretreatment values. [see Dosage and Administration] The safety of continuation or resumption of Herceptin in patients with Herceptin-induced left ventricular cardiac dysfunction has not been studied. Cardiac Monitoring Conduct thorough cardiac assessment, including history, physical examination, and determination of LVEF by echocardiogram or MUGA scan. The following schedule is recommended: • Baseline LVEF measurement 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 to clinical evidence of myocardial dysfunction or significant decline in LVEF. In Study 3, the number of patients who discontinued Herceptin due to cardiac toxicity was 2.6% (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 patients were receiving cardiac medication at last follow-up.

Approximately half of the surviving patients had recovery to a normal LVEF (defined as ≥ 50%) on continuing medical management 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 in patients with Herceptin-induced left ventricular cardiac dysfunction has not been studied.

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

Study Regimen 1 & 2a ACb Paclitaxel+ Herceptin 3 Chemo Herceptin monotherapy 4 ACb Docetaxel+ Herceptin 4 Docetaxel+Carbo+ Herceptin a b

Incidence of CHF Herceptin Control 2% (32/1677)

0.4% (7/1600)

2% (30/1678)

0.3% (5/1708)

2% (20/1068)

0.3% (3/1050)

0.4% (4/1056)

0.3% (3/1050))

Includes 1 patient with fatal cardiomyopathy.

Anthracycline (doxorubicin) and cyclophosphamide.

Table 2 Incidence of Cardiac Dysfunctiona in Metastatic Breast Cancer Studies

Study 5 (AC)b 5 (paclitaxel) 6

Event Cardiac Dysfunction Cardiac Dysfunction Cardiac Dysfunctionc

Incidence NYHA I-IV NYHA III-IV Herceptin Control Herceptin Control 28%

7%

19%

3%

11%

1%

4%

1%

7%

N/A

5%

N/A

a

Congestive heart failure or significant asymptomatic decrease in LVEF. bAnthracycline (doxorubicin or epirubicin) and cyclophosphamide. cIncludes 1 patient with fatal cardiomyopathy.

Infusion Reactions Infusion reactions consist of a symptom 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 Adverse Reactions]. In postmarketing reports, serious and fatal infusion reactions have been reported. Severe reactions which include bronchospasm, anaphylaxis, angioedema, hypoxia, and severe hypotension, were usually reported during or immediately following the initial infusion.

However, the onset and clinical course were variable including progressive worsening, initial improvement followed by clinical deterioration, or delayed postinfusion events with rapid clinical deterioration. For fatal events, death occurred within hours to days following a serious infusion reaction. Interrupt Herceptin infusion in all patients experiencing dyspnea, clinically significant hypotension, and intervention of medical therapy administered, which may include: epinephrine, corticosteroids, diphenhydramine, bronchodilators, and oxygen. Patients should be evaluated and carefully monitored until complete resolution of signs and symptoms. Permanent discontinuation should be strongly considered 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 infusion reaction. Prior to resumption of Herceptin infusion, the majority of patients who experienced a severe infusion reaction were pre-medicated with antihistamines and/or corticosteroids. While some patients tolerated Herceptin infusions, others had recurrent severe infusion reactions despite pre-medications. Exacerbation of ChemotherapyInduced Neutropenia In randomized, controlled clinical trials in women with metastatic breast cancer, the perpatient incidences of NCI CTC Grade 3-4 neutropenia and of febrile neutropenia were higher in patients receiving Herceptin in combination with myelosuppressive chemotherapy as compared to those who received chemotherapy 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 respiratory distress 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 protein overexpression is necessary for selection of patients appropriate for Herceptin therapy because these are the only patients studied and for whom benefit has been shown. Assessment for HER2 overexpression and of HER2 gene amplification should be performed by laboratories with demonstrated proficiency in the specific technology being utilized. Improper assay performance, including use of suboptimally fixed tissue, failure to utilize specified reagents, deviation from specific assay instructions, and failure to include appropriate controls for assay validation, can lead to unreliable results. Several FDA-approved commercial assays are available to aid in the selection of patients for Herceptin therapy. These include HercepTestTM and Pathway ® HER-2/neu (IHC assays) and PathVysion® and HER2 FISH pharmDxTM (FISH assays). Users should refer to the package inserts of specific assay kits for information on the validation and performance of each assay. Limitations in assay precision (particularly for the IHC method) and in the direct linkage between assay result and overexpression of the Herceptin target (for the FISH method) make it inadvisable to rely on a single method to rule out potential Herceptin benefit. A negative FISH result does not rule out HER2 overexpression and potential benefit from Herceptin. Treatment outcomes for metastatic breast cancer (Study 5) as a function of IHC and FISH testing are provided in Table 9. Treatment outcomes for adjuvant breast cancer (Studies 2 and 3) as a function of IHC and FISH testing are provided in Table 7.

HER2 Protein Overexpression Detection Methods HER2 protein overexpression can be established by measuring HER2 protein using an IHC method. HercepTest ®, one test approved for this use, was assessed for concordance with the Clinical Trial Assay (CTA), using tumor specimens collected and stored independently from those obtained in Herceptin clinical studies in women with metastatic breast cancer. Data are provided in the package insert for HercepTest ®. HER2 Gene Amplification Detection Method The presence of HER2 protein overexpression and gene amplification are highly correlated, therefore the use of FISH to detect gene amplification may be employed for selection of patients appropriate for Herceptin therapy. PathVysion®, one test approved for this use, was evaluated in an exploratory, retrospective assessment of available CTA 2+ or 3+ tumor specimens collected as part of patient screening for clinical studies in metastatic breast cancer (Studies 5 and 6). Data are provided in the package insert for PathVysion®. Embryo-Fetal Toxicity (Pregnancy Category D) Herceptin can cause fetal harm when administered to a pregnant woman. Post-marketing case reports suggest that Herceptin use during pregnancy increases 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 REACTIONS The following adverse reactions are discussed in greater detail in other sections of the label: • Cardiomyopathy [see Warnings and Precautions] • Infusion reactions [see Warnings and Precautions] • Exacerbation of chemotherapy-induced neutropenia [see Warnings and Precautions] • Pulmonary toxicity [see Warnings and Precautions] The most common adverse reactions in patients receiving Herceptin are fever, nausea, vomiting, infusion reactions, diarrhea, infections, increased cough, headache, fatigue, dyspnea, rash, neutropenia, anemia, and myalgia. Adverse reactions requiring interruption or discontinuation of Herceptin treatment include CHF, significant decline in left ventricular cardiac function, severe infusion reactions, and pulmonary toxicity [see Dosage and Administration]. Clinical Trials Experience Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice. Adjuvant Breast Cancer Studies The data below reflect exposure to Herceptin 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; the median treatment duration was 51 weeks and median number of infusions was 18. Among the 3386 patients enrolled 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 Adverse Event Preferred Term (n= 1678) Cardiac Hypertension 64 (4%) Dizziness 60 (4%) Ejection Fraction Decreased 58 (3.5%) Palpitations 48 (3%) Cardiac Arrhythmiasb 40 (3%) Cardiac Failure Congestive 30 (2%) Cardiac Failure 9 (0.5%) Cardiac Disorder 5 (0.3%) Ventricular Dysfunction 4 (0.2%) Respiratory Thoracic Mediastinal Disorders Nasopharyngitis 135 (8%) Cough 81 (5%) Influenza 70 (4%) Dyspnea 57 (3%) URI 46 (3%) Rhinitis 36 (2%) Pharyngolaryngeal Pain 32 (2%) Sinusitis 26 (2%) Epistaxis 25 (2%) Pulmonary Hypertension 4 (0.2%) Interstitial Pneumonitis 4 (0.2%) Gastrointestinal Disorders Diarrhea 123 (7%) Nausea 108 (6%) Vomiting 58 (3.5%) Constipation 33 (2%) Dyspepsia 30 (2%) Upper Abdominal Pain 29 (2%) Musculoskeletal & Connective Tissue Disorders Arthralgia 137 (8%) Back Pain 91 (5%) Myalgia 63 (4%) Bone Pain 49 (3%) Muscle Spasm 46 (3%) Nervous System Disorders Headache 162 (10%) Paraesthesia 29 (2%) Skin & Subcutaneous Tissue Disorders Rash 70 (4%) Nail Disorders 43 (2%) Pruritus 40 (2%) General Disorders Pyrexia 100 (6%) Edema Peripheral 79 (5%) Chills 85 (5%) Asthenia 75 (4.5%) Influenza-like Illness 40 (2%) Sudden Death 1 (0.06%) Infections Nasopharyngitis 135 (8%) UTI 39 (3%) Immune System Disorders Hypersensitivity 10 (0.6%) Autoimmune Thyroiditis 4 (0.3%)

Observation (n= 1708) 35 (2%) 29 (2%) 11 (0.6%) 12 (0.7%) 17 (1%) 5 (0.3%) 4 (0.2%) 0 (0%) 0 (0%) 43 (3%) 34 (2%) 9 (0.5%) 26 (2%) 20 (1%) 6 (0.4%) 8 (0.5%) 5 (0.3%) 1 (0.06%) 0 (0%) 0 (0%)

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 occurring during chemotherapy and/or Herceptin 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 as compared 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 number of infusions was 26 in the AC-TH arm and 30 in the TCH arm, including weekly infusions during the chemotherapy phase 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 toxicity profile 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, openlabel 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 patients who 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 patients received 4 mg/kg initial dose of Herceptin followed by 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 Reactions Occurring 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 Alone n = 352 n = 91 n = 95 n = 143 n = 135 Body as a Whole Pain 47 61 62 57 42 Asthenia 42 62 57 54 55 Fever 36 49 23 56 34 Chills 32 41 4 35 11 Headache 26 36 28 44 31 Abdominal pain 22 34 22 23 18 Back pain 22 34 30 27 15 Infection 20 47 27 47 31 Flu syndrome 10 12 5 12 6 Accidental injury 6 13 3 9 4 Allergic reaction 3 8 2 4 2 Cardiovascular Tachycardia 5 12 4 10 5 Congestive heart failure 7 11 1 28 7 Digestive Nausea 33 51 9 76 77 Diarrhea 25 45 29 45 26 Vomiting 23 37 28 53 49 Nausea and 8 14 11 18 9 vomiting Anorexia 14 24 16 31 26 Heme & Lymphatic Anemia 4 14 9 36 26 Leukopenia 3 24 17 52 34 Metabolic Peripheral edema 10 22 20 20 17 Edema 8 10 8 11 5 Musculoskeletal Bone pain 7 24 18 7 7 Arthralgia 6 37 21 8 9 Nervous Insomnia 14 25 13 29 15 Dizziness 13 22 24 24 18 Paresthesia 9 48 39 17 11 Depression 6 12 13 20 12 Peripheral neuritis 2 23 16 2 2 Neuropathy 1 13 5 4 4 Respiratory Cough increased 26 41 22 43 29 Dyspnea 22 27 26 42 25 Rhinitis 14 22 5 22 16 Pharyngitis 12 22 14 30 18 Sinusitis 9 21 7 13 6 Skin Rash 18 38 18 27 17 Herpes simplex 2 12 3 7 9 Acne 2 11 3 3 <1 Urogenital Urinary tract infection 5 18 14 13 7

16 (1%) 19 (1%) 10 (0.6%) 17 (1%) 9 (0.5%) 15 (1%) 98 (6%) 58 (3%) 17 (1%) 26 (2%) 3 (0.2%) 49 (3%) 11 (0.6%) 10 (0.6%) 0 (0%) 10 (0.6%) 6 (0.4%) 37 (2%) 0 (0%) 30 (2%) 3 (0.2%) 0 (0%) 43 (3%) 13 (0.8%) 1 (0.06%) 0 (0%)

a

The incidence of Grade 3/4 adverse reactions was <1% in both 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 as compared 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

a

Data 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 detail regarding adverse reactions observed in clinical

a

For 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 by paclitaxel (AC T) or paclitaxel plus Herceptin (AC TH). c Study 4 regimens: doxorubicin and cyclophosphamide followed 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 Baseline and 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 and to 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 and to 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 received Herceptin concurrently with anthracyclines. Infusion Reactions During the first infusion with Herceptin, the symptoms most commonly reported were chills and fever, occurring in approximately 40% of patients in clinical trials. Symptoms were treated with acetaminophen, diphenhydramine, and meperidine (with or without reduction in the rate of Herceptin infusion); permanent discontinuation of Herceptin for infusional toxicity was required 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

January/February 2009

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 was stopped. In one case, Herceptin was resumed after the amniotic fluid index improved, and oligohydramnios recurred. Women using Herceptin during pregnancy should be monitored for oligohydramnios. If oligohydramnios occurs, fetal testing should be done that is appropriate for gestational age and consistent with community standards of care. Additional intravenous (IV) hydration has been helpful when oligohydramnios has occurred following administration of other chemotherapy agents; however, the effects of additional IV hydration with Herceptin treatment are not known. Reproduction studies in cynomolgus monkeys at doses up to 25 times the recommended 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 tissues including cardiac and neural tissues; in mutant mice lacking HER2, embryos died in early gestation. Placental transfer of trastuzumab during the early (Days 20-50 of gestation) and late (Days 120-150 of gestation) fetal development period was observed in monkeys. [See Nonclinical Toxicology] Because animal reproduction studies 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 whether Herceptin is excreted in human milk, but human IgG is excreted in human milk. Published data suggest that breast milk antibodies do not enter the neonatal and infant circulation in substantial amounts. Trastuzumab was present in the breast milk of lactating cynomolgus monkeys given 12.5 times the recommended weekly human dose of 2 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 the potential for serious adverse reactions in nursing infants from Herceptin, a decision should be made whether to discontinue nursing, or discontinue drug, taking into account the elimination half-life of trastuzumab and the importance of the drug to the mother. Pediatric Use The safety and effectiveness of Herceptin in pediatric patients has not been established. Geriatric Use Herceptin has been 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 as compared 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 data collection and differences in study design of the 4 studies of Herceptin in adjuvant treatment of breast cancer preclude a determination of whether the toxicity profile of Herceptin in older patients is different from younger patients. The reported clinical experience is not adequate to determine whether the efficacy improvements (ORR, TTP, OS, DFS) of Herceptin treatment in older patients is different 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 COUNSELING INFORMATION • 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, weight gain of more than 5 pounds in 24 hours, dizziness or loss of consciousness [see Boxed Warning: Cardiomyopathy].

• Advise women with reproductive potential to use effective contraceptive methods during treatment and for a minimum of six months following Herceptin [see Pregnancy]. • Encourage pregnant women who are using Herceptin to enroll in the Cancer and Childbirth Registry [see Pregnancy].

HERCEPTIN® [trastuzumab] Manufactured by: 4839802 Genentech, Inc. Initial US Approval: Sept. 1998 1 DNA Way Revision Date: May 2008 South San Francisco, CA LK0726 7172910 94080-4990 9317800 ©2008 Genentech USA

News Notes ■ ONS Launches Survivorship, Gero-oncology Initiatives The Oncology Nursing Society (ONS) in December 2008 announced two new initiatives, one on survivorship and one on gero-oncology. The Survivorship Initiative will focus on providing resources for all nurses caring for patients who are survivors of adult cancers. The number of cancer survivors in the United States is estimated to be about 12 million and is growing. “One goal of the initiative is to raise awareness that survivorship care is every nurse’s responsibility,” said ONS president Brenda Nevidjon, RN, MSN, FAAN (www.ons.org). The Gero-oncology Advocacy Initiative is one of the strategic efforts planned by the ONS Geriatrics Task Force to address the education needs of nurses caring for older patients with cancer. More than 60% of new cancer diagnoses and 70% of cancer deaths occur in patients 65 years of age or older.

“As the population continues to age, all oncology nurses caring for adults must become knowledgeable about the special needs of older people with cancer,” said Nevidjon. In a related development, the American Academy of Nursing has received a $9.3-million grant from the John A. Hartford Foundation to prepare geriatric nursing faculty to teach the next generation of nurses about the special needs of older patients.

NEWS NOTES

LVEF <50% and Absolute Absolute LVEF Decrease 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) 9.1% 5.4% 2.2% 18.3% 2.4% AC T (n=1488) (136) (81) (33) (272) (36) Study 3 Herceptin 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)

severe in 1.4% and 9% of patients, on second or subsequent Herceptin infusions administered as monotherapy or in combination with chemotherapy, respectively. In the postmarketing setting, severe infusion reactions, including hypersensitivity, anaphylaxis, and angioedema have been reported. 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. 0 patients [Study 2]) were increased in patients receiving Herceptin and chemotherapy compared with those receiving chemotherapy alone. Following the administration of Herceptin as a single agent (Study 6), the incidence of NCI-CTC Grade 3 anemia was <1%. Neutropenia In randomized 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 2–5 neutropenia (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 in combination with myelosuppressive chemotherapy as compared to chemotherapy alone. Infection The overall incidences 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 compared with those receiving chemotherapy alone. The most common site of infections in the adjuvant setting involved the 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 with myelosuppressive chemotherapy as compared to chemotherapy alone. Pulmonary Toxicity Adjuvant Breast Cancer: Among women receiving adjuvant therapy for breast 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 and spontaneous reported Grade 2 dyspnea (3.4% vs. 1% [Study 2]) was higher in patients receiving Herceptin and chemotherapy compared with chemotherapy alone. The most 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 infiltrates occurred in 0.7% of patients receiving Herceptin compared with 0.3% of those receiving chemotherapy alone. Fatal respiratory failure occurred in 3 patients receiving Herceptin, 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 interstitial pneumonitis in Herceptin-treated patients compared to none 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 been reported in the post-marketing experience as part of the symptom complex of infusion reactions. Pulmonary events include bronchospasm, hypoxia, dyspnea, pulmonary infiltrates, pleural effusions, non-cardiogenic pulmonary edema, and acute respiratory distress syndrome. For a detailed description, see Warnings and Precautions.

Thrombosis/Embolism In 4 randomized, controlled clinical trials, the incidence of thrombotic adverse events was higher in patients receiving Herceptin and chemotherapy compared 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 receiving adjuvant therapy for breast cancer, the incidence of NCICTC 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 receiving Herceptin as a single agent for the treatment of metastatic breast cancer, 25% experienced diarrhea. An increased incidence of diarrhea was observed in patients receiving Herceptin in combination with chemotherapy for treatment of metastatic breast cancer. Glomerulopathy In the postmarketing 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. Pathologic findings included membranous glomerulonephritis, focal glomerulosclerosis, and fibrillary glomerulonephritis.

Complications included volume overload and congestive heart failure. Immunogenicity As with all therapeutic proteins, there is a potential for immunogenicity. Among 903 women with metastatic breast cancer, human antihuman antibody (HAHA) to Herceptin was detected in one patient using an enzyme-linked immunosorbent assay (ELISA). This patient did not experience an allergic reaction. Samples for assessment of HAHA were not collected in studies of adjuvant breast cancer. The incidence 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, sample handling, timing of sample collection, concomitant medications, 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 Pregnancy Teratogenic Effects: Category D [see Warnings and Precautions] Herceptin can cause fetal harm when administered to a pregnant woman. Post-marketing case reports suggest that Herceptin use during pregnancy increases the risk for oligohydramnios during the second and third trimester. If Herceptin is used during pregnancy or if a woman becomes pregnant while taking Herceptin,

■ Improved Stool DNA Test A simplified, noninvasive colorectal cancer screening test that detects tumor DNA in stool is an improvement over an earlier generation assay, according to a report in the American Journal of Gastroenterology.

Itzkowitz and colleagues found that the newgeneration test, which uses only two markers, demonstrated high sensitivity (83%) and specificity (82%) for colorectal cancer.

The investigators noted that the majority of cancers were detected regardless of tumor stage, tumor location, or patient age. The new version, they say, will make the test easier to perform, reduce the cost, and facilitate distribution to local laboratories.

■ Air Travel Presents Little Risk of Lymphedema for Breast Cancer Survivors Pressure changes in airplane cabins hold little risk for lymphedema for breast cancer survivors. A recent study by Kilbreath and colleagues, presented at the San Antonio Breast Cancer Symposium, found that only 5% of 63 women who had been treated for breast cancer developed a clinically significant increase in intracellular fluid in their “at-risk” arm during a long-distance flight.

Mastectomy with full axillary node dissection and long-haul travel were associated with greater risk. Extracellular fluid fluctuated somewhat but without a significant effect on impedance ratio. The impedance ratio increased by 2% or less in 48 women and 2% to 5% in 12. The researchers hope these findings will help dispel myths that have kept some breast cancer survivors from flying. (www.sabcs.org)

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3

NEWS NOTES

trials of adjuvant breast, metastatic breast cancer, or post-marketing experience. Cardiomyopathy Serial measurement of cardiac function (LVEF) was obtained in clinical trials in the adjuvant treatment of breast cancer. 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 was higher among patients receiving Herceptin and paclitaxel as compared to those receiving paclitaxel alone in Studies 1 and 2, and in patients receiving Herceptin monotherapy compared to observation in Study 3 (see Table 5, Figures 1 and 2).

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

Vol. 2, No. 1

January/February 2009

Hematologic Cancers FCR improves progression-free survival

CONTENTS

12

Editor’s Letter

8 Medical Minutes

Breast Cancer Obesity increases risk for contralateral breast cancer

27

6

Breast Cancer Skin moisturizers may expose patients to estrogen

19

News Notes

Hematologic Cancers Non-Hodgkin’s lymphomas, Part 3: Diagnostic strategies

19

3

33 Meetings

Continuing Education Decision aids as guide for cancer patients making clinical decisions

32

Oncology Nutrition

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Oncology Nurse

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EDITORIAL BOARD EDITOR-IN-CHIEF

Beth Faiman, RN, MSN, APRN, BC, AOCN Cleveland Clinic Taussig Cancer Institute Cleveland, OH 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

CONTENTS

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

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January/February 2009

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A Letter from the Editor EDITOR’S LETTER

F

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

EDITOR-IN-CHIEF

ebruary is National Cancer Prevention Month, and in recognition of this event, the American Society of Clinical Oncology has issued a policy statement highlighting oncologists’ role in cancer prevention (www.asco.org). “Oncologists are uniquely poised to guide patients and family members through the complicated issues of assessing and reducing their cancer risk,” writes ASCO president Richard L. Schilsky, MD. That is true, but oncology nurses and other members of the healthcare team also have a responsibility to counsel patients about prevention and treatment of cancer.

Choices are not always clear cut, however, as the article about anthracycline-based versus nonanthracycline-based regimens for breast cancer illustrates. As new therapies become available, healthcare providers have to weigh the alternatives and decide how best to apply them in their own practices. For patients, the vast amount of information can

be overwhelming. As reported at the San Antonio Breast Cancer Symposium, good communication between patients and providers about available treatments and their risks and benefits is needed to ensure mutual agreement about the goals of therapy.

It is also important to discuss diet and other lifestyle choices with our patients. As Amanda Saldivar explains in her article about alternative diets, patients with cancer often view dietary changes as a way to take control of their health. Certain changes, such as lowering consumption of fat and calories or increasing intake of fruits and vegetables, can be beneficial, but more extreme changes, as recommended in several popular alternative diets, can have harmful effects. As nurses, we are often the first ones patients turn to for advice, and we must be prepared to help our patients find reliable sources of information and make good choices about these and other matters.

Coming Soon 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 in Clinical Trials: The Coalition of Cancer Cooperative Groups

EDITOR’S LETTER

Reports from ASCO Gastrointestinal Cancers Symposium, Genitourinary Cancers Symposium, ONS 10th National Conference on Cancer Nursing Research

For a free subscription go to www.theoncologynurse.com 6

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In the continuing education article, Stacey and colleagues explain that many factors, including the patient’s values and beliefs, must be taken into consideration in choosing the best strategy for an individual patient, and simply providing patients with facts may not be sufficient. They explain the concept of shared decision making and review different strategies that have been used with varying degrees of success in helping patients make high-quality decisions about their care. Their case report provides an illustration of how a carefully thought-out decision aid can be used in the clinical setting.

We are always interested in innovative approaches to patient education and counseling. If there are certain methods or interventions that you have found effective in your own practice and you would like to share them with your colleagues, please write to us at Karen@greenhillhc.com.

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Readers are encouraged to contact the manufacturer with questions about the features or limitations of the products mentioned. Neither the Editorial Board nor the Publisher assumes any responsibility for any injury and/or damage to persons or property arising out of or related to any use of the material contained in this periodical. The reader is advised to check the appropriate medical literature and the product information currently provided by the manufacturer of each drug to be administered to verify the dosage, the method and duration of administration, or contraindications. It is the responsibility of the treating physician or other healthcare professional, relying on independent experience and knowledge of the patient, to determine drug dosages and the best treatment for the patient. Every effort has been made to check generic and trade names, and to verify dosages. The ultimate responsibility, however, lies with the prescribing physician.

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January/February 2009

Is peripheral neuropathy holding 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 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.

©2008 Celgene Corporation 10/08

CELG08083T

Medical Minutes MEDICAL MINUTES

BY JOHN SCHIESZER

New Approach to Reducing Lung Cancer Recurrence Showing Promise John Schieszer is an award-winning national journalist and radio broadcaster of The Medical Minute.

He can be reached at medminutes@aol.com.

A minimally invasive approach to treating high-risk patients with stage I non–small-cell lung cancer (NSCLC) may significantly reduce the risk of local disease reccurrence, according to researchers at Allegheny General Hospital in Pittsburgh, Pennsylvania. The procedure, which was developed at the hospital over the past 10 years, involves removing only the cancerous section of the lung and enveloping the surgical site in a mesh material that is embedded with radioactive seeds. The seeds emit a low dose of radiation over a prolonged period of time in an effort to eradicate any remaining cancer cells.

“The standard of care for patients with this particular disease is a lobectomy, or surgical removal of the entire lobe of the lung.

Many patients, however, are considered high-risk for this procedure because of cardiopulmonary complications or other comorbidities. In these cases, sublobar wedge resection is a more tolerable approach, but one that carries a much higher chance of local cancer recurrence,” said principal study investigator Athanasios Colonias, MD, a radiation oncologist at Allegheny General Hospital. “Our study suggests that when intraoperative 125l Vicryl mesh brachytherapy is added to sublobar resection, the local treatment failure rate is substantially reduced.”

Colonias and his colleagues examined the outcomes of 145 high-risk patients with stage I NSCLC who underwent sublobar resection with adjuvant intraoperative mesh brachytherapy between 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 an expected cancer recurrence rate of 20% with sublobar resection only, based on previously published data. No patient- or tumorspecific factors (age, histology, sex, stage, location of tumor, and tumor size) or surgical or dosimetric factors (margin status, open versus video-assisted approach, total activity, number of seeds, dose prescribed, and targeted area) were predictive of local recurrence. All the procedures were well tolerated by patients with regard to pulmonary function and morbidity.

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

He said a large, randomized, multicenter clinical trial with this approach is currently under way, which should establish the efficacy of the procedure more definitively. The study is being coordinated by the American College of Surgeons Oncology Group and involves more than a dozen major US hospitals.

New Study Suggests Mammograms Most Effective 12 Months after Radiation Treatment Breast cancer patients who receive breast-conserving therapy and propose a follow-up mammogram 6 to 12 months after radiation. radiation do not need a follow-up mammogram until 12 months after ASCO guidelines recommend a follow-up mammogram 1 year radiation, according to California researchers. Current American after the initial mammogram that led to diagnosis, but no earlier Society of Clinical Oncology (ASCO) and National Comprehensive than 6 months after radiation. Accounting for the time after the Cancer Network (NCCN) guidelines recommend follow-up mammo- initial diagnostic mammogram to have a biopsy, surgery, and radigrams between 6 and 12 months after radiation. ation therapy, following the ASCO guidelines would likely result Researchers at University of California campuses in Los in mammograms being done 6 to 9 months after the completion of Angeles and San Diego studied 408 women who were treated with radiation, according to Lin. breast-conserving therapy and radiation between 1995 and 2005 and had follow-up mammograms within 1 year after completing radiation. The median interval between radiation and the initial mammogram was 3.1 months.

They found that only 10 women had Acupuncture appears to be as effective and “Our study shows that suspicious findings on their mammolonger lasting in managing common debilitat- physicians and patients grams and, of those, only two were ing vasomotor symptoms associated with have an additional therfound to have recurrent cancer. Both breast cancer treatment—hot flashes, night apy for something that of these cases were noninvasive ductal sweats, and excessive sweating—than conven- affects the majority of carcinomas. tional drug therapy, and has no side effects. breast cancer survivors The cost of a mammogram is about Additional benefits of acupuncture treatment and actually has bene$115, and many women experience modfor breast cancer patients include an increased fits, as opposed to more erate to severe pain during the procedure sense of well-being, more energy and, in some side effects. The effects and high levels of anxiety during a needle cases, a higher sex drive, which were not expe- are more durable than a biopsy. The authors of this new study rienced in patients who underwent drug treat- drug commonly used to treat these vasomotor determined that because only 0.49 recurment for their hot flashes. symptoms and, ultimately, [the treatment] is rences were detected per 100 mammoThe investigators conducted a randomized more cost-effective for insurance companies,” grams and only noninvasive ductal carciclinical trial that compared acupuncture treat- said lead study author Eleanor Walker, MD, a noma was found, mammograms should ment with the selective serotonin-norepi- radiation oncologist at Henry Ford Hospital, not be performed until at least 1 year after nephrine reuptake inhibitor venlafaxine for 12 Detroit, Michigan. radiation to avoid the medical and psyweeks to determine whether acupuncture She said the reduction in hot flashes lasted chological costs associated with mamreduced vasomotor symptoms in breast cancer longer after acupuncture treatment than after mography. patients receiving hormonal therapy and pro- drug therapy. She noted that 80% of women “Omitting the initial postradiotherapy duced fewer side effects than venlafaxine. The treated for breast cancer suffer from hot flashes examination may improve the psychologstudy involved 47 breast cancer patients who after being treated with chemotherapy and/or ical well-being of patients, especially for received either tamoxifen or anastrozole and antiestrogen hormones, such as tamoxifen or women who already have been shown to had at least 14 hot flashes per week. The anastrozole. Most clinicians now treat the have breast cancer,” said lead study results showed that acupuncture reduced hot symptoms with steroids and/or antidepressant author Kevin Lin, MD, a radiation oncolflashes as effectively as venlafaxine, with no medications. However, these drugs have addiogist at Advanced Oncology Center, side effects. In addition, acupuncture provided tional side effects, such as weight gain, nausea, West Covina, California. several additional health benefits. constipation, and fatigue.

The most recent NCCN guidelines

Acupuncture May Help Reduce Side Effects of Breast Cancer Treatment

MEDICAL MINUTES 8

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Continued from cover

The overall rate of thromboembolic events was 16 (2.1%) in the nadroparin group versus 15 (3.9%) in the placebo group. or placebo for the duration of chemotherapy to a maximum of 4 months.

Treatment was initiated on day 1 of the first cycle or a new course of chemotherapy. At ASH, Agnelli presented primary efficacy and safety data for 769 nadroparin-treated patients versus 381 patients in the placebo group. Patients enrolled in the trial had a variety of metastatic or locally advanced cancers, including lung, gastrointestinal, pancreatic, breast, ovarian, and head and neck cancers.

The overall rate of thromboembolic events was 16 (2.1%) in the nadroparin group versus 15 (3.9%) in the placebo group. The difference was statistically significant (P = .024), for a relative risk reduction of 49.6%. The absolute rate of deep vein thrombosis was 1% in nadroparin-treated patients versus 2.1% among placebo patients. Similar reductions were achieved for pulmonary embolism, stroke, and visceral venous thrombosis. Analysis of thromboembolic events by treatment and cancer site showed that 5.4% occurred in the lung (3.5% of those in the nadroparin 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.

January/February 2009

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

Nadroparin was particularly effective in patients with lung cancer, reducing the risk of thromboembolic events by 40%, Agnelli said. The number needed to treat to prevent one thromboembolic event in lung cancer patients was 18.9.

Prophylactic treatment with nadroparin in this population did not increase the risk of adverse events. No

significant differences were observed between treatment groups in secondary end points, including major bleeds, minor bleeds, deaths at the end of treatment, and death at 12 months.

Even with such encouraging results, Agnelli said he was not hopeful that one study would change clinical practice. He suggested that future studies should focus on cancer patients at high risk for thromboembolic events, such as those with cancers of the lung and pancreas.

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

fessor of medicine at McMaster University in Hamilton, Ontario, Canada, noted that cancer-associated thromboembolic events have more than doubled in the past 20 years, and “we need to reduce this burden.” She noted that “the current guidelines do not recommend routine prophylaxis in outpatients requiring chemotherapy, but now with four randomized trials [including PROTECHT] showing a benefit, perhaps these guidelines will be changed.”

—Alice Goodman

In moderate-risk* regimens

Approach chemotherapy with confidence by reducing the risk of febrile neutropenia

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

Important Safety Information Splenic rupture (including fatal cases), acute respiratory distress syndrome, 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 placebotreated patients (31% vs. 26%). The most common adverse events reported in either placebo- or active-controlled trials were consistent with the underlying cancer diagnosis and its treatment with chemotherapy, with the exception of bone pain.

Please refer to brief summary of Neulasta® Prescribing Information. *Regimens associated with ≥ 17% risk of febrile neutropenia. © 2009 Amgen. All rights reserved. MC41456-C 12-08 Class I www.neulasta.com

HEMATOLOGIC CANCERS

of Perugia, Italy, during a presentation at the 2008 meeting of the American Society of Hematology (ASH).

Prophylactic blood thinners are used in cancer patients mainly for standard indications, such as a central venous catheter, but rarely in ambulatory patients receiving chemotherapy. The large, double-blind, multicenter PROphylaxis of ThromboEmbolism during ChemoTherapy (PROTECHT) study sought to shed some light on this issue by enrolling 1166 patients at 62 Italian centers and randomizing them in a 2:1 ratio to receive LMWH nadroparin 3800 IU

HEMATOLOGIC CANCERS

Nadroparin Halves the Risk

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

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

Start with support

G REEN H ILL H EALTHCARE C OMMUNICATIONS

9

HEMATOLOGIC CANCERS

Hematologic Cancers Rituximab Added to Fludarabine and Cyclophosphamide Improves Progression-free Survival SAN FRANCISCO—Treatment with fludarabine, cyclophosphamide, and rituximab (FCR) improved progressionfree survival (PFS) compared with standard fludarabine and cyclophosphamide (FC) in patients with chronic lymphocytic leukemia (CLL) in two separate pivotal phase 3 studies presented at the 2008 Annual Meeting of the American Society of Hematology (ASH).

Each study, one of previously untreated patients and one of patients with

relapsed or refractory CLL, is reputedly the largest randomized clinical trial ever reported of its respective patient group.

Results of these two trials are potentially practice-changing, with FCR poised to replace FC as the new standard of care, according to investigators.

The FCR regimen was first shown to be superior to FC alone in CLL by Michael Keating’s group at M.D. Anderson Cancer Center. CLL8 (previously untreated patients) and the

REACH study (relapsed or refractory patients), presented at ASH, provide confirmatory evidence for a survival benefit for FCR in CLL.

CLL8 CLL8, an international study conducted at 191 sites across 11 countries, included 817 previously untreated patients who received either FCR or FC. The primary end point was PFS. At 2 years, 76.6% of patients were alive

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

Start with support

HEMATOLOGIC CANCERS

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 receiving myelosuppressive anticancer drugs associated with a clinically significant incidence 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 REPORTED FOLLOWING THE ADMINISTRATION OF NEULASTA® AND ITS PARENT COMPOUND, FILGRASTIM. PATIENTS RECEIVING NEULASTA® WHO REPORT LEFT UPPER ABDOMINAL AND/OR SHOULDER TIP PAIN SHOULD BE EVALUATED FOR AN ENLARGED SPLEEN OR SPLENIC RUPTURE. Acute Respiratory Distress Syndrome (ARDS) Acute respiratory distress syndrome (ARDS) has been reported in patients receiving Neulasta®, and is postulated to be secondary to an influx of neutrophils to sites of inflammation in the lungs. Patients receiving Neulasta® who develop fever, lung infiltrates, or respiratory distress should be evaluated for the possibility of ARDS. In the event that ARDS occurs, Neulasta® should be discontinued and/or withheld until resolution of ARDS and patients should receive appropriate medical management for this condition.

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

Sickle Cell Disorders Severe sickle cell crises have been associated with the use of Neulasta® in patients with sickle cell disorders. Severe sickle cell crises, in some cases resulting in death, have also been associated with Filgrastim, the parent compound of pegfilgrastim. Only physicians qualified by specialized training or experience in the treatment of patients with sickle cell disorders should prescribe Neulasta® for such patients, 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 and 24 hours after administration of cytotoxic chemotherapy (see DOSAGE AND ADMINISTRATION) because of the potential for an increase in sensitivity of rapidly dividing myeloid cells to cytotoxic chemotherapy.

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

The administration of Neulasta® concomitantly with 5-fluorouracil or other antimetabolites has not been evaluated in patients. Administration of pegfilgrastim at 0, 1, and 3 days before 5-fluorouracil resulted in increased mortality in mice; administration of pegfilgrastim 24 hours after 5-fluorouracil did 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 and neutrophil precursors; however, the G-CSF receptor through which pegfilgrastim and Filgrastim act has been found on tumor cell lines, including some myeloid, T-lymphoid, lung, head and neck, and bladder tumor cell lines. The possibility that pegfilgrastim can act as a growth factor for any tumor type cannot be excluded. Use of Neulasta® in myeloid malignancies and myelodysplasia (MDS) has not been studied. In a randomized study comparing the effects of the parent compound of Neulasta®, Filgrastim, to placebo in patients undergoing remission induction and consolidation chemotherapy for acute myeloid leukemia, important differences in remission rate between the two arms were excluded. Disease-free survival and overall survival were comparable; however, the study was not designed to detect important differences in these endpoints.* Information for Patients Patients should be informed of the possible side effects of Neulasta® and be instructed to report them to the prescribing physician. Patients should be informed of the signs and symptoms of allergic drug reactions and be advised of appropriate actions. Patients should be counseled on the importance of compliance with their Neulasta® treatment, including regular monitoring of blood counts.

If it is determined that a patient or caregiver can safely and effectively administer Neulasta® (pegfilgrastim) at home, appropriate instruction on the proper use of Neulasta® (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 needles should be available.

Laboratory Monitoring To assess a patient’s hematologic status and ability to tolerate myelosuppressive chemotherapy, a complete blood count and platelet count should be obtained before chemotherapy is administered. Regular monitoring of hematocrit value and 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 monitoring of neutrophil counts.

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

Carcinogenesis, Mutagenesis, and Impairment of Fertility No mutagenesis studies were conducted with pegfilgrastim. The carcinogenic potential of pegfilgrastim has not been evaluated in long-term animal studies.

In a toxicity study of 6 months duration in rats given once weekly subcutaneous injections of up to 1000 mcg/kg of pegfilgrastim (approximately 23-fold higher than the recommended human dose), no precancerous or cancerous lesions were noted.

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

Pregnancy Category C Pegfilgrastim has been shown to have adverse effects in pregnant rabbits when administered subcutaneously every other day during gestation at doses as low as 50 mcg/kg/dose (approximately 4-fold higher than the recommended human dose). Decreased maternal food consumption, accompanied by a decreased maternal 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/dose resulted in an increased incidence of abortions. Increased post-implantation loss due to early resorptions was observed at doses of 200 to 1000 mcg/kg/dose, and decreased numbers of live rabbit fetuses were observed at pegfilgrastim doses of 200 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 at 1000 mcg/kg/dose every other day. Very low levels (< 0.5%) of pegfilgrastim crossed the placenta when administered subcutaneously to pregnant rats every other 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 did not result in any adverse maternal effects. There were no deleterious effects on the growth and development of the offspring and no adverse effects were found upon 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 mother justifies the potential risk to the fetus.

Nursing Mothers It is not known whether pegfilgrastim is excreted in human milk. Because many drugs 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 been established. 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 overall differences in safety or effectiveness were observed between patients age 65 and older and younger patients.

ADVERSE REACTIONS (See WARNINGS, Splenic Rupture, Acute Respiratory Distress Syndrome (ARDS), Allergic Reactions, and Sickle Cell Disorders.)

Clinical Trial Experience Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of Neulasta® cannot be directly compared to rates in the clinical trials of other drugs and may not reflect the rates observed in practice. The adverse reaction information from clinical trials does, however, provide a basis for identifying the adverse events that appear to be related 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 patients was 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 cytotoxic chemotherapy. 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. The incidence of other commonly reported adverse events were similar in the Neulasta®- and placebo-treated patients, and were consistent with the underlying cancer diagnosis and its treatment with chemotherapy. The data in Table 1 reflect those 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 Event

Neulasta® (n = 467) 48% 31% 29%

Placebo (n = 461) 47% 26% 28%

Alopecia Bone Painb Diarrhea Pyrexia (not including 23% 22% febrile neutropenia) Myalgia 21% 18% Headache 16% 14% Arthralgia 16% 13% Vomiting 13% 11% Asthenia 13% 11% Peripheral Edema 12% 10% Constipation 10% 6% a Events occurring in ≥ 10% of Neulasta ®-treated patients and at a higher incidence as compared to placebo-treated patients Bone pain is limited to the specified adverse event term “bone pain”

b

In the active controlled studies, common adverse events occurred at similar rates and severities in both treatment arms (Neulasta®, n = 465; Filgrastim, n = 331).

These adverse experiences occurred at rates between 72% and 15% and included: 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 analysis using multiple, related, adverse event terms.

In the placebo-controlled study, the incidence of bone pain was 57% in Neulasta®-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®-and 31% of placebo-treated patients utilized non-narcotic analgesics and 10% of Neulasta®- and 9% of placebo-treated patients utilized narcotic analgesics.

In the active-controlled studies, the use of non-narcotic and narcotic analgesics in association with bone pain was similar between Neulasta®-and Filgrastimtreated 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 receiving Neulasta®. Leukocytosis was not associated with any adverse effects.

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

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

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

Postmarketing Experience The following adverse reactions have been identified during postapproval of Neulasta®. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure.

• splenic rupture (see WARNINGS: Splenic Rupture) • acute respiratory distress syndrome (ARDS) (see WARNINGS: Acute Respiratory 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 patients experienced a mean maximum ANC of 55 x 109/L, with a corresponding mean maximum WBC of 67 x 109/L. The absolute maximum ANC observed was 96 x 109/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 after administration of cytotoxic chemotherapy (see PRECAUTIONS).

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

No dosing adjustment is necessary for renal dysfunction.

Neulasta® should be visually inspected for discoloration and particulate matter before administration. Neulasta® should not be administered if discoloration or particulates are observed.

Rx Only This product, its production, and/or its use may be covered by one or more US Patents, 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 *Heil G, Hoelzer D, Sanz MA, et al. A randomized, double-blind, placebocontrolled, phase III study of Filgrastim in remission induction and consolidation therapy for adults with de novo Acute Myeloid Leukemia.

Blood. 1997;90:4710-4718. v.8 Issue Date: 10/2007

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

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

“The management of CLL is set to change markedly, as physicians have more options and greater treatment expectations for their patients. The data from CLL8 suggest that rituximab combined with chemotherapy has the potential to become the new standard of care for CLL patients,” stated Michael Hallek, MD, University Hospital of Cologne, Germany, on behalf of the German CLL Study Group.

Complete response (CR) rate was 44.5% for FCR and 22.9% for FC (P = .01). Partial response (PR) was lower in the FCR group (3.3% vs 8.1%, P = .01), which Hallek attributed to the high rates of CR in the rituximab-containing arm. At a median follow-up of 25.5 months, median PFS was 42.8 months for FCR versus 32.3 months for FC (P = .000007).

No new safety concerns were reported with the addition of rituximab to standard chemotherapy. The rituximabcontaining regimen was associated with more neutropenia, but the rates of infection and other severe adverse events were not higher than with standard chemotherapy alone.

REACH trial REACH, a randomized, international trial conducted at 88 sites across 17 countries, randomized 552 patients with relapsed or refractory CLL to receive either FCR or FC. The primary end point, as in the CLL8 trial, was PFS. The lead investigator was Tadeusz Robak, MD, of the Medical University of Lodz, Poland.

Robak said, “Rituximab has already revolutionized the treatment of nonHodgkin’s lymphoma. The results in CLL underscore an important role of rituximab in the management of CLL, which is currently a life-threatening incurable disease.”

CR was 24.3% for FCR versus 13% for FC (P = .0007). PR rates were similar in the two groups. Overall response rates were 69.9% versus 58%, respectively (P = .0034). At a median follow-up time of 25.3 months, median PFS was 30.6 months for FCR versus 20.6 months for FC (P = .0002).

Adverse events were similar to what has been reported previously with these regimens. The rituximab-containing regimen was associated with a slight increase in febrile neutropenia, infusion reactions, benign and malignant neoplasms, and hepatitis B. A trend was observed toward improved overall survival for FCR versus FC but longer follow-up is needed to determine an overall survival benefit.

Both studies were supported by Roche.

—AG

10

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Strip away the claims

See for yourself what others have already confirmed 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.

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

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Visible leakage occurred outside of the ICU Medical System, the B. Braun OnGuard™ System and the Cardinal Health/Alaris System during all manipulations.

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?

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HEMATOLOGIC CANCERS

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

BY SANDRA E. KURTIN, RN, MS, AOCN, ANP-C ARIZONA CANCER CENTER, UNIVERSITY OF ARIZONA, TUCSON

S

uccessful treatment of nonHodgkin’s lymphoma (NHL) is based on a complete evaluation of the disease, including location and extent of organ involvement, and an adequate tissue diagnosis. Prognosis for patients with NHL varies widely, based on the information obtained during the

diagnostic process. In addition, response criteria widely used for malignant lymphomas include specific parameters for changes in the measurable disease from baseline following treatment.1 Accurate staging of lymphoma presents a unique challenge as the disease may be localized or diffuse and may involve any organ in

the body, making it difficult to differentiate it from other malignancies, infections, or benign etiologies.2 Therefore, a systematic diagnostic process is critical to making an accurate diagnosis.

suspected of having NHL includes a complete history and physical examination with particular attention to nodal sites, organomegaly, abdominal masses, and skin infiltrates. Complete laboratory analysis and selected imaging studies

Initial evaluation The initial evaluation of a patient

Continued on page 30

Table. Imaging Strategies for Non-Hodgkin’s Lymphoma

HEMATOLOGIC CANCERS

Imaging method

Advantages

Disadvantages/Limitations

Patient considerations

CT scan

• Most commonly used • Widespread availability and reproducibility across scanners • Open scanner with short scanning times—patient friendly • Relatively low cost • Current standard of care for initial staging of NHL

• Decreased specificity for normal sized • Requires fasting 4 hours before structures, slow-growing tumors, and lesions imaging of the abdomen or pelvis with poor contrast to surrounding structures • Oral contrast (taken 1 hour before • Not useful in detecting bone marrow scan) allows differentiation of the involvement bowel from surrounding structures • Exposure to ionizing radiation—up to 25 mSv • IV contrast is used to define softwith neck, chest, abdomen, and pelvis tissue changes with some risk of hypersensitivity and renal impairment Patient requires screening for both before use of IV contrast

PET scan

• Ability to detect metabolic changes in areas involved with lymphoma that are below CT criteria (< 1 cm) • May be helpful in detecting a preferred site for tissue biopsy • Persistently positive FDG-PET scans reported to correlate with an increased risk of relapse in DLBCL • Provides useful information in treatment planning for local radiotherapy

• Role in initial diagnosis is not clear • Limited value in indolent subtypes of NHL • Exposure to ionizing radiation— 3.3 mSv to 7.6 mSv • CT component is used for localization of FDG activity • Limited value in areas with high physiologic activity: brain, myocardium, gastrointestinal tract, urinary tract, muscles, salivary glands • Scanning time 30 to 40 minutes

• Imaging obtained within 3 weeks of administration of granulocyte colonystimulating proteins will be difficult to interpret owing to diffuse uptake in marrow-producing regions • Requires fasting 4 to 6 hours before procedure • Procedure starts 60 minutes after the injection of the FDG dose • Hyperglycemia, intense physical activity, active infection may interfere with accuracy

PET/CT fusion

• Provides higher resolution CT on the same machine as the FDG-PET, allowing more exact anatomic and functional imaging

• Expensive • Radiation exposure is similar to that with CT scan (25 mSv) • IV contrast is required for higher resolution CT with similar risks

• Preparation is similar to that for PET • Requires patient to lie still throughout procedure to reduce artifact

MRI

• No radiation exposure • Best method for soft-tissue contrast, particularly for bone or muscle imaging • Reduced risk of hypersensitivity

• Not available to patients with implanted pacemakers, defibrillators, pumps, or older Port-A-Caths • Not patient friendly—time and confinement • More limited availability and less uniformity in technique • Higher cost

• Requires long scanning time (up to 60 minutes for total spine) in a narrow space with loud clicking noise difficult for patients with claustrophobia, tremors, bowel or bladder control problems, or severe 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.

12

G REEN H ILL H EALTHCARE C OMMUNICATIONS

January/February 2009

Patient Support Coordinator Program A 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

To contact a PSC: Call 1-800-931-8691 Email patientsupport@celgene.com Fax 1-800-822-2496 www.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. © 2008 Celgene Corporation

07/08

CELG07002R7T

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ONS Congress CONFERENCE NEWS

Continued from cover

Model Program Provides Breast Cancer Education, Counseling, and Treatment for High-risk, Indigent Patients SEATTLE—A program that involves collaboration between advanced practice nurses (APNs) and genetic counselors provides a model for providing education, genetic counseling and testing, and medical management for indigent patients with a suspected hereditary predisposition for breast cancer.

Oncology nurse practitioner Wendy Vogel set up the Breast Cancer Awareness, Risk Assessment and Evaluation (Breast CARE) Program with genetic counselor Deborah Pencarinha in Tennessee that now is changing breast care significantly in their region of the country.

“It could be adopted at other centers. There are few programs like ours in the country right now. Other nurse practitioners could partner with genetic counselors in their own communities. We want people to know how they can get funding and how successful you can be when you work collaboratively,” said Vogel, who presented data from this program at the 2008 Oncology Nursing Society (ONS) Advanced Practice Nursing Conference and Institutes of Learning.

From 2006 until the present the program has provided education about breast and ovarian cancer for more than 10,340 healthcare providers,

high-risk individuals, indigent women, relatives, and community members in the Kingsport, Tennessee, metropolitan area. Thirty-five patients have been seen in the Breast CARE clinic, and 18 have received free BRCA analysis. A total of four BRCA carriers have so far been identified and followed. In addition, two patients have enrolled in clinical trials, and three patients received financial assistance for treatments, such as tamoxifen.

“Preventative care is an area where APNs can partner with other clinicians, combining their individual areas of expertise, thus increasing their potential impact on health outcomes. Ultimately, it is our goal to help prevent breast cancer deaths,” said Vogel in an interview with The Oncology Nurse. “When we identify a genetic mutation, we are searching for services, such as free or lowcost mammography or breast [magnetic resonance] screening, even prophylactic surgical services. We get them hooked up to the appropriate healthcare services for the close follow-up and care they need.”

For this program, funding and support was secured from the Susan G. Komen Foundation for a Cure local affiliate, the local hospital system, and the county health department. The Breast CARE Clinic is held six times a year, and the

oncology APN provides risk assessment, physical examinations (including clinical breast examination), and education about self-breast examinations. Recommendations are made for screening and preventive care. In addition, referrals for free or low-cost screening examinations are given as well as help for obtaining free or low-cost tamoxifen as indicated. In some cases, help is given for obtaining free or low-cost prophylactic surgery for breast and ovarian cancer.

The genetic counselor examines a threegeneration family history and makes a risk assessment, provides genetic counseling, and assists with genetic testing.

The genetic testing is paid for by the Breast CARE program. When a mutation is found, the genetic counselor assists the patient with disclosing the results to family members.

Much of the program is geared toward women who have been neglected in the past. The Breast CARE Program provides outreach to healthcare providers as well as public education for rural communities, less educated patients, and high-risk ethnic populations. It also provides a support group for patients and family members identified as high-risk based on family history and genetic mutations.

“Genetic testing is very expensive.

Many women can’t get it because they are underinsured,” said Vogel, who is an oncology nurse practitioner at Kingsport Hematology/Oncology, Kingsport, Tennessee. “We need to raise community awareness about this issue, and [APNs] are well suited to do this.”

—John Schieszer

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

January/February 2009

ropathic pain in cancer patients. It has been thought that neuropathic pain is more difficult to manage, but few studies have investigated this issue thoroughly in cancer patients.

The researchers used the Theory of Unpleasant Symptoms as the theoretical framework for this study. Tofthagen said etiology is a physiological factor, and it directly influences the pain experience. In addition, it is well established that painful neuropathic symptoms negatively influence physical performance and emotional well-being.

To help better examine this issue in cancer patients, the Florida researchers asked 170 outpatients with cancer pain to complete the Brief Pain Inventory.

The patients were divided into two groups: patients who described their pain using at least one neuropathic descriptor (burning, numbness, tingling, or electric-like) and patients who did not use any neuropathic descriptors. There were 75 patients in the neuropathic group and 95 patients in the other group.

The investigators found that patients who used at least one neuropathic descriptor had significantly higher levels of current pain, worst pain, and least pain compared with those patients in the second group. In addi-

Pain interference with general activity, mood, walking ability, normal work, relationships, and sleep was significantly worse in the patients with neuropathic symptoms.

tion, pain interference with general activity, mood, walking ability, normal work, relationships, and sleep was significantly worse in the patients with neuropathic symptoms. These patients also were more likely to describe their pain as continuous as opposed to intermittent. In addition, these patients had been in pain an average of 2.5 times longer than those cancer patients who did not use neuropathic descriptors.

“Nurses should care about this because we don’t have good treatments for neuropathic pain, and so we need to look for better ways of treating it and managing these patients,” said Tofthagen in an interview with The Oncology Nurse.

“Nurses should ask their patients about it…in order to know how it is impacting their quality of life. That can be the first step.”

She said an aggressive approach to neuropathic pain in cancer patients can include medical management, a neurology referral, physical therapy, and occupational therapy.

Tofthagen said more efforts are needed to better understand which interventions may be most effective in cancer patients with neuropathic pain.

—John Schieszer Continued on page 16

G REEN H ILL H EALTHCARE C OMMUNICATIONS

15

CONFERENCE NEWS

SEATTLE—Cancer patients with neuropathic symptoms appear to have higher pain levels, suffer from pain longer, and have more difficulty performing their usual activities of daily living than do patients without neuropathic symptoms, according to researchers at the University of South Florida.

“I have spent most of my career as a chemotherapy nurse, and I have seen this as a growing problem. I had a suspicion that neuropathic pain was more difficult to control, and it is becoming more common as we use chemotherapy drugs that are likely to cause peripheral neuropathy,” said study investigator Cindy Tofthagen, MSN, ARNP, who is an instructor of nursing at the University of South Florida, Tampa. “This is the first study to look at this specific patient population in this way. It is an understudied area, and the more we find out about the differences between patients who have neuropathic pain compared with other types of pain, it will help us to treat patients more appropriately.”

Tofthagen, who presented the study findings at the 2008 Oncology Nursing Society (ONS) Advanced Practice Nursing Conference and Institutes of Learning, said surgery, radiation, and chemotherapy are known to cause neu-

ONS Congress Continued from page 15

CONFERENCE NEWS

Advanced Practice Nurses Facilitate Mental Health Care for Oncology Patients SEATTLE—Advanced practice nurses (APNs) working either independently or collaboratively with psychiatrists may provide cost-effective, timely access to psychiatric/mental health services for oncology patients, according to Texas researchers.

Depression and anxiety are common among oncology patients and can negatively affect drug efficacy and treatment

compliance and result in adverse metabolic changes. To address these issues, a psychiatry section was created in 1990 at the M. D. Anderson Cancer Center, which provides consultation/liaison services, without a dedicated psychiatry unit.

Mary K. Hughes, BS, MS, RN, CNS, of the University of Texas M. D. Anderson Cancer Center, Houston, Texas, presented

an overview of the program’s success at the 2008 Oncology Nursing Society (ONS) Advanced Practice Nursing Conference and Institutes of Learning. She said that at their facility psychiatry is now a department made up of five APNs (three clinical nurse specialists [CNSs] and two nurse practitioners [NPs]) and four psychiatrists.

The APNs function both as independent

CONFERENCE NEWS

therapists and/or collaborators with the staff psychiatrists. The group provides multimodal therapy to both inpatients and outpatients. The five APNs evaluate patients independently; however, they request medical psychiatric assessment and intervention when warranted. Because CNSs do not have authority to prescribe medications, they mainly see outpatients. Conversely, the NPs mainly see inpatients because they have the authority to prescribe medications.

“We found that the patients do better. The patients tend to be less anxious and more focused and not so worried. We help them with their anxiety and the issues they are facing with their cancer. Sexual dysfunction is an issue, and substance abuse issues may also be involved. We have three subspecialists who can tailor treatment for these issues,” said Hughes.

“By utilizing [APNs] in psychiatry, it is possible to provide more patients with access to psychiatric care. Nurses are holistic, and we see patients as a whole and are not focused on a specific cancer. We see how their cancer affects them emotionally, spiritually, physically, and socially, and we try to help the patients live better. Most patients are grieving because they have lost their health, and this is different from depression. We help the patient identify their losses and grieve,” said Hughes in an interview with The Oncology Nurse.

Since 2003, each APN has been able to bill for services in the hospital and in the outpatient clinic. Currently, the APNs see approximately 50% of all the patients in the psychiatry department. She noted that outpatient consults to psychiatry are now seen within 7 days and inpatients are seen within 24 hours, thanks to the availability of APNs. Hughes said the program has worked so well that it may be an approach that other centers across the country want to adopt.

“The attending physicians may be uncomfortable with patients who cry a lot or are calling on the phone a lot. Then, they will refer [those patients] to the APNs who can coordinate their psychiatric care and treat them. We are the point people,” Hughes explained.

“This program works very, very well. Other hospitals may have different models, but this model is working quite well and it may offer some benefits that are not achieved with other programs.”

—John Schieszer

16

G REEN H ILL H EALTHCARE C OMMUNICATIONS

January/February 2009

For patients 55 years and older with AML following induction chemotherapy...

LEUKINE

Which CSF is proven to help prevent early death* by fighting fungal infections?

LEUKINE Goes 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.

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 treated with 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 on duration 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

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

Rx only

BRIEF SUMMARY CONSULT PACKAGE INSERT FOR FULL PRESCRIBING INFORMATION INDICATIONS AND USAGE Use Following Induction Chemotherapy in Acute Myelogenous Leukemia LEUKINE is indicated 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-threatening infections and infections resulting in death. The safety and efficacy of LEUKINE have not been assessed in patients 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 have been defined morphologically by the French-American-British (FAB) system of classification.

Use in Mobilization and Following Transplantation of Autologous Peripheral Blood Progenitor Cells LEUKINE is indicated for the mobilization of hematopoietic progenitor cells into peripheral blood for collection by leukapheresis. Mobilization allows for the collection of increased numbers of progenitor cells capable of engraftment as compared with collection without mobilization. After myeloablative chemotherapy, the transplantation of an increased number of progenitor cells can lead to more rapid engraftment, which may result in a decreased need for supportive care. Myeloid reconstitution is further accelerated by administration of LEUKINE following peripheral blood progenitor cell transplantation.

Use in Myeloid Reconstitution After Autologous Bone Marrow Transplantation LEUKINE is indicated for acceleration of myeloid recovery in patients with non-Hodgkin’s lymphoma (NHL), acute lymphoblastic 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 to be safe and effective in accelerating myeloid engraftment, decreasing median duration of antibiotic administration, reducing the median duration of infectious episodes and shortening the median duration of hospitalization. Hematologic response to LEUKINE can be detected by complete blood count (CBC) with differential cell counts performed twice per week.

Use in Myeloid Reconstitution After Allogeneic Bone Marrow Transplantation LEUKINE is indicated for acceleration of myeloid recovery in patients undergoing allogeneic BMT from HLA-matched related 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 median duration of hospitalization.

Use in Bone Marrow Transplantation Failure or Engraftment Delay LEUKINE is indicated in patients who have undergone allogeneic or autologous bone marrow transplantation (BMT) in whom engraftment is delayed or has failed. LEUKINE has been found to be safe and effective in prolonging survival of 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 who demonstrate 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 by complete blood count (CBC) with differential performed twice per week.

CONTRAINDICATIONS LEUKINE 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 not be administered simultaneously with cytotoxic chemotherapy or radiotherapy or within 24 hours preceding or following chemotherapy or radiotherapy. In one controlled study, patients with small cell lung cancer received LEUKINE and concurrent thoracic radiotherapy and chemotherapy or the identical radiotherapy and chemotherapy without LEUKINE. The patients randomized to LEUKINE had significantly higher incidence of adverse events, including higher mortality and a higher incidence of grade 3 and 4 infections and grade 3 and 4 thrombocytopenia.11 WARNINGS Pediatric Use Benzyl alcohol is a constituent of liquid LEUKINE and Bacteriostatic Water for Injection diluent. Benzyl alcohol has been reported to be associated with a fatal “Gasping Syndrome” in premature infants. Liquid solutions containing benzyl alcohol (including liquid LEUKINE ) or lyophilized LEUKINE reconstituted with Bacteriostatic Water for Injection, USP (0.9% benzyl alcohol) should not be administered to neonates (see PRECAUTIONS and DOSAGE AND ADMINISTRATION).

Fluid Retention Edema, capillary leak syndrome, pleural and/or pericardial effusion have been reported in patients after LEUKINE administration. In 156 patients enrolled in placebo-controlled studies using LEUKINE 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%; and pericardial 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 estimated to be less than 1%. In patients with preexisting pleural and pericardial effusions, administration of LEUKINE may aggravate fluid retention; however, fluid retention associated with or worsened by LEUKINE has been reversible after interruption or dose reduction of LEUKINE with or without diuretic therapy. LEUKINE should be used with caution in patients with preexisting fluid retention, pulmonary infiltrates or congestive heart failure.

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

Cardiovascular Symptoms Occasional transient supraventricular arrhythmia has been reported in uncontrolled studies during LEUKINE administration, particularly in patients with a previous history of cardiac 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 enrolled in uncontrolled clinical trials, administration of LEUKINE has induced elevation of serum creatinine or bilirubin and hepatic enzymes. Dose reduction or interruption of LEUKINE administration has resulted in a decrease to pretreatment values. However, in controlled clinical trials the incidences of renal and hepatic dysfunction were comparable between LEUKINE (250 mcg/m2/day by 2-hour IV infusion) and placebotreated patients. Monitoring of renal and hepatic function in patients displaying renal or hepatic dysfunction prior to initiation of treatment is recommended at least every other week during LEUKINE administration.

PRECAUTIONS General Parenteral administration of recombinant proteins should be attended by appropriate precautions in case an allergic or untoward reaction occurs. Serious allergic or anaphylactic reactions have been reported. If any serious allergic or anaphylactic reaction occurs, LEUKINE therapy should immediately be discontinued and appropriate therapy initiated.

A syndrome characterized by respiratory distress, hypoxia, flushing, hypotension, syncope, and/or tachycardia has been reported following the first administration of LEUKINE in a particular cycle. These signs have resolved with symptomatic treatment and usually do not recur with subsequent doses in the same cycle of 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, LEUKINE administration should be interrupted or the dose reduced by half. The decision to reduce the dose or interrupt treatment should be based on the clinical condition of the patient. Excessive blood counts have returned to normal or baseline levels within three to seven days following cessation of LEUKINE therapy. Twice weekly monitoring of CBC with differential (including examination for the presence of blast cells) should be performed to preclude development of excessive counts.

Growth Factor Potential LEUKINE is a growth factor that primarily stimulates normal myeloid precursors. However, the possibility that LEUKINE can act as a growth factor for any tumor type, particularly myeloid 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 be discontinued.

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

Use in Patients Receiving Purged Bone Marrow LEUKINE is effective in accelerating myeloid recovery in patients receiving bone marrow purged by anti-B lymphocyte monoclonal antibodies. Data obtained from uncontrolled studies suggest that if in vitro marrow purging with chemical agents causes a significant decrease in the number of responsive hematopoietic progenitors, the patient may not respond to LEUKINE. When the bone marrow purging process preserves a sufficient number of progenitors (>1.2 x 104/kg), a beneficial effect of LEUKINE on myeloid engraftment has been reported.16 Use in Patients Previously Exposed to Intensive Chemotherapy/Radiotherapy In patients who before autologous BMT, have received extensive radiotherapy to hematopoietic sites for the treatment of primary disease in the abdomen or chest, or have been exposed to multiple myelotoxic agents (alkylating agents, anthracycline antibiotics and antimetabolites), the effect of LEUKINE on myeloid reconstitution may be limited.

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

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

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

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

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

Carcinogenesis, Mutagenesis, Impairment of Fertility Animal studies have not been conducted with 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 not known whether LEUKINE can cause fetal harm when administered to a pregnant woman or can affect reproductive 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 are excreted 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, available safety data indicate that LEUKINE does not exhibit any greater toxicity in pediatric patients than in adults. A total of 124 pediatric subjects between the ages of 4 months and 18 years have been treated with LEUKINE in clinical trials at doses ranging from 60-1,000 mcg/m2/day intravenously and 4-1,500 mcg/m2/day subcutaneously. In 53 pediatric patients enrolled in controlled studies at a dose of 250 mcg/m2/day by 2hour IV infusion, the type and frequency of adverse events were comparable to those reported for the adult population. Liquid solutions containing benzyl alcohol (including liquid LEUKINE ) or lyophilized LEUKINE reconstituted with Bacteriostatic Water for Injection, USP (0.9% benzyl alcohol) 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 acute myelogenous leukemia (AML) study. Of the 52 patients treated with LEUKINE in this randomized study, 22 patients were age 65-70 years and 30 patients were age 55-64 years. The number of placebo patients in each age group were 13 and 33 patients respectively. This was not an adequate database from which determination of differences in efficacy endpoints or safety assessments could be reliably made and this clinical study was not designed to evaluate difference between these two age groups. Analyses of general trends in safety and efficacy were undertaken and demonstrate similar patterns for older (65-70 yrs) vs younger patients (55-64 yrs). Greater sensitivity of some older individuals cannot be ruled out.

ADVERSE REACTIONS Autologous 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 blood progenitor cell transplantation, events reported in at least 10% of patients who received IV LEUKINE or placebo were as reported in Table 6.

No significant differences were observed between LEUKINE and placebo-treated patients in the type or frequency of laboratory abnormalities, including renal and hepatic parameters. In some patients with preexisting renal or hepatic dysfunction enrolled in uncontrolled clinical trials, administration of LEUKINE has 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 placebotreated patients.

In the placebo-controlled trial of 109 patients after allogeneic BMT, events reported in at least 10% of patients 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 survival between the LEUKINE and placebo-treated patients.

Adverse events observed for the patients treated with LEUKINE in the historically-controlled BMT failure study 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 with LEUKINE in the graft failure study.

In uncontrolled Phase I/II studies with LEUKINE in 215 patients, the most frequent adverse events were fever, asthenia, headache, bone pain, chills and myalgia. These systemic events were generally mild or moderate and were usually prevented or reversed by the administration of analgesics and antipyretics such as acetaminophen. In these uncontrolled trials, other infrequent events reported were dyspnea, peripheral edema, 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 hydration status should be carefully monitored during LEUKINE administration.

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

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

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

In a historically-controlled study of 86 patients with acute myelogenous leukemia (AML), the LEUKINE treated group exhibited an increased incidence of weight gain (p=0.007), low serum proteins and prolonged prothrombin time (p=0.02) when compared to the control group. Two LEUKINE treated patients had progressive increase in circulating monocytes and promonocytes and blasts in the marrow which reversed when LEUKINE was discontinued. The historical control group exhibited an increased incidence of cardiac events (p=0.018), liver function abnormalities (p=0.008), and neurocortical hemorrhagic events (p=0.025).15 Antibody Formation Serum samples collected before and after LEUKINE treatment from 214 patients with a variety of underlying diseases have been examined for immunogenicity based on the presence of antibodies. Neutralizing antibodies were detected in five of 214 patients (2.3%) after receiving LEUKINE by continuous IV infusion (three patients) or subcutaneous injection (SC)(two patients) for 28 to 84 days in multiple courses. All five patients had impaired hematopoiesis before the administration of LEUKINE and consequently the effect of the development of anti-GM-CSF antibodies on normal hematopoiesis could not be assessed. Antibody studies of 75 patients with Crohn’s disease receiving LEUKINE by subcutaneous injection 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 are unknown. Drug-induced neutropenia, neutralization of endogenous GM-CSF activity and diminution of the therapeutic 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 of antibodies in such patients has not been assessed.

Overdosage The maximum amount of LEUKINE that can be safely administered in single or multiple doses has not been determined. Doses up to 100 mcg/kg/day (4,000 mcg/m2/day or 16 times the recommended dose) were administered to four patients in a Phase I uncontrolled clinical study by continuous IV infusion for 7 to 18 days. Increases in WBC up to 200,000 cells/mm3 were observed. Adverse events reported were dyspnea, malaise, nausea, fever, rash, sinus tachycardia, headache and chills. All these events were reversible after discontinuation of LEUKINE. In case of overdosage, LEUKINE therapy should be discontinued and the patient carefully monitored for WBC increase and respiratory symptoms.

Table 6

Percent of AuBMT Patients Reporting Events LEUKINE Placebo Events by Body System (n=79) (n=77) Body, General Fever 95 96 Mucous membrane disorder 75 78 Asthenia 66 51 Malaise 57 51 Sepsis 11 14 Digestive System Nausea 90 96 Diarrhea 89 82 Vomiting 85 90 Anorexia 54 58 GI disorder 37 47 GI hemorrhage 27 33 Stomatitis 24 29 Liver damage 13 14 Skin and Appendages Alopecia 73 74 Rash 44 38

LEUKINE Placebo Events by Body System (n=79) (n=77) Metabolic, Nutritional Disorder Edema 34 35 Peripheral edema 11 7 Respiratory System Dyspnea 28 31 Lung disorder 20 23 Hemic and Lymphatic System Blood dyscrasia 25 27 Cardiovascular System Hemorrhage 23 30 Urogenital System Urinary tract disorder 14 13 Kidney function abnormal 8 10 Nervous System CNS disorder 11 16

Table 7

Percent of Allogeneic BMT Patients Reporting Events LEUKINE Events by Body System (n=53) Body, General Fever 77 Abdominal pain 38 Headache 36 Chills 25 Pain 17 Asthenia 17 Chest pain 15 Back pain 9 Digestive System Diarrhea 81 Nausea 70 Vomiting 70 Stomatitis 62 Anorexia 51 Dyspepsia 17 Hematemesis 13 Dysphagia 11 GI hemorrhage 11 Constipation 8 Skin and Appendages Rash 70 Alopecia 45 Pruritis 23 Musculo-skeletal System Bone pain 21 Arthralgia 11 Special Senses Eye hemorrhage 11 Cardiovascular System Hypertension 34 Tachycardia 11

Placebo (n=56) 80 23 36 20 36 20 9 18 66 66 57 63 57 20 7 7 5 11 73 45 13 5 4 0 32 9

LEUKINE Placebo Events by Body System (n=53) (n=56) Metabolic/Nutritional Disorders Bilirubinemia 30 27 Hyperglycemia 25 23 Peripheral edema 15 21 Increased creatinine 15 14 Hypomagnesemia 15 9 Increased SGPT 13 16 Edema 13 11 Increased alk. phosphatase 8 14 Respiratory System Pharyngitis 23 13 Epistaxis 17 16 Dyspnea 15 14 Rhinitis 11 14 Hemic and Lymphatic System Thrombocytopenia 19 34 Leukopenia 17 29 Petechia 6 11 Agranulocytosis 6 11 Urogenital System Hematuria 9 21 Nervous System Paresthesia 11 13 Insomnia 11 9 Anxiety 11 2 Laboratory Abnormalities* High glucose 41 49 Low albumin 27 36 High BUN 23 17 Low calcium 2 7 High cholesterol 17 8

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

Table 8

Percent of AML Patients Reporting Events LEUKINE Events by Body System (n=52) Body, General Fever (no infection) 81 Infection 65 Weight loss 37 Weight gain 8 Chills 19 Allergy 12 Sweats 6 Digestive System Nausea 58 Liver 77 Diarrhea 52 Vomiting 46 Stomatitis 42 Anorexia 13 Abdominal distention 4 Skin and Appendages Skin 77 Alopecia 37

Placebo (n=47) 74 68 28 21 26 15 13 55 83 53 34 43 11 13 45 51

LEUKINE Placebo Events by Body System (n=52) (n=47) Metabolic/Nutritional Disorder Metabolic 58 49 Edema 25 23 Respiratory System Pulmonary 48 64 Hemic and Lymphatic System Coagulation 19 21 Cardiovascular System Hemorrhage 29 43 Hypertension 25 32 Cardiac 23 32 Hypotension 13 26 Urogenital System GU 50 57 Nervous System Neuro-clinical 42 53 Neuro-motor 25 26 Neuro-psych 15 26 Neuro-sensory 6 11

REFERENCES 11. Bunn P, Crowley J, Kelly K, et al. Chemoradiotherapy with or without granulocyte-macrophage colonystimulating factor in the treatment of limited-stage small-cell lung cancer: a prospective phase III randomized 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 colonystimulating factor in cancer patients: A phase Ib clinical study. In Behring Institute Research Communications, 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 myeloid leukemia with Ara-C and recombinant human granulocyte-macrophage colony-stimulating factor. Blood 1990; 75(9):1766-1769.

14. Vadhan-Raj S, Keating M, LeMaistre A, et al. Effects of recombinant human granulocyte-macrophage colony-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 colony stimulating factor after chemotherapy in patients with acute myeloid leukemia at higher age or after relapse. Blood 1991; 78(5):1190-1197.

16. Blazar BR, Kersey JH, McGlave PB, et al. In vivo administration of recombinant human granulocyte/macrophage colony-stimulating factor in acute lymphoblastic leukemia patients receiving purged 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 Technologies U.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.

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Use of Skin Moisturizers May Expose Breast Cancer Patients to Estrogen

Obesity Increases Risk for Contralateral Breast Cancer

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

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

Olson observed that topically applied estrogens are more efficiently absorbed into the body than estrogens administered orally because of the first-pass effect by the liver and added that estrogen receptor–positive breast cancer patients should avoid exogenously administered estrogen to minimize the risk of a recurrence. This is especially important in women taking aromatase inhibitors because topical estrogen may blunt the therapeutic effect of these agents.

“Just as patients can make informed choices regarding the use of hormone replacement therapy, they should have the right to make an informed choice regarding the use of a moisturizer,” Olson said. “In order to make that choice, they need to know what the moisturizer contains. And for estrogen receptor–positive patients, that means a moisturizer free of estrogen and other estrogen-active molecules.”

—Jill Stein

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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 EGFRInhibitor Therapy • Current and Future Perspectives on the Treatment of Colorectal Cancer Interactive online presentations with polling questions at www.COEXM.com

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Considerations in Multiple Myeloma: Hard-to-Treat Patients

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MULTIDISCIPLINARY TEAM PRESENTATIONS BY

SAN ANTONIO—Obesity seems to be a significant risk factor for the development of contralateral breast cancer, investigators from the Louisiana State University Health Sciences Center, Shreveport, announced at the 2008 San Antonio Breast Cancer Symposium.

Marco Quispe, MD, and his colleagues reviewed the electronic medical charts of patients with invasive breast cancer over a recent 25-year period. The analysis excluded patients with stage IV disease at the time of diagnosis.

Of the 647 patients who were diagnosed with invasive breast cancer, 72 (11%) had recurrent intramammary breast cancer, which was defined as a new diagnosis of invasive or in-situ breast cancer at least 6 months after the diagnosis of primary invasive Continued on page 20

January/February 2009

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

Kamakshi Rao, PharmD, BCOP University of North Carolina Hospitals

Shaji Kumar, MD Mayo Clinic

• 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

INTRODUCTION

Russell Hennessy russell@coexm.com

Dear Colleague: It is my distinct pleasure to offer this newsletter entitled “Considerations in Multiple Myeloma: Hard-to-Treat Patients,” the third issue in a series of newsletters featuring topics relevant to your multidisciplinary team approach to caring for patients with multiple myeloma (MM).

Together with a faculty of hematologists/oncologists, oncology nurses, and oncology pharmacists, we focus our discussion on one topic for each newsletter. While the previous issues focused on patients with renal dysfunction (another hard-to-treat population of MM patients) and on treatment-naive patients, this issue discusses treatment of patients with relapsed/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 care of patients with MM. Visit us at: www.coexm.com Sincerely,

Millennium Pharmaceuticals, Inc.

IN THIS ISSUE:

Copy Editor Bonnie Nickel Senior Production Manager Alaina Pede Directors of Client Services John W. Hennessy john@coexm.com

LETTER TO OUR READERS

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New Therapeutic Approaches to Metastatic Melanoma

Publisher Philip Pawelko phil@coexm.com

Editor in Chief Sagar Lonial, MD Emory University

Sagar Lonial, MD Associate Professor of Hematology and Oncology Emory University

Publisher Philip Pawelko phil@coexm.com Editorial Director Susan Berry susan@coexm.com dits e Cr d Copy Editor CE re E/ ffe Bonnie Nickel CM O

Senior Production Manager Alaina Pede Directors of Client Services John W. Hennessy john@coexm.com Russell Hennessy russell@coexm.com Circulation Department circulation@coexm.com Director of Human Resources Blanche Marchitto

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Emerging Therapies for Myelodysplastic Syndromes IN THIS ISSUE: • Updates from the 44th Annual Meeting of the American Society of Clinical Oncology

Senior Production Manager Alaina Pede

with Myelodysplastic Syndromes

by Erin P. Demakos, RN, CCRC Mount Sinai School of Medicine, New York, NY

Directors of Client Services John W. Hennessy john@coexm.com

MDS are older than 60 years; the condition is rare in young adults.1 MDS can cause many different signs and symptoms. Most patients experience complications of blood cell deficiencies that cause a wide array of highly debilitating symptoms. Many patients with MDS experience severe, chronic anemia, requiring red blood cell (RBC) transfusions as frequently as every 2 weeks. In addition to disrupting and diminishing quality of life, frequent transfusions are associated with an increased risk of iron overload, transfusion reactions, and infection from agents transmitted through the transfused blood.1,2 Leukopenia (especially neutropenia or granulocytopenia) can cause serious infections with high fevers. Thrombocytopenia can cause excessive bruising and bleeding, which can become lifethreatening as the disease progresses.1,2

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• 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

Circulation Department circulation@coexm.com Director of Human Resources Blanche Marchitto

Supported by an educational grant from

INTRODUCTION

T

he development of epidermal growth factor receptor inhibitors (EGFRIs) has expanded treatment options for patients with cancer. Although these agents are generally well tolerated, skin toxicities, including papulopustular rash, xerosis, pruritus, fissures, and hair and nail alterations, are often associated with their use. These adverse events can affect patients both physically and psychosocially and may lead to dose reduction, interruption of therapy, or discontinuation of therapy. Therefore, the timely and effective management of skin

toxicities related to treatment is imperative to ensure consistent EGFRI administration and maintenance of patient quality of life.

Oncology nurses who care for patients receiving EGFRI therapy must be equipped with practical strategies for assessing and managing toxicities related to treatment. This newsletter provides an overview of the pathophysiology and clinical presentation of skin reactions associated with EGFRI therapy, as well as current recommendations for grading and treating these toxicities.

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diagnosed at a localized stage and the 5year survival rate associated with this form of the disease is about 99%.1 In contrast, the 5-year survival rates for regional and distant stages of the disease are much lower (65% and 15%, respectively).1 Patients diagnosed with stage IV melanoma have very poor prognoses and relatively few treatment options. These patients continue to pose a significant challenge to clinicians.

Over the past decade, several novel agents have been developed for the treatment of metastatic melanoma. Encouraging safety and efficacy results from recent clinical trials evaluating many of these therapies were presented at the 44th annual meeting of the American Society of Clinical Oncology (ASCO), held May 30June 3, 2008, in Chicago, Illinois, and are highlighted in this publication.

Pfizer, Inc.

IN THIS ISSUE:

Russell Hennessy russell@coexm.com

INTRODUCTION yelodysplastic syndromes (MDS) are a group of blood disorders in which the bone marrow does not function properly and produces defective blood cells. These abnormal blood cells usually die before they leave the bone marrow or shortly after entering the bloodstream. As a result, patients with MDS have low blood cell counts, or cytopenias. Approximately 30% of patients with MDS will progress to acute myeloid leukemia (AML),1 a rapidly growing cancer of bone marrow cells that is difficult to treat and has a poor prognosis.

According to the American Cancer Society, an estimated 10,000 to 15,000 new cases of MDS occur annually.1 The number of new cases diagnosed each year is likely to increase in prevalence as the elderly population continues to grow.

About 80% to 90% of all patients with

Effective Management Strategies for Skin Toxicities Associated With Epidermal Growth Factor Receptor (EGFR)-Inhibitor Therapy

Copy Editor Bonnie Nickel

• Nursing Strategies and Interventions for Managing Patients

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Publisher Philip Pawelko phil@coexm.com Editorial Director Susan Berry susan@coexm.com

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elanoma, the most deadly form of skin cancer, arises from melanocytes, the pigment-producing cells of the skin. Melanoma is expected to be diagnosed in approximately 62,480 individuDirector of Human als (34,950 men and 27,530 women) and Resources deaths in the Blanche Marchitto September 2008 • Vol. 1 • No. 3 cause an estimated 8420 United States in 2008.1,2 The incidence of melanoma is increasing faster than any other malignancy. In 1935, an individual’s lifetime risk for developing invasive melanoma in this country was 1 in 1500; in 2010, this risk is projected to be 1 in 50.

According to the World Health Organization, approximately 132,000 melanoma skin cancers occur globally each year, and the incidence of melanoma is Supported by increasing faster than any other maligan educational grant from nancy worldwide.3-5 Approximately 80% of melanomas are Circulation Department circulation@coexm.com

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19

BREAST CANCER

SAN ANTONIO—Breast cancer patients who use topical moisturizers may be exposing themselves to estrogen without knowing it, investigators reported at the 2008 San Antonio Breast Cancer Symposium.

Adrienne Olson, PharmD, with Breastlink in Long Beach, California, and her colleagues used high-performance liquid chromatography to determine the estrogen content of 16 popular overthe-counter (OTC) skin moisturizers.

“My research was prompted by my experience during treatment for estrogen receptor–positive breast cancer,” Olson explained in an interview. “I was undergoing very heavy chemotherapy, and my skin had become very dry because of menopause brought on by chemotherapy,” she said. “I started applying a rejuvenating cream to my face, which began to look like the face of a 16-year-old. I strongly suspected that the product contained estrogen because only estrogen could restore the skin to such a youthful appearance.”

When she tested the OTC products for their estrogen content, she found that four samples contained > 0.40% estriol, one contained 0.17% estriol, and one contained 0.05% estrone. However, none of the creams tested had listed estrogen among its ingredients.

“Until the late 1970s, intact epidermis was generally considered to be a barrier to topically applied medications contained in creams and ointments,” Olson,

BREAST CANCER

Breast Cancer

Nonanthracycline Regimens

Obesity

Continued from cover

Continued from page 19

BREAST CANCER

which patients would do better with an anthracycline or who may do well with an alternative regimen. One determining factor may be a history or the presence of heart disease, diminished cardiac function, or other risks for cardiac problems.

William Gradishar, MD, professor of medicine at Northwestern University in Chicago, considers TCH an alternative to a doxorubicin, cyclophosphamide, docetaxel, trastuzumab combination (ACTH) for HER2-positive breast cancer. “I don’t know that [TCH] is better, but it’s a perfectly acceptable regimen,” he said, but noted that clinicians have long experience with anthracyclines, and the data for TCH are more limited. “I think people feel comfortable with the toxicity profile of ACTH,” he noted, and therefore continue to use it.

Mark Pegram, MD, professor of medical oncology in the Braman Family Breast Cancer Institute at the University of Miami in Florida, was a developer of the taxotere, carboplatin, trastuzumab regimen for the adjuvant treatment of HER2-positive early breast cancer, which the US Food and Drug Administration approved on May 22, 2008, as the first taxane-based, nonanthracyclinecontaining chemotherapy regimen for this indication.

“It’s a very, very active regimen in locally advanced breast cancer,” Pegram told The Oncology Nurse. “And based on the BCIRG 006 adjuvant study, we know that it’s a very robust regimen and safer than an anthracycline-based regimen with trastuzumab long term in the adjuvant setting.” The study showed that taxotere, carboplatin, and trastuzumab without anthracycline was as efficacious as an anthracycline followed by trastuzumab.

“So I think off-study [the taxotere, carboplatin, trastuzumab combination] is

“Certainly for older patients in whom cardiac toxicity is a particular concern, TCH is an especially promising regimen.” a perfectly acceptable standard regimen at this point....The community at large in North America is using the regimen with increasing frequency since probably the last year, year and a half,” Pegram estimated.

He said that a US Oncology trial showed that docetaxel/cyclophosphamide had superior efficacy to an anthracycline-based regimen. “So I feel comfortable prescribing nonanthracycline regimens. Not everybody does.”

Pegram noted that topoisomerase II alpha is the target of anthracyclines, and its expression is amplified only when HER2 is overexpressed. “It’s really the HER2-positive and ergo, Topo II-positive patient subset, that benefits from anthracyclines [in adjuvant trials], and all others probably don’t,” he said. “And HER2-positive patients, as long as they’re treated with trastuzumab, then you don’t need to give them an anthracycline.”

When TCH may be most useful Although everyone takes the acute toxicity of TCH seriously, the regimen may be particularly useful in the treatment of bulky disease or when a fast response is desired. “I’ve used TCH in the first-line setting for that group of patients—that is, high volume, organthreatening metastatic breast cancer previously untreated,” said Marlon Kleinman, MD, of Hematology/ Oncology of the North Shore, a private group practice in Skokie, Illinois.

In this setting, Dana Zakalik, MD, of

William Beaumont Hospital in Royal Oak, Michigan, said TCH did show a survival advantage, “one of the few regimens that showed that.”

Kleinman said TCH is also a reasonable regimen when there are cardiac risks, “so I’m not invoking the risk of an anthracycline by using TCH, although [trastuzumab] is not totally innocent regarding cardiac risk. So, I still go through the routine of evaluating [patients] from a cardiac perspective with MUGA [multiple-gated acquisition] scans, echo [cardiograms], [and] cardiology consults if necessary.”

Tatiana Prowell, MD, of the Avon Foundation Breast Cancer Center at Johns Hopkins University in Baltimore concurred. “We know that the best predictors for anthracyclineinduced cardiotoxicity are advancing age and pre-existing heart disease.

Certainly for older patients in whom cardiac toxicity is a particular concern, TCH is an especially promising regimen,” she said.

Development of less toxic regimens is definitely needed, Winer said. US Oncology is conducting the TC-TAC trial, comparing regimens of docetaxel and cyclophosphamide with or without doxorubicin for early-stage HER2-negative breast cancer patients. And the NSABP B38 trial compares standard doxorubicin doses with dose-dense doxorubicin in node-positive patients.

A secondary end point of the trial is toxicity of the different regimens.

—Daniel M. Keller

breast cancer. Of these cases, 28 were ipsilateral and 44 were contralateral.

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

The results showed that obesity at the time primary invasive breast cancer is diagnosed correlated with an increased risk for contralateral breast cancer in both univariate and multivariate analyses. The investigators also found that for intramammary occurrence, obese women were approximately five times as likely to develop contralateral breast cancer compared with nonobese women.

Several factors contribute to a poor prognosis in obese women with breast cancer, Quispe pointed out. For example, an obese patient is more likely to be diagnosed at a later stage due to the difficulty in identifying a palpable lesion in a larger breast. In addition, the treatment of breast cancer may be particularly challenging because obese patients have a higher rate of complications from surgery and radiotherapy.

Also, chemotherapy may be less effective in obese women because of systemic undertreatment and altered pharmacokinetics.

Finally, he said that additional studies are needed to further define the impact of obesity on breast cancer outcomes. The ability to define which patients are at increased risk for developing contralateral breast cancer will help better determine appropriate prevention strategies.

—Jill Stein

Providers/Patients Dispute Treatment Goals Continued from cover

BREAST CANCER

and three oncology nurses). Survey participants were women aged 18 years or older with breast cancer who were undergoing any chemotherapy or biologic therapy during a recent 12month period at university- or community-based cancer clinics.

“Research has shown that during their visit with oncologists, patients consistently identify prognosis and treatment as important topics they wish to address,” West and her colleagues wrote in their poster presentation. “Despite a recent emphasis on providing patients with more detailed information about their proposed treatments, the literature suggests that 20% to 50% of patients harbor miscon20

ceptions related to the therapeutic goal.” Evidence also suggests that providers are largely unaware of these misunderstandings, they added.

In the present study, patients were asked to predict the physician’s goal, physicians were asked to predict the patient’s goal, and nurses were asked to predict the patient’s and physician’s goals.

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

When response categories were “col-

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lapsed” into groups with similar broad treatment intent (palliative vs curative/ adjuvant), the level of agreement rose from 81% to 94%.

“Breast cancer patients actually have a very high uptake of information through friends, the Internet, and other sources,” said West, who is now with Baylor College of Medicine in Houston, Texas. “In fact, when physicians initiate a discussion of chemotherapy, patients are already highly knowledgeable. However, while they appear to be well informed as to which side effects they might experience and when they might experience such effects, they seem to be ‘missing the forest for the trees.’ In other words,

they don’t understand the broad goals of chemotherapy.”

West added that the most important goal for providers is “not to cover themselves by describing every possible side effect with patients” but instead to explain specifically the goal the therapy aims to achieve. “After a discussion of therapeutic goals, providers can then explain the risks and benefits of having to experience such side effects in order to obtain treatment benefits,” she added.

She noted that future research in larger, more diverse populations will help determine whether the findings from this study are generalizable.

—Jill Stein January/February 2009

Finally in the treatment of higher-risk MDS*â&#x20AC;Ś

* 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.

S U R V I V A L VIDAZA is the first and only agent proven to extend overall survival vs conventional care regimens (CCR) in patients with higher-risk MDS VIDAZA nearly doubled the 2-year overall survival rate1 1.0 0.9

Log–Rank P =.0001 HR=0.58 (95% CI, 0.43–0.77)

Proportion Surviving

0.8 0.7 0.6

24.5 months

0.5

15.0 months

0.4

VIDAZA

0.3

CCR

0.2 0.1 0.0 0

5

10

15 20 25 Time (Months) From Randomization

30

35

40

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 * 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

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.

For proven survival in higher-risk MDS

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Complimentary

CONTINUING EDUCATION AT WWW.COEXM.COM

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

Decision Aids as a Guide for Cancer Patients Making Clinical Decisions

BY DAWN STACEY, RN, MSCN, PhD, CON(C)1; RAJIV SAMANT, MD2; CAROL BENNETT, MSC3 1 School of Nursing; 2University of Ottawa and Ottawa Hospital Regional Cancer Centre; and 3Ottawa Health Research Institute, Clinical Epidemiology Program, Ontario, Canada 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 completion of the post-test.

DISCLAIMERS The opinions or views expressed in this continuing education activity are those of the faculty and do not necessarily reflect the opinions or recommendations of the University of

C

linical decision making by cancer patients is a complex process. While it is widely accepted that impressive advances over the past decade have led to disease-specific guidelines and clinical pathways for some cancers, which makes decision making fairly straightforward, many decisions are preference-sensitive and therefore more difficult. Some examples of preference-sensitive decisions for 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 across cancer screening and/or treatment options. Because there is no such thing as a “best choice” for everyone, decisions are defined as being of superior quality when they are based on current scientific evidence and take into account patients’ informed values and preferences.1-3 Unfortunately, there are multiple obstacles to high-quality decision making. For example, evidence seems to suggest that standard counseling in clinical practice does not produce high-quality decisions.4-7 In FACULTY/PLANNER DISCLOSURES All planners and faculty participating in continuing education activities provided by the University of Nebraska Medical Center, College of Nursing Continuing Nursing Education are expected to disclose to the audience any significant 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 activity. 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.

January/February 2009

EDITORIAL BOARD Carol 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

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

Patrick Medina, PharmD, BCOP University of Oklahoma College of Pharmacy Oklahoma City, OK 73126

LEARNING OBJECTIVES After completing this activity, the reader should be better able to: • Cite examples of preference-sensitive decisions patients with cancer may face.

Rajiv Samant, MD Faculty of Medicine University of Ottawa Ottawa, ON K1H 8M5

• 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 professionals, especially those caring for cancer patients.

COST This program is complimentary for all learners.

addition, although patients have a variety of means for accessing multiple sources of medical information, they often lack the breadth of knowledge or the confidence needed to be able to assess screening and treatment options effectively. They also may have unrealistic expectations as well as decisional conflict that thwart effective decision making.

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

Shared decision making Until recently, physicians and their “designates” were the sole providers of medical information and therefore the sole decision makers; a practice referred to as a “paternalistic model.” Over the past decade, however, with improved access to medical information, patients have become increasingly involved in clinical decision making. A shared decision-making approach in which patients discuss with their clinicians current evidence on treatment options and make a mutually agreed-on choice offers several benefits: • It provides individualized patient-centered care • It complies with legal and ethical patient rights

The authors, reviewers, and planning committee members listed below have stated they have no significant or substantial 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 continuing 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.

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

G REEN H ILL H EALTHCARE C OMMUNICATIONS

27

Complimentary

CONTINUING EDUCATION AT WWW.COEXM.COM

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

Clinicians need to use an individualized approach when determining whether a patient seeks to participate in decision making, and, if so, to what extent.

• It addresses the patient’s desire to be involved • It is accountable for screening and treatments used • It improves patient satisfaction with the decisionmaking process • It can potentially improve patient health outcomes.

Despite these benefits, many clinicians have not adopted the practice of shared decision making.8 Oncologists, in particular, often do not encourage patient involvement to the extent that patients would like.9-11 It may be that oncologists underestimate the extent to which their patients want to be involved in the decision-making process.5,6 Patient preferences are hard to predict, given that there do not seem to be any factors proven to correlate with patient preferences or preferred role in decision making. Thus, clinicians need to use an individualized approach when determining whether a patient seeks to participate in decision making, and, if so, to what extent.12,13

Interventions to promote patient involvement in decision making An array of interventions is available that aim to boost patient involvement in the decision-making process. The best interventions are those that help patients recognize that a decision needs to be made, understand the scientific evidence currently available, and clarify their values associated with the outcomes of screening and treatment options—all of which should help produce a top-quality decision.1 Conventional patient education materials have not proved to be sufficient. The following options have all demonstrated benefit.

Patient decision aids. These are tools that translate evidence into patient-friendly form by providing, at a minimum, information on the options, risks and benefits of screening and treatment options, and implicit methods to clarify personal values.14 Values can be clarified implicitly by providing details on what it is like to undergo the procedures and to live with the physical, social, and emotional consequences in a way that makes it possible for patients to formulate personal value judgments. Decision aids also may include information on the medical condition and the likelihood of the benefits and risk of the various options. Patient decision aids are usually self-administered and are available in several patient-friendly formats, for example, as paper handouts, videos or DVDs, or computer software. Some decision aids are administered by the practitioner and may involve more complex approaches. Given the relative ease of updating information and minimal dissemination costs, the Internet has become the primary resource for patient decision aids.

We reviewed 23 randomized controlled trials that focused on cancer-related decisions such as prostate and colon cancer screening, breast cancer genetic testing, and breast and prostate cancer treatment.15 The 23 trials were drawn from the 55 randomized controlled trials included in the Cochrane systematic review of patient decision aids.

Overall, patient decision aids were shown to consistently improve knowledge, decrease decisional conflict, and lead to choices that were compatible with patients’ values.15 When we compared cancer-specific decision aids with usual care, we found that individu28

als who received patient decision aids were more likely to participate in decision making and were better informed than persons not receiving such aids.

Patients exposed to cancer-specific decision aids that included descriptions of outcomes and probabilities more often had accurate risk perceptions than those who did not receive this information. Cancer-specific decision aids also can prevent overuse of some aggressive interventions as well as underuse of other interventions.

Although patient decision aids have been shown to be useful in oncology, they have not been routinely incorporated into oncology practices. Common obstacles to the use of these aids include a lack of skills among healthcare professionals in shared decision making, a lack of awareness of patient decision aids, and availability of patient decision aids on a limited number of decisions.16 Question prompt sheets. These are standardized sets of questions that guide patients on how to obtain information during the consultation.17 Consultation planning. This is a process whereby trained facilitators coach patients on how to develop their own list of questions to ask during their

consultation. Trained facilitators are usually nurses, patient navigators, or individuals who work at the resource center.18 Decision coaching. Decision coaching facilitates patient involvement in decision making.19 Decision coaches are health professionals who assess patients’ decisional conflict and related needs, guide patients through the decision-making process using decision aids and/or evidence-based information, and monitor for factors that can influence the patient’s implementation of the shared decision.

Future research Although cancer patients are seeking increased participation in clinical decision making with the ultimate goal of achieving better clinical decisions, more research is needed to help achieve these goals. Future studies are needed to: • assess the impact of patient decision aids on patient–clinician communication • identify ways to overcome barriers to the adoption of patient decision aids by routine oncology practices • determine effective ways to make patient decision aids easily accessible to patients • explore the implications of legally requiring that these interventions be included in the informed consent process • establish effective approaches to help oncologists and patients transition from the standard paternalistic doctor–patient model to a shared decisionmaking model.

COMMENTARY Decision Aids as a Guide for Cancer Patients Making Clinical Decisions: A Nurse’s Perspective

BY SHARON GENTRY, RN, MSN, AOCN Derrick L. Davis Forsyth Regional Cancer Center, Winston-Salem, North Carolina

T

he article by Stacey and colleagues reminds healthcare professionals of the transition from paternalistic patient non-decision making that our oldest patients may have experienced to the current active participation in medical decision making that our patients currently face in many healthcare settings.

Teamwork is essential for a satisfactory and high-quality medical journey for the patient. The patient brings to the shared decision-making process his or her knowledge, whether it is basic understanding of their disease or extensive understanding of treatment choices. This knowledge is colored with the patient’s values and culture. Healthcare professionals bring the current scientific evidence to best treat the specific disease, which the patient needs to understand to make a high-quality decision about his or her care.

Patient decision aids are the common link and solution to merge the team together. Although, as Stacey and colleagues discuss, studies have shown that decision aids can improve patients’ knowledge and help them make informed decisions about their care, they are not widely used in oncology practices. It takes a commitment from

G REEN H ILL H EALTHCARE C OMMUNICATIONS

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

It is important to point out that a decision tool is not simply a patient education sheet or other teaching material that is intended solely to increase a patient’s knowledge base. For example, a chemotherapy teaching sheet is not a decision aid. A question prompt sheet is not meant to be used alone but instead as a guide to address what information the patient needs. An example of a decision aid available on the Internet is Cancer NexProfiler (www.oncolink.upenn.edu). This is a free, interactive tool that allows a patient to get information about treatment options and outcomes that can be discussed with the healthcare team.

As healthcare professionals, we need to stay on the learning curve and increase our personal awareness of current decision aids that may be beneficial for patients.

To ensure quality decision making by our patients, the decision aids should be used early during the patient’s medical journey.

January/February 2009

Complimentary

CONTINUING EDUCATION AT WWW.COEXM.COM

Program #09CE 035 • RELEASE DATE: February 15, 2009 • EXPIRATION DATE: February 14, 2010 Conclusion Public surveys consistently indicate that people want to be involved in health decisions. However, when faced with values-sensitive decisions related to cancer screening and treatment, current clinical counseling is inadequate and patients need guidance to gain their desired role in decision making. Interventions to support patients’ involvement in decision making include patient decision aids, question prompt sheets, consultation planning, and decision coaching. Healthcare professionals have an important role in assessing factors influencing patients’ decision-making needs, providing support to address their needs by using effective interventions, and monitoring patients’ progress in making and implementing decisions.

Case Report Decision Coaching for Man with Early-stage Prostate Cancer A 51-year-old patient, recently diagnosed with early-stage prostate cancer by his urologist, was given educational material regarding treatment options and booked for a follow-up visit. When the oncology nurse did an initial assessment, she found that although Mr Smith felt that he had enough information about his options, he was not sure which option was best for him, primarily because he felt unclear about which risks and benefits of options were most important. The dialogue that

ensued clarified that, for Mr Smith, the benefit of treatment—increased chance of survival for men under age 65—outweighed the side effects of treatment and that he wanted to seek active treatment versus watchful waiting. He was still undecided regarding the best treatment option (radiation or surgery). The following dialogue provides an overview of the decision support that was provided in preparation for discussion with the urologist.

would have bowel irritation, such as diarrhea during treatment, but only five to 10 men will have longerterm diarrhea and need to be more careful about what they eat. Impotence can occur in at least half of the patients regardless of the treatment. The difference is that you will know if you are impotent within days after surgery and, if you are, it is usually permanent; for radiation therapy, the impotence has a more gradual onset and may not be permanent.”

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 to have a good sense of what is involved with these treatments. At this point, it would help if you could think about the side effects of these treatments and determine which ones are more important for you to avoid.

Would it help if I reviewed these side effects and the chance that they will occur?”

Clarify patient values “Have you thought about what it means to live with possible side effects of treatment such as urinary dribling, impotence, or diarrhea from bowel irritation? Is there one that is more important for you to avoid?”

Side effects of options “There are three main side effects of prostate cancer treatments. Bladder problems are more likely to occur with surgery; bowel irritation is more likely to occur with radiation; and impotence can occur to differing degrees 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 irritation, if 100 men like you had radiation, about 30 men

COMMENTARY Decision Aids as a Guide for Cancer Patients Making Clinical Decisions: A Pharmacist’s Perspective

BY PATRICK MEDINA, PHARMD, BCOP University of Oklahoma College of Pharmacy, Oklahoma City

P

harmacists tend to be data driven, often forgetting the importance of including patients in the decision-making process. It is often assumed that patients will want the treatment dictated by the literature using “evidence-based medicine.” However, the “data” often contradict this perception. Several surveys note that patients’ willingness to undergo treatment as well as their tolerability of certain cancer-related adverse effects is different from healthcare professionals’ perceptions.

The article by Stacey and colleagues reminds healthcare professionals that the medical information boom largely found on the Internet requires healthcare professionals to transition from paternalistic patient non-decision making to a shared decisionmaking approach.

Stacey and colleagues point out that current oncology practices have not routinely adopted this approach, despite several benefits cited in the article.

Patients who use these aids were better informed and more involved in their decision making—a goal that most practices should welcome. One reason is that conventional patient education materials may not be sufficient to do the job. This is an area where pharma-

cists should use their expertise and improve the resources available.

Because most patient decision aids are self-administered and available on the Internet, healthcare professionals, including pharmacists, can assist patients in finding well-validated decision aids that will be useful for their particular disease state. For instance, patients can use www.collaborativecare.net to assist them in making decisions about their breast cancer treatment.

In summary, the article by Stacey and colleagues highlights the importance of clinical practices incorporating a shared decision-making approach to improve their patients’ care. Although current tools have limitations, several have shown benefit in assisting patients who are making difficult decisions, and often the results contradict conventional wisdom. Pharmacists can assist this process by guiding patients to appropriate tools as well as improving the decision-making tools currently available.

As individualized care increases with genetic testing and pharmacogenomic profiling, use of decision-making tools will increase. These tools will need to be incorporated into clinical practice by healthcare professionals, including pharmacists.

Screen for decisional difficulties “Now that we have discussed the different options, are you leaning toward one treatment more than another, or is there anything else that you would like to discuss?”

Given his active lifestyle and the possible impact on sexual relations, Mr Smith clearly preferred to live with the potential complications of radiation and avoid the chance of urinary dribbling and impotence associated with surgery.

References 1. 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 medicines: 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 carcinoma: patient preferences and physician perceptions. Cancer. 2002;94:2076-2080.

13. Bruera E, Sweeney C, Calder K, et al. Patient preferences versus physician perceptions 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 intervention 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 decision making: a framework, evidence, and implications for nursing practice, education, and policy. Worldviews Evid Based Nurs. 2008;5:25-35.

Jill Stein contributed to the preparation of this manuscript.

January/February 2009

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HEMATOLOGIC CANCERS

Diagnostic Strategies Continued from page 12 complete the diagnostic process. The patient history will help to identify the behavior of lymphadenopathy, small- to medium-sized nodes that wax and wane in indolent subtypes or lymph nodes rapidly increasing in size in aggressive subtypes. The history also will establish the presence or absence of B symptoms (fever, night sweats, or weight loss).

The tissue diagnosis is best achieved by excisional lymph node biopsy, bone marrow biopsy, and aspirate, the details of which have been reviewed in Part 2 of this series (December 2008). Careful and systematic physical examination with use of a consistent measurement tool and documentation of each nodal site is critical for effective evaluation. In addition, the physical examination provides an excellent method to estimate disease response between imaging studies, with no risk to the patient. In patients with no palpable adenopathy or organomegaly, evaluation will rely on selected imaging studies or changes in laboratory parameters.

Classification systems The Ann Arbor Staging classification system, originally designed for Hodgkin’s lymphoma, is most commonly used to describe the distribution and number of nodal sites and the presence or absence of extranodal disease or constitutional symptoms.3 The Cotswoldmodified Ann Arbor classification system provides a staging framework more

consistent with the characteristics of NHL, including a designation of bulky disease and specific parameters for description of extranodal involvement.1 Bulky disease is defined as a single nodal mass exceeding 10 cm in maximum diameter or a mediastinal mass exceeding one third of the maximum transthoracic diameter. Bulky disease is considered an adverse prognostic indicator.

Extranodal involvement most often involves the spleen or bone marrow.

Hepatic involvement is most common in follicular lymphoma (FL) and diffuse large B-cell lymphoma (DLBCL). Gastrointestinal involvement is common in mantle cell lymphoma, mucosa-associated lymphoid tissue (MALT), and gastric lymphomas and will require specific diagnostic testing.

Prognostic indicators The two most common subtypes of NHL are FL and DLBCL. Both diseases have established prognostic grading systems that require accurate characterization of nodal areas, including the location and number of nodal sites. The presence of more than four nodal sites is considered an adverse prognostic variable in the Follicular Lymphoma International Prognostic Index.3 Nodal sites above and below the diaphragm or disseminated disease indicates advanced disease in the Ann Arbor classification.3 Two or more extranodal sites of disease are adverse prognostic findings in the

Recent FDA

Approvals • Postsurgical Treatment for GIST Patients

The 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 Cancer

HEMATOLOGIC CANCERS

The 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 Fludarabine The 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 provisions. Under these provisions, the company is required to perform an additional clinical trial.

• Drug Helps Mobilize Hematopoietic Stem Cells The 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 transplantation in patients with non-Hodgkin’s lymphoma and multiple myeloma. The product also has been granted orphan drug designation.

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G REEN H ILL H EALTHCARE C OMMUNICATIONS

Imaging studies are critical for the initial staging, prognostication, and evaluation of response to treatment for NHL. International Prognostic Index used for DLBCL.4 Although individual lymph node size is not a part of the prognostic systems, parameters are suggested for the initiation of therapy based on the size, number, and secondary effects of nodal sites. High tumor burden (ie, nodal masses > 7 cm, three nodes in three distinct areas each > 3 cm, symptomatic splenic enlargement, organ compression, malignant ascites or pleural effusion, rapid generalized progression of nodal sites, or lifethreatening organ involvement) is generally indicative of more advanced, aggressive disease and the need to initiate immediate therapy.5,6

Imaging studies Imaging studies are critical for the initial staging, prognostication, and evaluation of response to treatment for NHL. Radiologic assessment of treatment response has been the gold standard for estimating the risk of relapse.1 Historically, a patient with NHL required a number of invasive procedures to estimate the extent of disease.

Scientific and technologic advances have revolutionized the diagnostic process. The introduction of computed tomography (CT) in the 1970s provided a means for evaluating abnormal lymph nodes (> 1 cm) or extranodal sites. CT scans remain the standard imaging strategy for estimating the anatomic extent of disease.6,7 More recently, 18F-fluoro-2-deoxyglucose (FDG) positron emission tomography (PET), whole-body magnetic resonance imaging, and FDG-PET/CT fusion imaging have provided complimentary strategies for characterization of NHL. Each of these technologies has advantages and disadvantages in terms of sensitivity, specificity, risk to the patient, and cost (Table).

The risk of radiation exposure over time is of particular concern in a patient with potentially curable disease or who is expected to be treated over an extended period. Estimated risks for cancer as a result of radiation exposure during diagnostic imaging vary by modality but are based on the radiation burden (mSv) over time, children being at greatest risk.

The US Food and Drug Administration estimates a dose of 10 mSv may be associated with a 1:2000 risk of developing fatal cancer.7 The risk is reduced considerably after the age of 50. Patients of childbearing age will need particular attention, with careful screening and education to avoid exposure during pregnancy.

Recent analyses of PET and PET/CT in particular, which evaluate glycolytic activity as a surrogate for increased metabolic activity, have changed the recommendations for staging and restaging for NHL.6-8 These technolo-

gies provide functional imaging techniques and an advantage in certain circumstances, particularly the evaluation of patients for autologous stem cell transplant and local radiotherapy.9,10 Kwee and colleagues provide a comprehensive analysis of imaging technologies used in the staging of malignant lymphoma.7 The majority of published studies specific to imaging strategies for NHL have been based on retrospective analysis with no clear delineation of histiologic subtype.

Most trials included all types of lymphoma, including Hodgkin’s lymphoma, which has very specific recommendations for imaging. Invasive diagnostic technologies are still required for selected subtypes of NHL, including endoscopic evaluation for gastric or MALT lymphoma involving the stomach or small bowel, lumbar puncture for central nervous system lymphoma, and colonoscopy for mantle-cell or MALT lymphoma. Prospective trials analyzing imaging strategies concurrently with active therapies are under way and will provide data critical to refinement of standard imaging guidelines for NHL. Many questions remain, including the utility of each method in terms of the affect on prognosis, changes in therapeutic intervention, cost, and risks to the patient.

References 1. 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 treatment 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 radiotherapy in relapsed or refractory large B-cell lymphoma. 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.

January/February 2009

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Prescribe 6 boxes of GELCLAIR® for a 30 day supply GELCLAIR® is available at your local pharmacy and at:

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For additional information, visit www.gelclair.com or call 1-877-GELCLAIR. 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

ONCOLOGY NUTRITION

Oncology Nutrition Use of Alternative Diets

BY AMANDA SALDIVAR, MS, RD, LD TAUSSIG CANCER INSTITUTE, CLEVELAND, OHIO

P

atients often question their diets after learning about their cancer diagnosis, wondering what they should or should not eat. Many patients feel that by controlling their diets they have some sense of control over their health. Changes in diet can have several benefits to the patient with cancer, including helping to alleviate side effects from treatment (for example, following a low-fat, lowfiber diet to help manage nausea or diarrhea), increasing nutrient consumption (by following a plant-based diet), or maintaining a healthy weight to help lower recurrence (by limiting fat and calories).

Although these changes, with the guidance of a registered dietitian, can have a positive impact on the patient’s quality of life and disease management, when taken to the extreme, they can have the opposite effect.

Many alternative diets promote an increase in fruit, vegetable, and com-

plex carbohydrate consumption and, to a degree, lower intake of animal protein. However, they traditionally involve severe calorie and protein restriction and advocate use of supplementation with herbs and vitamins to help “detoxify” the body. One alternative diet is thought to be the basis for all other alternative diets.1 The Gerson regimen, developed by Max Gerson, a German physician who practiced in the United States from the late 1930s to 1950s, consists of a strict organic vegetarian diet combined with coffee enemas, herbal and nutrient supplementation, and pancreatic enzymes. The diet is purposely high in potassium and low in sodium, with no added fat and no animal protein for the first 4 weeks.2 Patients are required to consume a glass of juice made of specified fruits and vegetables that are pressed every hour for 13 hours to help the patient incorporate nutrients “from more than 20 pounds of fruits and vegetables” daily.3 Those following the diet may not use aluminum (they must cook in cast iron and may not have any canned fruits or vegetables) or consume drinking water, and all food must be fresh.3 Studies analyzing this method have been retrospective, and no prospective controlled studies have been able to duplicate the effects.1 There have been reports of electrolyte imbalance and infection from coffee enemas given four times per day.4,5 The cost to visit Gerson’s health

ONCOLOGY NUTRITION

©iStockphoto.com/David H Lewis

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G REEN H ILL H EALTHCARE C OMMUNICATIONS

When educating patients regarding alternative diets, I encourage them to review guidelines of the American Dietetic Association for spotting “junk science.” restoration center in California for a 6-day introductory course in the regimen is $2900 per person.3 The Gonzalez regimen is based on similar theories as the Gerson regimen, but there are more than 90 variations of the diet, ranging from strict vegetarian to a high-fat, high-meat diet.6 This difference is a result of the theory that disease is individualized based on a person’s metabolic profile and the chosen diet is designed to restore balance.6 The diet is combined with consumption of 130 to 160 capsules of porcine pancreatic enzymes and other types of supplements. This regimen has been shown to be beneficial in small sample sizes of patients with pancreatic cancer and is currently being studied in a trial sponsored by the National Center for Complimentary and Alternative Medicine.6 The macrobiotic diet was originally developed by George Osawha and popularized in the United States by Mischio Kushi.7 Kushi’s guidelines are based on eating foods grown in a person’s “climate”; as a result, this often limits options for foods from the groups that are a basis of the diet. Organically grown whole grains constitute 40% to 60% of food intake and vegetables (other than potatoes, tomatoes, eggplant, peppers, spinach, beets, and zucchini) 20% to 30%.7 The diet does include some protein sources; however, the 5% to 10% of volume from legumes and dried beans and limited amounts of fish (avoidance of all other sources of animal protein is recommended) does not allow for adequate protein intake, especially for a patient with cancer.

Specific fruit is allowed only two or three times per week, and water is allowed only in small amounts.7 As these are only guidelines, Kushi recommends an individualized consultation with a specialist at the Kushi Institute, which is available at $325 per session; however, patients are encouraged to participate in a week-long session to help understand how to implement the recommendations, costing $1950 with a $400 service fee for shuttling from the airport (this does not include lodging).7 Because of the emphasis on choosing only locally grown, in-season foods, there is a great risk for micronutrient and overall calorie deficiency for most Americans pursuing this regimen.

These three programs are the ones that patients most often ask about,

but there are several more variations and new diets promising outcomes that have not been proved under medical practitioners’ guidelines of evidence-based practice.

Counseling patients When educating patients regarding alternative diets, I encourage them to review guidelines of the American Dietetic Association for spotting “junk science.” These include evaluating a program’s claim to a quick fix, listing warnings or disclaimers, listing good or bad foods, basing recommendations on small studies, and sounding too good to be true.8 It is important to redirect patients to sources that will encourage healthy changes, such as the American Cancer Society’s Nutrition and Physical Activity Guidelines,9 the American Institute of Cancer Research (www. aicr.org) guidelines, and MyPyramid (www.mypyramid.gov). Trying to emphasize the risk versus the benefit of these programs can be challenging when working with patients who feel that these programs are going to be their “magic bullet.” To help them continue to feel in control, it is important to understand their desire to make changes. At the same time, patients need to understand the potential risks of alternative diets and they need education on what is needed to help them tolerate treatment.

References

1. National Cancer Institute. Gerson therapy PDQ. http://www.cancer.gov/cancertopics/ pdq/cam/gerson/HealthProfessional. Accessed October 15, 2008.

2. Questionable methods of cancer management: “nutritional” therapies. CA Cancer J Clin. 1993;43:309-319.

3. The Gerson Institute. Healing your body with the Gerson therapy. http://www.gerson.org/ g_therapy/default.asp. Accessed October 13, 2008.

4. Margolin KA, Green MR. Polymicrobial enteric septicemia from coffee enemas. West J Med. 1984;140:460.

5. Eisele JW, Reay DT. Deaths related to coffee enemas. JAMA. 1980;244:1608-1609.

6. National Cancer Institute. Gonzalez PDQ. http://www.cancer.gov/cancertopics/pdq/cam/go nzalez/HealthProfessional. Accessed October 15, 2008.

7. The Kushi Institute. http://www.kushiinsti tute.org/. Accessed October 10, 2008.

8. American Dietetic Association. Red flags of junk 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 Complete Guide—Nutrition and Physical Activity. http://www.cancer.org/docroot/PED/con tent/PED_3_2X_Diet_and_Activity_Factors_ That_Affect_Risks.asp?sitearea=PED. Accessed October 15, 2008.

January/February 2009

FEBRUARY 2009

MARCH 2009

©iStockphoto.com/Nicole Morse

2009 Society of Interventional Radiology Annual Meeting www.sirweb.org

26-28

©iStockphoto.com/Lorena Molinari

ORLANDO, FL 2009 Genitourinary Cancers Symposium www.asco.org

26-28 BARCELONA, SPAIN

©iStockphoto.com/Chris Pritchard

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

MARCH 2009

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 January/February 2009

8-10 TAMPA, FL

11-15 HOLLYWOOD, FL

American Society of Preventive Oncology 33nd Annual Meeting www.aspo.org

NCCN 14th Annual Conference: Clinical Practice Guidelines & Quality Cancer Care www.nccn.org

RITUXAN® (Rituximab) Brief summary—Please consult full prescribing information.

WARNING: FATAL INFUSION REACTIONS, TUMOR LYSIS SYNDROME (TLS), SEVERE MUCOCUTANEOUS REACTIONS, and PROGRESSIVE MULTIFOCAL LEUKOENCEPHALOPATHY (PML) Infusion Reactions: Rituxan administration can result in serious, including fatal infusion reactions. Deaths within 24 hours of Rituxan infusion have occurred. Approximately 80% of fatal infusion reactions occurred in association with the first infusion. Carefully monitor patients during infusions. Discontinue Rituxan infusion and provide medical treatment for Grade 3 or 4 infusion reactions [see Warnings and Precautions, Adverse Reactions]. Tumor Lysis Syndrome (TLS): Acute renal failure requiring dialysis with instances of fatal outcome can occur in the setting of TLS following treatment of non-Hodgkin’s lymphoma (NHL) patients with Rituxan [see Warnings and Precautions, Adverse Reactions]. Severe Mucocutaneous Reactions: Severe, including fatal, mucocutaneous reactions can occur in patients receiving Rituxan [see Warnings and Precautions, Adverse Reactions].

Progressive Multifocal Leukoencephalopathy (PML): JC virus infection resulting in PML and death can occur in patients receiving Rituxan [see Warnings and Precautions, Adverse Reactions].

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; Previously untreated follicular, CD20-positive, B-cell NHL in combination with CVP chemotherapy; Non-progressing (including stable disease), low-grade, CD20positive 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. WARNINGS AND PRECAUTIONS Infusion Reactions Rituxan can cause severe, including fatal, infusion reactions. Severe reactions typically occurred during the first infusion with time to onset of 30–120 minutes. Rituxan-induced infusion reactions and sequelae include urticaria, hypotension, angioedema, hypoxia, bronchospasm, pulmonary infiltrates, acute respiratory distress syndrome, myocardial infarction, ventricular fibrillation, cardiogenic shock, or anaphylactoid events. Premedicate patients with an antihistamine and acetaminophen prior to dosing. Institute medical management (e.g., glucocorticoids, epinephrine, bronchodilators, or oxygen) for infusion reactions as needed. Depending on the severity of the infusion reaction and the required interventions, consider resumption of the infusion at a minimum 50% reduction in rate after symptoms have resolved.

Closely monitor the following patients: those with preexisting cardiac or pulmonary conditions, those who experienced prior cardiopulmonary adverse reactions, and those with high numbers of circulating malignant cells (≥25,000/mm3). [See Boxed Warning, Warnings and Precautions, Adverse Reactions.] Tumor Lysis Syndrome (TLS) Rapid reduction in tumor volume followed by acute renal failure, hyperkalemia, hypocalcemia, hyperuricemia, or hyperphosphatemia, can occur within 12–24 hours after the first infusion. Fatal TLS cases have occurred after administration of Rituxan. A high number of circulating malignant cells (≥25,000/mm3) or high tumor burden confers a greater risk of TLS after rituximab. Consider prophylaxis for TLS in patients at high risk.

Correct electrolyte abnormalities, monitor renal function and fluid balance, and administer supportive care, including dialysis as indicated. [See Boxed Warning.]

Severe Mucocutaneous Reactions Mucocutaneous reactions, some with fatal outcome, can occur in patients treated with Rituxan. These reactions include paraneoplastic pemphigus, Stevens-Johnson syndrome, lichenoid dermatitis, vesiculobullous dermatitis, and toxic epidermal necrolysis. The onset of these reactions has varied from 1–13 weeks following Rituxan exposure. Discontinue Rituxan in patients who experience a severe mucocutaneous reaction. The safety of readministration of Rituxan to patients with severe mucocutaneous reactions has not been determined. [See Boxed Warning, Adverse Reactions.] Progressive Multifocal Leukoencephalopathy (PML) JC virus infection resulting in PML and death can occur in Rituxan-treated patients with hematologic malignancies or with autoimmune diseases. The majority of patients with hematologic malignancies diagnosed with PML received Rituxan in combination with chemotherapy or as part of a hematopoietic stem cell transplant. The patients with autoimmune diseases had prior or concurrent immunosuppressive therapy. Most cases of PML were diagnosed within 12 months of their last infusion of Rituxan.

Consider the diagnosis of PML in any patient presenting with new-onset neurologic manifestations. Discontinue Rituxan and consider discontinuation or reduction of any concomitant chemotherapy or immunosuppressive therapy in patients who develop PML. [See Boxed Warning, Adverse Reactions.] Hepatitis B Virus (HBV) Reactivation Hepatitis B Virus (HBV) reactivation with fulminant hepatitis, hepatic failure, and death can occur in patients with hematologic malignancies treated with Rituxan. The median time to the diagnosis of hepatitis was approximately 4 months after the initiation of Rituxan and approximately one month after the last dose. Screen patients at high risk of HBV infection before initiation of Rituxan. Closely monitor carriers of hepatitis B for clinical and laboratory signs of active HBV infection for several months following Rituxan therapy. Discontinue Rituxan and any concomitant chemotherapy in patients who develop viral hepatitis, and institute appropriate treatment including antiviral therapy. Insufficient data exist regarding the safety of resuming Rituxan in patients who develop hepatitis subsequent to HBV reactivation. [See Adverse Reactions.]

Other Viral Infections The following additional serious viral infections, either new, reactivated, or exacerbated, have been identified in clinical studies or postmarketing reports. The majority of patients received Rituxan in combination with chemotherapy or as part of a hematopoietic stem cell transplant. These viral infections included cytomegalovirus, herpes simplex virus, parvovirus B19, varicella zoster virus, West Nile virus, and hepatitis C. In some cases, the viral infections occurred as late as one year following discontinuation of Rituxan and have resulted in death. [See Adverse Reactions.] Cardiovascular Discontinue infusions for serious or life-threatening cardiac arrhythmias. Perform cardiac monitoring during and after all infusions of Rituxan for patients who develop clinically significant arrhythmias or who have a history of arrhythmia or angina.

[See Adverse Reactions.] Renal Severe, including fatal, renal toxicity can occur after Rituxan administration in patients with hematologic malignancies. Renal toxicity has occurred in patients with high numbers of circulating malignant cells (≥25,000/mm3) or high tumor burden who experience tumor lysis syndrome and in patients with NHL administered concomitant cisplatin therapy during clinical trials. The combination of cisplatin and Rituxan is not an approved treatment regimen. Use extreme caution if this non-approved combination is used in clinical trials and monitor closely for signs of renal failure. Consider discontinuation of Rituxan for patients with a rising serum creatinine or oliguria. Bowel Obstruction and Perforation Abdominal pain, bowel obstruction and perforation, in some

cases leading to death, can occur in patients receiving Rituxan in combination with chemotherapy. In postmarketing reports, the mean time to documented gastrointestinal perforation was 6 (range 1–77) days in patients with NHL. Perform a thorough diagnostic evaluation and institute appropriate treatment for complaints of abdominal pain, especially early in the course of Rituxan therapy.

[See Adverse Reactions.] Immunization The safety of immunization with live viral vaccines following Rituxan therapy has not been studied and vaccination with live virus vaccines is not recommended. For NHL patients, the benefits of primary or booster vaccinations should be weighted against the risks of delay in initiation of Rituxan therapy. Laboratory Monitoring Because Rituxan binds to all CD20positive B lymphocytes (malignant and non-malignant), obtain complete blood counts (CBC) and platelet counts at regular intervals during Rituxan therapy and more frequently in patients who develop cytopenias [see Adverse Reactions]. The duration of cytopenias caused by Rituxan can extend months beyond the treatment period. ADVERSE REACTIONS The most common adverse reactions of Rituxan (incidence ≥25%) observed in patients with NHL are infusion reactions, fever, chills, infection, asthenia, and lymphopenia. The most important serious adverse 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 obstruction and perforation. Clinical Trials Experience Non-Hodgkin’s Lymphoma Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice. The data described below reflect exposure to Rituxan in 1606 patients, with exposures ranging from a single infusion up to 6–8 months. Rituxan was 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 DLBCL NHL. 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 with chemotherapy for up to 8 doses, or following chemotherapy for up to 16 doses.

Infusion Reactions In the majority of patients with NHL, infusion reactions consisting of fever, chills/rigors, nausea, pruritus, angioedema, hypotension, headache, bronchospasm, urticaria, rash, vomiting, myalgia, dizziness, or hypertension occurred during the first Rituxan infusion. Infusion reactions typically occurred within 30 to 120 minutes of beginning the first infusion and resolved with slowing or interruption of the Rituxan infusion and with supportive care (diphenhydramine, acetaminophen, and intravenous saline). The incidence of infusion reactions was highest during the first infusion (77%) and decreased with each 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. The overall incidence of infections was 31% (bacterial 19%, viral 10%, unknown 6%, and fungal 1%). [See Warnings and Precautions.] In randomized, controlled studies where Rituxan was administered following chemotherapy for the treatment of follicular or low-grade NHL, the rate of infection was higher among patients who received Rituxan. In diffuse large B-cell lymphoma patients, viral infections occurred more frequently in those who received Rituxan. Cytopenias and hypogammaglobulinemia In patients with NHL receiving rituximab monotherapy, NCI-CTC Grade 3 and 4 cytopenias were reported in 48% of patients. These included lymphopenia (40%), neutropenia (6%), leukopenia (4%), anemia (3%), and thrombocytopenia (2%). The median duration of lymphopenia was 14 days (range, 1–588 days) and of neutropenia was 13 days (range, 2–116 days). A single occurrence of transient aplastic anemia (pure red cell aplasia) and two occurrences of hemolytic anemia following Rituxan therapy occurred during the single-arm studies. In studies of monotherapy, Rituxan-induced B-cell depletion occurred in 70% to 80% of patients with NHL. Decreased IgM and IgG serum levels occurred in 14% of these patients. Single-Agent Rituxan Adverse reactions in Table 1 occurred in 356 patients with relapsed or refractory, lowgrade or follicular, CD20-positive, B-cell NHL treated in single-arm studies of Rituxan administered as a single agent. Most patients received Rituxan 375 mg/m2 weekly for 4 doses.

Table 1 Incidence of Adverse Events in ≥5% of Patients with Relapsed or Refractory, LowGrade or Follicular NHL, Receiving Single-agent Rituxan (N = 356)a,b

Chemotherapy for DLBCL In Studies 6 and 7, the following adverse reactions, regardless of severity, were reported more frequently (≥5%) in patients age ≥60 years receiving R-CHOP as compared to CHOP alone: pyrexia (56% vs. 46%), lung disorder (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 3 and 4 adverse reactions and serious adverse reactions. In Study 7, a review of cardiac toxicity determined that supraventricular arrhythmias or tachycardia accounted 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 more frequently among patients in the R-CHOP arm compared with those in the CHOP arm: thrombocytopenia (9% vs. 7%) and lung disorder (6% vs. 3%). Other Grade 3 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 potential for immunogenicity. The observed incidence of antibody (including neutralizing antibody) positivity in an assay is highly dependent on several factors including assay sensitivity and specificity, assay methodology, sample handling, timing of sample collection, concomitant medications, and underlying disease. For these reasons, comparison of the incidence of antibodies to Rituxan with the incidence of antibodies to other products may be misleading. Using an ELISA assay, antihuman anti-chimeric antibody (HACA) was detected in 4 of 356 (1.1%) patients with low-grade or follicular NHL receiving single-agent Rituxan. Three of the four patients had an objective clinical response. The clinical relevance of HACA formation in rituximab treated patients is unclear. Postmarketing Experience The following adverse reactions have been identified during postapproval use of Rituxan in hematologic malignancies. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure.

Decisions to include these reactions in labeling are typically based on one or more of the following factors: (1) seriousness of the reaction, (2) frequency of reporting, or (3) strength of causal connection to Rituxan. Hematologic: prolonged pancytopenia, marrow hypoplasia, and late-onset neutropenia, hyperviscosity syndrome 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 multifocal leukoencephalopathy (PML), increase in fatal infections in HIV-associated lymphoma, and a reported increased incidence of Grade 3 and 4 infections in patients with previously treated lymphoma without known HIV infection.

Neoplasia: disease progression of Kaposi’s sarcoma. Skin: severe mucocutaneous reactions. Gastrointestinal: bowel obstruction and perforation. Pulmonary: fatal bronchiolitis obliterans and pneumonitis (including interstitial pneumonitis). DRUG INTERACTIONS Formal drug interaction studies have not been performed with Rituxan. USE IN SPECIFIC POPULATIONS Pregnancy Category C: There are no adequate and well-controlled studies of rituximab in pregnant women.

Postmarketing data indicate that B-cell lymphocytopenia generally lasting less than six months can occur in infants exposed to rituximab in-utero. Rituximab was detected postnatally in the serum of infants exposed in-utero. Non-Hodgkin’s lymphoma is a serious condition that requires treatment. Rituximab should be used during pregnancy only if the potential benefit to the mother justifies the potential risk to the fetus. Reproduction studies in cynomolgus monkeys at maternal exposures similar to human therapeutic exposures showed no evidence of teratogenic effects. However, B-cell lymphoid tissue was reduced in the offspring of treated dams. The B-cell counts returned to normal levels, and immunologic function was restored within 6 months of birth. Nursing Mothers It is not known whether Rituxan is secreted into human milk. However, Rituxan is secreted in the milk of lactating cynomolgus monkeys, and IgG is excreted in human milk. Published data suggest that antibodies in breast milk do not enter the neonatal and infant circulations in substantial amounts. The unknown risks to the infant from oral ingestion of Rituxan should be weighed against the known benefits of breastfeeding. Pediatric Use The safety and effectiveness of Rituxan in pediatric patients have not been established. Geriatric Use Diffuse Large B-Cell NHL Among patients with DLBCL evaluated in three randomized, activecontrolled trials, 927 patients received Rituxan in combination with chemotherapy.

Of these, 396 (43%) were age 65 or greater and 123 (13%) were age 75 or All Grades (%) Grade 3 and 4 (%) All Grades (%) Grade 3 and 4 (%) greater. No overall differences in effectiveness were observed between these Respiratory System Any Adverse Events 99 57 38 4 patients and younger patients. Cardiac adverse reactions, mostly supraventricular Body as a Whole Increased Cough 13 1 86 10 Rhinitis 12 1 Fever 53 1 arrhythmias, occurred more frequently among elderly patients. Serious pulmonary Bronchospasm 8 1 Chills 33 3 adverse reactions were also more common among the elderly, including Dyspnea 7 1 Infection 31 4 Sinusitis 6 0 Asthenia 26 1 pneumonia and pneumonitis. Low-Grade or Follicular Non-Hodgkin’s Metabolic and Nutritional Headache 19 1 Lymphoma Clinical studies of Rituxan in low-grade or follicular, CD20-positive, Abdominal Pain 14 1 Disorders 38 3 Pain 12 1 Angioedema 11 1 B-cell NHL did not include sufficient numbers of patients aged 65 and over to Back Pain 10 1 Hyperglycemia 9 1 Throat Irritation 9 0 Peripheral Edema 8 0 determine whether they respond differently from younger subjects.

Flushing 5 0 LDH Increase 7 0 OVERDOSAGE There has been no experience with overdosage in human clinical Heme and Lymphatic System 67 Digestive System 48 37 2 Lymphopenia 48 40 Nausea 23 1 trials. Single doses of up to 500 mg/m2 have been given in dose-escalation Leukopenia 14 4 Diarrhea 10 1 Neutropenia 14 6 Vomiting 10 1 clinical trials. NONCLINICAL TOXICOLOGY Carcinogenesis, Mutagenesis, Thrombocytopenia 12 2 Nervous System 32 1 Impairment of Fertility No long term animal studies have been performed to Anemia 8 3 Dizziness 10 1 Skin and Appendages Anxiety 5 1 44 2 establish the carcinogenic or mutagenic potential of Rituxan or to determine Musculoskeletal System Night Sweats 15 1 26 3 Rash 15 1 Myalgia 10 1 potential effects on fertility in males or females. PATIENT COUNSELING Pruritus 14 1 Arthralgia 10 1 INFORMATION Patients should be provided the Rituxan Medication Guide and Urticaria 8 1 Cardiovascular System 25 3 Hypotension 10 1 provided an opportunity to read prior to each treatment session. Because caution Hypertension 6 1 should be exercised in administering Rituxan to patients with active infections, it is a Adverse reactions observed up to 12 months following Rituxan. bAdverse reactions graded for severity by important that the patient’s overall health be assessed at each visit and any NCI-CTC criteria. questions resulting from the patient’s reading of the Medication Guide be In these single-arm Rituxan studies, bronchiolitis obliterans occurred during and discussed. Rituxan is detectable in serum for up to six months following up to 6 months after Rituxan infusion. Rituxan in Combination With completion of therapy. Individuals of childbearing potential should use effective Chemotherapy Adverse reactions information below is based on 1250 patients contraception during treatment and for 12 months after Rituxan therapy. who received Rituxan in combination with chemotherapy or following chemotherapy. Rituxan in Combination With Chemotherapy for Low-Grade NHL In Study 4, patients in the R-CVP arm experienced a higher incidence of infusional toxicity and neutropenia compared to patients in the CVP arm. The following adverse reactions occurred more frequently (≥5%) in patients receiving R-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 reactions Revised 9/2008 (4835505) were reported more frequently (≥5%) in patients receiving Rituxan following CVP Jointly Marketed by: compared to patients who received no further therapy: fatigue (39% vs. 14%), Biogen Idec Inc. 5200 Research Place San Diego, CA 92122 anemia (35% vs. 20%), peripheral sensory neuropathy (30% vs. 18%), infections Genentech USA, Inc. 1 DNA Way South San Francisco, CA 94080-4990 (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 that occurred more frequently (≥2%) in the Rituxan arm compared with those who received no further therapy (4% vs. 1%). Rituxan in Combination With ©2008 Biogen Idec Inc. and Genentech, Inc. 7140917 October 2008

G REEN H ILL H EALTHCARE C OMMUNICATIONS

MEETINGS

7-12 SAN DIEGO, CA

MEETINGS

Meetings

33

Leading patients toward improved outcomes

You help patients reach their treatment goals RITUXAN 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

To learn more, ask a RITUXAN representative or visit

www.rituxan.com/lymphoma

BOXED WARNINGS and Additional Important Safety Information The most important serious adverse reactions of RITUXAN are fatal infusion reactions, tumor lysis syndrome (TLS), severe mucocutaneous reactions, progressive multifocal leukoencephalopathy (PML), hepatitis B reactivation with fulminant hepatitis, other viral infections, cardiovascular events, renal toxicity, and bowel 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

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.

PROVE N. POWE R FU L.

©2008 Genentech, Inc., and Biogen Idec Inc. All rights reserved. 9231900 April 2008