May 2010 Vol 3, No 3 by The Oncology Nurse

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MAY 2010

www.TheOncologyNurse.com

VOL 3, NO 3

SECOND ANNUAL REVIEW

Emphasizing advances in patient management based on recently released data.

HEMATOLOGIC MALIGNANCIES

Treatment Updates: Acute Myeloid Leukemia Marc A. Earl, PharmD,

Update on Chronic Myeloid Leukemia

Multiple Myeloma: A Review

Brian G. Cochran, PharmD, BCOP

Stephanie S. Taber, PharmD, BCOP

Chemotherapyinduced Nausea and Vomiting

Patient Navigation: Year in Review 2009-2010

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

Sean T. Walsh

Advances in the Treatment of Colorectal Cancer

Personalizing Non–small-cell Lung Cancer Treatment

Marlo Blazer, PharmD, BCOP

Tara L. Rich, MSN, RN, CNP

Medical Management of Breast Cancer

Update on Castration-resistant Prostate Cancer: A Review of Systemic Innovations

BCOP

SUPPORTIVE CARE

Management of Chemotherapyinduced Peripheral Neuropathy Virginia Sun, RN, PhD(c)

SOLID TUMORS

Advances in Breast Surgery Laura Dominici, MD; and Mehra Golshan, MD

Advances in Skin Cancer: Focus on Melanoma

Cynthia Frankel, RN, OCN

Lois J. Loescher, PhD

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When treating patients with HER2+ breast cancer

No one touches their HER2-positive status is associated with more aggressive disease and poorer outcomes than HER2-negative breast cancer. Women who received 1 year of Herceptin had a lower risk of HER2+ breast cancer returning. We applaud you for playing such a critical role in helping patients with HER2+ breast cancer complete the full course of treatment with Herceptin.

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: s As part of a treatment regimen containing doxorubicin, cyclophosphamide, and either paclitaxel or docetaxel s With docetaxel and carboplatin s As a single agent following multi-modality anthracyclinebased therapy *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.

Metastatic indications Herceptin is indicated: s In combination with paclitaxel for first-line treatment of HER2-overexpressing metastatic breast cancer s As a single agent for treatment of HER2-overexpressing breast cancer in patients who have received one or more chemotherapy regimens for metastatic disease ÂŠ2009 Genentech USA

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 anthracyclinecontaining 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

So. San Francisco, CA

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lives like you

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. 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

9568900

01/09

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.

www.herceptin.com

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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 multimodality anthracycline based therapy. Metastatic Breast Cancer Herceptin is indicated: • In combination with paclitaxel for first-line treatment of HER2-overexpressing metastatic breast cancer • As a single agent for treatment of HER2overexpressing 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 1 & 2a 3 4 4

Regimen ACb!Paclitaxel+ Herceptin Chemo!Herceptin ACb!Docetaxel+ Herceptin Docetaxel+Carbo+ Herceptin

Incidence of CHF Herceptin Control 2% (32/1677) 2% (30/1678)

0.4% (7/1600) 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. b Anthracycline (doxorubicin) and cyclophosphamide a

Table 2 Incidence of Cardiac Dysfunctiona in Metastatic Breast Cancer Studies

Study 5 (AC)b 5 (paclitaxel)

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

Event Cardiac 28% 7% 19% 3% Dysfunction Cardiac 11% 1% 4% 1% Dysfunction Cardiac N/A 5% N/A 6 7% Dysfunctionc a Congestive heart failure or significant asymptomatic decrease in LVEF. b Anthracycline (doxorubicin or epirubicin) and cyclophosphamide c Includes 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 post-infusion 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 Chemotherapy-Induced 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 (5.2)]. 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. Postmarketing 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 64 (4%) Hypertension Dizziness 60 (4%) Ejection Fraction Decreased 58 (3.5%) Palpitations 48 (3%) b Cardiac Arrhythmias 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%) 58 (3.5%) Vomiting 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%) Pruritis 40 (2%) General Disorders Pyrexia 100 (6%) Edema Peripheral 79 (5%) Chills 85 (5%) Aesthenia 75 (4.5%) Influenza-like Illness 40 (2%) Sudden Death 1 (.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%) 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 (.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 noncardiac 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 the following investigator-attributed treatment-related adverse reactions NCICTC Grade 4 and 5 hematologic toxicities, Grade 3–5 nonhematologic 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 a Agent 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 7 11 1 28 7 heart failure 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 5 18 14 13 7 infection a Data for Herceptin single agent were from 4 studies, including 213 patients from Study 6. b Anthracycline (doxorubicin or epirubicin) and cyclophosphamide The following subsections provide additional detail regarding adverse reactions observed in clinical 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

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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 5a Per-patient Incidence of New Onset Myocardial Dysfunction (by LVEF) Studies 1, 2, 3 and 4 LVEF <50% and Absolute Decrease from Baseline

Studies 1 & 2b AC!TH (n=1606) AC!T (n=1488) Study 3 Herceptin (n=1678) Observation (n=1708) Study 4c TCH (n=1056) AC!TH (n=1068) AC!T (n=1050)

LVEF ≥10% ≥16% <50% decrease decrease

Absolute LVEF Decrease <20% and ≥10% ≥20%

22.8% 18.3% (366) (294) 9.1% 5.4% (136) (81)

11.7% (188) 2.2% (33)

33.4% (536) 18.3% (272)

9.2% (148) 2.4% (36)

8.6% (144) 2.7% (46)

7.0% (118) 2.0% (35)

3.8% (64) 1.2% (20)

22.4% (376) 11.9% (204)

3.5% (59) 1.2% (21)

8.5% (90) 17% (182) 9.5% (100)

5.9% (62) 13.3% (142) 6.6% (69)

3.3% (35) 9.8% (105) 3.3% (35)

34.5% (364) 44.3% (473) 34% (357)

6.3% (67) 13.2% (141) 5.5% (58)

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. b Studies 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 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 post-marketing 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 NCICTC 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 NCI-CTC Grade 2–5 diarrhea (6.2% vs. 4.8% [Study 1]) and of NCI-CTC Grade 3–5 diarrhea (1.6% vs. 0% [Study 2]), and of grade 1-4 diarrhea (7% vs. 1% [Study 3]) were higher in patients receiving Herceptin as compared to controls. In Study 4, the incidence of Grade 3–4 diarrhea was higher [5.7% AC-TH, 5.5% TCH vs. 3.0% AC-T] and of Grade 1–4 was higher [51% AC-TH, 63% TCH vs. 43% AC-T] among women receiving Herceptin. Of patients 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 anti-human 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

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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. Postmarketing 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, she should be apprised of the potential hazard to a fetus. In the postmarketing 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. Registry Pregnant women with breast cancer who are using Herceptin are encouraged to enroll in MotHER- the Herceptin Pregnancy Registry: phone 1-800-690-6720. 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 MotHER- the Herceptin Pregnancy Registry [see Pregnancy]. HERCEPTIN® [trastuzumab] Manufactured by: 4839803 Genentech, Inc. Initial US Approval: Sept. 1998 1 DNA Way Revision Date: March 2009 South San Francisco, CA LK0726 7172911 94080-4990 7172713 ©2009 Genentech, Inc.

News Notes Report Identifies Methods to Improve NCI Clinical Trials

Although clinical trials are essential to translating new knowledge into tangible benefits, the National Cancer Institute’s (NCI) Clinical Trials Cooperative Group Program is concerned that it may be falling short of its potential to conduct timely, large-scale, innovative clinical trials. At the NCI’s request, the Institute of Medicine (IOM) assessed the program and offered advice on improvements. Improving speed and efficiency. The IOM committee stressed that protocol development be coordinated and streamlined, that administrative functions be consolidated, that government oversight be streamlined, and that the NCI expand drug distribution and implement standardized case report forms and remote capture systems. Incorporating innovative science. To advance targeted therapies and biomarker identification, the NCI should mandate that biospecimens collected from patients in the course of Cooperative Group trials be submitted to standardized central biorepositories. Prioritizing and supporting trials. The NCI should shift its focus from oversight to the facilitation of Cooperative Group trials. In addition, the NCI should streamline its process for enrolling patients quickly after a trial is launched. Priority should be given to those trials deemed most likely to improve survival and quality of life. Patient and physician participation. To reduce career and financial concerns for physicians, NCI and other stakeholders should explore approaches such as salary support for protected research time. To facilitate patient enrollment, federal and state health benefit plans, private health plans, and the Centers for Medicare & Medicaid Services should establish consistent payment policies to cover patient care costs.

FDA Launches Infusion Pump Improvement Initiative

The US Food and Drug Administration’s (FDA) Infusion Pump Improvement Initiative seeks to address infusion pump safety problems. The initiative will use comprehensive actions to foster the development of safer, more effective infusion pumps, and support the safe use of these vital medical devices in three proactive strategies. Establish additional requirements for infusion pump manufacturers. The FDA has issued a total product life cycle draft guidance document for infusion pump manufacturers. Once finalized, manufacturers will be required to include additional design and engineering information as part of their premarket submissions and conduct additional testing of their devices. Proactively facilitate device improvements. To address one of the most commonly reported problems, the FDA is using its in-house expertise to help prevent malfunctions in infusion pump software. In addition, it is actively working with manufacturers, members of the academic community, and others to address identified infusion pump problems. Increase user awareness. The FDA will also launch a new infusion pump website, which will feature basic information about infusion pumps and commonly seen problems, as well as actions that could help prevent safety problems. ● MAY 2010 I VOL 3, NO 3

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Editorial Board EDITOR-IN-CHIEF

Beth Faiman,

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

Elizabeth Bilotti, RN, MSN, APRN, BC, OCN

Sharon S. Gentry, RN, MSN, AOCN Derrick L. Davis Forsyth Regional Cancer Center Winston-Salem, NC

Cassandra J. Hammond, RN, MSN, CRNP

John Theurer Cancer Center Hackensack University Medical Center Hackensack, NJ

Avid Education Partners, LLC Sharpsburg, MD

Deena Damsky Dell, RN, MSN, AOCN, BC

Taline Khoukaz, NP, MSN, ACNP-C

Fox Chase Cancer Center Philadelphia, PA

University of Southern California Norris Cancer Center & Hospital Los Angeles, CA

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

Karla Wilson, RN, MSN, FNP-C, CPON

Melinda Oberleitner, RN, DNS, APRN, CNS

Nutrition Karen Connelly, RD

Mayo Clinic Rochester, MN

College of Nursing and Allied Health Professions University of Louisiana Lafayette, LA

Gary Shelton, MSN, ARNP, AOCN

NYU Cancer Institute New York, NY

Lori Stover, RN, BSN

Wendy DiSalvo, BSN, MSN, FNP, AOCN

Sandra E. Kurtin, RN, MS, AOCN, ANP-C Arizona Cancer Center Tucson, AZ

Western Pennsylvania Cancer Institute Pittsburgh, PA

Denice Economou, RN, MN, AOCN

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

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

Dartmouth Hitchcock Medical Center Norris Cotton Cancer Center Lebanon, NH

City of Hope National Medical Center Duarte, CA

Constance Engelking, RN, MS, OCN The CHE Consulting Group, Inc. Mt. Kisco, NY

The Cancer Center at Hackensack University Medical Center Hackensack, NJ

Kena C. Miller, RN, MSN, FNP Roswell Park Cancer Institute Buffalo, NY

Saratoga, CA

City of Hope National Medical Center Duarte, CA

Somerset Medical Center Somerville, NJ

Pharmacy John F. Aforismo, BSc Pharm, RPh, FASCP

R. J. Health Systems International, LLC Wethersfield, CT

Susan Goodin, PharmD, FCCP, BCOP

Cancer Institute of New Jersey New Brunswick, NJ

Managed Care and Pharmaceutical Management Burt Zweigenhaft, BS

BioPharma Partners LLC New York, NY

Connie Visovsky, RN, PhD, APRN

University of Nebraska College of Nursing Omaha, NE

Isabell Castellano, RN

Bristol-Myers Squibb Children’s Hospital Robert Wood Johnson University Hospital New Brunswick, NJ

Lyssa Friedman, RN, MPA, OCN

Veracyte, Inc South San Francisco, CA

Amy Ford, RN, BSN, OCN Innovex Dallas, TX

MAY 2010 I VOL 3, NO 3

Patricia Molinelli, MS, RN, NP, APN-C, AOCNS Somerset Medical Center Somerville, NJ

Rita Wickham, OCN, PhD, RN

Rush University College of Nursing Rush-PresbyterianSt. Luke’s Medical Center Chicago, IL

Jeanne Westphal, RN

Meeker County Memorial Hospital Litchfield, MN

Social Work Barbara Savage, LISW

Cleveland Clinic Taussig Cancer Institute Cleveland, OH

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Readers o Readers off The Oncology Nurse

Thank you for being a part of the Second Annual National Safe Handling A Awareness Awar wareness Month and for encouraging best practices in pr preventing eventing hazar hazardous dous drug exposur exposure. e. If you did not have the opportunity to participate in the fr free ee Safe Handling A Awareness wareness Day CE webinar pr presented esented April 20, a rrecorded ecorded version is now available online.

SW754

TTo o take advantage ad of this fr free ee webinar – and additional nursing CE pr programs ograms of offered fered compliments of Carmel Pharma, the maker of www.carmelpharmausa.com/CE .carmelpharmausa.com/CE PhaSeal® – visit www or call 877-487-9250.

Protection P rotection ction is P Pr Prevention. revention.

TON_May2010_v3:TON 5/4/10 10:12 AM Page 6

INTRODUCTION

ncology nurses work in a variety of environments and are responsible for the care of different patient groups. Fortunately, advances in the past decades have resulted in better treatments and longer life expectancy for many patients. There is no greater challenge for nurses than remaining up-to-date on the latest in treatment and side Beth Faiman, RN, MSN, APRN, BC, effect management when we are also faced with delivering quality AOCN care in addition to our other Editor-in-Chief responsibilities. As an example of the rapid pace of developments in cancer care, as we were preparing this issue for publication, a new drug was approved for prostate cancer, a new indication for a drug used in the treatment of lung cancer was granted, and

PUBLISHING STAFF Publisher Philip Pawelko phil@greenhillhc.com Editorial Director Karen Rosenberg karen@greenhillhc.com Associate Editor Dawn Lagrosa dawn@greenhillhc.com Director, Client Services John W. Hennessy john@greenhillhc.com Production Manager Stephanie Laudien Business Manager Blanche Marchitto blanche@greenhillhc.com Executive Administrator Andrea Boylston Circulation Department circulation@greenhillhc.com Editorial Contact: Telephone: 732-992-1891 Fax: 732-656-7938

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MAY 2010 I VOL 3, NO 3

updated results of a study of drug therapy for multiple myeloma were published. Nevertheless, we cannot underestimate our roles and how influential we are as oncology nurses caring for patients. This annual review issue provides cutting-edge information from expert nurses, physicians, and pharmacists to keep us informed in these ever-changing times. Nurses are in the unique position to assist patients throughout the course of their disease, and improved knowledge of the diagnosis and management of various cancers helps us provide better care to our patients. Although new options for therapy are always welcome, they mean more complex decisions will have to be made about the choice of treatment for an individual patient, and nurses and other caregivers will have to be knowledgeable about their potential side effects and how best to manage them. We hope you will share this special issue with your friends and colleagues so that everyone can benefit from the information presented. ●

CONTENTS

MAY 2010 • VOL 3, NO 3

FEATURE ARTICLES SOLID TUMORS

8 Advances in breast surgery 12 Advances in skin cancer: focus on melanoma 16 Advances in the treatment of colorectal cancer 22 Update on castration-resistant prostate cancer: a review of systemic innovations 30 Personalizing non–small-cell lung cancer treatment 56 Medical management of breast cancer HEMATOLOGIC MALIGNANCIES

34 Treatment updates: acute myeloid leukemia 38 Update on chronic myeloid leukemia 50 Multiple myeloma: a review SUPPORTIVE CARE

41 Management of chemotherapy-induced peripheral neuropathy 46 Chemotherapy-induced nausea and vomiting: clinical updates 55 Patient navigation: year in review 2009-2010

DEPARTMENTS 3 News Notes

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A deeper exploration — uncovering new opportunities in oncology

At Genentech BioOncology, we’re leading the fight against cancer with innovative science. We believe that great science and the right people can lead to significant advances in cancer treatment. Dedicated scientists — Our researchers are dedicated to defining the molecular basis of cancer and developing groundbreaking treatments. Gold standard clinical development — We identify biomarkers and develop companion diagnostics wherever possible, with the goal of matching each patient with the most appropriate therapy. A commitment to patients — We actively pursue ways to ensure patient access to therapeutics through a variety of patient support programs so healthcare providers can remain focused on patient care. Our goal is to fundamentally change the way cancer is treated — not just with incremental advances, but with new standards of care.

www.BioOncology.com

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Solid Tumors

Advances in Breast Surgery By Laura Dominici, MD Attending Surgeon, Department of Surgery, Brigham and Women’s Hospital, Dana-Farber Cancer Institute, Harvard Medical School, Boston

Mehra Golshan, MD Director, Breast Surgical Service, Department of Surgery, Brigham and Women’s Hospital, Dana-Farber Cancer Institute, Harvard Medical School, Boston

Laura Dominici, MD

Mehra Golshan, MD

he discipline of breast surgery, like many specialties, has moved toward a minimally invasive approach to local therapy. Radical surgery had previously been the standard; however, surgical approaches continue to evolve as we gather more data about the oncologic safety of less invasive procedures. In addition, we are placing more emphasis on targeted therapy, and surgery is an integrated portion of patient care. Most patients are diagnosed with image-guided biopsies instead of surgical excision, allowing for better surgical planning and fewer procedures.1 Furthermore, most patients are being diagnosed at earlier stages due to the increased use of screening mammography, and therefore most are candidates for breast conservation. For women with early-stage breast cancer, the sentinel lymph node biopsy procedure is widely accepted and its application is growing, which spares more women the morbidity of axillary lymph node dissection. In some cases, we may still recommend or women may choose to undergo mastectomy, but we are improving our ability to provide cosmetically acceptable procedures with oncologically acceptable outcomes. Most women are candidates for immediate reconstruction and skin-sparing mastectomy. We are still exploring our ability to preserve the nipple-areola complex.

MAY 2010 I VOL 3, NO 3

Breast-conservation therapy Breast-conserving surgery is the treatment of choice for early-stage primary breast cancers.2 For this surgery, the goal is to remove the tumor with clear margins while preserving the cosmesis of the breast.3 This surgery is followed by radiation therapy to minimize the risk of local recurrence within the breast. The National Surgical Adjuvant Breast and Bowel Project (NSABP) B-06 study found that postlumpectomy radiation decreased the rate of local recurrence from 39% to 14%.4 The American College of Radiology and the American College of Surgeons issued guidelines for the selection of patients for breast-conserving surgery. They recommended5: • Patients with unifocal disease are appropriate candidates. • Diffuse calcifications may contraindicate breast-conserving surgery. En bloc removal of calcifications is preferred, but limited resection and close imaging followup are possible when the radiologist is confident that calcifications are benign. • Previous therapeutic radiation to the chest is a contraindication to breast-conserving surgery. • Radiation is traditionally contraindicated in pregnant women, but breast conservation can be offered to women using a thoughtful, multidisciplinary approach when delivering radiation postpartum does not cause too long a delay.6 • Inability to achieve negative margins on a lumpectomy specimen may result in increased risk of local recurrence, delay in adjuvant therapy, and a change in cosmetic outcome. • Certain connective tissue disorders may be associated with increased morbidity after delivery of radiation. • Tumors should be less than 5 cm, because clinical trials of breast-conserving surgery involved T1 and T2 lesions. Tumor size in comparison with breast size is also a consideration, both for ability to deliver adequate radiation and cosmesis. Patients with larger tumors may become candidates for breast-conserving surgery with the use of neoadjuvant or preoperative chemotherapy, endocrine

therapy, and/or targeted therapy. In the NSABP B-18 trial, patients with larger unifocal tumors were found to have improved ability to undergo breast-conserving surgery (68% vs 60%) with no statistically significant difference in local recurrence or survival at a median follow-up of 6 years.7,8 Previously, women with tumors involving the nipple-areola complex or the subareolar area were recommended to undergo mastectomy. We now understand that women with disease confined to that area who can achieve negative margins may be candidates for central lumpectomy. This course of action has been shown to be oncologically safe.9 These women can go on to have elective nipple-areola complex reconstruction after completion of radiation therapy. Mastectomy For women who prefer or are required to undergo mastectomy, advances in surgical technique afford them an oncologically safe procedure with greater attention paid to patient satisfaction and cosmetic outcome. Mastectomies can often be performed using a skin-sparing technique that preserves as much of the patient’s own skin as possible as well as the inframammary fold. The technique provides a natural envelope, which can be filled with implant or autogenous tissue during the reconstruction. This technique allows for a closer match to the contralateral breast when reconstruction is performed. With careful attention to flap thickness and removal of breast parenchyma, the rates of local recurrence are shown to be equivalent to that of standard mastectomy.10,11 Women who will definitely or may require postmastectomy radiation therapy (PMRT) are still recommended to undergo mastectomy, with most needing a delay in reconstruction. Women who may require PMRT, however, may be afforded the benefit of skin-sparing mastectomy and reconstruction with the use of tissue expanders. These women still derive the benefit of skin preservation as well as the psychological benefit of waking from surgery with a breast mound, without compromising the delivery of radiation therapy.12 The area of reconstruction in the setting of PMRT is still controversial, and most radiation oncologists and reconstruction surgeons would prefer a

delayed approach in this setting. Skin-sparing mastectomy has traditionally included removal of the nippleareola complex, but in appropriate candidates, preservation of the nipple-areola complex can be oncologically sound and provide excellent cosmetic results. There is growing interest in the safety of this procedure, particularly as the numbers of prophylactic mastectomy for risk reduction grow. In recent studies, rates of local recurrence have not been significantly different from those for mastectomy or skin-sparing mastectomy.13 Patients with small peripheral tumors, as well as those seeking prophylactic mastectomy, may undergo this procedure, potentially resulting in increased patient satisfaction and necessitating fewer reconstructive procedures. The best outcomes are seen in women with breasts that are nonptotic and small to medium in size, with no previous history of radiation to the breast, and with no prior periareolar incisions. With selection of appropriate candidates, attention to nipple/areolar anatomy, and appropriate use of intraoperative pathology and preoperative breast imaging, the rate of nipple necrosis is low and cosmetic outcomes are excellent.14,15 The oncologic safety of this procedure will be better determined when more of the current studies have long-term follow-up data available or when a randomized trial comparing the technique with traditional mastectomy techniques is undertaken. Management of axillary lymph nodes Lymphatic mapping and sentinel lymph node biopsy were introduced more than 15 years ago and are now the standard axillary evaluation for women with clinically node-negative, earlystage breast cancer in the United States. These procedures, their indications, and their outcomes have generated great research interest. The sentinel lymph node dissection procedure carries significantly less morbidity than the axillary lymph node dissection procedure.16 The decreased rates of wound infections, seromas, paresthesias, and incidence of lymphedema17 improves quality of life in women with early-stage breast cancer. This is particularly important as the number of breast cancer survivors increases worldwide. Current research

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Solid Tumors

More women are candidates for breast conservation surgery, either up front or with neoadjuvant therapy.

seeks to expand the indications for sentinel lymph node dissection. Patients who are clinically node negative and who undergo neoadjuvant chemotherapy are able to undergo axillary evaluation by sentinel lymph node biopsy before or after the administration of chemotherapy with accurate results.18,19 Further investigation is ongoing to determine whether women who are initially node positive with excellent clinical response to neoadjuvant chemotherapy may be candidates for sentinel lymph node biopsy and, if pathologically node negative, this may obviate the need for completion of node dissection.20 It has been shown to be safe for pregnant women to undergo mapping and sentinel lymph node biopsy.21 As the indications for the procedure expand, more women may be spared the morbidity of axillary lymph node dissection. The routine recommendation for complete axillary dissection in women with positive sentinel nodes or clinically positive nodes will continue to evolve toward axillary observation or axillary radiation as we gain better understanding of tumor biology. Minimally invasive ablation Nonsurgical removal or ablation of breast tumors is a field of growing interest. Difficulties in assessing margins, confirming complete destruction, and standardizing postprocedure imaging still prohibit acceptance of these techniques. Surgical removal of the primary breast tumor remains the gold standard. These techniques, however, may be useful for benign lesions as well as for palliative ablation of lesions for women with metastatic disease or women who are not candidates for surgery. Percutaneous excision Many women undergo percutaneous biopsy of a breast mass to rule out malignancy or help in the planning of local therapy. Percutaneous biopsy techniques under mammography or ultrasound can also be employed to excise benign and malignant breast lesions.22 The most likely indication for this technique will be for benign lesions, because margin assessment is not possible. There are also anatomic restrictions in that the lesion should not be too close to the skin, chest wall, or nipple-areolar complex. Radiofrequency ablation The effectiveness of radiofrequency ablation (RFA) in treatment of primary

breast tumors has also been investigated. Tumors are visualized with ultrasound or magnetic resonance imaging (MRI), and then a high-frequency alternating current creates frictional heating and ablates the lesion. This technique has shown promise in patients with small tumors (<2 cm), although good results depend on the imaging giving an appropriate estimation of tumor size. This treatment is not appropriate for poorly defined, extensive, multifocal, or multicentric tumors. In addition, the tumor must be an adequate distance (1 cm) from the chest wall and skin to avoid burns.23 Other studies suggest that the use of RFA after lumpectomy may reduce the need for reexcision for inadequate margins.24 This procedure could also be used for palliative ablation of tumors in women with metastatic disease or women who are deemed to be poor candidates for surgery. Focused ultrasound ablation This technique also uses thermal tumor ablation. A 1.5-MHz ultrasound source ablates the lesion, and high-resolution imaging monitors tumor destruction. No probe insertion is necessary. Thus far, the results are quite variable in regard to degree of tumor necrosis, ranging from 20% to 100%.25 Assessment of margins is also a concern. Tumors treated by focused ultrasound ablation must be more than 1 cm from the skin and chest wall to prevent thermal injury. Palliative therapy is a possible indication for this procedure, as is the treatment of tumors 2 cm or benign lesions.25 Laser ablation Less research has been done on the technique of laser ablation for early-stage breast cancer. This technique involves delivery of energy to the target via a fiberoptic probe inserted using imaging guidance. Ultrasound, mammography, and MRI have been used successfully in this treatment. Although not extensively studied, this technique may be effective for treatment of small primary breast tumors and appears to be well tolerated.26 Cryosurgery With cryosurgery, a freezing probe is used to destruct cells by membrane rupture during successive freeze-thaw cycles. Using image guidance, the growth of the zone of freezing can be monitored. This technique is successful at destroying the center of the lesion, but the periphery

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often contains viable cells, so the zone of ablation needs to be larger than the tumor. The US Food and Drug Administration has approved this technique for the destruction of fibroadenomas. Invasive tumors up to 1.5 cm without an extensive intraductal component also appear to be adequately treated by cryosurgery.27 Conclusion The management of breast disease has undergone a transformation from surgery as the mainstay of therapy into a multidisciplinary approach to treatment involving surgeons, radiation oncologists, medical oncologists, reconstruction surgeons, pathologists, and radiologists. Further, more emphasis is being placed on the psychological and cosmetic outcome of surgery. More women are candidates for breast conservation surgery, either up front or with neoadjuvant therapy. Most women who undergo mastectomy have the benefit of a skin-sparing technique and the option of immediate reconstruction. Sentinel lymph node biopsy can be performed in women with early-stage breast cancer to avoid the morbidity of axillary lymph node dissection, and indications for sentinel lymph node biopsy continue to grow. Treatment will evolve further as we emphasize the use of targeted therapies tailored to an individual patient’s breast cancer. In the future, minimally invasive techniques may be used to treat residual disease after successful treatment with targeted therapy. As we continue to demonstrate oncologic safety and equivalent outcomes to more invasive techniques, these approaches will continue to grow in acceptance. ● References

1. Smith DN, Christian R, Meyer JE. Large-core needle biopsy of nonpalpable breast cancers. The impact on subsequent surgical excisions. Arch Surg. 1997;132:256-260. 2. Mamounas, E. NSABP breast cancer clinical trials: recent results and future directions. CMR. 2003;1:309-326. 3. Newman LA, Kuerer HM. Advances in breast conservation therapy. J Clin Oncol. 2005; 23:1685-1697. 4. Fisher B, Anderson S, Bryant J, et al. Twenty-year follow-up of a randomized trial comparing total mastectomy, lumpectomy, and lumpectomy plus irradiation for the treatment of invasive breast cancer. N Engl J Med. 2002;347:1233-1241. 5. Morrow M, Strom EA, Bassett LW, et al; for American College of Radiology; American College of Surgeons; Society of Surgical Oncology; College of American Pathology. Standard for breast conservation therapy in the management of invasive breast carcinoma. CA Cancer J Clin. 2002;52:277-300. 6. Rosenkranz KM, Lucci A. Surgical treatment of pregnancy associated breast cancer. Breast Dis. 2006;23:87-93. 7. Fisher B, Brown A, Mamounas E, et al. Effect of preoperative chemotherapy on local-regional disease in women with operable breast cancer: findings from National Surgical Adjuvant Breast and Bowel Project B-18. J Clin Oncol. 1997;15:2483-2493. 8. Wolmark N, Wang J, Mamounas E, et al.

Preoperative chemotherapy in patients with operable breast cancer: nine-year results from National Surgical Adjuvant Breast and Bowel Project B-18. J Natl Cancer Inst Monogr. 2001; 30:96-102. 9. Kawase K, DiMaio D, Tucker SL, et al. Paget’s disease of the breast: there is a role for breastconserving therapy. Ann Surg Oncol. 2005; 12:391-397. 10. Carlson GW, Styblo TM, Lyles RH, et al. The use of skin sparing mastectomy in the treatment of breast cancer: the Emory experience. Surg Oncol. 2003;12:265-269. 11. Kroll SS, Khoo A, Singletary SE, et al. Local recurrence risk after skin-sparing and conventional mastectomy: a 6-year follow-up. Plast Reconstr Surg. 1999;104:421-425. 12. Kronowitz SJ, Robb GL. Radiation therapy and breast reconstruction: a critical review of the literature. Plast Reconstr Surg. 2009;124:395-408. 13. Gerber B, Krause A, Dieterich M, et al. The oncological safety of skin sparing mastectomy with conservation of the nipple-areola complex and autologous reconstruction: an extended follow-up study. Ann Surg. 2009;249:461-468. 14. Vlajcic Z, Zic R, Stanec S, et al. Nipple-areola complex preservation: predictive factors of neoplastic nipple-areola complex invasion. Ann Plast Surg. 2005;55:240-244. 15. Petit JY, Veronesi U, Orecchia R, et al. Nipple sparing mastectomy with nipple areola intraoperative radiotherapy: one thousand and one cases of a five years experience at the European Institute of Oncology of Milan (EIO). Breast Cancer Res Treat. 2009;117:333-338. 16. Mansel RE, Fallowfield L, Kissin M, et al. Randomized multicenter trial of sentinel node biopsy versus standard axillary treatment in operable breast cancer: the ALMANAC trial. J Natl Cancer Inst. 2006;98:599-609. 17. Lucci A, McCall LM, Beitsch PD, et al. Surgical complications associated with sentinel lymph node dissection (SLND) plus axillary lymph node dissection compared with SLND alone in the American College of Surgeons Oncology Group Trial Z0011. J Clin Oncol. 2007;25:3657-3663. 18. Mamounas EP. Sentinel lymph node biopsy after neoadjuvant systemic therapy. Surg Clin North Am. 2003;83:931-942. 19. Breslin TM, Cohen L, Sahin A, et al. Sentinel lymph node biopsy is accurate after neoadjuvant chemotherapy for breast cancer. J Clin Oncol. 2000;18:3480-3486. 20. Surgery to remove the sentinel lymph node and axillary lymph nodes after chemotherapy in treating women with stage II, stage IIIA, or stage IIIB breast cancer. ClinicalTrials.gov identifier: ACOSOG-Z1071. www.clinicaltrials.gov/ ct2/show/NCT00881361?term=ACOSOGZ1071&rank=1. Updated January 6, 2010. Accessed January 7, 2010. 21. Keleher A, Wendt R 3rd, Delpassand E, et al. The safety of lymphatic mapping in pregnant breast cancer patients using Tc-99m sulfur colloid. Breast J. 2004;10:492-495. 22. Fine RE, Whitworth PW, Kim JA, et al. Lowrisk palpable breast masses removed using a vacuum-assisted hand-held device. Am J Surg. 2003;186:362-367. 23. Fornage BD, Sneige N, Ross MI, et al. Small (< or = 2-cm) breast cancer treated with US-guided radiofrequency ablation: feasibility study. Radiology. 2004;231:215-224. 24. Klimberg VS, Kepple J, Shafirstein G, et al. eRFA: excision followed by RFA—a new technique to improve local control in breast cancer. Ann Surg Oncol. 2006;13:1422-1433. 25. Schmitz AC, Gianfelice D, Daniel BL, et al. Image-guided focused ultrasound ablation of breast cancer: current status, challenges, and future directions. Eur Radiol. 2008;18:1431-1441. 26. Dowlatshahi K, Francescatti DS, Bloom KJ, et al. Image-guided surgery of small breast cancers. Am J Surg. 2001;182:419-425. 27. Vlastos G, Kinkel K, Pelte MF, et al. MRI-guided cryotherapy as a treatment option for early stage breast cancer: preliminary results. Breast Cancer Res Treat. 2004;88(suppl):S168.

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YOU INFUSE ANTHRACYCLINES, BUT ARE YOU PREPARED FOR AN EXTRAVASATION? TWO PRICE OPTIONS AVAILABLE

Totect® Kit (dexrazoxane) for injection is for intravenous infusion only. Totect is indicated for the treatment of extravasation resulting from intravenous anthracycline chemotherapy.

First and only FDA approved treatment for anthracycline extravasation. Supplied as a convenient and accessible complete three day treatment kit for single patient use, which should be proactively stocked on-site and infused as soon as possible and within 6 hours of an anthracycline extravasation. Demonstrates 98% overall efficacy based on two biopsy-confirmed clinical trials1,2 in reducing or avoiding surgical intervention (i.e., surgical debridement, plastic surgery and their related costs), thereby reducing postponement of a patient’s chemotherapy treatments and the avoidance of long-term consequences. Cited in nursing guidelines3,4 and oncology safety standards5.

For more information, call 866-478-8274 or visit our website at www.totect.com To order Totect®, contact one of our authorized distributors. ASD Healthcare Cardinal Specialty McKesson/OTN Oncology Supply US Oncology (800) 746-6273 (866) 677-4844 (800) 482-6700 (800) 633-7555 (888) 987-6679 Mouridsen HT et al. Treatment of anthracycline extravasation with savene (dexrazoxane). Results from two prospective clinical multicentre studies. Ann Oncol 2007; 18:546-550. 2 Totect® package insert. 3 Polovich M, White JM, Olsen, M (eds.). Chemotherapy and Biotherapy Guidelines and Recommendations for Practice (ed 3). Pittsburgh, PA, Oncology Nursing Society, 2009. 4 Alexander M, Corrigan A, Gorski L, Hankins J, Perucca R. (eds). Infusion Nurses Society Infusion Nursing an Evidence-Based Approach (ed 3). Boston, MA, Infusion Nurses Society, 2009. 5 Jacobsen J., et al. American Society of Clinical Oncology/Oncology Nursing Society Chemotherapy Administration Safety Standards. Oncology Nursing Forum, 2009; 36:651-658. © 2010 TopoTarget USA. All rights reserved. TOT0112/4-10 Totect and its logo mark are registered trademarks of TopoTarget A/S 1

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Totect® – Brief prescribing information Please refer to the package insert for full prescribing information. Each Totect carton contains 10 vials of Totect® (dexrazoxane for injection) 500 mg and 10 vials of 50 mL diluent. Indication: Treatment of extravasation resulting from IV anthracycline chemotherapy. Dosage and administration: Totect is a cytotoxic drug. Vial contents must be mixed and diluted before use. Totect should not be mixed or administered with any other drug during the infusion. Administration of Totect should begin as soon as possible and within 6 hours following the anthracycline extravasation. Totect should be given as an intravenous (IV) infusion once daily for 3 consecutive days. The dose of Totect is based on the patient’s body surface area: day one, 1000 mg/m2; day two, 1000 mg/m2; day three, 500 mg/m2. For patients with a body surface area of > 2 m2, a dose of 2000 mg should be given on days 1 and 2, and a dose of 1000 mg should be given on day 3. Treatment on Day 2 and Day 3 should start at the same hour (+/- 3 hours) as on the first day. The Totect dose should be reduced 50% for patients with creatinine clearance values of <40 mL/minute. Cooling procedures such as ice packs should be removed from the affected area at least 15 minutes prior to Totect administration. Totect (dexrazoxane for injection) must be reconstituted with diluent supplied in the carton. The patient’s Totect dose is diluted in 0.9% 1000 mL NaCl prior to administration. Procedures for proper handling and disposal of anticancer drugs should be considered. Several guidelines on this subject have been published.3-5 Direct contact of Totect® with the skin or mucous membranes prior to and following reconstitution should be avoided. If contact occurs, wash immediately and thoroughly with water. Contraindications: None. Warnings and Precautions: Myelosuppression: treatment with Totect is associated with leukopenia, neutropenia, and thrombocytopenia. Hematological monitoring should be performed. Use in Pregnancy: Pregnancy Category D. Totect can cause fetal harm when administered to a pregnant woman. There is no adequate information about the use of Totect in pregnant women. If this drug is used during pregnancy, or if the patient becomes pregnant while taking this drug, the patient should be apprised of the potential hazard to the fetus. Adverse reactions: The most common adverse reactions (≥ 16%) are nausea, pyrexia, injection site pain and vomiting.

www.totect.com

Rx only

Totect® is a registered trademark of TopoTarget A/S US Patent No. 6,727,253B2 NDC 38423-110-01

Drug Interactions: No drug interactions have been identified. Based on anecdotal reports concurrent use of topical dimethyl sulfoxide (DMSO) at the site of tissue injury may reduce the benefit of Totect. Additionally, nonclinical studies using a mouse model that simulates extravasation of anthracyclines has shown that concomitant treatment with topical DMSO decreases the efficacy of systemic dexrazoxane. Use in Specific Populations: Nursing Mothers: Discontinue drug or nursing, taking into consideration the importance of drug to the mother. Renal Impairment: Reduce the Totect dose by 50% In patients with creatinine clearance values <40 mL/min. Pediatric Use: The safety and effectiveness of Totect in pediatric patients have not been established. Geriatric Use: This drug is known to be substantially excreted by the kidney, and the risk of toxic reactions to this drug may be greater in patients with impaired renal function. Because elderly patients are more likely to have decreased renal function, care should be taken in dose selection, and it may be useful to monitor renal function. Overdosage: There are no data on overdosage. There is no known antidote for dexrazoxane. Carcinogenesis, Mutagenesis, Impairment of Fertility: The carcinogenic potential of dexrazoxane has not been investigated. Nevertheless, a study by the National Cancer Institute has reported that long term dosing with razoxane (the racemic mixture of dexrazoxane, ICRF-187, and its enantiomer ICRF-186) is associated with the development of malignancies in rats and possibly in mice. Dexrazoxane was not mutagenic to bacteria in vitro (Ames assay), but caused significant chromosomal aberrations in mammalian cells in vitro. It also increased the formation of micronucleated polychromatic erythrocytes in mice. Thus, dexrazoxane is mutagenic and clastogenic. The possible adverse effects of Totect on the fertility of humans and experimental animals, male or female, have not been adequately studied. Testicular atrophy was seen with dexrazoxane administration at doses as low as 30 mg/kg weekly for 6 weeks in rats (about 1/5 the human dose on a mg/m2 basis) and as low as 20 mg/kg weekly for 13 weeks in dogs (about half the human dose on a mg/m2 basis).

Manufactured by: Ben Venue Laboratories, Inc. Bedford, OH 44146 Hameln Pharmaceuticals GmbH 31789 Hameln Germany

Manufactured for: TopoTarget A/S Symbion Science Park Fruebjergvej 3 DK-2100 Copenhagen Denmark

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Solid Tumors

Advances in Skin Cancer: Focus on Melanoma By Lois J. Loescher, PhD, RN Associate Professor, University of Arizona, Skin Cancer Institute at the Arizona Cancer Center, Tucson

Lois J. Loescher, PhD, RN

ne in five Americans will develop skin cancer in his or her lifetime.1 More than 1 million cases of nonmelanoma skin cancer (NMSC) are estimated to go unreported each year. In 2009, more than 68,720 new cases of melanoma occurred, and melanoma caused 8650 deaths.1 Skin cancer is a costly disease, and its financial burden increases with advanced stages. A 2009 study of mela-

surveillance and detection, and removal of suspicious lesions.3 Finding skin cancer in its early stages is critical for favorable prognosis.4 To determine the prevalence and predictors of skin cancer screening among US adults, Lakhani and colleagues analyzed selfreported data from the 2000 and 2005 National Health Interview Surveys.5 Adult respondents (n, not reported) were asked if they had ever had a headto-toe skin examination for cancer by a dermatologist or other physician. Respondents answering “yes” were asked the date of their most recent total body skin examination (TBSE). Over a 5year period, TBSE prevalence increased from one in seven to one in six respondents. Significantly higher per-

These findings indicate that relatively few patients with thin melanoma have a positive SLN and that clinical or histopathologic criteria for reliably identifying patients with thin melanoma who might benefit from this intervention remain inadequate.

noma costs documented that the 5-year costs of melanoma when diagnosed at stage IV reached $159,808, which represents a 3438% increase from the costs of melanoma diagnosed in situ ($4648). Costs of stage IIIc and IV melanoma were 23 times greater than costs of earlystage disease.2 The overall burden of skin cancer merits a brief review of recent reports on secondary prevention, prognostic markers, therapies, symptom management, and survivorship. The foundation for this review consists of a selection of large epidemiologic studies, randomized phase 3 clinical trials, systematic reviews, or meta-analyses presented at the 2009 annual meetings of the American Academy of Dermatology, American Society of Clinical Oncology, European Society for Medical Oncology, and Society for Investigative Dermatology. Secondary prevention The increasing burden of skin cancer has led to more intensive efforts in secondary prevention, which focuses on risk assessment and education, skin

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centages of women as well as adults aged 50 years and older reported having TBSE. Approximately one in five non-Hispanic white (NHW) participants reported having TBSE, which was significantly higher than TBSE prevalence reported by respondents in other racial/ethnic groups. TBSE prevalence was highest among individuals reporting a personal history of skin cancer (69%). Persons who reported a family history of melanoma were more than twice as likely (odds ratio [OR], 2.42; 95% confidence interval [CI], 1.90-3.08) to have had TBSE, and those with a family history of NMSC were nearly twice as likely (OR, 1.76; 95% CI, 1.40-2.21) than respondents without these histories. Overall, TBSE prevalence increased with more education, physical activity, sun sensitivity, recent sunburn, and sun-protective behaviors. Other systems-related factors have been associated with differences in the stage of melanoma at diagnosis and in melanoma survival, particularly among ethnic groups. These differences between the two most common types of

Medicare healthcare delivery systems, health maintenance organization (HMO) and fee-for-service (FFS), were analyzed in 40,633 patients from 1991 through 2005 using the Surveillance, Epidemiology and End Results (SEER)-Medicare database. Specifically evaluated were differences in melanoma stage at diagnosis and median survival in HMO versus FFS groups by NHW versus Hispanic ethnicity. Among NHWs, the HMO group had an earlier stage at diagnosis than the FFS group when melanoma was the first or subsequent cancer diagnosis. Hispanic HMO patients were significantly less likely than FFS patients to receive a diagnosis at a later stage versus earlier stages (OR, 0.50; 95% CI, 0.31-0.81). Among HMO patients, there were no statistically significant differences in stage at diagnosis or survival by race/ethnicity. Among FFS patients, Hispanic patients were more than twice as likely to be diagnosed at a later stage (OR, 2.31; CI, 1.75-3.03) than NHW patients; however, median survival for all stages was slightly longer for FFS patients than for HMO patients (45.0 and 43.0 months, respectively; P <.01). This study is a reminder that there are differences in stage at diagnosis and survival between patients in HMOs and those in FFS healthcare plans and by race/ethnicity. Stronger skin cancer educational interventions for Hispanics along with TBSE have the potential to increase diagnosis at an earlier stage.6 Prognostic markers Ulceration. Several melanoma studies have focused on prognostic markers, including melanoma ulceration, sentinel node (SN) tumor burden, and molecular biomarkers. Ulcerated melanomas are known to have a worse prognosis than nonulcerated melanomas. Investigators from the European Organisation for Research and Treatment of Cancer (EORTC) Melanoma Group conducted a post hoc meta-analysis of the two largest phase 3 trials (EORTC 18952 and 18991) ever conducted in patients (n = 2644) with stage IIb to III melanoma.7 The goal of this analysis was to determine the predictive value of ulceration on response to adjuvant interferon (IFN) alpha-2b on relapse-free survival (RFS), distant metastasis-free survival (DMFS), and overall survival

(OS), both overall and by stage (IIb, IIIN1, or III-N2). In the ulcerated group, the impact of IFN was much greater than in the nonulcerated group for RFS (P = .02), DMFS (P <.001), and OS (P <.001). The greatest reductions occurred in patients with ulceration and stages IIb/III-N1; no reductions occurred in patients without ulceration. The results strongly indicate that patients with an ulcerated primary melanoma are far more sensitive to IFN than patients with nonulcerated primary tumors. SN tumor burden. Despite the lack of clear evidence of survival benefit of sentinel lymph node (SLN) biopsy, this technique has been increasingly applied in the staging of patients with thin (1 mm) melanomas. Findings from a metaanalysis of 3651 patients enrolled in 34 studies reporting rates of SLN positivity were used to estimate the risk, potential predictors, and outcome of SLN positivity.8 Significant heterogeneity (high quality and low quality) among studies was detected (P = .005; test of noncombinability), suggesting high variation among study outcomes. Eighteen studies had a primary focus on SLN biopsy for melanomas 1 mm, with the remainder including all melanomathickness groups. These studies reported selected clinical and histopathologic data on SLN-positive patients only (n = 113). Among the tumors from these patients, six (6.1%) of 698 were ulcerated, 17 (31.5%) of 54 showed regression, and 48 (47.5%) of 101 were invasive to Clark level IV or V. Of 14 (41.2%) studies that provided recurrence and/or survival data, four melanoma-related deaths in SLN-positive patients and four deaths in SLNnegative patients were reported. These findings indicate that relatively few patients with thin melanoma have a positive SLN and that clinical or histopathologic criteria for reliably identifying patients with thin melanoma who might benefit from this intervention remain inadequate. Also unclear is whether patients with minimal SLN tumor burden, who might be at risk for late recurrences (>5 years), can be managed safely without complete lymph node dissection. The EORTC Melanoma Group reported findings from two large panEuropean long-term (5-10 years) follow-up studies of 595 and 663 patients, Continued on page 14

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STRONG. FROM THE START.

HELP ESTABLISH A SUCCESSFUL CINV PREVENTION STRATEGY FROM THE FIRST CYCLE When your patients experience acute chemotherapyinduced nausea and vomiting (CINV) during their first cycle of chemotherapy, they may have an increased risk of CINV on subsequent days and in subsequent cycles.1-3 ALOXI®: Starts strong to prevent CINV4 A single IV dose lasts up to 5 days after MEC4,5* Can be used with multiple-day chemotherapy regimens6† * Moderately emetogenic chemotherapy. † Based on sNDA approval in August 2007, the restriction on repeated dosing of ALOXI (palonosetron HCl) injection within a 7-day interval was removed.

Indication ALOXI® (palonosetron HCl) injection 0.25 mg is indicated for the prevention of acute and delayed nausea and vomiting associated with initial and repeat courses of moderately emetogenic chemotherapy, and acute nausea and vomiting associated with initial and repeat courses of highly emetogenic chemotherapy. Important Safety Information • ALOXI is contraindicated in patients known to have hypersensitivity to the drug or any of its components • Most commonly reported adverse reactions in chemotherapy-induced nausea and vomiting include headache (9%) and constipation (5%) Please see the following brief summary of prescribing information. REFERENCES: 1. The Italian Group for Antiemetic Research. Dexamethasone alone or in combination with ondansetron for the prevention of delayed nausea and vomiting induced by chemotherapy. N Engl J Med. 2000;342:1554-1559. 2. Hickok JT, Roscoe JA, Morrow GR, et al. 5-hydroxytryptamine-receptor antagonists versus prochlorperazine for control of delayed nausea caused by doxorubicin: a URCC CCOP randomised controlled trial. Lancet Oncol. 2005;6:765-772. Epub September 13, 2005. 3. Cohen L, de Moor CA, Eisenburg P, Ming EE, Hu H. Chemotherapy-induced nausea and vomiting: incidence and impact on patient quality of life at community oncology settings. Support Care Cancer. 2007;15:497-503. Epub November 14, 2006. 4. Gralla R, Lichinitser M, Van der Vegt S, et al. Palonosetron improves prevention of chemotherapy-induced nausea and vomiting following moderately emetogenic chemotherapy: results of a double-blind randomized phase III trial comparing single doses of palonosetron with ondansetron. Ann Oncol. 2003;14:1570-1577. 5. Eisenberg P, Figueroa-Vadillo J, Zamora R, et al. Improved prevention of moderately emetogenic chemotherapy-induced nausea and vomiting with palonosetron, a pharmacologically novel 5-HT3 receptor antagonist: results of a phase III, single-dose trial versus dolasetron. Cancer. 2003;98:2473-2482. 6. ALOXI® (palonosetron HCl) injection full prescribing information.

www.ALOXI.com

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Solid Tumors Advances in Skin Cancer: Focus on Melanoma Continued from page 12 respectively, with minimal SN tumor burden (<1 mm) as defined by the Rotterdam criteria.9,10 These patients had very low relapse rates and excellent melanoma-specific survival that paralleled that of SLN-negative patients. The authors point out

ALOXI® (palonosetron HCl) injection BRIEF SUMMARY OF PRESCRIBING INFORMATION INDICATIONS AND USAGE Chemotherapy-Induced Nausea and Vomiting ALOXI is indicated for: • Moderately emetogenic cancer chemotherapy – prevention of acute and delayed nausea and vomiting associated with initial and repeat courses • Highly emetogenic cancer chemotherapy – prevention of acute nausea and vomiting associated with initial and repeat courses DOSAGE AND ADMINISTRATION Recommended Dosing Chemotherapy-Induced Nausea and Vomiting Dosage for Adults - a single 0.25 mg I.V. dose administered over 30 seconds. Dosing should occur approximately 30 minutes before the start of chemotherapy. Instructions for I.V. Administration ALOXI is supplied ready for intravenous injection. ALOXI should not be mixed with other drugs. Flush the infusion line with normal saline before and after administration of ALOXI. Parenteral drug products should be inspected visually for particulate matter and discoloration before administration, whenever solution and container permit. CONTRAINDICATIONS ALOXI is contraindicated in patients known to have hypersensitivity to the drug or any of its components. [see Adverse Reactions (6) in full prescribing information ] WARNINGS AND PRECAUTIONS Hypersensitivity Hypersensitivity reactions may occur in patients who have exhibited hypersensitivity to other 5-HT 3 receptor antagonists. ADVERSE REACTIONS 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 reported in practice. In clinical trials for the prevention of nausea and vomiting induced by moderately or highly emetogenic chemotherapy, 1374 adult patients received palonosetron. Adverse reactions were similar in frequency and severity with ALOXI and ondansetron or dolasetron. Following is a listing of all adverse reactions reported by ≥ 2% of patients in these trials (Table 1). Table 1: Adverse Reactions from ChemotherapyInduced Nausea and Vomiting Studies ≥ 2% in any Treatment Group ALOXI Ondansetron Dolasetron Event 0.25 mg 32 mg I.V. 100 mg I.V. (N=410) (N=633) (N=194) Headache 60 (9%) 34 (8%) 32 (16%) Constipation 29 (5%) 8 (2%) 12 (6%) Diarrhea 8 (1%) 7 (2%) 4 (2%) Dizziness 8 (1%) 9 (2%) 4 (2%) Fatigue 3 (< 1%) 4 (1%) 4 (2%) Abdominal Pain 1 (< 1%) 2 (< 1%) 3 (2%) Insomnia 1 (< 1%) 3 (1%) 3 (2%) In other studies, 2 subjects experienced severe constipation following a single palonosetron dose of approximately 0.75 mg, three times the recommended dose. One patient received a 10 mcg/kg oral dose in a postoperative nausea and vomiting study and one healthy subject received a 0.75 mg I.V. dose in a pharmacokinetic study. In clinical trials, the following infrequently reported adverse reactions, assessed by investigators as treatment-related or causality unknown, occurred following administration of ALOXI to adult patients receiving concomitant cancer chemotherapy: Cardiovascular: 1%: non-sustained tachycardia, bradycardia, hypotension, < 1%: hypertension, myocardial ischemia, extrasystoles, sinus tachycardia, sinus arrhythmia, supraventricular extrasystoles and QT prolongation. In many cases, the relationship to ALOXI was unclear. Dermatological: < 1%: allergic dermatitis, rash. Hearing and Vision: < 1%: motion sickness, tinnitus, eye irritation and amblyopia. Gastrointestinal System: 1%: diarrhea, < 1%: dyspepsia, abdominal pain, dry mouth, hiccups and flatulence.

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that no increases in relapses of any kind have been seen with 5 to 10 years of follow-up and predict that 10-year survival rates will be excellent. Given the increasing diagnosis of thin melanomas, in addition to the costs and potential morbidity associated with SLN

General: 1%: weakness, < 1%: fatigue, fever, hot flash, flu-like syndrome. Liver: < 1%: transient, asymptomatic increases in AST and/or ALT and bilirubin. These changes occurred predominantly in patients receiving highly emetogenic chemotherapy. Metabolic: 1%: hyperkalemia, < 1%: electrolyte fluctuations, hyperglycemia, metabolic acidosis, glycosuria, appetite decrease, anorexia. Musculoskeletal: < 1%: arthralgia. Nervous System: 1%: dizziness, < 1%: somnolence, insomnia, hypersomnia, paresthesia. Psychiatric: 1%: anxiety, < 1%: euphoric mood. Urinary System: < 1%: urinary retention. Vascular: < 1%: vein discoloration, vein distention. Postmarketing Experience The following adverse reactions have been identified during postapproval use of ALOXI. 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. Very rare cases (<1/10,000) of hypersensitivity reactions and injection site reactions (burning, induration, discomfort and pain) were reported from postmarketing experience of ALOXI 0.25 mg in the prevention of chemotherapy-induced nausea and vomiting. DRUG INTERACTIONS Palonosetron is eliminated from the body through both renal excretion and metabolic pathways with the latter mediated via multiple CYP enzymes. Further in vitro studies indicated that palonosetron is not an inhibitor of CYP1A2, CYP2A6, CYP2B6, CYP2C9, CYP2D6, CYP2E1 and CYP3A4/5 (CYP2C19 was not investigated) nor does it induce the activity of CYP1A2, CYP2D6, or CYP3A4/5. Therefore, the potential for clinically significant drug interactions with palonosetron appears to be low. Coadministration of 0.25 mg I.V. palonosetron and 20 mg I.V. dexamethasone in healthy subjects revealed no pharmacokinetic drug-interactions between palonosetron and dexamethasone. In an interaction study in healthy subjects where palonosetron 0.25 mg (I.V. bolus) was administered on day 1 and oral aprepitant for 3 days (125 mg/80 mg/80 mg), the pharmacokinetics of palonosetron were not significantly altered (AUC: no change, Cmax: 15% increase). A study in healthy volunteers involving single-dose I.V. palonosetron (0.75 mg) and steady state oral metoclopramide (10 mg four times daily) demonstrated no significant pharmacokinetic interaction. In controlled clinical trials, ALOXI injection has been safely administered with corticosteroids, analgesics, antiemetics/antinauseants, antispasmodics and anticholinergic agents. Palonosetron did not inhibit the antitumor activity of the five chemotherapeutic agents tested (cisplatin, cyclophosphamide, cytarabine, doxorubicin and mitomycin C) in murine tumor models. USE IN SPECIFIC POPULATIONS Pregnancy Teratogenic Effects: Category B Teratology studies have been performed in rats at oral doses up to 60 mg/kg/day (1894 times the recommended human intravenous dose based on body surface area) and rabbits at oral doses up to 60 mg/ kg/day (3789 times the recommended human intravenous dose based on body surface area) and have revealed no evidence of impaired fertility or harm to the fetus due to palonosetron. There are, however, no adequate and well-controlled studies in pregnant women. Because animal reproduction studies are not always predictive of human response, palonosetron should be used during pregnancy only if clearly needed. Labor and Delivery Palonosetron has not been administered to patients undergoing labor and delivery, so its effects on the mother or child are unknown. Nursing Mothers It is not known whether palonosetron is excreted in human milk. Because many drugs are excreted in human milk and because of the potential for serious adverse reactions in nursing infants and the potential for tumorigenicity shown for palonosetron in the rat carcinogenicity study, a decision should be made whether to discontinue nursing or to discontinue the drug, taking into account the importance of the drug to the mother.

biopsy, alternative strategies to identify patients at risk for nodal disease, including molecular prognostic factors, are urgently needed.8 However, there is a dearth of validated biomarkers for assessing prognosis and monitoring after complete resection of melanoma

Pediatric Use Safety and effectiveness in patients below the age of 18 years have not been established. Geriatric Use Population pharmacokinetics analysis did not reveal any differences in palonosetron pharmacokinetics between cancer patients ≥ 65 years of age and younger patients (18 to 64 years). Of the 1374 adult cancer patients in clinical studies of palonosetron, 316 (23%) were ≥ 65 years old, while 71 (5%) were ≥ 75 years old. No overall differences in safety or effectiveness were observed between these subjects and the younger subjects, but greater sensitivity in some older individuals cannot be ruled out. No dose adjustment or special monitoring are required for geriatric patients. Of the 1520 adult patients in ALOXI PONV clinical studies, 73 (5%) were ≥65 years old. No overall differences in safety were observed between older and younger subjects in these studies, though the possibility of heightened sensitivity in some older individuals cannot be excluded. No differences in efficacy were observed in geriatric patients for the CINV indication and none are expected for geriatric PONV patients. However, ALOXI efficacy in geriatric patients has not been adequately evaluated. Renal Impairment Mild to moderate renal impairment does not significantly affect palonosetron pharmacokinetic parameters. Total systemic exposure increased by approximately 28% in severe renal impairment relative to healthy subjects. Dosage adjustment is not necessary in patients with any degree of renal impairment. Hepatic Impairment Hepatic impairment does not significantly affect total body clearance of palonosetron compared to the healthy subjects. Dosage adjustment is not necessary in patients with any degree of hepatic impairment. Race Intravenous palonosetron pharmacokinetics was characterized in twenty-four healthy Japanese subjects over the dose range of 3 – 90 mcg/kg. Total body clearance was 25% higher in Japanese subjects compared to Whites, however, no dose adjustment is required. The pharmacokinetics of palonosetron in Blacks has not been adequately characterized. OVERDOSAGE There is no known antidote to ALOXI. Overdose should be managed with supportive care. Fifty adult cancer patients were administered palonosetron at a dose of 90 mcg/kg (equivalent to 6 mg fixed dose) as part of a dose ranging study. This is approximately 25 times the recommended dose of 0.25 mg. This dose group had a similar incidence of adverse events compared to the other dose groups and no dose response effects were observed. Dialysis studies have not been performed, however, due to the large volume of distribution, dialysis is unlikely to be an effective treatment for palonosetron overdose. A single intravenous dose of palonosetron at 30 mg/kg (947 and 474 times the human dose for rats and mice, respectively, based on body surface area) was lethal to rats and mice. The major signs of toxicity were convulsions, gasping, pallor, cyanosis and collapse. PATIENT COUNSELING INFORMATION See FDA-Approved Patient Labeling (17.2) in full prescribing information Instructions for Patients • Patients should be advised to report to their physician all of their medical conditions, any pain, redness, or swelling in and around the infusion site [see Adverse Reactions (6) in full prescribing information]. • Patients should be instructed to read the patient insert. Rx Only Mfd by OSO Biopharmaceuticals, LLC, Albuquerque, NM, USA or Pierre Fabre, Médicament Production, Idron, Aquitaine, France and Helsinn Birex Pharmaceuticals, Dublin, Ireland.

ALOXI® is a registered trademark of Helsinn Healthcare SA, Switzerland, used under license. Distributed and marketed by Eisai Inc., Woodcliff Lake, NJ 07677. © 2009 Eisai Inc. All rights reserved. Printed in USA. AL449 08/09

in patients with stage IV disease. Two studies addressed this void. In a prospective, multicenter (29 sites) international trial, investigators evaluated the clinical utility of multimarker quantitative reverse-transcription polymerase chain reaction (qRT-PCR) for detecting circulating tumor cells (CTCs).11,12 Pre- and intratreatment serial blood samples from 244 patients enrolled in a phase 3 trial of postoperative adjuvant therapy (bacille Calmette-Guerin [BCG] plus placebo or BCG plus melanoma vaccine) were assessed by qRT-PCR for MART1, MAGEA3, and PAX3 gene messenger ribonucleic acid (mRNA). Median clinical follow-up time was 21.8 and 24.2 months for disease-free survival (DFS) and OS, respectively. MART1, MAGEA3, and PAX3 were detected in 26%, 23%, and 29% of patients, respectively. Biomarker-negative patients had significantly higher DFS than biomarker-positive patients (risk ratio [RR], 1.56; 95% CI, 1.14-2.15; P = .006) and significantly higher OS than patients with one to two (RR, 2.37; CI, 1.144.94; P = .021) or three positive biomarkers (RR, 2.90; 95% CI, 1.28-6.53; P = .01). Having one to two (RR, 2.44; 95% CI, 1.1-5.12; P = .019) or three positive biomarkers was a significant prognostic factor for poor OS (RR, 3.08; 95% CI, 1.36-6.98; P = .007).11 The second study addressed the presence of tumor infiltrating lymphocytes (TIL) as markers for metastatic disease in 504 patients who initially presented with local disease.12 Of these patients, 370 died of melanoma, with a median survival of 1.4 years after discovery of metastases. The presence of TIL was significantly and independently associated with survival (HR, 0.74; 95% CI, 0.59-0.93, P = .01). These studies suggest that multimarker qRT-PCR analysis of CTC and detection of TIL may have clinical utility as prognostic markers for stage IV melanoma patients.11,12 However, further investigation is needed. Medical therapies The greatest treatment challenge in melanoma is treatment of advanced disease. This section focuses on medical therapies for advanced melanoma. Patients with metastatic melanoma generally have a poor prognosis, with a median survival of 6 to 9 months. A small proportion of patients achieve long-term survival (LTS); however, it is unclear whether LTS reflects sensitivity to systemic therapy, indolent tumor biology, or host immune factors. There is limited information on the frequency and duration of complete response (CR) following dacarbazine or temozolomide therapy or whether LTS occurs only in patients who achieve CR.

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An epidemiologic study of 397 patients treated with either dacarbazine or temozolomide over an 18-year period sought to document LTS (defined as 18 months posttherapy).13 Specific outcomes were CR (no evidence of disease by diagnostic imaging), progressive disease (PD; any tumor growth), and partial response (PR) or stable disease (SD). Of the 45 patients who met the criterion of LTS, the best response to

was halted after increased deaths occurred on the ELPAC arm, which may or may not have been related to the treatment. The investigators continue to collect OS data to determine whether the observed imbalance in OS persists as the data mature. A prospective, randomized phase 3 trial of high-dose (HD) interleukin (IL)-2 alone (arm 1) versus gp100:209217(210M) synthetic peptide cancer

The authors concluded that response rate and PFS were superior with peptide vaccine plus HD IL-2 compared with HD IL-2 alone, and stated that this study represents the first evidence of clinical benefit of vaccination in patients with melanoma.

dacarbazine or temozolomide was CR, 18%; PR/SD, 67%; and PD, 13%. The 5-year OS and progression-free survival (PFS) rates were 33% and 12%, respectively. Eleven patients survived more than 5 years (range, 5-27.5 years), and six patients remained in remission (5 CR, 1 PR). Disease progression occurred in five patients in less than 1 year; however, they remained alive for at least 5 years (range, 5.2-17.9 years). The authors concluded that although LTS occurs in patients with metastatic melanoma treated with dacarbazine or temozolomide, few patients have a sustained response to chemotherapy; most cases of LTS are likely the result of indolent disease or host biology. PFS (defined as >90% power to detect a 2-month improvement) was the end point in a 2-year study of 651 patients with stage IV metastatic melanoma who were randomized to receive either 213 mg/m2 of elesclomol (an investigative drug that increases oxidative stress in cancer cells leading to mitochondria-induced apoptosis) in combination with 80 mg/m2 of paclitaxel (ELPAC) or 80 mg/m2 of paclitaxel alone.14 Both regimens were given weekly for 3 weeks followed by 1 week of rest, until disease progression. Patients were stratified by prior noncytotoxic treatment, M1 grade, and lactate dehydrogenase. Median PFS in the ELPAC arm was 3.5 months (95% CI, 2.7-3.7) compared with 1.9 months (95% CI, 1.9-3.3) in the paclitaxel alone arm (HR, 0.88; 95% CI, 0.671.16; P = .3695). Improved PFS in the ELPAC arm did not achieve statistical significance, however. The median number of cycles was three in the ELPAC arm and two in the paclitaxel alone arm. In February 2009, the study

vaccine plus Montanide ISA followed by HD IL-2 (arm 2) was conducted in 185 patients with stage IV or locally advanced stage III melanoma treated at 21 centers.15 The primary outcome was clinical response; secondary outcomes included toxicity and PFS. Numbers of patients enrolled, treated, and evaluable for response in arm 1 were 94, 93, and 93, respectively; in arm 2, 91, 86, and 86. Toxicities were consistent with those that were seen with HD IL-2 ± vaccine. Arm 2 demonstrated significant improvement in overall response rate (22.1% vs 9.7%, P = .0223, chisquare) and PFS (2.9 months [1.7-4.5] vs 1.6 [1.5-1.8], P = .0101). Median OS was 17.6 months (11.8-26.6) in arm 2 versus 12.8 months (8.7-16.3) in arm 1 (P = .0964). The authors concluded that response rate and PFS were superior with peptide vaccine plus HD IL-2 compared with HD IL-2 alone, and stated that this study represents the first evidence of clinical benefit of vaccination in patients with melanoma. Symptom management HD IFN for patients with melanoma has consistently demonstrated benefits as an adjuvant treatment. Side effects and impaired quality of life (QOL) affect patients’ motivation to continue treatment. A 4-year evaluation of selfreported QOL in 300 patients enrolled in an adjuvant, randomized, controlled phase 3 trial of pulsed, HD intravenous (IV) IFN alpha-2b and subcutaneous (SC) IFN treatment revealed that HD IV IFN treatment led to a globally decreased QOL score in 84% of patients.16 Impaired QOL during HD IV IFN was caused mainly by physical symptoms. During SC IFN treatment, global QOL remained reduced by an

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average of 24% in a majority of patients, despite dose adjustments. Fatigue was the most important determinant of reduced QOL, especially during continuous treatment. Depression was minor and rated as less important than physical and cognitive impairment. These findings demonstrate that fatigue remains the symptom that most affects QOL in patients receiving IFN. Survivorship issues Patients with melanoma are at high risk for subsequent primary cancers. An epidemiologic study evaluated 79,901 white patients who survived at least 2 months after melanoma diagnosis and reported to one of nine population-based cancer registries in the SEER program between 1973 and 2004.17 Of those patients, 7943 developed one or more subsequent primary tumors; 24% of which were cutaneous melanoma. Patients aged 30 years and younger had a markedly higher relative risk of developing subsequent melanoma (observed to expected ratio [O/E], 14.44; 95% CI, 12.40-16.71) as did female patients (O/E, 14.04; 95% CI, 12.00-16.33) or patients with their initial melanoma on the head and neck (O/E, 10.04; 95% CI, 9.2110.92). Risk of subsequent cancers did not vary substantially by histology. The authors concluded that patients with cutaneous melanoma have an approximate ninefold increased risk of developing a subsequent melanoma compared with the general population and require active surveillance for future melanoma. Conclusion With the increasing incidence of skin cancer and costs associated with it, we must focus on risk assessment and education as well as skin surveillance and detection. To do this, we must keep abreast of the latest studies on prognostic markers and QOL for patients receiving adjuvant therapies and those who are survivors of the disease. ● References 1. Cancer Facts and Figures, 2009. American Cancer Society. www.cancer.org/downloads/STT/500809 web.pdf. Accessed February 19, 2010. 2. Alexandrescu DT. Melanoma costs: a dynamic model comparing estimated overall costs of various clinical stages. Dermatol Online J. November 15, 2009. dermatology.cdlib.org/1511/ originals/melanoma_costs/alexandrescu.html. Accessed February 22, 2010. 3. Rigel DS, Friedman RJ, Kopf AW, Polsky D. ABCDE—an evolving concept in the early detection of melanoma. Arch Dermatol. 2005; 141:1032-1034. 4. Balch CM, Buzaid AC, Soong SJ, et al. Final version of the American Joint Committee on

Cancer staging system for cutaneous melanoma. J Clin Oncol. 2001;19:3635-3648. 5. Lakhani N, Shaw K, Saraiya M. Skin cancer screening among US adults: 2000 and 2005 national health interview surveys. J Am Acad Dermatol. 2009;60(suppl 1):Abstract P1900. 6. Rouhani P, Kirsner R. Health care delivery system effect on disparities in melanoma outcomes among Medicare-aged Hispanic patients. J Am Acad Dermatol. 2009;60(suppl 1):Abstract P604. 7. Eggermont AM, Suciu S, Testori A, Patel P, Spatz A, for the EORTC Melanoma Group. Ulceration of primary melanoma and responsiveness to adjuvant interferon therapy: analysis of the adjuvant trials EORTC18952 and EORTC18991 in 2,644 patients. J Clin Oncol. 2009;27(15S):Abstract 9007. 8. Warycha M, Polsky D, Osman I, Mazumdar M. Metaanalysis of sentinel lymph node positivity in thin melanoma (1 mm). J Am Acad Dermatol. 2009;60(suppl 1):Abstract P601. 9. van Akkooi AC, Rutkowski P, van der Ploeg IM, et al. Long-term follow-up of patients with minimal sentinel node tumor burden (<0.1 mm) according to Rotterdam criteria: a study of the EORTC Melanoma Group. J Clin Oncol. 2009;27(15S):Abstract 9005. 10. van Akkooi ACJ, Rutkowski P, van der Ploeg IM, et al. Excellent long-term survival of patients with minimal sentinel node tumor burden (<0.1 mm) according to Rotterdam criteria: a study of the EORTC melanoma group. Eur J Cancer Supplements. 2009;7:Abstract 9302. 11. Hoshimoto S, Shingai T, Wang H, et al. MMAIT-IV Clinical Trial Group Centers. Validation of a multimarker blood assay for postoperative assessment of stage IV melanoma patients in a prospective international phase III trial. J Clin Oncol. 2009;27(15S):9045. 12. Wriston CC, Troxel DB, Shin A, et al. Tumor infiltrating lymphocytes are a prognostic marker for survival in patients who develop melanoma metastases. J Invest Dermatol. 2009;129(S1): Abstract 363. 13. Kim C, Lee CW, Klasa R, Shah A, Savage KJ. Long-term survival of patients with metastatic melanoma (MM) treated with dacarbazine (DTIC) or temozolomide (TMZ). J Clin Oncol. 2009;27(15S):Abstract 9054. 14. Hauschild A, Eggermont AM, Jacobson E, O’Day SJ. Phase III, randomized, double-blind study of elesclomol and paclitaxel versus paclitaxel alone in stage IV metastatic melanoma (MM). J Clin Oncol. 2009;27(18S):Abstract LBA9012. 15. Schwartzentruber DJ, Lawson D, Richards J, et al. A phase III multi-institutional randomized study of immunization with the gp100: 209217(210M) peptide followed by high-dose IL-2 compared with high-dose IL-2 alone in patients with metastatic melanoma. J Clin Oncol. 2009;27(18S):Abstract CRA9011. 16. Mohr P, Hauschild A, Rass K, et al; for the DeCOG Melanoma Study Group. Quality-oflife (QoL) impairment in melanoma patients receiving high-dose interferon alpha 2b (IFNa2b). J Clin Oncol. 2009;27(15S):e20011. 17. Bradford PT, Freedman DM, Goldstein AM, Tucker MA. Increased risk of second primary cancers after diagnosis of melanoma. J Invest Dermatol. 2009;129(S1):S138.

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Advances in the Treatment of Colorectal Cancer By Marlo Blazer, PharmD, BCOP Specialty Practice Pharmacist, Hematology/Oncology, The Arthur G. James Cancer Hospital and Richard J. Solove Research Institute, The Ohio State University Medical Center, Columbus

olorectal cancer (CRC) is the third most common cancer worldwide, and the fourth most common cause of death from cancer.1,2 It is estimated that in 2009, 146,970 men and women will have been diagnosed with cancer of the colon and rectum in the United States, and that 49,920 will have died from the disease.3 From 2002 to 2006 the median age of diagnosis was 71 years.3

fluorouracil in the first line. Oxaliplatin plus infusional fluorouracil (as in leucovorin/fluorouracil/oxaliplatin [FOLFOX] 4) has been shown to be superior to irinotecan plus bolus fluorouracil (IFL) and is equivalent to irinotecan plus infusional fluorouracil (as in leucovorin/ fluorouracil/irinotecan [FOLFIRI]).4,5 Further, FOLFOX6, which, for practical reasons, has largely taken the place of FOLFOX4, was studied as first-line therapy followed by FOLFIRI versus FOLFIRI followed by FOLFOX6.6 This study revealed no significant differences in overall survival (OS; 21.5 vs 20.6 months), initial response rates (54% vs 56%), or progression-free survival (PFS; 8 vs 8.5 months) when either an oxali-

A second-line, phase 3 trial was published in 2007, which showed that bevacizumab combined with FOLFOX4 improved survival over FOLFOX4 alone.

Stage at diagnosis is the most important determinant of 5-year survival. Data from 2002 show that 39% of patients with CRC were diagnosed at the localized stage (tumor, node, metastasis [TNM] stage I and II), 37% were diagnosed as “regional disease” or involving lymph nodes (TNM stage III), and 19% were diagnosed with metastatic disease (TNM stage IV), leaving 5% unstaged at diagnosis.3 The 5-year survival rates were 90.8% for localized disease, 69.5% for regional disease, and 11.3% for metastatic disease, and 38.4% for unstaged disease.3 The treatment options for metastatic CRC (mCRC) have greatly increased in the past decade, and the therapeutic efficacy of multiple-drug regimens has improved. This, in turn, has made treatment choices for first, second, and subsequent lines of therapy a complex decision. Further, issues not yet fully elucidated remain at the crux of this complexity. This review will focus on the treatment of metastatic/advanced disease and these issues. Irinotecan or oxaliplatin: Is there a best first-line choice? Most patients will receive some combination of oxaliplatin or irinotecan plus

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platin-based or an irinotecan-based regimen was used as first-line therapy. The question of whether there is a better first-line regimen, it seemed, could be put to rest. With the approval of bevacizumab and its rise to the standard of care in first-line treatment, this question has again resurfaced. Bevacizumab was first studied in combination with bolus fluorouracil/ leucovorin and with IFL, and was shown to improve OS in combination with IFL compared with IFL alone by just more than 3 months (18.3 vs 15.1 months).7 This study resulted in the approval of bevacizumab in the United States in March 2004. At the time of approval, IFL was beginning to lose favor, largely due to higher toxicities and less efficacy when compared with infusional fluorouracil regimens (ie, FOLFOX6 or FOLFIRI). The question then became: Would bevacizumab add efficacy to these other, more common first-line regimens? In a small phase 2 study with oxaliplatin-based therapy, bevacizumab did appear to improve OS when added to FOLFOX4; however, that comparison was to historical controls.8 A secondline, phase 3 trial was published in 2007, which showed that bevacizumab

combined with FOLFOX4 improved survival over FOLFOX4 alone.9 Patients in this trial had to have progressed on irinotecan and could not have received bevacizumab as first-line therapy. However, validation in phase 3 studies of bevacizumab’s ability to improve survival in combination with either FOLFOX6 or FOLFIRI in the first line did not come until almost 4 years after its initial approval.10,11 In one trial, bevacizumab or placebo was combined with three different oxaliplatin-based regimens (one using bolus fluorouracil, one with infusional fluorouracil, and one with capecitabine).10 The results were contrary to the earlier phase 2 trials. Bevacizumab had no significant impact on OS or PFS. Critics will cite that the stopping rules of the trial may have resulted in undue bias, because only 29% of patients were taken off therapy because of disease progression. The remaining patients had their therapy discontinued because of toxicity (largely oxaliplatin-induced neurotoxicity). It should also be noted, however, that response rates measured at 3 months (when most patients were still on therapy) were also not significantly impacted by the addition of bevacizumab (49% vs 47%). Another issue that may have contributed to these results is the dose of bevacizumab. In the secondline trial previously mentioned, the dose of bevacizumab was 10 mg/kg combined with FOLFOX4. This is double the conventional 5-mg/kg dose used in CRC regimens and in the first-line trial. The question of whether bevacizumab in combination with oxaliplatin-based therapy in the first line adds any benefit or only significant cost is an ongoing debate, given the results of this phase 3 trial. To date, however, the only positive phase 3 data to support this combination is with bevacizumab dosed at 10 mg/kg in patients who have failed irinotecan and who are bevacizumab-naïve. In contrast, another phase 3 trial evaluated the addition of bevacizumab to irinotecan-containing regimens. The trial was initially designed to compare three different irinotecan-containing regimens: IFL versus FOLFIRI versus capecitabine/irinotecan (CAPIRI). However, during the accrual period (February 2003 to December 2004) bevacizumab gained approval. The CAPIRI arm was discontinued, and a second study period was initiated in which bevacizumab was

added to the IFL and the FOLFIRI arms. The results showed that patients treated with bevacizumab plus FOLFIRI had greater OS and PFS (28 and 11.2 months) when compared with patients treated with FOLFIRI alone (23.1 and 7.6 months).11-13 Further, the investigators concluded that bevacizumab plus FOLFIRI was superior to bevacizumab plus IFL.11 It should be noted that the former comparison cannot be statistically validated because of the different accrual periods. However, given the current data from phase 3 trials, bevacizumab, when added to irinotecan-containing regimens in the first line, does seem to provide a consistent benefit in both prolonged PFS and OS. Should bevacizumab be continued after progression? Since bevacizumab’s approval, it has become standard to add it to first-line therapy in mCRC. The question that has yet to be answered is whether there is any benefit in continuing bevacizumab after a patient has progressed on it within the first-line regimen. It has been theorized that not only does bevacizumab, as a vascular endothelial growth factor inhibitor, impair a tumor’s ability to secure a blood supply via antiangiogenesis, but that it also stabilizes the existing vasculature by inhibiting formation of collateral vessels that are too small to deliver cytotoxics to the tumor bed. Should this be the case, it would make sense to change cytotoxic regimens, but to continue the bevacizumab to add synergy via continued enhancement of drug delivery. However, this theorized benefit has yet to be tested in a randomized controlled trial. In an observational study, Grothey and colleagues compared one cohort in which patients received bevacizumab beyond first progression with two matched cohorts, one in which the patients were treated beyond progression without bevacizumab and another in which patients were not treated after progression.13 The results seem to indicate that there is, indeed, benefit to continuing bevacizumab into secondline treatment. When compared with the cohort treated beyond progression without bevacizumab, the cohort that received bevacizumab beyond progression had a longer OS (31.8 vs 19.9 months) and longer beyond-first-progression survival (19.2 vs 9.5 months).

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The bevacizumab-beyond-first-progression group not only had a higher percentage of patients with better performance status (reported as Eastern Cooperative Oncology Group 0), but also 45% of the group were not receiving bevacizumab at the time of first progression. It should be noted, however, that this was an observational study. There is concern regarding selection bias, specifically which patients were prescribed bevacizumab in the second line versus which were not. The bevacizumabbeyond-first-progression group not only had a higher percentage of patients with better performance status (reported as Eastern Cooperative Oncology Group 0), but also 45% of the group were not receiving bevacizumab at the time of first progression.13 In addition, progression was assessed by the treating physician with no control over the measure used (ie, response evaluation criteria in solid tumors vs other clinical evaluation) to standardize what progression actually meant.13 In other words, we cannot conclude from this study that the patients in the bevacizumab-beyondfirst-progression cohort actually progressed by RECIST definition on bevacizumab in the first line. Therefore, until a randomized controlled study can answer this question, there are no data to support continued bevacizumab use after progression on bevacizumab in mCRC. Can patients with mCRC take a break from treatment? Although there has been great improvement in OS for patients with metastatic disease, the thought of being treated with some form of intravenous chemotherapy every 2 weeks for the rest of one’s life can be daunting. So, the question of breaks from therapy has been an interesting one, keeping in mind that the goal for these patients is palliative care. Three studies have attempted to answer this question. Labianca and colleagues looked at a stop-and-go version of FOLFIRI in which previously untreated patients received either FOLFIRI in a stop-and-go pattern involving 2-month rotations of “on therapy” followed by “chemotherapy-free intervals” (arm A, n = 163) or continuously until progression (arm B, n = 168). OS benefit was comparable in arm A and arm B (16.9 vs 17.6 months).14 Two other studies employed the same idea using FOLFOX. In the OPTIMOX1 study, patients received either FOLFOX until tumor progression (arm A, n = 309) or FOLFOX with a

higher dose of oxaliplatin (FOLFOX7) for 3 months followed by 6 months of fluorouracil/leucovorin only. FOLFOX7 was then restarted at 6 months or at progression, whichever came first (arm B, n = 303).15 In OPTIMOX2, FOLFOX was given either as in arm B of the OPTIMOX1 study with a “maintenance phase” of only leucovorin/fluorouracil (n = 100) or with a chemotherapy-free interval (n = 102).16 In evaluating the latter two trials, it appears that a maintenance phase of leucovorin/fluorouracil did not impact the OS benefit of oxaliplatin-based therapy in the first line (19.3 months for FOLFOX4 vs 21.2 months for FOLFOX7 with maintenance phase).15 In the second trial, however, the investigators used an end point called duration of disease control (DDC), which is the first PFS (time to progression back to baseline tumor size) plus the second PFS (time to progression after reinitiating FOLFOX7).16 In this trial, DDC was better with a maintenance approach rather than a chemotherapy-free interval (12.9 vs 11.7 months, P = .41), as was PFS (8.7 vs 6.9 months, P = .009). From these trials, and with the goal of palliation in mind, it is feasible to propose a break in treatment to patients who have achieved a response to first-line therapy. Further, it seems that this break may favor more of a maintenance approach with infusional fluorouracil than a complete chemotherapy-free interval. However, a patient’s clinical symptoms, toxicities to chemotherapy, and quality of life play a major role in determining how and when this break should be executed. EGFR inhibition: When, how, and with what other agents With two inhibitors of the epidermal growth factor receptor (EGFR), cetuximab and panitumumab, on the market and given the cost of these therapies, EGFR inhibition is an important topic to discuss in mCRC. It is well documented that both of these agents have no benefit in patients with a mutated KRAS gene.17,18 The mutated gene encodes for a “gain-in-function” for the KRAS protein, which is downstream from the EGFR signal transduction pathway. With the commercial avail-

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Chemotherapeutic Regimens for Treatment of Metastatic Colorectal Cancer Chemotherapeutic Regimens

Grade 3/4 Adverse Drug Reactions FOLFOX41

Oxaliplatin 85 mg/m2 on day 1

Neutropenia: 41%

Leucovorin 200 mg/m2 on days 1 and 2

Paresthesia: 12%

Fluorouracil 400 mg/m2 IV bolus followed by Diarrhea: 11% 600 mg/m2,a IV over 22 hours on days 1 and 2 (Cycle repeated every 14 days)

N/V: 5%/6% FOLFOX62

Oxaliplatin 100 mg/m2,b on day 1

Neutropenia: 44%

Leucovorin 200 mg/m2 on day 1

Neuropathy: 34%

Fluorouracil 400 mg/m2 IV bolus followed by 2400-3000 mg/m2,a CIV over 46 hours on day 1

Diarrhea: 11%

(Cycle repeated every 14 days) IFL3 Irinotecan 125 mg/m2 IV over 90 min

Neutropenia: 53.8%

Leucovorin 20 mg/m2 as IV bolus

Diarrhea: 22.7%

Fluorouracil 500 mg/m2 as IV bolus

Vomiting: 9.7%

(Repeated weekly for 4 weeks followed by 2 weeks off in each 6-week cycle)

FN: 7.1%

FOLFIRI2 Irinotecan 180 mg/m2 on day 1

Neutropenia: 24%

Leucovorin 200 mg/m2 on day 1

Diarrhea: 14%

Fluorouracil 400 mg/m2 IV bolus followed by 2400-3000 mg/m2,b CIV over 46 hours on day 1

N/V: 13%/10%

(Cycle repeated every 14 days) Does not typically exceed 2400 mg/m2 in United States; btypically given at dose of 85 mg/m2.

CIV indicates continuous intravenous infusion; FN, febrile neutropenia; FOLFIRI, leucovorin/fluorouracil/irinotecan; FOLFOX, leucovorin/fluorouracil/oxaliplatin; IFL, irinotecan plus bolus fluorouracil; IV, intravenous; N/V, nausea/vomiting. 1. André T, Boni C, Mounedji-Boudiaf L, et al; for the Multicenter International Study of Oxaliplatin/5Fluorouracil/Leucovorin in the Adjuvant Treatment of Colon Cancer (MOSAIC) Investigators. N Engl J Med. 2004;350:2343-2351. 2. Tournigand C, André T, Achille E, et al. FOLFIRI followed by FOLFOX6 or the reverse sequence in advanced colorectal cancer: a randomized GERCOR study. J Clin Oncol. 2004;22:229-237. 3. Saltz LB, Cox JV, Blanke C, et al; for the Irinotecan Study Group. Irinotecan plus fluorouracil and leucovorin for metastatic colorectal cancer. N Engl J Med. 2000;343:905-914.

ability of KRAS testing, it has become the standard of care to test for the mutation before initiating therapy with EGFR inhibitors to spare those who would not respond to therapy the toxicities and expense of these agents. Both EGFR inhibitors are currently indicated after failure of oxaliplatinand irinotecan-containing regimens. Panitumumab is currently labeled only for monotherapy by the US Food and

Drug Administration and cetuximab’s labeling is for either monotherapy or in combination with irinotecan only. However, both these agents are currently being studied in combination with more agents, and both have been studied with bevacizumab. Studies looking at combination cytotoxics in patients with nonmutated KRAS have had encouraging results, although studies indicate that Continued on page 20

MAY 2010 I VOL 3, NO 3

TON_May2010_v3_TON 5/3/10 6:31 PM Page 18

1st in a series on understanding MDS

Clinical challenge: Treatment selection for patients with lower-risk MDS* Supportive care: The most common initial MDS treatment 90% of patients with newly diagnosed myelodysplastic syndromes (MDS) present with anemia, and most patients eventually become red blood cell (RBC) transfusion dependent.1 For years, MDS was treated with best supportive care—RBC or platelet transfusions and antibiotics.2 With the advent of hematopoietic growth factor therapy, supportive care expanded to include erythropoiesis-stimulating agents (ESAs), with or without G-CSF,† which were used to reduce the need for transfusions.3,4

Survival decreases with increasing transfusion requirements5 Therefore, it is critical to achieve transfusion independence in patients with transfusiondependent MDS. While ESAs can effectively relieve the symptoms of anemia, they are not sufficient to provide RBC transfusion independence in all MDS patients.6-9 Some of your patients with lower-risk MDS may need treatment other than growth factors (GFs).

Use baseline serum erythropoietin (sEPO) levels to guide treatment decisions Because the response to ESAs declines with increasing baseline sEPO levels, it is critical to measure endogenous levels of erythropoietin before initiating treatment with ESAs. As many as 85% of patients with MDS have elevated baseline sEPO levels,10 making them less likely to respond to growth factors. Patients with high sEPO levels (>500 U/L) and high transfusion needs (≥2 RBC units/month) have a low chance of response to erythropoietin.3 Current treatment guidelines recommend that the determination of baseline sEPO levels should be a required part of the initial evaluation of patients with cytopenias.11

*MDS, myelodysplastic syndromes; lower-risk MDS, Low- and Intermediate-1–risk MDS per International Prognostic Scoring System (IPSS). G-CSF, granulocyte colony-stimulating factor. Growth factor therapy includes ESA ± G-CSF or granulocyte/macrophage (GM)-CSF.3

†

11/08

CELG08071T

TON_May2010_v3_TON 5/3/10 6:31 PM Page 19

Two variables can be used to predict response to growth factor therapy: Baseline sEPO levels and RBC transfusion burden 9

GOOD Transfusion Requirement sEPO Level

Chance of responding to ESAs‡

INTERMEDIATE

POOR

Low (<2 units/month)

High (≥2 units/month)

Low (<2 units/month)

High (≥2 units/month)

Low (≤500 U/L)

High (>500 U/L)

74%

23%

Adapted from Hellström-Lindberg et al (2003).9

Consider baseline sEPO levels and transfusion burden when determining the most appropriate initial treatment option for your RBC transfusion-dependent patients with lower-risk MDS. It is also important to continually evaluate these patients.

If your patients have a predicted intermediate or poor response to ESAs, you may want to consider non-growth factor therapies.3 §

The Hellström-Lindberg study defined complete erythroid response as an increase in hemoglobin (HgB) to ≥11.5 g/dL. Partial response was defined as an increase in HgB of ≥1.5 g/dL in patients with anemia who are not transfusion dependent, and for RBC transfusion-dependent patients, a stable HgB level for ≥4 weeks and transfusion independence.9 § Non-growth factor therapy includes differentiation agents, immunomodulators, and nonablative cytotoxic therapies.3 ‡

References: 1. Italian Cooperative Study Group For rHuEpo in Myelodysplastic Syndromes. A randomized double-blind placebo-controlled study with subcutaneous recombinant human erythropoietin in patients with low-risk myelodysplastic syndromes. Br J Haematol. 1998;103:1070-1074. 2. Nimer SD. ASH 50th anniversary review: Myelodysplastic syndromes. Blood. 2008;111(10):4841-4851. 3. Sekeres MA, Fu AZ, Maciejewski JP, Golshayan A-R, Kalaycio ME, Kattan MW. A decision analysis to determine the appropriate treatment for low-risk myelodysplastic syndromes. Cancer. 2007;109(6):1125-1132. 4. Fenaux P, Kelaidi C. Treatment of the 5q- syndrome. American Society of Hematology Education Program–Myelodysplastic Syndromes. Hematology. 2006;192-198. 5. Malcovati L, Della Porta MG, Cazzola M. Predicting survival and leukemic evolution in patients with myelodysplastic syndrome. Haematologica. 2006;91(12):1588-1590. 6. Jädersten M, Montgomery SM, Dybedal I, Porwit-MacDonald A, Hellström-Lindberg E. Long-term outcome of treatment of anemia in MDS with erythropoietin and G-CSF. Blood. 2005;106(3):803-811. 7. Miller KB, Kim HT, Greenberg P, et al. Phase III prospective randomized trial of EPO with or without G-CSF versus supportive therapy alone in the treatment of myelodysplastic syndromes (MDS): results of the ECOG-CLSG trial (E1996). Blood. 2004;104(11):24a. Abstract 70. 8. Musto P, Lanza F, Balleari E, et al. Darbepoetin alpha for the treatment of anaemia in low-intermediate risk myelodysplastic syndromes. Br J Haematol. 2004;128(2):204-209. 9. Hellström-Lindberg E, Gulbrandsen N, Lindberg G, et al. A validated decision model for treating the anaemia of myelodysplastic syndromes with erythropoietin + granulocyte colony-stimulating factor: significant effects on quality of life. Br J Haematol. 2003;120(6):1037-1046. 10. Hofmann W-K, Koeffler HP. Myelodysplastic syndrome. Annu Rev Med. 2005;56:1-16. 11. National Comprehensive Cancer Network®. Myelodysplastic Syndromes. V.1.2009. NCCN Clinical Practice Guidelines in Oncology ™. http:www.nccn.org. Accessed September 26, 2008.

718.482.1800

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Solid Tumors Advances in the Treatment of Colorectal Cancer Continued from page 17 Targeted Agents for Treatment of Metastatic Colorectal Cancer Targeted Agents

Adverse Events Bevacizumab

5 mg/kg every 2 weeks in the first line with FOLFIRI and with FOLFOX4, and 10 mg/kg every 2 weeks in the second line in combination with FOLFOX4

When added to traditional cytotoxic regmens, increased incidence of: • intestinal perforation • hemorrhage • hypertension • arteriothromboembolic events • proteinuria

Panitumumab 6 mg/kg every 2 weeks (FDA labeled currently as monotherapy only)

Skin toxicity: grade 3/4, 16%; all grades, 90% Hypomagnesemia: all grades, 39% Diarrhea: all grades, 21% Severe infusion reaction: 1% Cetuximab

FDA labeled dosing, 400 mg/m2 loading dose with 250 mg/m2 weekly, for subsequent doses as either monotherapy or in combination with irinotecan only

Skin toxicity: grade 3/4, 8%; all grades, 76.3% Hypomagnesemia: all grades, 33.8% Diarrhea: grade 3/4, 28.4% (irinotecan alone, 15.7%)

FDA indicates US Food and Drug Administration; FOLFIRI, leucovorin/fluorouracil/irinotecan; FOLFOX, leucovorin/ fluorouracil/oxaliplatin.

EGFR inhibition with bevacizumab may have a negative impact.19-21 Panitumumab has been studied in a phase 3 trial in combination with FOLFIRI in patients who had progressed on oxaliplatin and/or bevacizumab.22 This trial reported an increase of 2 months for both PFS and OS when pan-

21 months with FOLFIRI alone to 24.9 months with the addition of cetuximab (P = .022).24,25 In contrast, cetuximab, when combined with oxaliplatin-based therapy, failed to show significant survival benefit in the first line in patients with nonmutated KRAS (17 months with cetuximab vs 17.9 months with-

Both agents have utility beyond first-line therapy and may have benefit in the first line, although the gold standard first-line biologic remains bevacizumab.

itumumab was added to FOLFIRI; however, the increase in OS was not statistically significant. Panitumumb has also been studied in the first line with FOLFOX therapy. Although OS in the panitumumab arm had not yet been reached at 20.3 months, panitumumab did increase PFS in patients without the KRAS mutation by 1.5 months compared with FOLFOX alone.23 Cetuximab has been studied in the first line with both FOLFIRI and with oxaliplatin combined with either fluorouracil or capecitabine. In patients without the KRAS mutation, OS was increased from

MAY 2010 I VOL 3, NO 3

out cetuximab, P = ns).26 Both agents have utility beyond firstline therapy and may have benefit in the first line, although the gold standard first-line biologic remains bevacizumab. Currently, neither of the EGFR inhibitors should be used in combination with bevacizumab or in patients with the KRAS mutation. Further, cetuximab in combination with oxaliplatin-containing regimens appears to have no impact on OS. Conclusion Management of the patient with

mCRC is complex, with many cytotoxic regimens to choose from. We can draw from multiple phase 3 studies regarding choice of therapy, but with data being constantly generated, it seems that “standard of care” is a moving target. Healthcare providers need to balance efficacy data with toxicity management and with cost. All members of the multidisciplinary team can use the data presented to raise these questions in an attempt to get patients the most effective treatments in terms of clinical efficacy, toxicity, and cost. ● References

1. Parkin DM, Bray F, Ferlay J, Pisani P. Global cancer statistics, 2002. CA Cancer J Clin. 2005;55:74-108. 2. Colon and rectum cancer (invasive). National Cancer Institute, SEER cancer statistics review, 1975-2004. http://seer.cancer.gov/csr/1975_ 2004/results_merged/sect_06_colon_rectum.pdf. Based on November 2006 SEER data submission, posted to the SEER website, 2007. Accessed February 9, 2010. 3. SEER stat fact sheets, 1975-2006. Colon and rectum. National Cancer Institute. http//seer. cancer.gov/statfacts/html/colorect.html. Based on November 2008 SEER data submission, posted to the SEER website, 2009. Accessed February 9, 2010. 4. Sanoff HK, Sargent DJ, Campbell ME, et al. Five-year data and prognostic factor analysis of oxaliplatin and irinotecan combinations for advanced colorectal cancer: N9741. J Clin Oncol. 2008;26:5721-5727. 5. Colucci G, Gebbia V, Paoletti G, et al; for the Gruppo Oncologico Dell’Italia Meridionale. Phase III randomized trial of FOLFIRI versus FOLFOX4 in the treatment of advanced colorectal cancer: a multicenter study of the Gruppo Oncologico Dell’Italia Meridionale. J Clin Oncol. 2005; 23:4866-4875. 6. Tournigand C, Andre T, Achille E, et al. FOLFIRI followed by FOLFOX6 or the reverse sequence in advanced colorectal cancer: a randomized GERCOR study. J Clin Oncol. 2004; 22:229-237. 7. Hurwitz HI, Fehrenbacher L, Hainsworth JD, et al. Bevacizumab in combination with fluorouracil and leucovorin: an active regimen for first-line metastatic colorectal cancer. J Clin Oncol. 2005; 23:3502-3508. 8. Hochester HS, Hart LL, Ramanathan RK, et al. Safety and efficacy of oxaliplatin and fluoropyrimidine regimens with or without bevacizumab as first-line treatment of metastatic colorectal cancer: results of the TREE study. J Clin Oncol. 2008;26:3523-3529. 9. Cohen MH, Gootenberg J, Keegan P, Pazdur R. FDA drug approval summary: bevacizumab plus FOLFOX4 as second-line treatment of colorectal cancer. Oncologist. 2007;12:356-361. 10. Saltz LB, Clarke S, Diaz-Rubio E, et al. Bevacizumab in combination with oxaliplatinbased chemotherapy as first-line therapy in metastatic colorectal cancer: a randomized phase III study. J Clin Oncol. 2008;26:2013-2019. 11. Fuchs CS, Marshall J, Mitchell E, et al. Randomized, controlled trial of irinotecan plus infusional, bolus, or oral fluoropyrimidines in first-line treatment of metastatic colorectal cancer: results from the BICC-C study. J Clin Oncol. 2007;25:4779-4786. 12. Fuchs CS, Marshall J, Barrueco J. Randomized, controlled trial of irinotecan plus infusional, bolus, or oral fluoropyrimidines in first-line treatment of metastatic colorectal cancer: updated results from the BICC-C study. J Clin Oncol. 2008;26:689-690.

13. Grothey A, Sugrue MM, Purdie DM, et al. Bevacizumab beyond first progression is associated with prolonged overall survival in metastatic colorectal cancer: results from a large observational cohort study (BRiTE). J Clin Oncol. 2008;26:5326-5334. 14. Labianca R, Floriani I, Cortesi E, et al; for the Italian Group for the Study of Digestive Tract Cancer. Alternating versus continuous “FOLFIRI” in advanced colorectal cancer (ACC): a randomized “GISCAD” trial. J Clin Oncol. 2006;24(18S):Abstract 3505. 15. Tournigand C, Cervantes A, Figer A, et al. OPTIMOX1: a randomized study of FOLFOX4 or FOLFOX7 with oxaliplatin in a stop-and-go fashion in advanced colorectal cancer—a GERCOR study. J Clin Oncol. 2006;24:394-400. 16. Maindrault-Goebel F, Lledo G, Chibaudel B, et al. OPTIMOX2, a large randomized phase II study of maintenance therapy or chemotherapyfree intervals (CFI) after FOLFOX in patients with metastatic colorectal cancer (MRC). A GERCOR study. J Clin Oncol. 2006;24 (18S): Abstract 3504. 17. Amado RG, Wolf M, Peeters M, et al. Wildtype KRAS is required for panitumumab efficacy in patients with metastatic colorectal cancer. J Clin Oncol. 2008;26:1626-1634. 18. Leivre A, Bachet JB, Boige V, et al. KRAS mutations as an independent prognostic factor in patients with advanced colorectal cancer treated with cetuximab. J Clin Oncol. 2008; 26:374-379. 19. Hecht JR, Mitchell E, Chidiac T, et al. An updated analysis of safety and efficacy of oxaliplatin(Ox)/bevacizumab (bev) +/- panitumumab (pmab) for first-line treatment (tx) of metastatic colorectal cancer (mCRC) from a randomized, controlled trial (PACCE). Presented at: 2008 ASCO Gastrointestinal Cancers Symposium; January 2008; Orlando, Florida. Abstract 273. 20. Hecht JR, Mitchell E, Chidiac T, et al. Interim results form PACCE: irinotecan (iri)/bevacizumab (bev) +/- panitumumab (pmab) as firstline treatment (tx) for metastatic colorectal cancer (mCRC). Presented at: 2008 ASCO Gastrointestinal Cancers Symposium; January 2008; Orlando, Florida. Abstract 279. 21. Tol J, Koopman M, Cats A, et al. Chemotherapy, bevacizumab, and cetuximab in metastic colorectal cancer. N Engl J Med. 2009;360:563-572. 22. Peeters M, Price T, Hotko Y, et al. Randomized phase 3 study of panitumumab with FOLFIRI vs FOLFIRI alone as second-line treatment (tx) in patients (pts) with metastatic colorectal cancer (mCRC). Eur J Cancer. 2009;7(suppl):Abstract 14LBA. 23. Douillard J, Siena S, Cassidy J, et al. Randomized phase 3 study of panitumumab with FOLFOX4 compared to FOLFOX4 alone as 1stline treatment (tx) for metastatic colorectal cancer (mCRC): the PRIME trial. Eur J Cancer. 2009;7(suppl):Abstract 10LBA. 24. Van Cutsem E, Lang I, D’haens G, et al. KRAS status and efficacy in the first-line treatment of patients with metastatic colorectal cancer (mCRC) treated with FOLFIRI with or without cetuximab: the CRYSTAL experience. J Clin Oncol. 2008;26(suppl):Abstract 2. 25. Van Cutsem E, Lang I, D’Haens G, et al. KRAS status and efficacy in the CRYSTAL study: 1stline treatment of patients with metastatic colorectal cancer (mCRC) receiving FOLFIRI with or without cetuximab. Ann Oncol. 2008;19(suppl 8):Abstract 710. 26. Maughan T, Adams RA, Smith CG, et al. Addition of cetuximab to oxaliplatin-based combination chemotherapy (CT) in patients with KRAS wild-type advanced colorectal cancer (ACRC): a randomised superiority trial (MRC COIN). Eur J Cancer. 2009;7(suppl): Abstract 6LBA.

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For more information about GEMZAR, please see your Lilly sales professional or visit GEMZAR.com.

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Solid Tumors

Update on Castrationresistant Prostate Cancer: A Review of Systemic Innovations By Megan McKee, PharmD, BCPS Oncology Pharmacy Resident, Investigational Drug Section, Cancer Therapy and Research Center, University of Texas Health Sciences Center, San Antonio

Anita Aracelli Garcia, PharmD, BCOP Left to right: Anita Aracelli Garcia, PharmD, BCOP; Scott Soefje, PharmD, BCOP; Megan McKee, PharmD, BCPS; Bradi L. Frei, PharmD, BCPS, BCOP

pproximately 192,000 men developed prostate cancer in 2009 and 27,000 died from the disease.1 Prostate cancer is the most frequently diagnosed cancer in North America and the second most common cause of cancer death in men. Although the number of new cases of prostate cancer has increased in the past decade, the absolute number of deaths has slowly declined.1 As the incidence of prostate cancer increases, controversies continue about the best possible methods for screening, detection, and treatment. The optimal management of prostate cancer is dependent on patient age, overall health, and tumor risk assessment. Just as the history of prostate cancer ranges from an incidental finding to widespread metastatic disease, management varies widely. Localized prostate cancer is treated with radical

gen levels is to reduce circulating androgens by surgical or chemical castration with the use of luteinizing hormonereleasing hormone agonists. Unfortunately, although castration removes the gonadal testosterone source, androgens from other sources many continue to act as ligands and result in androgenreceptor signaling. Androgen-mediated effects on prostate cancer cells may also be blocked with androgen-receptor antagonists or a combination of therapies. An increasing prostate-specific antigen (PSA) level after definitive local therapy is termed recurrence. Most patients will experience progression within a median of 12 to 20 months4 and will eventually develop androgenindependent prostate cancer. Androgen-independent prostate cancer is also known as hormone-resistant prostate cancer, hormone-refractory

In this multicenter, randomized, double-blind, placebo-controlled study, sipuleucel-T extended median survival by 4.1 months and improved 3-year survival by 38%.

prostatectomy, external-beam radiation therapy, brachytherapy, or observation alone. Treatment of locally advanced disease involves a multimodality approach, including radiation, androgen ablation, and possible androgen-deprivation therapy.2 Unfortunately, even after initial successful treatment of localized prostate cancer, recurrence is common, with approximately 10% to 50% of men progressing to advanced or metastatic disease.3 Prostate cancer is an androgendependent malignant disease, and androgen-deprivation therapy is commonly used following local therapy (Figure). One method to suppress andro-

MAY 2010 I VOL 3, NO 3

prostate cancer, and more recently referred to as castration-resistant prostate cancer (CRPC). Therapies for patients who develop CRPC include withdrawal of the androgen-receptor antagonist, secondary hormonal therapy, and chemotherapy. Hormone-refractory prostate cancer arises when disease progression continues despite antiandrogen withdrawal. CRPC represents a spectrum of disease ranging from asymptomatic patients to those with metastasis or debilitating cancer symptoms. Current therapies for CRPC Mitoxantrone, an anthracenedione, has been studied in patients with

Clinical Oncology Pharmacist, Investigational Drug Section, Cancer Therapy and Research Center, University of Texas Health Sciences Center, San Antonio

Bradi L. Frei, PharmD, BCPS, BCOP Assistant Professor, Feik School of Pharmacy, University of the Incarnate Word Clinical Oncology Pharmacist, Investigational Drug Section, Cancer Therapy and Research Center, University of Texas Health Sciences Center, San Antonio

Scott Soefje, PharmD, BCOP Director, Investigational Drug Section, Cancer Therapy and Research Center, University of Texas Health Sciences Center, San Antonio metastatic CRPC. Three randomized controlled trials compared mitoxantrone and low-dose corticosteroids with the same corticosteroid alone.5-7 All three randomized controlled trials have reported overall survival (OS) results but none detected an improvement due to mitoxantrone. In addition to examining survival, the two trials by Tannock and associates assessed pain and quality of life through self-reported questionnaires.7,8 In these early trials, objective response rates were low, and median survival did not exceed 12 months. Mitoxantrone was approved in 1996 by the US Food and Drug Administration (FDA) based on the finding of symptomatic improvement in a large randomized, phase 3 trial.8 It was almost a decade later when newer regimens, particularly those including taxanes, were shown to improve objective tumor response and increase survival. Docetaxel was approved by the FDA in 2004 for advanced prostate cancer following the results of the TAX 327 trial.7 In this trial, 1006 men were randomized to docetaxel plus prednisone or mitoxantrone plus prednisone. Median survival of all patients treated with docetaxel was 18.2 months compared with 16.5 months for those treated with mitoxantrone. Following this trial, Southwest Oncology Group (SWOG) 9916 compared docetaxel and estramustine with mitoxantrone and prednisone. The docetaxel arm was favored, with a median OS of 17.5 months compared

with 15.6 months for mitoxantrone.5 Hormone manipulations, systemic chemotherapy, palliation of bone pain with bisphosphonates, and externalbeam irradiation are included in the treatment of CRPC. In addition to the chemotherapeutic agents discussed, vinblastine, vinorelbine, paclitaxel, cyclophosphamide, 5-fluorouracil, carboplatin, and prednisone have been studied extensively. Unfortunately, the results of many of the trials with conventional cytotoxic agents were disappointing, leaving an apparent need to identify novel agents and drug targets that not only improve quality of life, but also prolong survival. This review will focus on newly approved and investigational agents in CRPC. New therapy Sipuleucel-T (Provenge). SipuleucelT, a novel cellular immunotherapy, was FDA-approved for the treatment of metastatic CRPC on April 29, 2010. Given the possibility that there are many active targets in prostate cancer (including PSA and prostatic acid phosphatase [PAP]), biologic targeted therapies make sense in this disease state.9 Sipuleucel-T is derived from autologous peripheral blood cells that are collected during leukapheresis.10 After removing erythrocytes, granulocytes, platelets, and lymphocytes, the remaining product consists of dendrites, T-cells, monocytes, and natural killer cells. The cellular product con-

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Solid Tumors sisting of a patient’s antigen-presenting cells is processed and cultured ex vivo with a recombinant fusion protein containing PAP. A phase 3 randomized, placebo-controlled trial evaluated the safety and efficacy of sipuleucel-T for metastatic, asymptomatic CRPC (D9901).11 One hundred twenty-seven men with a progressive PSA level and an Eastern Cooperative Oncology Group performance score of zero or one were enrolled. Patients were randomized to receive a single sipuleucel-T infusion on weeks 1, 2, and 4 or placebo infusions given on the same schedule. Patients in the placebo group were allowed to receive salvage treatment with sipuleucel-T if disease progression occurred after week 8 of therapy. The primary outcome was time to progression (TTP). A difference for median TTP was not detected when comparing the treatment arm with placebo; however, patients in the treatment arm had improved OS of approximately 4.5 months compared with the placebo (P = .01). At a 36month follow-up, 34% of patients receiving sipuleucel-T were alive compared with 11% of patients receiving placebo (P = .0046). Sipuleucel-T was well tolerated, the most common adverse events reported being fever and chills lasting for 1 to 2 days. This trial had several limitations, including the small number of patients and the use of TTP as a primary outcome. A second phase 3 trial (D9902)10 was terminated early when the results from D9901 were published demonstrating a lack of improvement with sipuleucel-T. Following termination, 98 men enrolled in D9902 and were followed for further safety and efficacy data. The investigators revised secondary end points for D9902 to include OS and renamed the trial D9902A. Again, no difference was detected in TTP or OS in the 98 subjects.10 Approval was based on a third trial of more than 500 patients, Identification of Men with a Genetic Predisposition to ProstAte Cancer: Targeted Screening in BRCA1 and BRCA2 Mutation Carriers and Controls (IMPACT), or D9902B.12 In this multicenter, randomized, doubleblind, placebo-controlled study, sipuleucel-T extended median survival by 4.1 months and improved 3-year survival by 38%. As reported at the 2009 American Urological Association annual meeting, sipuleucel-T successfully met the prespecified statistical significance defined by the protocol and reduced the overall risk of death by 22.5% compared with placebo (P = .032).12 Overall, sipuleucel-T appears to be well tolerated, with most adverse events of grade 1 or 2 severity resolving within 48 hours10-12 (Table 1). No difference in significant serious adverse

events has been reported for patients treated with sipuleucel-T compared with placebo. Various administration frequencies were examined throughout the phase 1, 2, and 3 trials. Most recently, a biweekly dosing interval has been used to avert delays in ther-

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apies at weeks 0, 2, and 4 following standard leukapheresis. Although the primary end point of TTP has not been met in the studies discussed, final results are pending from the ongoing phase 2 Treatment of Prostate Cancer with Active Cellular

Immunotherapy (ProACT) trial.10 Investigational systemic therapies Atrasentan (ABT-627 or Xinlay). Endothelins have been implicated in numerous physiologic and pathologic Continued on page 24

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For insurance verification…prior authorization…patient assistance program information…and billing and claims processing support. Amgen Assist™ and Amgen Inc. do not guarantee success in obtaining reimbursement. Third party payment for medical products and services is affected by numerous factors, not all of which can be anticipated or resolved by our Amgen Assist™ staff. ©Amgen. All rights reserved. MC48319 11/09

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MAY 2010 I VOL 3, NO 3

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Solid Tumors Update on Castration-resistant Prostate Cancer Continued from page 23 Table 1. Common Toxicities Associated with Novel Therapies

Sipuleucel-T

Atrasentan

Zibotentan

Abiraterone acetate

MDV3100

Toxicity

Gradea

Incidence

Comments

Phase of Source Study

Chills

Grade 1 and 2

>20%

Resolved within 48 hours

Phase 1

Fatigue

Grade 1 and 2

>20%

Phase 1 and 2

Pyrexia

Grade 1 and 2

>20%

Phase 1 and 2

Peripheral edema

Grade 2

35%

Nasal stuffiness

Grade 1

29%

Phase 1 and 2

Headache

Grade 1 and 2

20%

Phase 1, 2, and 3

Headache

Grade 2

50%

Likely due to vasodilatory pharmacology of agent

Phase 1 and 2

Peripheral edema

Grade 1 and 2

30%

Managed with furosemide

Phase 1 and 2

Fatigue

All grades

30%

Managed with furosemide

Phase 1 and 2

Hypokalemia

All grades

88%

Managed by eplerenone

Phase 2

Hypertension

All grades

40%

Managed by eplerenone

Phase 2

Fluid overload

All grades

31%

Managed by eplerenone

Phase 2

Rash

All grades

2 patients

Dose-limiting toxicity

Phase 1

Seizure

Not reported

Dose-limiting toxicity

Phase 1

Fatigue

Not reported

Dose reductions required secondary to fatigue

Phase 1

One patient discontinued drug in phase 2 trial

Phase 2 and 3

Grading criteria established by Common Terminology for Grading Adverse Events.

Figure. Androgen-signaling Axis and Targets for Novel Therapies AR indicates androgen receptor; ARE, androgen-response element; DHEA, dehydroepiandrosterone; DHEA-S, dehydroepiandrosterone sulphate; DHT, dihydrotestoterone. Reprinted with permission from reference 27.

MAY 2010 I VOL 3, NO 3

conditions, including cancer.13 Evidence suggests that endothelin-1, a small vasoconstrictor peptide, is produced by several tumor cell lines. Endothelin-1 levels are increased in prostate cancer and modulate mitogenesis and apoptosis on binding to the endothelin-A (ETA) receptor. Multiple in vivo models have examined the role of endothelin antagonism in tumorigenesis. Atrasentan, an orally bioavailable investigational agent, is a selective ETA receptor antagonist that exhibits low-level inhibition of the endothelin-B (ETB) receptor in addition to inhibition of the ETA receptor.14 Xenograft studies conducted with atrasentan in combination with paclitaxel demonstrated a significant reduction in tumor growth compared with monotherapy alone.15 Following additional phase 1 and 2 trials, multiple phase 3 trials have focused on the efficacy of atrasentan in CRPC (Table 2). Beginning in June 2001, a multinational, phase 3, randomized, controlled, double-blind study was conducted in patients with metastatic CRPC.16 Eighthundred nine patients were randomized to receive atrasentan 10 mg by mouth daily (n = 408) or placebo (n = 401). The primary end point was time to disease progression, defined by the first occurrence to a radiographic or clinical event, including bone lesion and metastatic

pain. Atrasentan did not reduce the risk of disease progression (P = .136) compared with placebo; however, increases from baseline in bone alkaline phosphatase and PSA were significantly lower with atrasentan treatment.16 Given the relative success in patients with metastatic cancer, a follow-up phase 3, randomized controlled trial was conducted in patients with nonmetastatic CRPC. Patients who had adequate androgen suppression and no radiographic evidence of metastases were randomized to receive atrasentan 10 mg daily or placebo. Secondary end points included time to PSA progression and OS. A 3-month delay in the median TTP was demonstrated with atrasentan compared with placebo (P = .288). Although there was no difference in the median OS, atrasentan lengthened the PSA doubling time and slowed the increase in bone alkaline phosphatase (P <.01).16-18 Phase 1 and 2 trials with atrasentan have demonstrated safety and tolerability with mild side effects, including edema, rhinitis, and headache17,18 (Table 1). To date, phase 3 trials of atrasentan as monotherapy have not established significant changes in disease progression but have demonstrated changes in objective markers including PSA. The phase 3 SWOG S0421 trial continues to Continued on page 26

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Soild Tumors Update on Castration-resistant Prostate Cancer Continued from page 24 Table 2. Additional Studies Investigating Systemic Therapy in Castration resistant Prostate Cancer Study

Design

Population

Treatment

Primary end point

Secondary end point

Comments

Sipuleucel-T Burch PA , et al. Clin Cancer Phase 1, single-arm Res. 2000;6:2175-2182.

N = 13 Progressive (increasing levels of PSA) CRPC

Infusions of autologous presenting cells (APC8015) at weeks 0 and 4, followed by recombinant fusion protein (PA2024 without T cells) at weeks 8, 12, and 16

Response to treatment: Tolerability: grade 3 fatigue three patients experienced a reported in one patient decrease in PSA by 50% or more from baseline, and nine men had a stimulation of T cells by 75%

Small EJ, et al. J Clin Oncol. Phase 1/2 2000;18:3894-3903.

N = 13 Progressive CRPC

Sipuleucel-T at weeks 0, 4, and 8

Change in PSA: six patients had at least a 25% reduction from baseline in serum PSA

Median TTP: 12 weeks for phase 1 patients, and 29 weeks for phase 2 patients

Burch PA, et al. Prostate. 2004;60:197-204.

N = 21 Progressive CRPC

All patients received two infusions of APC8015 at weeks 0 and 2, followed by subcutaneous injections of PA2024 at weeks 4, 8, and 12

Median TTP: 118 days

Change in PSA: serum PSA levels were reduced by 25% to 50% in two patients; one patient had an initial increase followed by a decrease to undetectable levels by week 24

N = 127 Metastatic, asymptomatic CRPC

Sipuleucel-T versus placebo TTP: 11.7 versus 10 weeks (HR, 1.45; 95% CI, 0.99 2.11; P = .052)

Phase 2

Small EJ, et al. J Clin Oncol. Phase 3, placebo-controlled 2006;24:3089-3094.

Well-tolerated

OS: 25.9 versus 21.4 months (HR, 1.7; 95% CI, 1.13-2.56; P = .01)

Atrasentan Michaelson MD, et al. Cancer. 2006;107:530-535.

Phase 3, placebo-controlled

N = 44 CRPC men with metastatic bone involvement

Atrasentan versus atrasentan plus zoledronic acid

Bone turnover makers: no difference between groups in serum levels of bonespecific alkaline phosphatase

Minimal clinical efficacy, with no objective responses and only one PSA response

Abiraterone acetate Attard G, et al. J Clin Oncol. 2008;26:4563-4571.

Phase 1, single-center, open-label

N = 21 Chemotherapy-naïve, CRPC

Abiraterone acetate

PSA decline of 50% after 1 month and maintained for 3 months: 57% experienced PSA decline

62% of patients with measurable disease attained a PR

Plateau of endocrine effects reported at doses >750 mg No treatment-related grade 3 or 4 toxicities

Attard G, et al. J Clin Oncol. 2009;27:3742-3748.

Phase 1/2 single-center, open-label

Chemotherapy-naïve men with CRPC N = 54 (n = 42 included in antitumor efficacy analysis)

Abiraterone acetate

Sustained PSA decline 50% at any time after 12 weeks: 67%

TTP: 225 days (95% CI, 162-287 days); 37.5% of patients with measurable disease attained a PR

Adverse reactions: 88% hypokalemia; 49% hypertension (eplerenone used to control mineralcorticoid symptoms); asymptomatic grade 3 elevation in transaminases

Maximum tolerated dose: 240 mg/day

Change in PSA: 32% to 58% decline

DLT at 600 mg/day including rash and seizure; fatigue resulted in dose reductions at 360 mg/day and 480 mg/day

MDV3100 Scher HI, et al. Proc Am Soc Phase 1/2, dose-finding Clin Oncol. 2009;27 with extension at optimal (15 suppl):5011. dose

N = 140 Phase 1: Metastatic progressive CRPC Phase 2: Chemotherapynaïve and postchemotherapy CRPC

MDV3100

CI indicates confidence interval; CRPC, castration-resistant prostate cancer; DLT, dose-limiting toxicity; HR, hazard ratio; OS, overall survival; PFS, progression-free survival; PR, partial response; PSA, prostate-specific antigen; TTP, time to progression.

investigate docetaxel plus atrasentan compared with docetaxel alone.19 Zibotentan (ZD4054). Zibotentan, another endothelin receptor antagonist, is being investigated in CRPC.20 Zibotentan is an orally bioavailable inhibitor of the ETA receptor. Pre-

MAY 2010 I VOL 3, NO 3

clinical mouse models demonstrated high affinity for the ETA receptor without measurable activity on the ETB receptor. A multicenter, open-label, phase 1 study begun in June 2003 was conducted to determine the safety and tolerability of zibotentan in patients with metastatic

CRPC.20 Sixteen patients were enrolled and treated with escalating doses of oral zibotentan starting at 10 mg once daily. The primary outcome, maximum tolerated dose, was determined to be 15 mg, and secondary end points, including disease assessment, revealed stable disease in

nine of the 16 patients. Following the completion of the phase 1 trial, a phase 2 randomized, double-blind, placebo-controlled trial was conducted in patients with CRPC and bone metastasis.21 A total of 312 patients were randomized in Continued on page 28

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Solid Tumors Update on Castration-resistant Prostate Cancer a 1:1:1 design to receive zibotentan 10 mg, zibotentan 15 mg, or placebo. The primary end point was progression-free survival (PFS) with secondary end points including OS, time to PSA progression, and safety. Preliminary analyses did not reveal a difference in PFS between the control and placebo arms; however, a median OS of 24.5 months was found in the 10-mg zibotentan arm and 23.5 months in the 15-mg zibotentan arm,

dose of 1000 mg daily was identified for abiraterone acetate and was further investigated in a phase 2 trial. During the phase 2 clinical trial, the chemotherapy-naïve CRPC patients were given abiraterone acetate 1000 mg daily to evaluate the possibility of a durable response to treatment in a larger cohort of patients.26 Forty-two patients were included in the efficacy analysis. Of these 42 patients, 67% met the primary

The more recent agents, abiraterone and MDV3100, have been described as “super androgen inhibitors” by reducing androgen production in the testis, adrenals, and prostate.

compared with 17.3 months in the placebo arm (P = .008). The early results of the phase 2 trials suggest that zibotentan may provide clinical efficacy in prostate cancer. Phase 3 trials are currently being performed to further investigate the efficacy of zibotentan in CRPC. The Endothelin A Antagonist in Hormone Resistant Prostate Cancer with Bone Metastases (ENTHUSE M1) trial is randomizing chemotherapy-naïve CRPC patients to receive zibotentan 10 mg daily or placebo with best supportive care.22 The primary end point in this study is OS with an estimated accrual of 1000 patients. Other phase 3 trials are addressing combination therapies with docetaxel to determine potential additive or synergistic effects of zibotentan and chemotherapy (Table 2). Abiraterone acetate (CB7630). Abiraterone acetate is an orally available, selective and irreversible inhibitor of cytochrome P17, a key enzyme in the generation of androgens and estrogens by the adrenal gland and tumor tissue.23 In 2004, the first human studies reported successful suppression of testosterone levels in noncastrated patients given a 12day regimen of daily abiraterone acetate. Suppression of testosterone was not sustained, however, because of effects of luteinizing hormone.24 Therefore, further investigations with this agent required concomitant castration. Attard and colleagues25 reported a phase 1 trial with abiraterone acetate in chemotherapy-naïve men with CRPC. This dose-escalating trial investigated doses ranging from 250 mg to 2000 mg daily. Although no dose-limiting toxicity was found, a plateau effect was identified for the endocrine effects of abiraterone acetate in doses exceeding 750 mg. In addition to endocrine levels, a decline in PSA 50% occurred after 1 month of continuous therapy and was maintained for 3 months in 57% of patients. A target

MAY 2010 I VOL 3, NO 3

end point of a decline in PSA 50% after 12 weeks of abiraterone acetate treatment confirmed by an additional PSA test 4 weeks later. PSA declines of 90% were observed in 19% of patients. Median time to PSA progression on abiraterone acetate alone for all phase 2 patients was 225 days (95% confidence interval, 162-287 days). Thirty-seven percent of patients with measurable disease attained a partial response by independent radiologic evaluation. For patients who had disease progression, an a priori addition of daily dexamethasone of 0.5 mg was allowed. Tumor response was 33% in patients who received dexamethasone in addition to abiraterone acetate at disease progression.26 These early clinical trials demonstrated good tolerability in addition to tumor response. There were no treatment-related grade 3 or 4 toxicities during the phase 1 trial and limited toxicities in the phase 2 trial. However, abiraterone acetate treatment causes impairment of androgen biosynthesis and increased production of deoxycorticosterone and corticosterone, resulting in secondary mineralocorticoid syndrome (Table 1). In the phase 1 trial by Attard and colleagues, the incidence of hypertension appeared to be similar across all doses with a rate of 33%; this estimate may not be accurate, however, given the limited number of patients in the phase 1 trial. According to phase 1 and 2 clinical trial data, abiraterone acetate has been shown to be safe and moderately effective in CRPC. Several phase 3 studies are currently under way and will provide further information concerning this agent’s potential future role in prostate cancer care. MDV3100. Drug resistance in CRPC is thought to be due to increased androgen receptors. Current antiandrogens

Continued from page 26

have agonistlike properties when androgen receptors are overexpressed. MDV3100 is a second-generation antiandrogen that attempts to overcome this resistance (Figure).27 Built on the structure backbone of a nonsteroidal thiohydantoin agonist, MDV3100 was selected from a panel of about 200 derivatives for its high affinity and selectivity for androgen receptors.28 In preclinical studies, MDV3100 demonstrated a five-time to eight-time greater affinity for androgen receptors, and was only two to three times less selective than native dihydrotestosterone. It showed androgen-receptor antagonism in cells engineered to express increased numbers of androgen receptors and increased activity in mouse models of CRPC when compared with bicalutamide. The in vitro and in vivo activity, combined with optimal pharmacokinetic and structure activity relationship properties, resulted in MDV3100 moving from preclinical testing into human trials.28 At the 2009 annual meeting of the American Society of Clinical Oncology, data from phase 1 and 2 trials of MDV3100 were presented. After a safe dose was determined in the phase 1 portion with 114 patients, the phase 2 portion enrolled patients into one of two groups: one consisting of chemotherapynaïve patients (n = 65), the other consisting of postchemotherapy patients (n = 49). The investigators followed PSA, circulating tumor cells (CTCs), tumor response time, and time on treatment in a total of 140 patients. At the 600-mg daily dose, two of three patients experienced dose-limiting toxicities of rash and seizure (Table 1). At the next two lower doses (480 mg/day and 360 mg/day), fatigue was a problem, and thus the dose was reduced to 240 mg daily, which was determined to be the optimal dose. A dose-responsive decline in PSA was noted, with 58% of patients responding at the 240-mg and 360-mg doses compared with only 32% of patient at the 60mg and 150-mg doses. At 12 weeks, a PSA decline of greater than 50% was noted in 57% of the chemotherapynaïve patients and 45% of the postchemotherapy patients. No progression was seen on radiograph in 74% of patients with measurable disease in the soft tissue or in 62% of patients with bone lesions. Ninety-two percent of patients with CTC in the favorable range (defined as less than five cells) maintained the response over time. The authors concluded that MDV3100 was a promising compound and that the 240mg/day dose should be developed further.29 A phase 3 trial evaluating MDV3100 versus placebo in docetaxelresistant metastatic prostate cancer is under way.30

In a phase 3 study presented at the 2010 Genitourinary Cancers Symposium, the second-generation taxane cabazitaxel combined with prednisone significantly improved OS by 30% in men with metastatic CRPC who progressed after treatment with a docetaxel-containing regimen.31 Median OS was 15.1 months in men who received cabazitaxel plus prednisone compared with 12.7 months in those who received mitoxantrone with predisone. PFS was also significantly greater in the cabazitaxel group (2.8 vs 1.4 months). Discussion Long-term survival after the diagnosis of prostate cancer is dependent on age at diagnosis, comorbid illnesses, stage, and grade of disease. With an increase in awareness and screenings, more men are being diagnosed at earlier stages; however, given the slow progression of the disease most patients present with advanced or metastatic disease. In patients with localized or locally advanced disease, adjuvant hormonal therapy is used to decrease androgens and eradicate residual disease. Initially, prostate cancer patients have effective responses with surgical or medical castration; however, up to half of these men will relapse, and nearly all relapsed patients will progress to CRPC. Systemic therapy has become an important component for the treatment of CRPC, but even chemotherapy agents have little success in extending survival. Important innovations including therapies targeting both signal transduction and hormonal manipulation have been studied. SipuleucelT, a novel immunotherapy made by combining autologous dendritic cells with a recombinant fusion protein, has demonstrated survival advantage in the pivotal phase 3 IMPACT trial. In addition, atrasentan and zibotentan are two investigational agents that target endothelin receptors. Atrasentan has been extensively studied, and recently two randomized, placebo-controlled, phase 3 trials have been reported in the CRPC setting. Atrasentan did not affect time to disease progression compared with placebo, despite evidence of biologic effects on PSA and bone alkaline phosphatase. In contrast, zibotentan, which potentially is more selective, was shown in a double-blind, phase 2 trial, to produce a significant improvement in OS compared with placebo. Finally, the more recent agents, abiraterone and MDV3100, have been described as “super androgen inhibitors” by reducing androgen production in the testis, adrenals, and prostate. Abiraterone acetate, an enzyme inhibitor, has shown early success Continued on page 32

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Solid Tumors

Personalizing Non–small-cell Lung Cancer Treatment By Tara L. Rich, MSN, RN, CNP Certified Nurse Practitioner, Thoracic Oncology Taussig Cancer Institute, Cleveland Clinic, Ohio

Tara L. Rich, MSN, RN, CNP

ung cancer is the leading cause of cancer death in both men and women in the United States.1 It is estimated that in 2009, 219,440 men and women were diagnosed with lung cancer and 159,390 men and women died from the disease.2 From 1975 to 2001, non–small-cell lung cancer (NSCLC) 5-year survival rates have increased from 11.9% to 15.6%. These statistics are independent of sex, race, age, and stage at diagnosis, and make acutely evident that there have been few advances in the treatment of NSCLC. This lack of progress may be a result of not analyzing the patient population

the setting of adjuvant use. The International Adjuvant Lung Trial (IALT) compared platinum-based doublets (cisplatin plus etoposide, vinorelbine, vinblastine, or vindesine) versus observation in postoperative stage I to IIIA patients.4 The result was a 5% improvement in disease-free survival as well as 5-year OS with adjuvant chemotherapy. That same year, JBR.10 compared cisplatin/vinorelbine versus observation in patients with stage I to II NSCLC and confirmed that adjuvant cisplatin-based chemotherapy provides benefit.5 The results were grossly positive with a difference of 15% in 5-year survival between the two arms (69% cisplatin/vinorelbine arm vs 54% observation arm). As with palliative regimens, these results offer convincing evidence for meaningful survival with platinumbased doublets in the adjuvant setting, but improving survival hinges on the hope of finding new drugs and better

Patients with squamous cell histology demonstrated a significant improvement in survival with the gemcitabine/cisplatin compared with cisplatin/pemetrexed. thoroughly. It is only in the past 5 years that researchers have put more emphasis on analyzing patient- and disease-related factors, including race, age, sex, histology, and genomic testing results. Recent trial results are leading us to a new horizon of patient-centered cancer care, which includes genomic testing, histology-focused treatment plans, and the concept of maintenance drugs. Chemotherapy doublet du jour Published in 2002, the Eastern Cooperative Oncology Group (ECOG) 1594 study compared platinum-based doublets in the treatment of advanced NSCLC.3 The four doublets in the trial included cisplatin/paclitaxel, cisplatin/ gemcitabine, cisplatin/docetaxel, and carboplatin/paclitaxel. No differences in overall survival (OS) between the four doublets were found. Although these findings increased options in terms of selecting chemotherapy based on side effect profile, they offer only modest hope for better outcomes. In 2004, several studies looked at the efficacy of platinum-based doublets in

MAY 2010 I VOL 3, NO 3

understanding the utility of the drugs currently available. Focusing on details With this groundwork laid, we can begin to look at personalizing medicine for patients with NSCLC. In 2008, the JMBD phase 3 randomized study compared gemcitabine/cisplatin with pemetrexed/cisplatin in the treatment of advanced NSCLC.6 The researchers performed two analyses, one in which they did not look at the histology and one in which histology was included. In the analysis not including histology, the regimens were equivalent, with a median survival of 10.3 months in each arm. In the analysis including histology, a significant difference in OS was found. Patients with squamous cell histology demonstrated a significant improvement in survival with the gemcitabine/cisplatin compared with cisplatin/pemetrexed. Conversely, patients with adenocarcinoma and large cell histologies demonstrated a significant improvement in survival with cisplatin/pemetrexed. One of the targets of

Maintenance therapy Recently, three trials opened the door to the idea of maintenance therapy. In 2008, the hypothesis of maintenance pemetrexed after first-line therapy for advanced NSCLC was tested in a double-blind study.8 The study included all histologies of NSCLC. Patients were treated with four cycles of one of six approved platinum-based doublets. They were then randomized to either maintenance pemetrexed plus best support care (BSC) or placebo plus BSC. The primary end point was progression-free survival (PFS), with a secondary end point of OS. The result was a significant increase in both PFS and OS. In July 2009, the US Food and Drug Administration (FDA) approved pemetrexed for maintenance therapy in patients with advanced nonsquamous NSCLC, after receiving four cycles of a platinum-based doublet in the first-line setting. In 2009, a phase 3 clinical trial by Fidias and colleagues compared immediate versus delayed second-line docetaxel (75 mg/m2, 21-day cycle) after four cycles of first-line gemcitabine (days 1 and 8)/carboplatin (day 1).9 In the delayed arm, docetaxel was started at the first sign of disease progression. The results showed a significant increase in PFS in the immediate docetaxel arm. However, this increase was not statistically significant, possibly because of the small number of patients in the trial. The same hypothesis was tested with erlotinib in the SATURN study.10 After four cycles of chemotherapy, patients were randomized to either immediate erlotinib or observation. Patients in the erlotinib arm showed a clinically meaningful improvement in both PFS and OS. On the basis of this trial, erlotinib was approved by the FDA as maintenance therapy for NSCLC in April 2010.11

tion with the standard doublet of paclitaxel/carboplatin.12 The trial compared six cycles of paclitaxel/carboplatin with bevacizumab (15 mg/kg) followed by maintenance bevacizumab until progressive disease versus six cycles of paclitaxel/carboplatin alone. Results showed a statistically significant improvement in OS with the paclitaxel/carboplatin with bevacizumab arm. The overall response rate was 35%, compared with 15% with paclitaxel/ carboplatin alone. Patients with squamous histology, history of hemoptysis, untreated brain metastasis, uncontrolled hypertension, who were taking anticoagulants, or had had a recent cerebrovascular accident were excluded because of the increased risk of bleeding.13 Because of the study’s design, in which bevacizumab was used as maintenance until progressive disease, we continue to use it as maintenance therapy in this setting. To date, there have been no studies comparing bevacizumab maintenance with placebo. In 2005, the BR.21 trial showed that erlotinib, a small molecule designed to target the human epidermal growth factor receptor (EGFR)/HER1 pathway by inhibiting the tyrosine kinase activity of HER1, was better than BSC as a second- or third-line therapy for patients with NSCLC.14 Patients were allowed to have received one or two previous lines of therapy. The doubleblind study demonstrated a statistically significant improvement in both OS and PFS. In 2008, the preliminary results of the Iressa Pan-Asia Study (IPASS) were reported.15 Gefitinib, a tyrosine kinase inhibitor (TKI), was compared with paclitaxel/carboplatin as a firstline therapy. The primary end point was PFS, with a secondary end point of OS. EGFR mutation status was also analyzed. The results showed that patients who were EGFR-mutation positive had a significant increase in OS with gefitinib, compared with standard chemotherapy. Conversely, patients who were EGFR- mutation negative had an increased response to standard chemotherapy in comparison with gefitinib.

Targeted agents In 2005, the ECOG 4599 trial introduced the use of bevacizumab, a monoclonal antibody against the vascular endothelial growth factor, in conjunc-

Genomic testing: markers of chemotherapy response As previously discussed, thymidalate synthetase expression in adenocarcinoma potentially affects the utility of peme-

pemetrexed is thymidalate synthetase.7 Therefore, the differential benefit of pemetrexed may be due to lower expression of thymidalate synthetase in adenocarcinoma, compared with squamous cell carcinoma.

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Solid Tumors trexed. Another potential marker of chemotherapy response is the excision repair cross-complementation group 1 (ERCC1) protein. In 2006, the IALT Bio Investigators performed a subgroup analysis of the IALT trial, looking at expression of the ERCC1 protein and the outcomes of receiving adjuvant cisplatin-based chemotherapy.16 The investigators used immunohistochemical (IHC) analysis to determine the expression of the ERCC1 protein in operative specimens of NSCLC. The IALT trial compared the effect of adjuvant cisplatin-based chemotherapy on survival, which was now being compared with ERCC1 expression. The investigators looked for a validated clinical or biologic predictor of the benefit of chemotherapy. Among 761 tumor specimens, ERCC1 expression was positive in 335 (44%) and negative in 426 (56%). The results indicated that a benefit from cisplatinbased adjuvant chemotherapy was associated with the absence of ERCC1. Adjuvant chemotherapy significantly

prolonged survival in patients who were ERCC1-negative. Conversely, patients with ERCC1-positive tumors who received adjuvant chemotherapy did not have prolonged survival. Among the patients who did not receive adjuvant chemotherapy, those with ERCC1-positive tumors survived longer than those with ERCC1-negative tumors. These findings indicate that people with ERCC1-negative tumors benefit from adjuvant chemotherapy, whereas patients with ERCC1-positive tumors do not. Further, these results suggest that the development of genomic profiles, including ERCC1, may help us better select which patients will benefit from adjuvant chemotherapy. Genomic testing: markers of TKI response As discussed, the IPASS trial revealed the relationship between EGFRmutation status and response to TKI therapy.14 Another potential novel molecular marker, a fusion of echino-

These results suggest that the development of genomic profiles, including ERCC1, may help us better select which patients will benefit from adjuvant chemotherapy. derm microtubule-associated proteinlike 4 (EML4) and the anaplastic lymphoma kinase (ALK), has recently been identified in a small subset of NSCLC.17 Shaw and colleagues examined the clinical characteristics, as well as treatment outcomes, of NSCLC patients with and without the EML4-ALK oncogene. EML4-ALK was identified using fluorescent in situ hybridization for ALK rearrangements and was confirmed by IHC for ALK expression. Patients with NSCLC were selected for genetic screening on the basis of two or more of the following characteristics: female sex, Asian ethnicity, never/light smoking history, and adenocarcinoma

histology. Of the 141 tumors screened, 19 (13%) were EML4-ALK mutant, 31 (22%) were EGFR mutant, and 91 (65%) were wild-type (WT/ WT) for both ALK and EGFR. Compared with the EGFR-mutant and WT/WT cohorts, patients with EML4-ALK– mutant tumors were significantly younger and more likely to be men. Patients with EML4-ALK–positive tumors, like patients who have EGFR mutations, also were more likely to be never/light smokers compared with the WT/WT cohort. Eighteen of 19 EML4ALK–positive tumors were adenocarcinomas, predominantly the signet-ring Continued on page 32

Case Study

47-year-old woman was referred by her primary care physician. She had a 3-month history of a very mild nonproductive cough followed by a 4-week history of left hip pain, which led her to the primary care physician’s office. Her physician first ordered a hip radiograph, which revealed some abnormality but was not conclusive. He also ordered a chest film, which revealed a left upper lobe (LUL) mass, followed by a chest computed tomography (CT) scan with contrast that confirmed the LUL mass and revealed a slightly enlarged (1.4 cm) contralateral mediastinal lymph node. Her medical history showed no known exposures. She was a preschool teacher for 8 years, but is now a homemaker raising two children. She has never smoked and drinks socially. Her husband does not smoke and works as an engineer at an electrical firm. She has a history of a cesarean section and tonsillectomy, but no other significant health problems. Her mother had a history of breast cancer, but has been in remission for 10 years. Her paternal grandfather, a long-standing smoker, died of lung cancer at the age of 79 years. Diagnostic workup The first steps were to complete the staging process and obtain a biopsy specimen for histologic diagnosis. Although the tumor was extremely

suspicious on the CT scan, it could have been infectious or benign in etiology. After reviewing the films with both the pulmonologist and interventional radiologist, it was decided that the best method to obtain tissue would be a bronchoscopy. She was sent for the bronchoscopy, where the surgeon was able to biopsy the LUL mass. The surgeon attempted to biopsy the contralateral mediastinal lymph node that was enlarged on the CT scan but was unable to obtain a sufficient sample. Then the patient was sent for a wholebody positron-emission tomography (PET)/CT scan (which did not include the head) and brain magnetic resonance imaging with contrast. Results The PET/CT scan revealed a PETavid bone lesion in the left pelvis, the 4.1 cm  3.2 cm LUL lung mass, which is highly PET-avid, and moderate activity in the enlarged contralateral mediastinal lymph node. The bronchoscopy revealed that the LUL mass was positive for adenocarcinoma. The diagnosis was T2 N2 M1, stage IV, adenocarcinoma of the lung. Patient-centered plan of care In view of the diagnosis of adenocarcinoma, especially in the setting of a nonsmoking history, we sent the tissue for epidermal growth factor receptor–mutation analysis. The results came back negative. This status ruled

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out the idea of treating with a tyrosine kinase inhibitor as first-line therapy. If EML4-ALK fusion oncogene testing were standardized and available outside the setting of a clinical trial, we would have sent the tissue for that analysis as well. We are still collecting information on this new finding, so it did not have utility in our treatment decisions for this patient. Therefore, we discussed standard chemotherapy, including bevacizumab eligibility. She had nonsquamous histology, a noncavitating mass, and no significant

health risks that would prohibit her from receiving bevacizumab. We decided on the combination of paclitaxel/carboplatin/bevacizumab. Because bevacizumab was given as maintenance until progressive disease in clinical trials, we planned to give it until progressive disease. We considered the idea that erlotinib may have a role as a maintenance drug for patients as well, but at this time there is no direct comparison of erlotinib versus bevacizumab maintenance in this setting. ●

MAY 2010 I VOL 3, NO 3

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Solid Tumors Personalizing Non–small-cell Lung Cancer Treatment Continued from page 31 cell subtype. Among patients with metastatic disease, EML4-ALK positivity was associated with resistance to EGFR TKIs. Patients in the EML4-ALK cohort and the WT/WT cohort showed similar response rates to platinum-based combination chemotherapy and no difference in OS. These findings provide information about the clinical characteristics of NSCLC patients who harbor this fusion, as well as the lack of benefit from EGFR TKIs in this population. Currently, Pfizer has a phase 3 clinical trial investigating an oral c-Met and ALK inhibitor, PF-02341066, versus standard-of-care chemotherapy in patients with advanced NSCLC carrying the EML4-ALK oncogene who have progressed on one prior treatment with a platinum-based chemotherapy.18 The primary end point is PFS, and secondary outcomes include OS, objective response rate, duration of response, disease-control rate, and patient-reported outcomes. Patients will be randomized to receive PF-02341066 (250 mg orally twice daily), pemetrexed (500 mg/m2 on day 1 of each 21-day cycle), or docetaxel (75 mg/m2 on day 1 of each 21-day cycle).

Conclusion The past 5 years have brought us to an era with choices and possibilities in treating lung cancer—an era of personalizing NSCLC treatment. These new advances give us hope for improving outcomes and survival; hope that we can pass on to our patients. ● References 1. American Cancer Society. Cancer Facts and Figures 2009. Atlanta, GA: American Cancer Society; 2009. 2. Ries LAG, Eisner MP, Kosary CL, et al, eds. SEER Cancer Statistics Review, 1975-2001. National Cancer Institute. http://seer.cancer. gov/csr/1975_2001/. 2004. Accessed January 21, 2010. 3. Schiller JH, Harrington D, Belani CP, et al; for the Eastern Cooperative Oncology Group. Comparison of four chemotherapy regimens for advanced non-small-cell lung cancer. N Engl J Med. 2002;346:92-98. 4. Le Chevalier T; for the IALT Investigators. Results of the randomized international adjuvant lung cancer trial (IALT): cisplatin-based chemotherapy (CT) vs no CT in 1867 patients (pts) with resected non-small cell lung cancer (NSCLC). Proc Am Soc Clin Oncol. 2003; 22:Abstract 6. 5. Winton TL, Livingston R, Johnson D, et al. A prospective randomised trial of adjuvant vinorelbine (VIN) and cisplatin (CIS) in completely resected stage 1B and II non small cell

lung cancer (NSCLC) Intergroup JBR.10. J Clin Oncol. 2004;22(14S):Abstract 7018. 6. Scagliotti GV, Parikh P, von Pawel J, et al. Phase III study comparing cisplatin plus gemcitabine with cisplatin plus pemetrexed in chemotherapy-naive patients with advancedstage non-small-cell lung cancer. J Clin Oncol. 2008;26:3543-3551. 7. Scagliotti G, Monica V, Ceppi P, et al. Baseline thymidylate synthase expression according to histological subtypes of non-small cell lung cancer. J Clin Oncol. 2009;27(15S):Abstract 7521. 8. Ciuleanu TE, Brodowicz T, Belani CP, et al. Maintenance pemetrexed plus best supportive care (BSC) versus placebo plus BSC: as phase III study. J Clin Oncol. 2008;26(May 20 suppl):Abstract 8011. 9. Fidias PM, Dakhil SR, Lyss AP, et al. Phase III study of immediate compared with delayed docetaxel after front-line therapy with gemcitabine plus carboplatin in advanced non-small-cell lung cancer. J Clin Oncol. 2009;27:591-598. 10. Cappuzzo F, Ciuleanu T, Stelmakh L, et al; for the SATURN Investigators; Istituto Clinico Humanitas IRCCS. SATURN: a double-blind, randomized, phase III study of maintenance erlotinib versus placebo following nonprogression with first-line platinum-based chemotherapy in patients with advanced NSCLC. J Clin Oncol. 2009;27(15S):Abstract 8001. 11. Erlotinib approved as maintenance therapy for non-small cell lung cancer. NCI Cancer Bulletin. April 20, 2010. 12. Sandler AB, Gray R, Brahmer J, et al. Randomized phase II/III trial of paclitaxel (P) plus carboplatin (C) with or without beva-

cizumab (NSC # 704865) in patients with advanced non-squamous non-small cell lung cancer (NSCLC): an Eastern Cooperative Oncology Group (ECOG) Trial—E4599. J Clin Oncol. 2005;23(16S pt 1):Abstract LBA4. 13. Johnson DH, Fehrenbacher L, Novotny WF, et al. Randomized phase II trial comparing bevacizumab plus carboplatin and paclitaxel with carboplatin and paclitaxel alone in previously untreated locally advanced or metastatic non-small-cell lung cancer. J Clin Oncol. 2004;22:2184-2191. 14. Shepherd FA, Rodrigues Pereira J, Ciuleanu T, et al; for the National Cancer Institute of Canada Clinical Trials Group. Erlotinib in previously treated non-small-cell lung cancer. N Engl J Med. 2005;353:123-132. 15. The IPASS study. www.iressa.com/ipass-study/. Accessed February 5, 2010. 16. Olaussen KA, Dunant A, Fouret P, et al; for the IALT Bio Investigators. DNA repair by ERCC1 in non-small-cell lung cancer and cisplatin-based adjuvant chemotherapy. N Engl J Med. 2006; 355:983-991. 17. Shaw AT, Yeap BY, Mino-Kenudson M, et al. Clinical features and outcome of patients with non-small-cell lung cancer who harbor EML4ALK. J Clin Oncol. 2009;27:4247-4253. 18. Pfizer presents data with novel investigational agents in select patient groups with non-small cell lung cancer [press release]. May 30, 20009. www.pfizer.com/news/press_releases/pfizer_press_ releases.jsp?rssUrl=http://mediaroom.pfizer.com/ portal/site/pfizer/index.jsp?ndmViewId=news_vie w&ndmConfigId=1016273&newsId=200905300 05019&newsLang=en. Accessed January 29, 2010.

PROSTATE CANCER

Update on Castration-resistant Prostate Cancer Continued from page 28 in phase 1 and 2 trials in reducing PSA levels and decreasing tumor size. MDV3100, an oral antiandrogen, has demonstrated androgen suppression in preclinical studies as well as the ability to induce cell death in bicalutamideresistant tumors. Phase 1 and 2 trials have found that MDV3100 can reduce PSA levels and decrease CTC. Conclusion Sipuleucel-T offers a new treatment option for men with metastatic CRPC. In addition, a number of different agents are currently being investigated in this disease. Therapies that work through enzyme inhibition, receptor blockade, and even immunogenetic stimulation can manipulate the growth and progression of prostate tumors. Research efforts are ongoing, and it is hoped that publication of results of current trials will provide additional data to support the use of these agents in improving outcomes and survival for patients with CRPC. ● References

1. Jemal A, Siegal R, Ward E, et al. Cancer statistics 2009. CA Cancer J Clin. 2009;59:225-249. 2. Moul JW, Armstrong AJ, Hollenbeck BK, et al. Prostate cancer. In: Pazdur R, Wagman LD, Camphausen KA, Hoskins WJ, eds. Cancer Management: A Multidisciplinary Approach. 11th ed. Lawrence, KS: CMP; 2008:393-423. 3 Goktas S, Crawford ED. Optimal hormonal therapy for advanced prostatic carcinoma. Semin Oncol. 1999;26:162-173. 4. Sharifi N, Gulley JL, Dahut WL. Androgen deprivation therapy for prostate cancer. JAMA.

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2005;294:238-244. 5. Petrylak DP, Tangen CM, Hussain MA, et al. Docetaxel and estramustine compared with mitoxantrone and prednisone for advanced refractory prostate cancer. N Engl J Med. 2004;351:1513-1520. 6. Oudard S, Banu E, Beuzeboc P, et al. Multicenter randomized phase II study of two schedules of docetaxel, estramustine, and prednisone versus mitoxantrone plus prednisone in patients with metastatic hormone-refractory prostate cancer. J Clin Oncol. 2005;23:3343-3351. 7. Tannock IF, de Wit R, Berry WR, et al; for the TAX 327 Investigators. Docetaxel plus prednisone or mitoxantrone plus prednisone for advanced prostate cancer. N Engl J Med. 2004;351:1502-1512. 8. Tannock IF, Osobo D, Stockler MR, et al. Chemotherapy with mitoxantrone plus prednisone or prednisone alone for symptomatic hormone-resistant prostate cancer: a Canadian randomized trial with palliative end points. J Clin Oncol. 1996;14:1756-1764. 9. Hurwitz AA, Yanover P, Markowitz, et al. Prostate cancer: advances in immunotherapy. BioDrugs. 2003;17:131-138. 10. Dendreon Corporation. Cellular, Tissue and Gene Therapies Advisory Committee. Sipuleucel-T briefing document. BLS STN 1251970. March 27, 2007. www.fda.gov/ohrms/dockets/ac/07/ briefing/2007-4291B1_01.pdf. Accessed January 3, 2010. 11. Small EJ, Schellhammer PF, Higano CS, et al. Placebo-controlled phase III trial of immunologic therapy with Sipuleucel-T (APC8015) in patients with metastatic, asymptomatic hormone refractory prostate cancer. J Clin Oncol. 2006;24:3089-3094. 12. Schellhammer PF, Higano C, Berger ER, et al; for the IMPACT Study Investigators. A randomized, double-blind, placebo-controlled, multi-center, phase III trial of sipuleucel-T in men with metastatic, androgen independent prostatic adenocarcinoma (AIPC). Presented at: American Urological Association 104th Annual Scientific Meeting; April 28, 2009; Chicago, IL. Late Breaking Abstract 9. 13. Nelson JB. Endothelin receptor antagonists. World J Urol. 2005;23:19-27. 14. Herrmann E, Bögemann M, Bierer S, et al. The

endothelin axis in urologic tumors: mechanisms of tumor biology and therapeutic implications. Expert Rev Anticancer Ther. 2006;6:73-81. 15. Godara G, Cannon GW, Cannon GM, et al. Role of endothelin axis in progression to aggressive phenotype of prostate adenocarcinoma. Prostate. 2005;65:27-34. 16. Carducci MA, Saad F, Abrahamsson PA, et al; for the Atrasentan Phase III Study Group Institutions. A phase 3 randomized controlled trial of the efficacy and safety of atrasentan in men with metastatic hormone-refractory prostate cancer. Cancer. 2007;110:1959-1966. 17. Nelson JB, Love W, Chin JL, et al; for the Atrasentan Phase 3 Study Group. Phase 3, randomized, controlled trial of atrasentan in patients with nonmetastatic, hormone-refractory prostate cancer. Cancer. 2008;113:2478-2487. 18. Zonnenberg BA, Groenewegen G, Janus TJ, et al. Phase I dose-escalation study of the safety and pharmacokinetics of atrasentan: an endothelin receptor antagonist for refractory prostate cancer. Clin Cancer Res. 2003;9:2965-2972. 19. Docetaxel and prednisone with or without atrasentan in treating patients with stage IV prostate cancer and bone metastases that did not respond to previous hormone therapy. Clinical trials.gov identifier NCT00134056. First received: August 22, 2005. Last updated: March 30, 2010. www.clinicaltrials.gov/ct2/show/NCT00134056? term=docetaxel+and+prednisone&rank=13. Accessed April 1, 2010. 20. Schelman WR, Liu G, Widing G, et al. A phase I study of zibotentan (ZD4054) in patients with metastatic, castrate-resistant prostate cancer. Invest New Drugs. 2009 Sep 19. Epub ahead of print. 21. James ND, Caty A, Borre M, et al. Safety and efficacy of the specific endothelin-A receptor antagonist ZD4054 in patients with hormoneresistant prostate cancer and bone metastases who were pain free or mildly symptomatic: a double-blind, placebo controlled randomized, phase II trial. Eur Urol. 2009;55:1112-1123. 22. A Phase III Trial of ZD4054 (Endothelin-A Antagonist) in Hormone Resistant Prostate Cancer With Bone Metastases (ENTHUSE M1). Clinicaltrials.gov identifier NCT0055 4229. First received: November 2, 2007. Last updated: January 14, 2010. http://clinicaltrials. gov/ct2/show/NCT00554229. Accessed February

20, 2010. 23. Potter GA, Barrie E, Jarman M, Rowlands MG. Novel steroidal inhibitors of human cytochrome P450 (17-hydroxylase-C17,20-lyase): potential agents for the treatment of prostatic cancer. J Med Chem. 1995;38:2463-2471. 24. O’Donnell A, Judson I, Dowsett M, et al. Hormonal impact of the 17alpha-hydroxylase/ C(17,20)-lyase inhibitor abiraterone acetate (CB7630) in patients with prostate cancer. Br J Cancer. 2004;90:2317-2325. 25. Attard G, Reid A, Yap T, et al. Phase I clinical trial of a selective inhibitor of CYP17, abiraterone acetate, confirms that castration-resistant prostate cancer commonly remains hormone driven. J Clin Oncol. 2008;26:4563-4571. 26. Attard G, Reid A, A’Hern R, et al. Selective inhibition of CYP17 with abiraterone acetate is highly active in the treatment of castrationresistant prostate cancer. J Clin Oncol. 2009; 27:3742-3748. 27. Chen Y, Clegg NJ, Scher HI. Anti-androgens and androgen-depleting therapies in prostate cancer: new agents for an established target. Lancet Oncol. 2009;10:981-991. 28. Tran C, Ouk S, Clegg NJ, et al. Development of a second-generation antiandrogen for treatment of advanced prostate cancer. Science. 2009; 324:787-790. 29. Scher HI, Beer TM, Higano CS, et al. Antitumor activity of MDV3100 in a phase I/II study of castration-resistant prostate cancer (CRPC). J Clin Oncol. 2009;27(15S):Abstract 5011. 30. Safety and efficacy study of MDV3100 in patients with castration-resistant prostate cancer who have been previously treated with docetaxel-based chemotherapy. Clinicaltrials.gov identifier NCT00974311. First received: September 9, 2009. Last updated: March 10, 2010. www.clinicaltrials.gov/ct2/show/NCT00 974311?term=MDV3100&rank=2. Accessed April 1, 2010. 31. Sartor AO, Oudard S, Ozguroglu M, et al. Cabazitaxel or mitoxantrone with prednisone in patients with metastatic castration-resistant prostate cancer (mCRPC) previously treated with docetaxel: final results of a multinational phase III trial (TROPIC). Presented at 2010 Genitourinary Cancers Symposium. March 5, 2010. San Francisco, CA.

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Hematologic Malignancies

Treatment Updates: Acute Myeloid Leukemia By Marc A. Earl, PharmD, BCOP Hematology/Oncology Clinical Specialist, Cleveland Clinic, Ohio

Marc A. Earl, PharmD, BCOP

cute myeloid leukemia (AML) is a heterogeneous disease affecting approximately 13,000 people in the United States each year.1 For younger adults (<60 years) standard induction treatment includes 7 days of cytarabine and 3 days of an anthracycline. Adults 60 years and older may also be treated with this regimen or a less intensive approach using outpatient chemotherapy or supportive care. The intensive chemotherapy regimens have been in use since the 1970s, with little improvement in complete response (CR) rate or overall survival (OS). Many of the clinical trials that have been reported in the past year investigate the ability to improve the efficacy of these intensive chemotherapy regimens by increasing dose intensity or adding novel agents to induction therapy. More intensive regimens One significant update was an intensified induction approach in adults who were younger than 60 years. In the Eastern Cooperative Oncology Group

E1900 phase 3 trial, investigators randomized patients to either intensified daunorubicin (90 mg/m2 intravenous [IV]  3 days) or standard daunorubicin (45 mg/m2 IV  3 days).2 All patients also received 7 days of cytarabine (100 mg/m2 continuous IV infusion). End points were evaluated in a total of 547 patients. The median age was 48 years, with other demographics, cytogenetics, and characteristics well matched at baseline. Median OS was significantly increased in the intensified-daunorubicin arm at 23.7 months compared with 15.7 months in the standard arm (P <.003). The CR rate was also higher in the intensified-daunorubicin arm (71% vs 57%; P <.001). The combination of an increased CR rate and an OS advantage is important, especially considering that previous trials with more intensive induction regimens have shown an increased CR rate without a significant increase in OS, presumably because of the increased toxicity profiles of the more intensive regimens. In the current trial, both regimens had similar overall toxicity. The death rate during the induction period was 5.5% for the intensified-daunorubicin group and 4.5% for the standard-dose group (P = .6). Cardiotoxicity with higher doses of daunorubicin was not significantly higher than with the standard dose. Symptomatic heart failure

was seen in 7.9% in the intensifieddaunorubicin group and 7.2% in the standard-dose group (P = NS). The investigators concluded that an intensified induction regimen using >45 mg/m2 of daunorubicin for 3 days (along with cytarabine) should be the new standard treatment for adults with AML who are younger than 60 years. Because oncologists may be uncomfortable prescribing such a high dose, some oncology associations recommend giving at least 60 mg/m2 of daunorubicin for 3 days during AML induction for younger adults, which may be more acceptable to providers. It should be noted that it is unknown whether 60 mg/m2 of daunorubicin would provide the same benefit as the 90-mg/m2 dose used in this trial. Novel regimens Many of the updates in AML were presented at the 2009 annual meeting of the American Society of Hematology (ASH). In one trial (MRC-AML 15), the Medical Research Council investigated various induction and consolidation regimens (Figure).3 Patients were randomized to induction therapy with two courses of cytarabine/daunorubicin (DA), cytarabine/daunorubicin/etoposide (ADE), or fludarabine/cytarabine/ idarubicin/granulocyte colony-stimulating factor (FLAG-IDA). As consolidation therapy, patients were random-

Randomize DA (n = 994) Daunorubicin 50 mg/m2 days 1, 3, 5 Ara-C 100 mg/m2 every 12 hrs days 1-10

ADE (n = 989) Daunorubicin 50 mg/m2 days 1, 3, 5 Ara-C 100 mg/m2 every 12 hrs days 1-8 Etoposide 100 mg/m2 days 1-5

FLAG-IDA (n = 635) Fludarabine 30 mg/m2 days 2-6 Ara-C 2 g/m2 days 2-6 Idarubicin 10 mg/m2 days 4-6

ADE (n = 633) Daunorubicin 50 mg/m2 days 1, 3, 5 Ara-C 100 mg/m2 every 12 hrs days 1-8 Etoposide 100 mg/m2 days 1-5

Randomize – Consolidation 2 cycles MACE (cycle 1) Amsacrine 100 mg/m2 days 1-5 Ara-C 200 mg/m2 days 1-5 Etoposide 100 mg/m2 days 1-5

Ara-C 1.5 g/m2 twice daily days 1, 3, 5

Ara-C 3 g/m2 twice daily days 1, 3, 5

(n = 329)

(n = 328)

MidAC (cycle 2) Mitoxantrone 10 mg/m2 days 1-5 Ara-C 1 g/m2 days 1-3 (n = 723)

Randomize – Additional 1 cycle

Ara-C 1.5 g/m2 twice daily days 1, 3, 5

No additional therapy

(n = 112)

(n = 115)

Figure. Induction and Consolidation Regimens in MRC-AML15 Source: Reference 2.

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ized to amsacrine/cytarabine/etoposide (MACE)/mitozantrone/cytarabine (MidAC) or two courses of high-dose cytarabine. There was also a randomization for an additional cycle of high-dose cytarabine. All the groups were well matched at baseline. Eighty-four percent of patients were between 15 and 59 years of age at diagnosis, and 90% had de novo AML. The majority (70%) of cytogenetic profiles were intermediate prognostic. Although there was a statistically significant increase in CR rate for DA compared with ADE, the rates are clinically similar. OS was also similar in all induction arms (Table 1). When focusing on the consolidation data, no major difference in OS was noted between MACE/MidAC and high-dose cytarabine (52% vs 54%; P = .2). OS also did not differ whether the patient received four or five courses of therapy (58% vs 60%; P = .7). The most meaningful information from this trial may come from the comparison of cytarabine dosed at 1.5 g/m2  6 versus 3 g/m2  6. The 5-year OS was not significantly different between the two groups (54% vs 52%; P = .7).2 The negligible difference in clinical outcomes produced by these two different dosing regimens suggests that it may be in the best interest of the patient to forego the risks of cerebellar toxicity associated with higher doses of cytarabine, and instead treat patients with the 1.5-g/m2 consolidation regimen. The preliminary results of the Southwestern Oncology Group S0106 trial also were presented at ASH. This trial randomized adults aged between 18 and 60 years with de novo AML to receive gemtuzumab ozogamicin in addition to standard 7+3 therapy (daunorubicin 60 mg/m2 IV days 1-3 and cytarabine 100 mg/m2/day continuous IV infusion days 1-7) with or without gemtuzumab ozogamicin for induction.4 Prior studies had shown that adding gemtuzumab to induction therapy may increase diseasefree survival (DFS) without increasing toxicity.5 In the current trial, the treatment arm received daunorubicin 45 mg/m2 IV on days 1 to 3, cytarabine 100 mg/m2 IV on days 1 to 7, and gemtuzumab 6 mg/m2 IV on day 4. Patients in the control arm received daunorubicin at 60 mg/m2 IV on days 1 to 3 and cytarabine 100 mg/m2 continuous IV infusion on days 1 to 7. Those who entered into CR Continued on page 36

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Hematologic Malignancies Treatment Updates: Acute Myeloid Leukemia Table 1. Complete Response (CR) and Overall Survival (OS) Rates from MRC-AML15 End point CR 5-year OS

Treatment DA 77% 42%

ADE 81% 39%

P value 0.04 0.7

CR 5-year OS

FLAG-IDA 84% 46%

ADE 81% 41%

0.2 0.5

ADE indicates cytarabine/daunorubicin/etoposide; DA, cytarabine/daunorubicin; FLAG-IDA, fludarabine/cytarabine/idarubicin/granulocyte colony-stimulating factor. Source: Reference 2.

Table 2. Baseline Characteristics for SWOG S0106

Median age, years Cytogenetics, % Favorable Intermediate Poor Indeterminate/unavailable

7+3 and gemtuzumab (n = 297)

7+3 alone (n = 299)

15 41 19 26

12 42 20 26

7+3 indicates daunorubicin 60 mg/m2 IV days 1-3 and cytarabine 100 mg/m2/day continuous IV infusion days 1-7; SWOG, Southwestern Oncology Group. Source: Reference 3.

after induction were given three cycles of consolidation therapy with cytarabine 3 g/m2 IV  6 doses. There was an additional randomization to three doses of gemtuzumab 5 mg/m2 IV or observation.4 Both groups in this trial were well matched (Table 2). At the second interim analysis, 596 patients were available for evaluation. The addition of gemtuzumab to standard 7+3 therapy was found not to affect the CR rate. The CR rate was 66% in the gemtuzumab arm and 69% in patients receiving standard 7+3 therapy. There was also no statistically significant difference in DFS (hazard ratio [HR], 1.35; 95% confidence interval [CI], 0.85-2.14; P = .9) or OS (HR, 1.15; 95% CI, 0.86-1.35; P = .35). Despite no benefit in efficacy, more adverse events were seen in the gemtuzumab group. Grade 4 and 5 infections were more frequent (11% vs 6%) in the gemtuzumab group as were deaths during induction (9% vs 2%).4 Based on the lack of efficacy benefit (CR, DFS, and OS) along with an increase in adverse events, the study was stopped before full accrual. Although gemtuzumab is US Food and Drug Administration–approved for relapsed AML in older adults, it appears that for younger adults, adding it to induction therapy provides no benefit. Lenalidomide is approved for low- or intermediate-1-risk myelodysplastic syndrome. It is not completely clear why

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lenalidomide is effective, but its efficacy is thought to be due to immunomodulatory and antiangiogenic effects. It is hypothesized that there are common features between myelodysplastic syndrome and AML. Based on this theory, lenalidomide was studied as initial therapy for adults 60 years and older in an open-label, phase 2 trial.6 Patients had to have untreated AML with a good performance status. In the induction phase, patients received 50 mg of lenalidomide daily for 28 days. Those patients not in CR underwent another 28-day induction cycle with the same dosing scheme. Afterward, nonprogressing patients received lenalidomide 10 mg daily for up to twelve 28-day cycles. Therapy was stopped for progressive disease or severe toxicity. Patients were allowed to receive transfusions and growth factors during the trial. Thirty-three patients with a median age of 71 years (60-88 years) were enrolled. Seventy percent had de novo AML, and 36% had poor-risk cytogenetics. The CR rate was 30%, including three cytogenic CRs, two morphologic CRs, and five CRs with with incomplete blood count recovery. The 60-day mortality rate was 27%, with the majority of the deaths resulting from disease progression. The most common toxicities experienced were related to myelosuppression and infections. One of the benefits of this proposed

Continued from page 34

therapy is that it can be taken orally. The median time spent in the hospital was 6 days (range, 0-40 days) for the entire group. Those who achieved CR had a median hospitalization time of 3 days (range, 0-14 days). For patients who elect to receive intensive induction therapy, a typical hospital stay can last 4 to 6 weeks. The mortality rate of 27% seen with lenalidomide is consistent with that of intensive induction therapy. This high-dose lenalidomide regimen is promising for older patients with AML. Further studies are ongoing to delineate the mechanism of action of lenalidomide and to discover ways to enhance the CR duration for these patients. The benefit of this therapy is not only that it is an oral option to treat AML, but also that it may be a novel approach for older adults. One area of interest in AML research has been the effect of different tyrosine kinases on cell proliferation and apoptosis. A recent focus has been FMS-like tyrosine kinase 3 (FLT3) internal tandem duplication (ITD) domain mutations. More than 20% of de novo AML is associated with an FLT3 ITD mutation.7 Recent trials show that this mutation is associated with worse OS and an increase in relapse rates. Because of the incidence and pathophysiology of the FLT3 mutation it has become a target for pharmacologic therapy.8 One agent that has shown to be synergistic following chemotherapy and may affect FLT3 is lestaurtinib.9 In a phase 2 study, patients (n = 224) with relapsed AML and mutated FLT3 status were randomized to receive mitoxantrone/etoposide/cytarabine or highdose cytarabine alone, or either chemotherapy regimen followed by lestaurtinib 80 mg twice daily starting on day 7 or 8. The median age at relapse was 55 years, and 88% of patients had an FLT3 ITD mutation. The CR rate was not significantly different between the two groups (26% vs 21%; P = .35). OS was also not significantly different (P = .92). Lestaurtinib was well tolerated, and the side effect profile for the lestaurtinib arm was similar to that of the control arm. One of the secondary end points of the study was the pharmacokinetic profile of lestaurtinib. The investigators noted that the level of FLT3 inhibition was low (58% adequately inhibited at day 15) and not sustained at this level (27% had adequate inhibition at days 15 and 42). Further investigation showed that achieving FLT3 inhibition may have correlated with CR rate. In patients who had ample FLT3 inhibition on day 15, the CR rate was 39% compared with 9% in patients who did not have FLT3 inhibition. This finding may have been due to the dosing used

in this trial or the pharmacokinetics of the drug. Further trials are looking at other methods to achieve more adequate FLT3 inhibition and the affect this may have on AML outcomes. Summary Much of the information presented in 2009 focused on more intensive or novel chemotherapy regimens to treat AML. Some of the data (high-dose lenalidomide, FLT3 inhibitors) were positive, and although other data (gemtuzumab) showed that no extra benefit was achieved, all the trials provide valuable information about a vastly heterogeneous disease. The most exciting news from 2009 were the data pertaining to higher doses of daunorubicin used during AML induction for adults 60 years and younger. It remains unclear the precise dose of daunorubicin that provides the most benefit without undue side effects, but the increase in CR rate and OS were welcomed news for a difficult-to-treat disease. ● References 1. American Cancer Society. Cancer facts and figures 2009. www.cancer.org. Acessed April 21, 2010. 2. Fernandez HF, Sun Z, Litzow MR, et al. A randomized trial of anthracycline dose intensification during induction of younger patients with acute myeloid leukemia: results of Eastern Cooperative Oncology Group study E1900. J Clin Oncol. 2009;27(15S):Abstract 7003. 3. Burnett AK, Hills RK, Milligan D, et al; for the NCRI AML Working Group. Attempts to optimise induction and consolidation chemotherapy in patients with acute myeloid leukaemia: results of the MRC-AML15 trial. Blood (ASH Annual Meeting Abstracts). 2009;114:Abstract 484. 4. Petersdorf S, Kopecky K, Stuart RK, et al. Preliminary results of Southwest Oncology Group study S0106: an international intergroup phase 3 randomized trial comparing the addition of gemtuzumab ozogamicin to standard induction therapy versus standard induction therapy followed by a second randomization to post-consolidation gemtuzumab ozogamicin versus no additional therapy for previously untreated acute myeloid leukemia. Blood (ASH Annual Meeting Abstracts). 2009;114:Abstract 790. 5. Burnett AK, Kell WJ, Goldstone AH, et al. The addition of gemtuzumab ozogamicin to induction chemotherapy for AML improves disease free survival without extra toxicity: preliminary analysis of 1115 patients in the MRC AML15 trial. Blood (ASH Annual Meeting Abstracts). 2006;108: Abstract 13. 6. Vij R, Nelson A, Uy GL, et al. A phase II study of high dose lenalidomide as initial therapy for acute myeloid leukemia in patients > 60 years old. Blood (ASH Annual Meeting Abstracts). 2009;114: Abstract 842. 7. Applebaum F, Meshinchi S. Structural and functional alterations of FLT3 in acute myeloid leukemia. Clin Cancer Res. 2009;15:4263-4269. 8. El-Shami K, Stone R, Smith D. FLT3 inhibitors in acute myeloid leukemia. Expert Rev Hematol. 2008;1:153-160. 9. Levis M, Ravandi F, Wang ES, et al. Results from a randomized trial of salvage chemotherapy followed by lestaurtinib for FLT3 mutant AML patients in first relapse. Blood (ASH Annual Meeting Abstracts). 2009;114:Abstract 788.

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The Essential Role of Immunotherapy in Follicular Lymphoma Management LOG ON TODAY TO PARTICIPATE www.coexm.com/ace03.asp Release Date: March 19, 2010 Expiration Date: March 18, 2011

TARGET AUDIENCE This activity is intended for hematologists, oncologists and other healthcare professionals who are involved with the care of patients with follicular lymphoma.

STATEMENT OF NEED Non-Hodgkin's lymphoma (NHL), the most common hematologic malignancy, represents a large proportion of the case load for the typical oncology practitioner. That load is likely to grow, since NHL is increasing in prevalence. The introduction of rituximab, the monoclonal antibody against CD20, changed the treatment landscape of lymphoma and it has been advanced further by immunotherapies that combine CD20-directed targeting with radiotherapy. The recent rapid advances in therapeutics and impressive research across this broad, heterogeneous group of malignancies represent an educational challenge for the clinician trying to stay current and provide the most appropriate, up-to-date therapy tailored for the individual patient. Immunotherapy plays a key role at all stages of the disease in reaching the goal of the highest quality response.

EDUCATIONAL OBJECTIVES On completion of this activity, participants should be able to: • Define the goals of therapy for follicular lymphoma (FL) • Describe strategies for patient selection for immunotherapy (including radioimmunotherapy [RIT]), in both the up-front and relapsed/refractory setting • Define different immunotherapy approaches in terms of efficacy, safety, and tolerability • Propose strategies to overcome adverse events and access issues that create barriers to the provision of optimal immunotherapy in FL

FACULTY Stephanie A. Gregory, MD

Professor of Medicine Director, Section of Hematology Rush University Medical Center Chicago, Illinois

David Maloney, MD, PhD

Associate Professor of Medicine Division of Oncology University of Washington Member Fred Hutchinson Cancer Research Center Seattle, Washington

With commentary by: Peter S. Conti, MD, PhD

Professor Nuclear Medicine Keck School of Medicine University of Southern California Los Angeles, California

This activity is supported by an educational grant from Spectrum Pharmaceuticals.

This activity has been approved for 1.0 AMA PRA Category 1 Credits™. For further information and to participate, please go to: www.coexm.com/ace03.asp

In collaboration with

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Hematologic Malignancies

Update on Chronic Myeloid Leukemia By Brian G. Cochran, PharmD, BCOP Oncology Clinical Pharmacist, Indiana University Simon Cancer Center, Indianapolis, Indianapolis

Brian G. Cochran, PharmD, BCOP

n 2000, before imatinib was marketed, it was estimated that there would be 4400 new diagnoses of chronic myeloid leukemia (CML) and 2300 patients would die as a result of the disease in the United States.1 In 2009, the number of estimated new cases of CML increased to 5050, but the number of patients who were expected to succumb to the cancer decreased to 470 patients.2 The US Food and Drug Administration’s (FDA) approval of imatinib in 2001 was seen as a giant leap toward improving and prolonging the lives of patients diagnosed with CML. In the imatinib era, research in CML has focused on improving the utility of imatinib, developing

more potent tyrosine kinase inhibitors (TKIs), and working to overcome drug resistance and intolerability. The clinical course of CML is characterized by three phases: chronic phase (CP), accelerated phase (AP), and blast crisis (BC), with the majority of patients diagnosed in CP. Historically, patients progressed within 3 to 5 years to AP and BC, which are ultimately fatal if untreated.3 The improvements in treating CML are related to it being the first cancer defined by a specific karyotypic abnormality, specifically a reciprocal chromosomal translocation between chromosomes 9 and 22.4 This chromosomal translocation, referred to as the Philadelphia (Ph) chromosome, results in the production of the BCR-ABL tyrosine kinase protein. Imatinib inhibits the activity of the BCR-ABL protein with high selectivity. Based on results from the International Randomized Study of Interferon and STI571 published in 2003, imatinib has become the standard frontline therapy for Ph-positive (Ph+) CML.5,6

Association Between Adherence Rate to Imatinib and Probability of a Major Molecular Response (MMR)

MMR

100%

50%

At 6 Years

>90% Adherence 90% Adherence

Association Between Adherence Rate to Imatinib and Probability of a Complete Molecular Response (CMR) 50%

CMR

40% 30% 20% 10%

Dasatinib was originally evaluated with twice-daily dosing but has since been shown to have comparable efficacy and less toxicity when given once daily.

Imatinib The 8-year follow-up results to this clinical trial, which recently became available, demonstrated an estimated event-free survival (EFS) of 81%, with freedom from progression to AP/BC at 92% in the imatinib arm.7 Most occurrences of progression to AP and BC occurred early, and the risk of progression decreased after 3 years of treatment. Also noted, imatinib’s adverse event profile did not change over time. The FDA-approved dose of imatinib for first-line treatment of CP CML is 400 mg/day or 600 mg/day in AP or BC.8 For patients with disease progression or intolerance to imatinib, current TKI options include higher-dose imatinib, dasatinib, or nilotinib (Table). Allogeneic stem-cell transplant (SCT) is also an option. In CP CML, increasing the dose of imatinib to 800 mg/day when the initial dose failed to achieve a complete cytogenetic response (CCyR) has been evaluated. In this analysis, 13 (38%) of 34 patients achieved a CCyR with the higher dose.12 Recently, a phase 3 trial compared imatinib 400 mg/day with 800 mg/day as initial treatment in CP CML.13 The primary objective was major molecular response (MMR) at 12 months with several secondary objectives, including time to MMR and time to CCyR. No significant difference was observed for the primary objective, but MMR and CCyR occurred sooner at the higher dose. At 6 months, 17.2% of patients on the lower dose and 33.5% of patients on the higher dose had achieved an MMR. Adverse effects, including rash, edema, and gastrointestinal problems, occurred more often at the higher dose, but overall, both doses were considered well tolerated. Continued follow-up is still needed to determine whether earlier response affects survival.

At 6 Years

>90% Adherence 90% Adherence

Figure. Importance of Imatinib Adherence to Molecular Response

Dasatinib Dasatinib is FDA-approved for adults with CML that is resistant or intolerant to prior therapy. The recommended dose is 100 mg/day for CP CML and 140 mg/day for patients in AP or BC CML.9

Dasatinib’s inhibition of unmutated BCR-ABL is 300 times more potent in vitro than imatinib’s and it has the ability to overcome mutations that lead to imatinib resistance, with the notable exception of the T315I mutation. A randomized, open-label study found that patients resistant or intolerant to imatinib achieved a complete hematologic response (CHR) of 92%, a major cytogenetic response (MCyR) of 63%, and a CCyR of 50%, with 93% of patients who achieved a MCyR maintaining response for 18 months.9 Dasatinib was originally evaluated with twice-daily dosing but has since been shown to have comparable efficacy and less toxicity when given once daily. In CP CML, 3-year follow-up data showed that patients treated with 100 mg once daily had fewer drug-related pleural effusions and cytopenias than those who received other dosing regimens (70 mg twice daily, 140 mg daily, or 50 mg twice daily).14 In AP CML, 15month median follow-up data evaluating dasatinib 140 mg once daily versus 70 mg twice daily have also become available. Efficacy results with the two regimens were similar, with a major hematologic response (MHR) of 66% versus 68%, MCyR of 39% versus 43%, and overall survival (OS) rates of 63% versus 72%, respectively. Patients who received once-daily dosing had significantly fewer pleural effusions at 20% versus 39% (P <.001).15 Preliminary results are currently available for an ongoing phase 2 trial evaluating dasatinib in the frontline setting of CML at 100 mg once daily or 50 mg twice daily.16 Of the 50 patients who had been evaluated for at least 3 months, 49 (98%) had achieved a CCyR, and 41 (82%) had achieved an MMR. No difference in efficacy was seen between the two arms, and 90% of patients achieved a CCyR within the first 6 months of treatment. As with the use of high-dose imatinib as frontline therapy, it is unclear whether the earlier response will translate into improved survival. The adverse effect profile has been similar to that in past trials con-

Source: Reference 20.

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Hematologic Malignancies taining high-dose imatinib. One side effect that had not been prominently reported in previous trials with dasatinib was peripheral neuropathy, which was seen in 31% of patients. Most events were grade 1 or 2 severity, but 5% were grade 3, requiring dose interruption and dose reduction. Toxicity with once- and twice-daily dosing was similar, with a trend toward more pleural effusions with twice-daily dosing. Nilotinib Nilotinib is FDA-approved for treatment of CP and AP Ph+ CML in adult patients resistant or intolerant to prior therapy that included imatinib.10 Nilotinib has been shown to prolong the QT interval, and five sudden deaths have been reported in patients receiving nilotinib, prompting a black-box warning. It is recommended that patients initiated on this drug obtain electrocardiograms at baseline, after week 1, and then periodically thereafter or with any dose adjustment.10 Nilotinib is a 25 times more potent inhibitor of BCR-ABL than imatinib, with the ability to overcome imatinib resistance related to multiple mutations, with the exception of T315I. Data are available after a minimum of 19 months of followup in patients with CP CML treated with nilotinib following imatinib failure.17 At a dose of 400 mg twice daily, nilotinib induced a CHR of 94%, with 59% of patients achieving an MCyR at a median of 2.8 months. At 24 months, 78% of patients maintained an MCyR, with an estimated OS rate of 88%. Nilotinib was well tolerated; pleural or pericardial effusions (grade 3/4) were uncommon (<1%), which distinguishes it from dasatinib. The grade 3/4 adverse events that were most often reported included asymptomatic laboratory abnormalities and hematologic toxicities. To date, this ongoing study has provided no further update with regard to QT prolongation. Follow-up data after a minimum of 11 months of treatment with nilotinib in AP CML are available.18 At a median time to first hematologic response (HR) of 1 month, 56% of patients had a confirmed HR, with 31% achieving a CHR. At 24 months, 54% of these patients had maintained their HR. An MCyR was achieved in 32% of patients and a CCyR in 20% of patients. This response was long lasting, with 70% of these patients maintaining their MCyR at 24 months and 83% maintaining their CCyR at 12 months. The estimated OS at 24 months was 67%, with a similar side-effect profile as reported for CP treatment. Data evaluating nilotinib in the frontline setting are now available from a phase 2 clinical trial that used the approved dose of 400 mg twice daily

Table. FDA-approved Oral TKIs for Adult Ph+ CML Drug

Dosing per FDA approval

Main adverse effects

Warnings/precautions

Drug interactions

Imatinib8

• CP: 400 mg once daily

In 30%: • edema • diarrhea • rash • nausea • vomiting • fatigue • muscle cramps

The following have occurred and should be monitored:

• CYP3A4 inducer/inhibitor

• AP/BC: 600 mg once daily • Take with meal and full glass of water

• musculoskeletal pain • abdominal pain

• Patients should not receive warfarin

• grade 3/4 hemorrhage

• Systemic exposure to acetaminophen is expected to increase

• severe congestive heart failure • severe hepatotoxicity • bullous dermatologic reactions • gastrointestinal perforations • fetal harm

Dasatinib9

• CP: 100 mg once daily • AP/BC: 140 mg once daily • Take with or without a meal

Nilotinib10

• CP: 400 mg twice daily • AP: 400 mg twice daily • BC: Not FDA-approved • Must be taken approximately 12 hours apart with water • No food for at least 2 hours before the dose and at least 1 hour after the dose

In 20%: • fluid retention events • diarrhea • skin rash • nausea • fatigue • headache • myelosuppression • dyspnea • hemorrhage

The following have occurred and should be monitored:

In >10%: • diarrhea • rash • nausea • vomiting • fatigue • headache • constipation • pruritus

Contraindicated in patients with: • hypokalemia • hypomagnesemia • long QT syndrome

• CYP3A4 inducer/inhibitor • Avoid other drugs that prolong the QT interval

• severe bleedingrelated events

• Antacids: if needed, administer the antacid at least 2 hours prior to or 2 hours after the dose

• QT prolongation • fetal harm

• H2 antagonist/proton pump inhibitor

• CYP3A4 inducer/inhibitor • Avoid other drugs that prolong the QT interval • Inhibitor of CYP2C8, CYP2C9, and CYP2D6

The following have occurred and should be monitored: • QT prolongation • elevated serum lipase • LFT abnormalities • hypophosphatemia • hypokalemia • hypocalcemia • hyponatremia • hyperkalemia • fetal harm

• May also induce CYP2B6, CYP2C8, and CYP2C9 • May alter serum concentration of other drugs • No drug interaction reported with warfarin11

AP indicates accelerated phase; BC, blast crisis; CML, chronic myeloid leukemia; CP, chronic phase; CY, cytochrome P450; FDA, US Food and Drug Administration; LFT, liver function test; Ph+, Philadelphia-positive; TKI, tyrosine kinase inhibitor.

administered on an empty stomach and provided information on 51 patients with a median follow-up of 3 months.19 Of those evaluated, 50 (98%) had achieved a CCyR, and 39 (76%) had achieved an MMR. Responses occurred more quickly than historically reported with standard-dose imatinib, with 90% of patients achieving CCyR by 3 months and 96% achieving CCyR by 6 months. Grade 3 or 4 toxicities did occur but were rare and were similar to those previously reported. There were two reported incidences each of hypertension and QT prolongation, but none were grade 3 or 4. Prospective clinical trials are ongoing to determine whether

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nilotinib will be superior to imatinib with regard to EFS and OS in newly diagnosed patients. Patient adherence Ensuring patient adherence is pivotal to optimizing expected outcomes with drug therapy in CML. Healthcare providers can provide education to enable patients to achieve the best outcome on these oral therapies. Patient adherence to imatinib was measured in 87 consecutive patients with CP CML over 3 months. All patients had received imatinib 400 mg/day as firstline therapy for a median of 59.7 months before enrollment.20 Several

prognostic factors and imatinib plasma levels were also evaluated. Although the median adherence rate was 97.6%, 23 (26.4%) patients had an adherence rate of 90%, and in 12 patients, 80%. Adherence was found to be the sole independent factor for complete molecular response (CMR) and one of two predictors for MMR. None of the patients with a 90% adherence rate achieved CMR at 6 years, and only 28.4% achieved MMR (Figure). Patients who had been prescribed an increased dose of imatinib had worse adherence rates, reported at a median of 86.4%. This study concluded that patient adherContinued on page 40

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Hematologic Malignancies Update on Chronic Myeloid Leukemia Continued from page 39 ence to therapy was the major determinant of response to imatinib. Second-line therapy after imatinib There are no prospective, comparative clinical trials to delineate a secondline therapy when standard-dose imatinib achieves a suboptimal response or when a patient is not able to tolerate the drug. A recent retrospective analysis evaluated the adverse events experienced by patients who either had their imatinib dose increased after suboptimal response or were switched to dasatinib after initial imatinib failure. Four hundred seventy-four patients had their dose of imatinib increased at some point to >400 mg/day, whereas 175 patients were switched to dasatinib. The study did not record the dosing schedule of dasatinib.21 Patients who switched treatments experienced a significantly higher risk of adverse effects, including fluid retention, pleural effusion, thrombocytopenia, neutropenia, dyspnea, constipation, nausea, vomiting, and congestive heart failure. A previously published phase 2 trial evaluated imatinib 400 mg twice daily

one patient was in AP, and two patients were in BC. The remaining patients were being treated for Ph+ acute lymphoblastic leukemia. The 1year OS rates following transplant were 69% for CP, 71% for AP, and 16% for BC CML. The OS remained similar at 3 years for CP and AP, but no patients were still alive who were in BC at transplantation. Novel agents Lack of a suitable donor and/or medical comorbidities preclude the wide application of allogeneic SCT in CML. Intensive research is centered on the development of novel compounds that are active in this disease. Three such compounds show promise. Bosutinib is an oral TKI with dual inhibition of SRCABL and has shown activity in patients with CP CML who failed prior imatinib or other TKI therapy.24 This drug is currently being compared with imatinib in a phase 3 trial for initial treatment in newly diagnosed CP CML.25 Omacetaxine is a first-in-class taxine and does not depend on tyrosine kinase inhibition for activity.26 The safety and

Omacetaxine is a first-in-class taxine and does not depend on tyrosine kinase inhibition for activity.

versus dasatinib 70 mg twice daily in patients who failed first-line imatinib. In this trial, more grade 3 and 4 pleural effusions and dyspnea occurred with dasatinib than with high-dose imatinib. The incidence of grade 3 and 4 diarrhea, fatigue, and headache was similar with high-dose imatinib and dasatinib.22 It is important to note that the recommended starting dose of dasatinib was changed to 100 mg once daily after it was shown that 100 mg once daily was equally efficacious as 70 mg twice daily with significantly fewer adverse events. Allogeneic SCT The presence of the T315I mutation precludes treatment with any of the commercially available TKIs indicated for CML and, consequently, these patients have a poor prognosis. Outside of a clinical trial, allogeneic SCT is the recommended option for patients harboring this mutation if a suitable donor is available.6 Prior treatment with TKIs has not been shown to adversely impact outcome for patients undergoing allogeneic SCT.6 In a retrospective review, the impact of the T315I mutation on transplant outcome was evaluated.23 Of the 33 patients meeting study criteria, 26 patients were in CP,

MAY 2010 I VOL 3, NO 3

efficacy of this compound was evaluated in a phase 2/3 clinical trial in patients who were considered imatinib-resistant and positive for the T315I mutation. The drug was administered with an induction and maintenance schedule. The induction schedule was 1.25 mg/m2 subcutaneously (SC) twice daily for 14 days every 28 days until HR. After an HR was achieved, the dose was adjusted to 1.2 mg/m2 SC twice daily for 7 days every 28 days. At the time of publication of the abstract, data were available for 66 patients, with 40 patients in CP, 16 patients in AP, and 10 patients in BC. The most promising results were in patients who initiated treatment in CP, with an overall CHR rate of 85% with a median duration of 7.7+ months. The MCyR was 15%, with a median duration of 6+ months. An MMR occurred in 15% of patients, with a reduction of baseline T315I mutated clone in 56.7% of CP patients. The median OS is not yet available for CP patients. The most commonly reported grade 3/4 toxicities were thrombocytopenia, anemia, and neutropenia. Grade 3/4 nonhematologic toxicities were uncommon. The final agent with data reported in this patient population is another oral TKI. This agent, AP24534, was evalu-

ated in a phase 1 clinical trial in patients refractory to other available options.27 At the time of the abstract release, 12 enrolled patients had the T315I mutation, and nine of these patients remained on study without progression. Patients in CP had the greatest HR, with a CHR in 83%. Patients in AP achieved an MHR, and one patient in BC had resolution of extramedullary symptoms. At abstract submission, two patients had achieved a CCyR after 2 and 5 months. The dose of 30 mg administered orally once daily produced no dose-limiting toxicities and achieved blood levels that allowed in vitro inhibition of the T315I mutation. This drug was considered generally well tolerated, with side effects including myelosuppression, QT prolongation, and dry eye. Conclusion Progress in treating CML continues at a rapid pace. Within a 10-year period, three new highly effective drugs became available, which have greatly improved and prolonged the lives of patients diagnosed with CML. The healthcare team’s ability to work together in assisting patients in acquiring the appropriate drug, educating patients on the management of side effects, and encouraging medication adherence provides the best chance for successful treatment and survival. ● References

1. American Cancer Society. Cancer Facts & Figures 2000. Atlanta, GA: American Cancer Society; 2000. 2. American Cancer Society. Cancer Facts & Figures 2009. Atlanta, GA: American Cancer Society; 2009. 3. Di Bacco A, Keeshan K, McKenna SL, Cotter TG. Molecular abnormalities in chronic myeloid leukemia: deregulation of cell growth and apoptosis. Oncologist. 2000;5:405-415. 4. Kavalerchik E, Goff D, Jamieson CH. Chronic myeloid leukemia stem cells. J Clin Oncol. 2008;17:2911-2915. 5. O’Brien SG, Guilhot F, Larson RA, et al; for the IRIS Investigators. Imatinib compared with interferon and low-dose cytarabine for newly diagnosed chronic-phase chronic myeloid leukemia. N Engl J Med. 2003;348:994-1004. 6. Baccarani M, Cortes J, Pane F, et al; for European LeukemiaNet. Chronic myeloid leukemia: an update of concepts and management recommendation of European Leukemia Net. J Clin Oncol. 2009;27:6041-6051. 7. Deininger M, O’Brien SG, Guilhot F, et al. International randomized study of interferon vs STI571 (IRIS) 8-year follow up: sustained survival and low risk for progression or events in patients with newly diagnosed chronic myeloid leukemia in chronic phase (CML-CP) treated with imatinib. Blood (ASH Annual Meeting Abstracts). 2009;114:Abstract 1126. 8. Gleevec (imatinib mesylate) [package insert]. East Hanover, NJ: Novartis Pharmaceuticals Corp; 2009. 9. Sprycel (dasatinib) [package insert]. Princeton, NJ: Bristol-Myers Squibb Co; 2009. 10. Tasigna (nilotinib) [package insert]. East Hanover, NJ: Novartis Pharmaceuticals Corp; 2009. 11. Yin O, Gallagher NJ, Fischer D, et al. Effect of nilotinib on the pharmacokinetics and pharmacodynamics of warfarin. J Clin Oncol. 2009;27 (15S):Abstract 7063. 12. Kantarjian HM, Talpaz M, O’Brien S, et al.

Dose escalation of imatinib mesylate can overcome resistance to standard-dose therapy in patients with chronic myelogenous leukemia. Blood. 2003;101:473-475. 13. Cortes JE, Baccarani J, Guilhot F, et al. Phase III, randomized, open-label study of daily imatinib mesylate 400 mg versus 800 mg in patients with newly diagnosed, previously untreated chronic myeloid leukemia in chronic phase using molecular end points: tyrosine kinase inhibitor optimization and selectivity study. J Clin Oncol. 2010;28:424-430. 14. Stone RM, Kim DW, Kantarjian HM, et al. Dasatinib dose-optimization study in chronic phase chronic myeloid leukemia (CML-CP): three-year follow-up with dasatinib 100 mg once daily and landmark analysis of cytogenetic response and progression-free survival (PFS). J Clin Oncol. 2009;27(15S):Abstract 7007. 15. Kantarjian H, Cortes J, Kim DW, et al. Phase 3 study of dasatinib 140 mg once daily versus 70 mg twice daily in patients with chronic myeloid leukemia in accelerated phase resistant or intolerant to imatinib: 15-month median follow-up. Blood. 2009;113:6322-6329. 16. Cortes JE, Jones D, O’Brien S, et al. Results of dasatinib therapy in patients with early chronic-phase chronic myeloid leukemia. J Clin Oncol. 2010;28:398-404. 17. Kantarjian H, Giles F, Bhalla K, et al. Nilotinib in chronic myeloid leukemia patients in chronic phase (CML-CP) with imatinib (IM) resistance or intolerance: longer follow-up results of a phase II study. J Clin Oncol. 2009;27(15S): Abstract 7029. 18. Le Coutre PD, Giles F, Hochhaus A, et al. Nilotinib in chronic myeloid leukemia patients in accelerated phase (CML-AP) with imatinib (IM) resistance or intolerance: longer follow-up results of a phase II study. J Clin Oncol. 2009; 27(15S):Abstract 7057. 19. Cortes JE, Jones D, O’Brien S, et al. Nilotinib as front-line treatment for patients with chronic myeloid leukemia in early chronic phase. J Clin Oncol. 2010;28:392-397. 20. Bazeos A, Khorashad J, Mahon FX et al. Longterm adherence to imatinib therapy is the critical factor for achieving molecular responses in chronic myeloid leukemia patients. Blood (ASH Annual Meeting Abstracts). 2009;114:Abstract 3290. 21. Wu E, Guo A, Williams D, et al. Adverse events associated with escalating imatinib versus switching to dasatinib in patients with chronic myelogenous leukemia. J Clin Oncol. 2009;27(15S):Abstract 7092. 22. Kantarjian H, Pasquini R, Hamerschlak N, et al. Dasatinib or high-dose imatinib for chronicphase chronic myeloid leukemia after failure of first-line imatinib: a randomised phase 2 trial. Blood. 2007;109:5143-5150. 23. Nicolini FE, Zhou W, Martinelli G, et al. Impact of allogeneic stem cell transplantation as salvage therapy after T315I mutation detection in chronic myeloid leukemia (CML) and Ph+ acute lymphoblastic leukemia (ALL) patients. Blood (ASH Annual Meeting Abstracts). 2009;114:Abstract 645. 24. Bruemmendorf TH, Cervantes F, Kim D, et al. Bosutinib is safe and active in patients (pts) with chronic phase (CP) chronic myeloid leukemia (CML) with resistance or intolerance to imatinib and other tyrosine kinase inhibitors. J Clin Oncol. 2008;26(15S):Abstract 7001. 25. Compare bosutinib to imatinib in subjects with newly diagnosed chronic phase Philadelphia chromosome positive CML. ClinicalTrials.gov identifier: NCT00574873. www.clinicaltrials. gov/ct2/show/NCT00574873?term=3160A43000&rank=1:. December 10, 2009. Accessed February 1, 2010. 26. Cortes-Franco J, Khoury HJ, Nicolini FE, et al. Safety and efficacy of subcutaneous-administered omacetaxine mepesuccinate in imatinibresistant chronic myeloid leukemia (CML) patients who harbor the Bcr-Abl T315I mutation—results of an ongoing multicenter phase 2/3 study. Blood (ASH Annual Meeting Abstracts). 2009;114:Abstract 644. 27. Cortes J, Talpaz M, Deininger M, et al. A phase 1 trial of oral AP24534 in patients with refractory chronic myeloid leukemia and other hematologic malignancies: first results of safety and clinical activity against T315I and resistant mutations. Blood (ASH Annual Meeting Abstracts). 2009;114:Abstract 643.

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Supportive Care

Management of Chemotherapyinduced Peripheral Neuropathy By Virginia Sun, RN, PhD(c) Senior Research Specialist, Division of Nursing Research & Education, Department of Population Sciences, City of Hope, Duarte, California

ne of the most debilitating toxicities related to chemotherapy is peripheral neuropathy. Neuropathy is defined as a condition arising from the damage and dysfunction of the peripheral nerves (motor, sensory, autonomic) that connect the brain and spinal cord to the rest of the body.1 Chemotherapy-induced peripheral neuropathy (CIPN) is defined as toxic neuropathy that results from the direct injury of the peripheral nervous system by chemotherapeutic agents.2 The incidence of CIPN is variable (30%-40%) and is largely dependent on several factors, including patient age, dose intensity, cumulative dose, duration of therapy, use of regimens containing multiple neurotoxic chemotherapy agents, and any

In general, motor symptoms are uncommon and may manifest as weakness of the lower limbs. On examination, reflexes may be diminished or absent, and some patients may present with abnormal proprioception, which can lead to falls and other safety concerns. Several diagnostic features can aid clinicians in the differential diagnosis of CIPN, including predominant sensory symptoms and onset after chemotherapy administration (Table 1). With platinum agents, a “coasting” effect may be present, which is characterized by progressive symptoms for weeks to months after treatment completion.6 A notable exception to symptom characterization for CIPN can be found with the platinum agent oxaliplatin.

A new tool, the Total Neuropathy Score, was recently reported to be more sensitive in detecting changes in CIPN compared with the NCI-CTCAE.

preexisting conditions that are associated with peripheral neuropathy, such as diabetes and alcohol abuse.3 When symptoms are severe or irreversible, CIPN can lead to serious clinical and quality-of-life (QOL) consequences for patients. This article presents an overview of the current strategies for assessment, prevention, and management of CIPN. Presentation and assessment Chemotherapeutic and biologic agents associated with symptomatic neuropathy include the platinum compounds, vinca alkaloids, taxanes, and others such as bortezomib, ixabepilone, and thalidomide. Agents associated with CIPN cause structural damage to peripheral nerves that result in abnormal sensory processing of the peripheral and/or central nervous systems.4,5 CIPN can affect both small fiber axons (temperature, pinpricks) and large sensory axons (vibrations, proprioception).3 CIPN typically manifests as sensory symptoms, such as paresthesia and dysesthesia (numbness and tingling). Patients often describe the neuropathic pain as burning, shock-like, or electric. Other sensations, such as allodynia (normal touch perceived as painful) and hyperpathia (normal painful sensations perceived as excruciating), may occur.

Peripheral neuropathy in colorectal cancer (CRC) is primarily related to oxaliplatin. The dose-limiting toxicity of this agent is a neurotoxicity that induces two distinct neuropathies: a transient acute syndrome and a cumulative chronic neurotoxicity. Acute oxaliplatin-induced peripheral nerve hyperexcitability, referred to as “acute channelopathy,” is characterized by an increased excitability of nerve and muscle cells triggered by exposure to cold.7 The acute neuropathy observed with oxaliplatin occurs in 85% to 95% of all patients.7 Symptoms include distal or perioral paresthesias or dysesthesias that peak within the first 24 to 48 hours after treatment.8 These symptoms can occur during or immediately after the first oxaliplatin infusion but are generally mild, short-lived, and completely reversible within hours or days. Between 1% and 2% of patients also report a pharyngolaryngeal dysesthesia, which they describe as the sensation of difficulties in breathing or swallowing.8 Symptoms related to oxaliplatinassociated chronic neurotoxicity are gradually prolonged and eventually persist between treatments and increase with cumulative doses of greater than 1000 mg/m2.9 The chronic neurotoxicity may lessen over time, with partial recoveries seen at 13 weeks after treatment.7,10

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The onset of symptoms of CIPN can be sudden or progressive. Symptom severity ranges from mild discomfort to severe disabilities that result in significant loss of function and diminishing QOL. In severe cases, CIPN can be extremely painful, and can result in dose reductions, treatment delays, and discontinuation of treatment. These represent significant limitations to the successful treatment of cancer and directly impact patient outcomes and overall survival. The assessment of CIPN continues to be a clinical challenge for healthcare professionals because of great variability in symptom characteristics and lack of empirical evidence on optimal evaluation methods. The first step in assessing CIPN is to take a comprehensive history that includes information such as neuropathic symptom characteristics, duration and onset of symptoms, comorbidities, and history of chemotherapeutic/medication administration. A physical examination that includes assessment of reflexes (ankle jerks) and sensory evaluation (vibrations, proprioception, pinpricks, temperature) should also be performed. The clinician should assess whether symptoms are severe enough to mandate intervention and which options for intervention are optimal based on symptom severity. The need for modification or discontinuation of present cancer treatments should also be determined.1 Several grading systems have been developed in recent years for CIPN assessment, including the National Cancer Institute-Common Terminology Criteria for Adverse Events (NCICTCAE), Ajani Sensory Neuropathy, World Health Organization Toxicity Criteria, and that of the Eastern Cooperative Oncology Group.1,11,12 Data comparing these scales in the assessment of CIPN show great variability in interobserver agreement, which highlights variations in grading and interpretation disparities.13 A new tool, the Total Neuropathy Score, was recently reported to be more sensitive in detecting changes in CIPN compared with the NCI-CTCAE.14,15 The ChemotherapyInduced Peripheral Neuropathy Outcome Measures Study (CI-PERINOMS) is a current international collaborative effort that is aiming to identify the best methods to assess and monitor CIPN.16 Objective, quantitative measures such as electromyography, nerve-conduction

Virginia Sun, RN, PhD(c)

studies, and sensory-threshold testing have also been used in the assessment of CIPN. To date, these measures have not been completely adopted into clinical settings because of concerns such as cost, need for subspecialty expertise, invasiveness, and potential low patient adherence.1,17 Research also shows that objective neurophysiologic findings correlate poorly with subjective, patient-reported outcomes, with a trend toward underassessment.18-21

Table 1. Diagnostic Features of CIPN • Symmetrical, distal, length-dependent glove-and-stocking distribution • Sensory symptoms (frequency and severity) predominant • Mild or no motor symptoms • Onset after administration of chemotherapy • Dose-dependent • Onset that is either progressive, rapid, or “coasting” CIPN indicates chemotherapy-induced peripheral neuropathy. Source: Reference 1.

Prevention Table 2 provides a list of agents that have been tested for prevention of CIPN. A calcium plus magnesium (Ca/Mg) infusion has been tested as a neuroprotectant for oxaliplatin-induced neuropathy in two randomized controlled trials, the North Central Cancer Treatment Group’s N04C7 and the Combined Oxaliplatin Neurotoxicity Prevention Trial (CONcePT). Unfortunately, both trials were terminated early after reports of diminished response to chemotherapy in the CONcePT study,22 although subsequent radiology review suggested no effect on tumor response.3,23 The N04C7 trial reported a reduction in CIPN incidence in the arm that received the Ca/Mg infusions.24 Results from a randomized trial testing the efficacy of xaliproden, a nonpeptide Continued on page 42

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Supportive Care Management of Chemotherapy-induced Peripheral Neuropathy Continued from page 41 neurotrophic agent, show a lower incidence of grade 3 neuropathy in patients treated with 5-fluorouracil/leucovorin/ oxaliplatin (FOLFOX4), but without reductions in overall neurotoxicity incidence.25 A double-blind, multicenter trial, NEUROXA, is currently randomizing patients on a FOLFOX4 regimen.1 Vitamin E has been tested as a neuroprotectant in patients receiving cisplatin-based chemotherapy. Three small, open-label studies randomized patients receiving cisplatin-based chemotherapy to vitamin E or control. The incidence of CIPN was significantly lower in the

Table 2. Agents Tested for Prevention of CIPN • Calcium and magnesium infusions • Xaliproden • Vitamin E • Glutamine/glutathione • Acetyl L-carnitine • Amifostine • Nimodipine • rHuLIF • Alpha-lipoic acid • Vitamins B12/B6 CIPN indicates chemotherapy-induced peripheral neuropathy. Source: Reference 1.

Table 3. Agents Used Off-label for Treatment of CIPN Antiepileptics • Gabapentin • Pregabalin • Lamotrigine Antidepressants Serotonin and norepinephrine reuptake inhibitors • Duloxetine • Venlafaxine Tricyclic antidepressants • Amitriptyline • Nortriptyline • Desipramine Opioids • Tramadol • Morphine (alone or with gabapentin) • Oxycodone (alone or with gabapentin) • Methadone Other agents/procedures • Local anesthetics (5% lidocaine patch) • 0.75% capsaicin • Intravenous lidocaine • Acupuncture CIPN indicates chemotherapy-induced peripheral neuropathy. Sources: References 1 and 3.

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active arms (21%-31%) than in the control group (69%-86%). Toxicity severity scores were also reduced in the active arms.26-28 An interim report from an ongoing double-blind, randomized, placebo-controlled trial of patients receiving cisplatin therapy showed a significantly reduced median toxicity score in the active arm. At the 2009 annual meeting of the American Society of Clinical Oncology, Kottschade and colleagues presented findings from a phase 3 double-blind, placebo-controlled study, N05C3, of vitamin E in the prevention of CIPN in patients receiving therapy with taxanes and/or platinum compounds.29 The primary end point was incidence of grade 2+ sensory neuropathy as measured by NCI-CTCAE. Although vitamin E was well-tolerated, it did not appear to reduce the incidence of sensory neuropathy. Other agents, such as amifostine, nimodipine, and rHuLIF, did not show clinical benefits in randomized trials.30-32 Newer agents, such as glutamine, acetyl L-carnitine, alpha-lipoic acid, and vitamins B12/B6, are currently being tested in large-scale, phase 3, randomized trials.33-35 Treatment Despite the growing number of clinical trials testing various therapeutic options, currently there is no standard, evidence-based treatment to specifically manage CIPN.36 Numerous pharmacologic agents have been tested to eliminate symptomatic neuropathy associated with chemotherapy. Table 3 lists pharmacologic agents being used as offlabel treatments for symptomatic CIPN. Gabapentin, an antiepileptic agent, is probably one of the most widely used drugs for neuropathic pain. In several randomized trials involving mixed disease populations, gabapentin was effective in relieving pain and improving QOL.37-39 In a double-blind, controlled, crossover trial, however, gabapentin was no better than placebo for treatment of CIPN.32 Pregabalin, another antiepileptic agent with similar mechanisms of action as gabapentin, is approved for diabetic neuropathy and postherpetic neuralgia.40-44 Lamotrigine was tested in a multicenter, double-blind, placebocontrolled, randomized trial for the treatment of pain and other neuropathic symptoms due to CIPN. However, there were no differences in average pain scores for the lamotrigine and placebo arms.45 Antidepressants have also been tested for the treatment of CIPN. Duloxetine, a serotonin and norepinephrine reuptake inhibitor (SNRI), has been shown to reduce pain associated with diabetic neuropathy.46 Another SNRI,

Patients’ awareness of CIPN was often inaccurate and its occurrence surprising, because most did not recall being educated about CIPN or advised to anticipate the symptoms. venlafaxine, was recently shown to reduce the incidence of acute oxaliplatin-induced neuropathic pain compared with placebo (35% vs 67%).47 SNRIs, however, have contraindications for patients taking tamoxifen as well as other drugs that affect serotonin reuptake.48,49 Tricyclic antidepressants (TCAs) such as amitriptyline, nortriptyline, and desipramine also are commonly used for the treatment of diabetic neuropathy. Negative results were reported in two small randomized, placebo-controlled trials that tested the efficacy of amitriptyline and nortriptyline for CIPN.30,31 TCAs have substantial side effects (anticholinergic, cardiac) as well as pharmacologic interactions with drugs metabolized by cytochrome P450, further limiting their potential use. As a rule, TCAs are not recommended for the first-line treatment of CIPN.1 Recently, a topical gel formulation of baclofen, amitriptyline, and ketamine (BAK-PLO) yielded moderate improvements in CIPN symptoms in a randomized trial in patients with CIPN.50 Opioids such as tramadol, morphine, and oxycodone (in combination with gabapentin) have shown efficacy in diabetic neuropathy.51-53 The lidocaine patch (5%) was shown to alleviate allodynia in patients with postherpetic neuralgia, but it did not have a significant impact for postsurgical pain in cancer patients.54,55 Complementary and alternative therapies such as acupuncture have also been tested for CIPN,56,57 and preliminary results are encouraging, with pain intensity decreased by 36% with acupuncture versus 2% with placebo.56 Quality of life Understanding the relationship between CIPN and QOL in cancer is important not only for patients but also for healthcare practitioners caring for individuals with cancer. To thoroughly understand how CIPN affects the QOL of patients, it is necessary to capture the overall experience of living with CIPN from the patient’s perspective. Few qualitative studies have been conducted in recent years that attempted to understand CIPN from the subjective perspective. Bakitas conducted an excellent qualitative study that described the CIPN symptom experience and the effect of symptoms on everyday life.58 Patients described CIPN as “back-

ground noise” that can be overshadowed by other treatment- and diseaserelated issues, but the unpleasantness of CIPN can interfere with daily activities and socialization.58 Patients’ awareness of CIPN was often inaccurate and its occurrence surprising, because most did not recall being educated about CIPN or advised to anticipate the symptoms. When monitoring CIPN, clinicians primarily focused on how the symptoms affected motor functionality (dexterity, gait) but rarely asked about the effect on daily living.58 CIPN caused disruptions in daily living, leisure, work, and family roles.58 Patients who reported a pain component to their CIPN often experienced functional difficulties, fatigue, sleep disturbance, and mood disturbances.58 Patients also described the use of multiple processes in learning to live with CIPN.58 Similar results have been described in another qualitative study conducted by Closs and colleagues59 as well as in our work at City of Hope, where we explored the impact of CIPN on QOL in a cohort (n = 53) of CRC patients.60 In our study, significant differences in QOL were found after initiation of treatment with an oxaliplatin-based regimen. Patterns for neuropathy and toxicity grading also suggested that patients may notice symptoms of neuropathy as early as 24 hours after treatment initiation, with temporary relief at 1 week, and then noticeable symptoms again at the 1- and 2-month assessments. By 2 months after treatment initiation, more grade 2 and 3 neurotoxicities were observed.60 Although subjects did not find the dysesthesias and coldrelated allodynia distressing, they found the acute sensations surprising when first experienced, and made adjustments in eating and drinking habits related to cold foods and beverages to cope with these neuropathic symptoms.60 Clinical and scientific implications Based on the current evidence available in the literature, it is clear that much work needs to be done to determine the most effective methods for assessment and treatment of CIPN. The prompt assessment of symptoms related to CIPN is essential for determining appropriate and effective management strategies. The assessment of CIPN should continue throughout treatment and beyond, because chronic CIPN can

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Supportive Care

occur months and years beyond treatment.4 It is important to understand that many agents may be needed for adequate treatment of CIPN and that the clinical context should be used to guide the choice of medications.1 The general approach should be to choose an agent based on clinical context, efficacy, and safety, and to titrate the agent to maximum tolerated dose.1 Patients need to be educated on what to expect with CIPN. It is evident from

Rehabilitation experts, such as physical and occupational therapists if available, should be included in the interdisciplinary care of cancer patients with CIPN. some of the current evidence that clinicians are not doing an optimal job of providing patients with timely information on CIPN. Beyond pharmacologic treatments, it may also be helpful to discuss nonpharmacologic supportive care strategies to cope with CIPN, such as personal safety measures to prevent burns or falls that may be related to sensory motor deficits.10 Functional deficits, such as decreased balance, gait abnormalities, and muscle weakness, can occur with CIPN.61,62 Rehabilitation experts, such as physical and occupational therapists if available, should be included in the interdisciplinary care of cancer patients with CIPN. When functional deficits are a concern, patient and family caregivers should be educated on potential environmental hazards and the need for home and environmental modifications. These include installing adequate light, removing hazardous items such as throw rugs, modifying tasks, providing adaptive equipment, ensuring protection against extreme temperatures (hot and cold), and wearing proper footwear.1 Finally, studies that characterize the time of onset, duration, and resolution or persistence of symptoms are needed to develop a more comprehensive and subjective understanding of CIPN.63 ● References

1. Stubblefield MD, Burstein HJ, Burton AW, et al. NCCN task force report: management of neuropathy in cancer. J Natl Compr Canc Netw. 2009;7(suppl 5):S1-S28. 2. Kaley TJ, DeAngelis LM. Therapy of chemotherapy-induced peripheral neuropathy. Br J Haematol. 2009;145:3-14. 3. Wolf S, Barton D, Kottschade L, et al. Chemotherapy-induced peripheral neuropathy: prevention and treatment strategies. Eur J Cancer. 2008;44:1507-1515. 4. Windebank AJ, Grisold W. Chemotherapy-

induced neuropathy. J Peripher Nerv Syst. 2008;13:27-46. 5. Park SB, Goldstein D, Lin CS, et al. Acute abnormalities of sensory nerve function associated with oxaliplatin-induced neurotoxicity. J Clin Oncol. 2009;27:1243-1249. 6. Siegal T, Haim N. Cisplatin-induced peripheral neuropathy. Frequent off-therapy deterioration, demyelinating syndromes, and muscle cramps. Cancer. 1990;66:1117-1123. 7. Grothey A. Oxaliplatin—safety profile: neurotoxicity. Semin Oncol. 2003;30(4 suppl 15):5-13. 8. Lehky TJ, Leonard GD, Wilson RH, et al. Oxaliplatin-induced neurotoxicity: acute hyperexcitability and chronic neuropathy. Muscle Nerve. 2004;29:387-392. 9. Wilson RH, Lehky T, Thomas RR, et al. Acute oxaliplatin-induced peripheral nerve hyperexcitability. J Clin Oncol. 2002;20:1767-1774. 10. Wickham R. Chemotherapy-induced peripheral neuropathy: a review and implications for oncology nursing practice. Clin J Oncol Nurs. 2007;11:361-376. 11. Ajani JA, Welch SR, Raber MN, et al. Comprehensive criteria for assessing therapyinduced toxicity. Cancer Invest. 1990;8:147-159. 12. Oken MM, Creech RH, Tormey DC, et al. Toxicity and response criteria of the Eastern Cooperative Oncology Group. Am J Clin Oncol. 1982;5:649-655. 13. Postma TJ, Heimans JJ, Muller MJ, et al. Pitfalls in grading severity of chemotherapyinduced peripheral neuropathy. Ann Oncol. 1998;9:739-744. 14. Cavaletti G, Frigeni B, Lanzani F, et al. The Total Neuropathy Score as an assessment tool for grading the course of chemotherapyinduced peripheral neurotoxicity: comparison with the National Cancer Institute-Common Toxicity Scale; for the Italian NETox Group. J Peripher Nerv Syst. 2007;12:210-215. 15. Cavaletti G, Jann S, Pace A, et al; for the Italian NETox Group. Multi-center assessment of the Total Neuropathy Score for chemotherapy-induced peripheral neurotoxicity. J Peripher Nerv Syst. 2006;11:135-141. 16. CI-PERINOMS Sudy Group. CI-PERINOMS: chemotherapy-induced peripheral neuropathy outcome measures study. J Peripher Nerv Syst. 2009;14:69-71. 17. Sioka C, Kyritsis AP. Central and peripheral nervous system toxicity of common chemotherapeutic agents. Cancer Chemother Pharmacol. 2009;63:761-767. 18. Berger T, Malayeri R, Doppelbauer A, et al. Neurological monitoring of neurotoxicity induced by paclitaxel/cisplatin chemotherapy. Eur J Cancer. 1997;33:1393-1399. 19. Chaudhry V, Rowinsky EK, Sartorius SE, et al. Peripheral neuropathy from taxol and cisplatin combination chemotherapy: clinical and electrophysiological studies. Ann Neurol. 1994; 35:304-311. 20. du Bois A, Neijt JP, Thigpen JT. First line chemotherapy with carboplatin plus paclitaxel in advanced ovarian cancer—a new standard of care? Ann Oncol. 1999;10(suppl):35-41. 21. Forsyth PA, Balmaceda C, Peterson K, et al. Prospective study of paclitaxel-induced peripheral neuropathy with quantitative sensory testing. J Neurooncol. 1997;35:47-53. 22. Hochster HS, Grothey A, Childs BH. Use of calcium and magnesium salts to reduce oxaliplatin-related neurotoxicity. J Clin Oncol. 2007;25:4028-4029. 23. Hochster HS, Grothey A, Shpilsky A, Childs B. Effect of intravenous calcium and magnesium versus placebo on response to FOLFOX4 + bevacizumab in the CONcePT trial. ASCO Gastrointestinal Cancer Symposium. 2008: Abstract 280. 24. Nikcevich DA, Grothey A, Sloan JA, et al. Effect of intravenous calcium and magneisum (IV CaMg) on oxaliplatin-induced sensory neurotoxicity (sNT) in adjuvant colon cancer: results from a phase III placebo-controlled, double-blind NCCTG trial N04C7. J Clin Oncol. 2008;26(18S):Abstract 4009. 25. Cassidy J, Bjarnason G, Hickish T, et al. Randomized double-blind (DB) placebo (Plcb)

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controlled phase III study assessing the efficacy of xaliproden (X) in reducing the cumulative peripheral sensory neuropathy (PSN) induced by the oxaliplatin (Ox) and 5-FU/LV combination (FOLFOX4) in first line treatment of patients (pts) with metastatic colorectal cancer (MCRC). J Clin Oncol. 2006;24(18S):Abstract 3507. 26. Bove L, Picardo M, Maresca V, et al. A pilot study on the relation between cisplatin neuropathy and vitamin E. J Exper Clin Cancer Res. 2001;20:277-280. 27. Pace A, Savarese A, Picardo M, et al. Neuroprotective effect of vitamin E supplementation in patients treated with cisplatin chemotherapy. J Clin Oncol. 2003;21:927-931. 28. Argyriou AA, Chroni E, Koutras A, et al. Vitamin E for prophylaxis against chemotherapy-induced neuropathy: a randomized controlled trial. Neurology. 2005:64:26-31. 29. Kottschade L, Sloan JA, Mazurczak M, et al. The use of vitamin E for protection of chemotherapy-induced peripheral neuropathy: a phase III double-blind, placebo controlled study-N05C3. J Clin Oncol. 2009;27(15S): Abstract 9532. 30. Hammack JE, Michalak JC, Loprinzi CL, et al. Phase III evaluation of nortriptyline for alleviation of symptoms of cis-platinum-induced peripheral neuropathy. Pain. 2002;98:195-203. 31. Kautio AL, Haanpaa M, Saarto T, Kalso E. Amitriptyline in the treatment of chemotherapy-induced neuropathic symptoms. J Pain Symptom Manage. 2008;35:31-39. 32. Rao RD, Michalak JC, Sloan JA, et al; for the North Central Cancer Treatment Group. Efficacy of gabapentin in the management of chemotherapy-induced peripheral neuropathy: a phase 3 randomized, double-blind, placebocontrolled, crossover trial (N00C3). Cancer. 2007;110:2110-2118. 33. Cascinu S, Catalano V, Cordella L, et al. Neuroprotective effect of reduced glutathione on oxaliplatin-based chemotherapy in advanced colorectal cancer: a randomized, double-blind, placebo-controlled trial. J Clin Oncol. 2002;20:3478-3483. 34. Lin PC, Lee MY, Wang WS, et al. N-acetylcysteine has neuroprotective effects against oxaliplatin-based adjuvant chemotherapy in colon cancer patients: preliminary data. Support Care Cancer. 2006;14:484-487. 35. Wang WS, Lin JK, Lin TC, et al. Oral glutamine is effective for preventing oxaliplatininduced neuropathy in colorectal cancer patients. Oncologist. 2007;12:312-319. 36. Visovsky C, Collins M, Abbott L, et al. Putting evidence into practice: evidence-based interventions for chemotherapy-induced peripheral neuropathy. Clin J Oncol Nurs. 2007;11:901-913. 37. Backonja M, Beydoun A, Edwards KR, et al. Gabapentin for the symptomatic treatment of painful neuropathy in patients with diabetes mellitus: a randomized controlled trial. JAMA. 1998;280:1831-1836. 38. Baillie JK, Power I. Morphine, gabapentin, or their combination for neuropathic pain [author reply]. N Engl J Med. 2005;352:2650-2651. 39. Ho TW, Backonja M, Ma J, et al. Efficient assessment of neuropathic pain drugs in patients with small fiber sensory neuropathies. Pain. 2009;141:19-24. 40. Freynhagen R, Strojek K, Griesing T, et al. Efficacy of pregabalin in neuropathic pain evaluated in a 12-week, randomised, double-blind, multicentre, placebo-controlled trial of flexible- and fixed-dose regimens. Pain. 2005; 115:254-263. 41. Lesser H, Sharma U, LaMoreaux L, Poole RM. Pregabalin relieves symptoms of painful diabetic neuropathy: a randomized controlled trial. Neurology. 2004;63:2104-2110. 42. Richter RW, Portenoy R, Sharma U, et al. Relief of painful diabetic peripheral neuropathy with pregabalin: a randomized, placebo-controlled trial. J Pain. 2005;6:253-260. 43. Rosenstock J, Tuchman M, LaMoreaux L, Sharma U. Pregabalin for the treatment of painful diabetic peripheral neuropathy: a double-blind, placebo-controlled trial. Pain. 2004;

110:628-638. 44. Tolle T, Freynhagen R, Versavel M, et al. Pregabalin for relief of neuropathic pain associated with diabetic neuropathy: a randomized, double-blind study. Eur J Pain. 2008;12:203-213. 45. Rao RD, Flynn PJ, Sloan JA, et al. Efficacy of lamotrigine in the management of chemotherapy-induced peripheral neuropathy: a phase 3 randomized, double-blind, placebo-controlled trial, N01C3. Cancer. 2008;112:2802-2808. 46. Quilici S, Chancellor J, Lothgren M, et al. Meta-analysis of duloxetine vs. pregabalin and gabapentin in the treatment of diabetic peripheral neuropathic pain. BMC Neurol. 2009;9:6. 47. Durand JP, Deplanque G, Gorent J. Efficacy of venlafaxine for the prevention and relief of acute neurotoxicity of oxaliplatin: results of EFFOX, a randomized, double-blinded, placebo-controlled prospective study. J Clin Oncol. 2009;27(15S):Abstract 9533. 48. Raskin J, Pritchett YL, Wang F, et al. A doubleblind, randomized multicenter trial comparing duloxetine with placebo in the management of diabetic peripheral neuropathic pain. Pain Med. 2005;6:346-356. 49. Wernicke JF, Pritchett YL, D’Souza DN, et al. A randomized controlled trial of duloxetine in diabetic peripheral neuropathic pain. Neurology. 2006;67:1411-1420. 50. Barton D, Wos E, Qin R, et al. A randomized controlled trial evaluating a topical treatment for chemotherapy-induced neuropathy: NCCTG trial N06CA. J Clin Oncol. 2009;27(15S): Abstract 9531. 51. Gimbel JS, Richards P, Portenoy RK. Controlled-release oxycodone for pain in diabetic neuropathy: a randomized controlled trial. Neurology. 2003;60:927-934. 52. Hanna M, O’Brien C, Wilson MC. Prolongedrelease oxycodone enhances the effects of existing gabapentin therapy in painful diabetic neuropathy patients. Eur J Pain. 2008;12:804-813. 53. Watson CP, Moulin D, Watt-Watson J, et al. Controlled-release oxycodone relieves neuropathic pain: a randomized controlled trial in painful diabetic neuropathy. Pain. 2003;105: 71-78. 54. Cheville AL, Sloan JA, Northfelt DW, et al. Use of a lidocaine patch in the management of postsurgical neuropathic pain in patients with cancer: a phase III double-blind crossover study (N01CB). Support Care Cancer. 2009;17:451-460. 55. Meier T, Wasner G, Faust M, et al. Efficacy of lidocaine patch 5% in the treatment of focal peripheral neuropathic pain syndromes: a randomized, double-blind, placebo-controlled study. Pain. 2003;106:151-158. 56. Alimi D, Rubino C, Pichard-Leandri E, et al. Analgesic effect of auricular acupuncture for cancer pain: a randomized, blinded, controlled trial. J Clin Oncol. 2003;21:4120-4126. 57. Wong R, Sagar S. Acupuncture treatment for chemotherapy-induced peripheral neuropathy—a case series. Acupunct Med. 2006;24:87-91. 58. Bakitas MA. Background noise: the experience of chemotherapy-induced peripheral neuropathy. Nurs Res. 2007;56:323-331. 59. Closs SJ, Staples V, Reid I, et al. Managing the symptoms of neuropathic pain: an exploration of patients’ experiences. J Pain Symptom Manage. 2007;34:422-433. 60. Sun V, Otis-Green S, Shibata S, et al. Symptom concerns and QOL in oxaliplatin-induced peripheral neuropathy. ASCO Gastrointestinal Cancers Symposium. 2008:Abstract 503. 61. Visovsky C, Daly BJ. Clinical evaluation and patterns of chemotherapy-induced peripheral neuropathy. J Am Acad Nurse Pract. 2004; 16:353-359. 62. Wampler MA, Hamolsky D, Hamel K, et al. Case report: painful peripheral neuropathy following treatment with docetaxel for breast cancer. Clin J Oncol Nurs. 2005;9:189-193. 63. Hausheer FH, Schilsky RL, Bain S, et al. Diagnosis, management, and evaluation of chemotherapy-induced peripheral neuropathy. Semin Oncol. 2006;33:15-49.

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Supportive Care

Chemotherapy-induced Nausea and Vomiting: Clinical Updates By Sandra E. Kurtin, RN, MS, AOCN, ANP-C Clinical Assistant Professor of Medicine and Nursing, University of Arizona Nurse Practitioner, Arizona Cancer Center, Tucson

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

CHEMOTHERAPY

hemotherapy-induced nausea and vomiting (CINV) remains common despite the availability of new antiemetic agents and the development of clinical guidelines by the American Society of Clinical Oncology, the National Comprehensive Cancer Network, and the Multinational Association of Supportive Care in Oncology.1-3 It is estimated that 70% to 80%

Acute First 24 hours

of patients who receive chemotherapy experience CINV; approximately 10% to 44% experience anticipatory nausea and vomiting. Nausea is reported more frequently than vomiting by patients receiving chemotherapy and appears to be more bothersome.1-4 If the evidenced-based guidelines for the prevention and treatment of CINV were followed, it is estimated that the majority of these episodes could be effectively prevented or controlled. Several suggested potential reasons for the failure to control CINV adequately include lack of familiarity with the physiology of CINV and mechanism of action of antiemetics; reimbursement policies and expense of new agents; availability of agents based on formula-

• Mediated primarily by serotonin • Related to emetogenic potential of the regimen • Intensity peaks at 5–6 hours • Pharmacologic management is primary strategy

Delayed 24 hours to 7 days

• Substance P plays the primary role • Effective management of acute CINV will reduce the severity • More common with long half-life • Cisplatin is the most common drug with peak intensity at 48–72 hours

Anticipatory – Occurs before drug administration • Experiential—More difficult to control, ongoing • Nausea is more common than vomiting • Effective treatment of acute and delayed CINV is key Ref Refractory and breakthrough gh • Ongoing—May be a result of underlying processes

Figure. Patterns of Chemotherapy-induced Nausea and Vomiting

ries; underestimation of the magnitude of CINV; and the failure of patients and providers to communicate the symptoms adequately using common terminology.5 CINV can significantly affect a patient’s quality of life as well as the ability or desire to continue treatment, and is associated with several potentially serious clinical consequences, including nutritional deficits, electrolyte abnormalities, and emotional distress.6 Familiarity with the risk factors, physiology, and evidenced-based prophylaxis of CINV will promote effective management. Pathways and patterns Nausea and vomiting is a complex process regulated by key pathways mediated by neurotransmitters. The primary pathways involved in CINV include the central pattern generator, located in the medulla and activated by neurologic input from sensory centers; the cerebral cortex and limbic system that respond to sights, smells, situations, and emotions; and the vagal and sympathetic/ visceral pathways located in the upper small intestine and mediated by neurotransmitters that affect the dorsal vagal complex, resulting in activation of the central pattern generator and the emetic reflex.1 The most common neurotransmitters known to play roles in CINV include 5-hydroxytryptamine type 3 (5-HT3), neurokinin 1 (NK1), dopamine, and substance P.1 Commonly used antiemetic agents inhibit one or more of these neurotransmitters, reducing the stimulation of the emetic reflex, and are assigned either a high or low therapeutic index (Table 1).1,3,6 CINV can be further categorized

Table 1. Commonly Prescribed Antiemetics 5-HT3 receptor antagonists, high TI

NK1 receptor antagonists, high TI

Dopamine receptor antagonists, low TI

• Dolasetron, oral or IV

• Aprepitant, oral

• Substitute benzamides: ◆ metoclopramide, oral or IV

• Corticosteroids, high TI, oral or IV

• Granisetron, oral, IV, transdermal

• Fosaprepitant, IV

• Phenothiazines: ◆ prochlorperazine, oral or IV ◆ promethazine, oral or IV

• Cannabinoids, low TI: ◆ dronabinol oral

• Butophenones: ◆ haloperidol, oral or intramuscular

• Benzodiazepines, high TI: ◆ lorazepam, oral or IV

• Ondansetron, oral or IV • Palonosetron, IV

5-HT3 indicates 5-hydroxytryptamine type 3; IV, intravenous; NK1, neurokinin 1; TI, therapeutic index. Sources: References 1, 3, and 6.

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Other

based on the time of onset. There are four recognized patterns of CINV, each with distinct characteristics, proposed mediators, and strategies for prevention (Figure). These include acute CINV, delayed CINV, anticipatory CINV, and refractory/breakthrough CINV. Similarly, chemotherapeutic agents are associated with high, moderate, or low potential for nausea and vomiting (Table 2).2,4 Effective management of CINV requires consideration of the emetogenic potential of each agent, the duration of effect (halflife), and number of days for each regimen. Moderately emetogenic chemotherapy (MEC) to highly emetogenic chemotherapy (HEC) generally requires a combination of antiemetic agents with a high therapeutic index and varied mechanism of action (Table 3).7 The risk of CINV lasts up to 2 days after the last dose of treatment with MEC and up to 3 days after the last dose of treatment with HEC.7 Drugs with a longer half-life or regimens given over several days will require dosing of antiemetic agents over multiple days or use of long-acting antiemetic agents. Familiarity with the pathways and patterns of CINV, knowledge of the emetogenic potential of individual agents or regimens, and a risk analysis of the individual patient will provide the best opportunity for effective management. Treatment of underlying conditions such as constipation, gastroparesis, gastrointestinal reflux disease, esophagitis, or mucositis should be approached aggressively as these factors will contribute to nausea and vomiting. Patients with a history of nausea related to other medications, younger patients, patients with low alcohol use, women with a history of morning sickness, and patients who are prone to motion sickness are more likely to experience CINV.6 Nausea and vomiting that does not respond to aggressive interventions should be evaluated for other causes, such as bowel obstruction, leptomeningeal disease, or other medications. Patient education about diet, effective use of antiemetic agents, adequate hydration, avoidance of aggravating factors, a regular bowel regimen, and reportable signs and symptoms may reduce the incidence of severe nausea and vomiting. Continued on page 48

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TON_May2010_v3_TON 5/3/10 6:33 PM Page 48

Supportive Care Chemotherapy-induced Nausea and Vomiting: Clinical Updates Continued from page 46 Table 2. Highly or Moderately Emetogenic Chemotherapy Agents Highly emetogenic chemotherapy

Moderately emetogenic chemotherapy

Carmustine >250 mg/m , oral

Carboplatin

Cisplatin >50 mg/m

Azacitidine

Cyclophosphamide 1500 mg/m

Epirubicin

Dacarbazine

Etoposide, oral

Dactinomycin

Cytarabine >1 g/m2

Lomustine, oral

Cyclophosphamide <1500 mg/m2

Mechlorethamine

Cyclophosphamide, oral

Pentostatin

Daunorubicin

Procarbazine, oral

Decitabine

Streptozotocin

Doxorubicin

AC combination: doxorubicin or daunorubicin with cyclophosphamide

Idarubicin

Ifosfamide

for HEC, it is not likely to provide adequate coverage of delayed CINV; however, if given daily for 3 to 4 days, these agents would likely provide equal benefit. Granisetron is now available in a transdermal patch, delivering 3.1 mg/ day of medication. The patch must be applied between 24 and 48 hours before exposure to the MEC or HEC to be effective and must remain in place at least 24 hours after exposure to the treatment. It can be left in place for up to 7 days.8 Although the 5-HT3 RAs are considered the gold standard for the treatment of MEC or HEC and are thought to be similar in efficacy, they differ in their potential for interaction with cytochrome (CYP) P450 enzymes. Granisetron does not appear to require the

tant, the only US Food and Drug Administration–approved NK1 inhibitor, in combination with ondansetron and dexamethasone compared with standard 5-HT3 and dexamethasone. Patients (n = 1105) were evaluated for acute and delayed CINV. The combination of aprepitant, ondansetron, and dexamethasone eliminated emesis and the need for any breakthrough medication in 73% of the patients compared with 52% receiving a 5-HT3 RA and dexamethasone alone.11 Aprepitant is both an inhibitor (CYP3A4) and an inducer (CYP29A) of CYP450 pathways.9 Inhibition of CYP3A4 results in a doubling of plasma glucocorticoid levels, and induction of the CYP2A results in a 33% reduction of warfarin concentrations with as much as a 10% drop in

Imatinib Irinotecan

Nausea and vomiting that does not respond to aggressive interventions should be evaluated for other causes, such as bowel obstruction, leptomeningeal disease, or other medications.

Oxaliplatin >75 mg/m2 Temozolomide, oral Vinorelbine Sources: References 2, 4, and 5.

Serotonin receptor antagonists Integration of the 5-HT3 receptor agonists (RAs) into the treatment of CINV has improved the management of CINV. The Cochrane Pain, Palliative and Supportive Care Group7 reviewed 16 randomized trials (n = 7808) evaluating 5-HT3 RA in adult populations. The majority (nine) of the trials compared granisetron with ondansetron. In these studies, granisetron and ondansetron showed similar benefits in controlling acute and chronic CINV and had similar toxicity profiles, the most common adverse events being headache and diarrhea, with the possible exception of less constipation with ondansetron. Changes in electrocardiogram readings, including prolongation of the PR, QRS, QT, and QTc intervals, have been reported. Cases of atrial fibrillation, myocardial ischemia, and ventricular tachycardia have been reported with ondansetron used in the postoperative setting.7 A small number of trials evaluated the newer agents; however, none of these trials included tropisetron, dolasetron, ramosetron, or palonosetron, thus limiting any comparison with other agents. A single study (n = 1114) comparing palonosetron plus dexamethasone with granisetron plus dexamethasone suggested improved control of delayed nausea and vomiting with palonosetron plus dexamethasone; however, a subsequent study comparing ondansetron plus dexamethasone to palonosetron plus dexamethasone showed no difference.7 Palonosetron plus dexametha-

MAY 2010 I VOL 3, NO 3

sone has shown benefit in preventing acute and delayed CINV, thus providing an option for patients who may benefit from a single dose or intravenous (IV) administration. But additional comparative trials will be necessary before it can be stated that palonsetron is superior to the other 5-HT3 RAs. It is important to consider the equivalent dosing of the 5-HT3 RA to provide effective coverage. A single dose of a short-acting 5-HT3 RA is not equivalent to a single dose of a longacting 5-HT3 RA because of the difference in half-life. For example, a single dose of granisetron 2 mg given orally or 1 g intravenously has a half-life of 9 hours. In comparison, a single 0.25-mg dose of palonosetron given intravenously has a half-life of 40 hours. If the granisetron is given as a single dose

CYP pathways for metabolism and does not interfere with any of the CYP enzymes involved in metabolism. Ondansetron, tropisetron, dolasetron, and palonosetron involve the CYP2D6 pathway, increasing the potential for drug–drug interactions.9 NK1 inhibition The most recent development in understanding CINV has been identification of the tachykinin pathway mediated by substance P, a neurotransmitter that acts on both peripheral and central NK1 receptor sites. NK1 receptor sites are most abundant in the nucleus tractis solitaires of the mid-brain and the vagal afferent pathways located in the enterchromafin cells of the gut.10 Two multicenter, parallel, double-blind studies using a HEC regimen (cisplatin >50 mg/m2) evaluated the efficacy of aprepi-

international normalized ratio levels 7 to 10 days after exposure to aprepitant.11 Reduction of the dexamethasone dose by 50% is recommended when given in combination with aprepitant. Unique needs of the elderly Cancer is predominantly a disease of older people, with 75% of cases in persons older than 65 years of age. One of two men and one of three women will develop cancer during their lifetime.12 Approximately 12 million people will be diagnosed with cancer worldwide each year, and it is estimated this number will increase to 25 million in the year 2030, primarily because of an aging population.13 Therefore, the number of older patients receiving cancer treatment including chemotherapy is likely to increase. Continued on page 54

Table 3. Risk-based Antiemetic Regimens High risk

Moderate risk

Low risk

Minimal risk

• 5-HT3 receptor antagonist on day 1

• 5-HT3 receptor antagonist on days 1 to 3

• Dexamethasone 12 mg oral/IV daily

• No routine prophylaxis, prescribe as needed

• Dexamethasone 12 mg on days 1 to 4

• Dexamethasone 12 mg on days 1 to 3

• Prochlorperazine or metoclopramide oral or IV every 4 to 6 hours, as needed

• Aprepitant 125 mg oral on day 1 and 80 mg oral on days 2 to 3

• H2 blocker or PPI

• Lorazepam oral, IV, or sublingual on days 1 to 4 and every 4 to 6 hours, as needed

• Lorazepam oral, IV, or sublingual every 4 to 6 hours, as needed

• Lorazepam oral or IV every 4 to 6 hours, as needed

• H2 blocker or PPI

5-HT3 indicates 5-hydroxytryptamine type 3; H2, histamine-2; PPI, proton pump inhibitor. Source: Reference 7.

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TON_May2010_v3_TON 5/3/10 6:33 PM Page 49

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Hematologic Malignancies

Multiple Myeloma: A Review By Stephanie S. Taber, PharmD, BCOP Clinical Assistant Professor, University of Michigan College of Pharmacy and Health System, Ann Arbor

Stephanie S. Taber, PharmD, BCOP

ultiple myeloma (MM), although currently incurable, has seen significantly improved response and overall survival (OS) rates with the inclusion of targeted therapy in its treatment schema. MM therapy has evolved greatly over the past several years and, with innovative research and medications, this disease may soon be curable. This article will focus on the novel agents revolutionizing therapy of MM. Background Primarily a disease of the elderly, MM is the second most common hematologic malignancy in the United States, second only to non-Hodgkin’s lymphoma.1 The median average age at diagnosis is 62 years for men and 61 years for women, with fewer than 2% of cases occurring in patients younger than 40 years.1 The number of MM cases in 2009 was an estimated 20,580, and the disease is more prevalent in men and blacks.2 Patients receiving standard therapy have a median survival of 3 to 4 years after diagnosis, whereas those who receive an autologous stem cell transplant may survive 5

to 7 years; survival ranges from weeks to >10 years.1 MM is a clonal B-cell disease; malignant plasma cells accumulate in the bone marrow and ultimately cause cytopenias, bone resorption, and monoclonal protein production.3 The clinical picture of MM can range from asymptomatic monoclonal gammopathy of unknown significance (MGUS) to smoldering MM (SMM) and ultimately to symptomatic disease. Patients with MGUS have a 1% per year chance of advancing to MM, and those with SMM have an even higher risk of progression (10% per year for the first 5 years).4 Improved therapy has begged the question of whether to treat MM in these earlier clinical states, but currently therapy is reserved for patients who have symptomatic disease. Typically, treatment is initiated when evidence of at least one of the following criteria are met: hypercalcemia, anemia, renal insufficiency, or bone lesions (CRAB criteria).5 Diagnosis, staging, and prognosis The MM diagnosis is confirmed by obtaining quantitative serum immunoglobulins, serum and urine protein electrophoresis, and immunofixation or serum immunoglobulin free light chain assay, skeletal survey, and bone marrow biopsy.2 The presence of monoclonal gammopathy on electrophoresis and plasmacytosis (10% plasma cells in the bone marrow) indicates MM. In addition, measuring beta-2-microglobulin levels is standardly performed to assess tumor burden. Of note, fewer than 3% of patients may present with nonsecre-

tory myeloma, and thus may have little to no monoclonal protein in the serum or urine.2 Historically, the Durie-Salmon staging system has been used to categorize MM patients into stage I, II, or III, depending on the level of anemia, hypercalcemia, presence of bone lesions, and levels of monoclonal pro-

Conventional cytogenetic studies may reveal chromosomal abnormalities in only one third of patients with MM, whereas FISH may show abnormalities in more than 90%. tein in the serum and urine.2 More recently, the International Staging System (ISS) has been widely employed. The ISS classifies MM using serum values of beta-2-microglobulin and albumin, tests that are easily reproducible and highly prognostic.2 The ISS cannot distinguish MGUS and SMM from active myeloma, however, and cannot be used for therapeutic risk stratification given that beta-2-microglobulin levels may be increased because of either myeloma tumor burden or renal failure.6 The ability of the ISS to determine prognosis will continue to evolve as the effect of the targeted therapies becomes more apparent. The role of cytogenetics in MM prognosis is becoming ever more important. It is recommended that both conventional cytogenetic testing as well as fluorescence in situ hybridization (FISH) be

Table 1. Dose Modifications for Peripheral Neuropathy Drug

Grade of toxicity

Dose modification

Pharmaceutical intervention?

Bortezomib

Grade 1 (mild)

Continue therapy

n/a

Grade 1 with pain or grade 2

Dose reduction to 1 mg/m2

Yes

Grade 3

Hold until resolution to baseline Restart 0.7 mg/m2 Consider once-weekly schedule

Yes

Grade 4

Discontinuation of therapy

n/a

Grade 1 (mild)

Continue therapy

n/a

Grade 2

Intermittent symptoms: continue therapy Continuous symptoms: hold and reduce dose upon resolution

Yes

Grade 3

Hold therapy until patient at baseline, restart at reduced dose

Yes

Grade 4

Discontinuation of therapy

n/a

Thalidomide

Source: Reference 9.

MAY 2010 I VOL 3, NO 3

used to capture the characteristics that place patients in standard- or high-risk categories.6 Conventional cytogenetic studies may reveal chromosomal abnormalities in only one third of patients with MM, whereas FISH may show abnormalities in more than 90%.6 Poor prognosis has been associated with t(4;14), t(14;16), t(14;20), del(17) (p13),

or del(13). In contrast, the presence of t(11;14), t(6;14), or hyperdiploidy has conferred a more favorable prognosis. Again, the novel agents used in MM treatment today may change the prognostic ability of these abnormalities. For example, bortezomib has been shown to overcome the poor prognosis garnered by del(13), t(4;14), and del(17)(p13).5 Future study will elucidate how cytogenetics or FISH will affect risk stratification. Novel agents Thalidomide, lenalidomide, and bortezomib have significantly changed the landscape of MM therapy. These agents now play a huge role in the treatment of newly diagnosed (both in transplant-eligible and -ineligible patients) and relapsed/refractory disease, and are also being evaluated in the maintenance setting. Thalidomide. The proposed mechanisms of action for thalidomide include antiangiogenesis effects, inhibition of tumor necrosis factor-alpha, and increased cell-mediated cytotoxicity.7 However, its mechanism of action in MM therapy is not fully explained. Thalidomide’s teratogenicity is well known, and thus it is obtained solely through the System for Thalidomide Education and Prescribing Safety (S.T.E.P.S.) programs. Thalidomide dosing varies, but typically ranges from 200 mg to 400 mg oral daily.7 Lower doses may be used when thalidomide is taken in combination with other chemotherapy or in elderly patients unable to tolerate the side effects. Bedtime is the preferable administration time due to the drug’s potential to cause drowsiness; it should be taken with water at least 1 hour after a meal.8

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TON_May2010_v3_TON 5/3/10 6:33 PM Page 51

Hematologic Malignancies Thalidomide’s side effects may be dose dependent, and common adverse reactions include somnolence, fatigue, constipation, and rash. In addition, neutropenia, edema, and hypothyroidism are possible. Peripheral neuropathy is also associated with thalidomide, and dose adjustment or discontinuation of the drug may be necessary8 (Table 1). Venous thromboembolism (VTE) is a significant complication of thalidomide treatment, particularly when the drug is used in combination with dexamethasone or other cytotoxic agents. Although a full discussion of VTE in MM is beyond the scope of this article, VTE prophylaxis is an important step in the management of the patient with MM. Lenalidomide. A more potent analog of thalidomide, lenalidomide was designed to increase efficacy and decrease nonhematologic toxicities compared with thalidomide. Like thalidomide, lenalidomide exerts its activity by inhibiting angiogenesis. It also inhibits adhesion of myeloma cells to bone marrow stromal cells and causes apoptosis of myeloma cells.7 The approved lenalidomide dose is 25 mg orally daily on days 1 to 21 with dexamethasone 40 mg orally on days 1 to 4, 9 to 12, and 17 to 20 of each 28day cycle for the first four cycles. From the fifth cycle and forward, the lenalidomide dose remains the same, but the dexamethasone dose decreases to 40 mg daily on days 1 to 4 only. This agent is cleared renally, which may necessitate dosage adjustments in patients with renal dysfunction.10 All patients, prescribers, and pharmacists must register with the RevAssist program to obtain this medication. Unfortunately, VTE is still a major side effect with this agent, and patients should receive VTE prophylaxis if possible. Lenalidomide does not cause the same degree of somnolence, constipation, or peripheral neuropathy as thalidomide. Myelosuppression (neutropenia and thrombocytopenia) is seen with this drug and may lead to dose modification10 (Table 2). Bortezomib. Bortezomib is a first-inclass proteasome inhibitor that targets the 26S proteasome, ultimately leading to cell death. Bortezomib not only targets the myeloma cell, but also inhibits the binding of the myeloma cell to bone marrow stromal cells.7 Bortezomib is administered as a 3- to 5-second bolus intravenous injection, at a dose ranging from 0.7 mg/m2 to 1.3 mg/m2 on days 1, 4, 8, and 11 of each 21day cycle. No dosage adjustments are necessary for mild renal impairment (<1.5  upper limit of normal). Patients on dialysis, however, should receive bortezomib after dialysis because dialysis may reduce bortezomib concentrations.

Table 2. Dose Modifications for Myelosuppression Drug

Condition

Recommendation

Bortezomib

Neutropenia (grade 4)

Hold dose: once resolved, reduce dose by 25%

Thrombocytopenia (grade 4)

Hold dose: once resolved, reduce dose by 25%

Thrombocytopenia (if falling <25 x 109/L)

Hold dose: once resolved, reduce dose by 25%

Neutropenia (first grade 3 episode)

Hold dose: once resolved and neutropenia only toxicity, restart at 25 mg (or previous dose) Hold dose: once resolved and any other toxicity, restart at 15 mg or reduce dose from previous (do not dose <5 mg) Hold dose: consider adding G-CSF to next cycle

Neutropenia (subsequent grade 3 episode)

Hold dose: once resolved, restart at 5 mg less than previous dose (do not dose <5 mg)

Thrombocytopenia (first episode <30 x 109/L)

Hold dose: once resolved, restart at 15 mg or reduce dose 5 mg from previous (do not dose <5 mg)

Thrombocytopenia (each subsequent episode <30 x 109/L)

Hold dose: once resolved, reduce dose 5 mg from previous (do not dose <5 mg)

Neutropenia (<0.75 x 109/L)

Consider withholding therapy if clinically appropriate

Lenalidomide

Thalidomide G-CSF indicates granulocyte colony-stimulating factor. Sources: References 8, 10, and 11.

Patients with moderate or severe hepatic impairment should be started at a dose of 0.7 mg/m2; the dose may be titrated up or down as necessary. Bortezomib undergoes hepatic metabolism through cytochrome P450 enzymes 3A4, 2C19, and 1A2, and should be used cautiously with concomitant 3A4 inhibitors.11 The most common adverse reactions reported with bortezomib include peripheral neuropathy), gastrointestinal disorders, and thrombocytopenia. Bortezomib-induced peripheral neuropathy is generally manageable and reversible, and often resolves or subsides following dose reduction or after treatment has ended11 (Table 1).

(VGPR), and longer progression-free survival (PFS) than MP.12-14 In addition, Facon and colleagues for Intergroupe Francophone du Myélome (IFM) 99-06 showed improved OS with MPT versus MP (51.6 vs 33.2 months).14 Such results have propelled MPT to become a standard of care in elderly patients with MM and those unable to receive a transplant. As expected, the MPT regi-

Treatment After a diagnosis of stage II or III MM, patients are evaluated as candidates for high-dose therapy and stem cell transplantation based on age and comorbidities. The National Comprehensive Cancer Network (NCCN) has established guidelines to address treatment in the various MM patient populations.2 Transplant-ineligible patients. Until the advent of the immunomodulating agents and proteosome inhibitors, the mainstay of therapy for newly diagnosed patients ineligible for transplant, was melphalan plus prednisone (MP). Several studies have compared MP with MP plus thalidomide (MPT) in elderly patients with newly diagnosed disease who are unable to receive standard induction therapy followed by autologous bone marrow transplant. MPT has produced higher overall response rates (ORR), very good partial response

men is associated with increased incidences of thromboembolism, infections, and neurologic toxicity as compared with MP.12-14 Elderly patients are often more sensitive to thalidomide’s toxicities, and the recommended starting dose is 100 mg oral daily. Likewise, the combination of MP plus bortezomib (VMP) has also demonstrated positive results in newly diagnosed transplant-ineligible patients. In the phase 3 international VISTA trial, San Miguel and colleagues compared standard MP with VMP in transplant-ineligible patients with MM.15 Results of this study demonstrated significant improvement in ORR, time to progression (TTP), and OS with VMP compared with MP. A recent update of this study by Mateos and colleagues confirmed this survival advantage. At a median follow-up of 3 years, 69% of patients in the VMP group were alive, compared with 54% in the MP

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group.16 Peripheral neuropathy, gastrointestinal side effects, and herpes zoster infection were more commonly reported in the VMP arm. VMP, like MPT, is considered a standard of care in the elderly population. Lenalidomide is also a valuable drug in the transplant-ineligible population. In a study by Zonder and associates, lenalidomide plus high-dose dexam-

The combination of MP plus bortezomib (VMP) has also demonstrated positive results in newly diagnosed transplant-ineligible patients. ethasone (LD) had a higher complete response (CR) rate and 1-year PFS when compared with dexamethasone alone.17 The combination of lenalidomide plus low-dose dexamethasone (Ld) showed an OS advantage when compared with LD.18 Toxicities were fewer in the Ld arm,18 and thus Ld is considered a viable option in patients who cannot receive a transplant. Transplant-eligible patients. Primary induction therapy options for transplant-eligible patients include bortezomib/dexamethasone (VD), bortezomib/doxorubicin/dexamethasone (PAD), bortezomib/thalidomide/dexamethasone (VTD), and lenalidomide/dexamthasone; all regimens are NCCN category I recommendations.2 Rajkumar and colleagues studied Ld (40 mg on days 1, 8, 15, and 22) versus LD (40 mg on days 1-4, 9-12, and 1720) in a large randomized phase 3 trial. Continued on page 52

MAY 2010 I VOL 3, NO 3

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Hematologic Malignancies Multiple Myeloma: A Review Continued from page 51 The results showed significantly better PFS and OS at 1 and 2 years with Ld than with LD.18 The IFM performed a large randomized trial comparing VD induction versus vincristine/doxorubicin/dexamethasone (VAD), and found that the VD arm showed improved ORR and duration of response. Data on PFS and OS are still needed, however.19 Likewise, VTD, when given before transplantation, led to a VGPR in 61% of patients compared with 30% of those given thalidomide/dexamethasone (TD) (P <.001). In addition, 33% of patients receiving VTD achieved near-complete response or CR versus 12% in the TD arm (P <.001).20 Of interest, VTD overcame the adverse cytogenetics on response (del[13]), whereas TD did not.20 Lastly, Sonneveld and colleagues per-

phase 3 trial in which bortezomib was compared with bortezomib plus liposomal doxorubicin.23 Patients were bortezomib-naïve with recurrent disease. Median TTP was 6.5 months in the bortezomib alone arm, and increased to 9.3 months in the combination group (P = .000004). Survival rate at 15 months was also superior in the combination group (76% vs 65%; P = .03), although response rates were similar between the groups. The bortezomib plus liposomal doxorubicin group did, however, experience more grade 3 and 4 toxicities, such as neutropenia, thrombocytopenia, diarrhea, and hand-foot syndrome.23 Lenalidomide has also proved effective in the relapsed and refractory MM patient population. LD was compared with dexamethasone in two trials, which showed a significantly increased median

Palumbo and colleagues, with the IFM, suggest that patients with zero or one of the risk factors should receive aspirin as prophylaxis, whereas those with two or more factors should use LMWH or full-dose warfarin. formed a phase 3 trial comparing PAD with VAD. Three hundred patients with newly diagnosed stage II or III disease were randomized to receive PAD or VAD. In the PAD arm, 41% of patients achieved at least a VGPR, whereas only 17% of patients in the VAD arm achieved this result (P = .001). After transplant, 15% of the PAD group reached CR, versus 4% in the VAD group (P = .05). Partial respose (PR) or better was seen after transplant in 92% and 77% of patients, respectively.21 Relapsed and relapsed/refractory. The three NCCN category I regimens that are indicated for salvage therapy in the relapsed and relapsed/refractory patient population include bortezomib alone, bortezomib plus liposomal doxorubicin, and LD.2 Bortezomib was superior to high-dose dexamethasone in a phase 3 clinical trial conducted by Richardson and colleagues for the APEX Investigators. Bortezomib showed an ORR of 38% compared with 18% for the dexamethasone arm (P <.001). In addition, CR was seen in 6% of patients in the bortezomib group, with only 1% in the dexamethasone arm achieving the same result (P <.001). Median TTP and 1-year survival rate favored the bortezomib arm (P <.001 and P = .003, respectively).22 The combination of bortezomib and liposomal doxorubicin has also gained NCCN category I status as a result of a

MAY 2010 I VOL 3, NO 3

TTP in their combination arms (11 vs 4.7 months, respectively). Median OS in both studies, at approximately 30 months, was also higher in the combination group.24,25 Other regimens that may be considered in the relapsed and relapsed/ refractory population include VD, dexamethasone alone, dexamethasone/ thalidomide/cisplatin/doxorubicin/ cyclophosphamide/etoposide (DTPACE), and TD; all are NCCN category IIA recommendations.2 [Tables summarizing induction trials for newly diagnosed patients who are ineligible or eligible for transplant and for relapsed/refractory MM are available at www.TheOncology Nurse.com or by writing to editorial@ greenhillhc.com.] Supportive care Myelosuppression. Although thalidomide, lenalidomide, and bortezomib have greatly improved MM therapy, they all have the potential to cause some degree of myelosuppression; dosage adjustments for neutropenia and/or thrombocytopenia may be necessary7,8,10,11,26 (Table 2). Neutropenia (all grades) is seen in 28% of patients taking lenalidomide, and limited data in lenalidomide trials suggest growth factor support may be helpful for these patients through the neutropenic period.27 Bortezomib-related neutropenia is predictable and usually self-limiting,

thus dosage reductions are not recommended until the patient is experiencing grade 4 neutropenia.11 Likewise, severe neutropenia is not widely seen with thalidomide use, and doses are typically reduced solely for grade 4 neutropenia.8 Bortezomib-related thrombocytopenia is usually transient and returns to baseline in the rest period between treatment cycles. If a patient does develop grade 4 toxicity, current recommendations include holding the bortezomib dose until the platelet count recovers and then decreasing the dose by 25%.11 Likewise, lenalidomide’s package insert calls for dose reduction by 5-mg increments when the platelet count falls to less than 30  109/L.10 Peripheral neuropathy. Peripheral neuropathy is another potential toxicity associated with bortezomib and thalidomide use. Bortezomib-related peripheral neuropathy appears to occur at a dose threshold, and incidence peaks around cycle five of therapy. Fortunately, the neuropathy is often reversible upon drug discontinuation. In the case of thalidomide, peripheral neuropathy may be cumulative and therefore is frequently irreversible.9 Dosage reduction or cessation of therapy in severe cases may be warranted; Table 1 lists potential dose alterations. Pharmacologic interventions such as tricyclic antidepressants, gabapentin, pregabalin, duloxetine, and lidocaine patches have been used with some success in the treatment of peripheral neuropathy, and may be used along with dosage adjustments to allow continuation of therapy if at all possible.9 Venous thromboembolism. VTE is a serious complication of lenalidomide and thalidomide therapy. Factors that contribute to VTE include hyperviscosity, previous VTE, dexamethasone and other chemotherapy use in MM therapy, immobility, other comorbid conditions (cardiac disease, diabetes mellitus, renal dysfunction, blood clotting disorder), presence of a central catheter, surgery, and the use of erythropoiesis-stimulating agents.28 Thus, VTE prophylaxis is a major component of care for MM patients. Aspirin, low-molecular-weight heparins (LMWHs), and warfarin have all been used for VTE prophylaxis in this patient population, but strong data illustrating which agent is most effective in the MM patient are lacking. Palumbo and colleagues, with the IFM, suggest that patients with zero or one of the risk factors should receive aspirin as prophylaxis, whereas those with two or more factors should use LMWH or fulldose warfarin.28 Patient-specific characteristics, degree of thrombocytopenia,

renal impairment, and contraindications to anticoagulation must be considered when choosing a method for VTE prophylaxis.28 Skeletal lesions. Bone disease is very common in patients with MM, and, as mentioned previously, is one of the markers of active disease.29 Affected patients may have significant pain, and the American Society of Clinical Oncology has created guidelines for the prevention and management of MM-related bone disease. It is recommended that intravenous bisphosphonates such as pamidronate and zoledronic acid be administered on a monthly basis to patients with lytic bone destruction or spine compression fractures. Pamidronate is dosed at 90 mg over 2 to 6 hours; the dose of zoledronic acid is 4 mg over 15 minutes. Although there are no formal recommendations on pamidronate dosing in the setting of renal dysfunction, it is often recommended that the dose be decreased to 60 mg monthly. In patients with a creatinine clearance of less than 30 mL/min, zoledronic acid should not be given. The starting dose for zoledronic acid for patients with a clearance greater than 30 mL/min ranges from 3 mg to 4 mg, depending on the degree of renal impairment.29 A rare but serious complication of intravenous bisphosphonate therapy is osteonecrosis of the jaw. In an effort to reduce the incidence or severity of the condition, it is recommended that all MM patients receive a comprehensive dental examination as well as any preventive dental procedures before initiating bisphosphonate therapy. Oral infections should be promptly treated, and major dental work should be avoided if at all possible while patients are receiving active bisphosphonate therapy.29 Conclusion MM is a disease whose treatment is in process. Novel therapeutic agents such as thalidomide, lenalidomide, and bortezomib have dramatically improved response and survival rates in patients with this disease, but more research is certainly needed to cure this cancer. ● References

1. Raab MS, Podar K, Breitkreutz I, et al. Multiple myeloma. Lancet. 2009;374:324-339. 2. National Comprehensive Cancer Network. Clinical Practice Guidelines in Oncology: Multiple Myeloma. V.3.2010. www.nccn.org/profession als/physician_gls/PDF/myeloma.pdf. Accessed February 12, 2010. 3. Fonseca R, Bergsagel PL, Drach J, et al; for the International Myeloma Working Group. International Myeloma Working Group molecular classification of multiple myeloma: spotlight review. Leukemia. 2009;23:2210-2221.

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Current activities at www.COEXM.com include:             

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Hematologic Malignancies Multiple Myeloma: A Review Continued from page 52 4. Kumar SK, Mikhael JR, Buadi FK, et al. Management of newly diagnosed symptomatic multiple myeloma: updated Mayo Stratification of Myeloma and Risk-Adapted Therapy (mSMART) consensus guidelines. Mayo Clin Proc. 2009;84:1095-1110. 5. Palumbo A, Rajkumar SV. Treatment of newly diagnosed myeloma. Leukemia. 2009;23:449-456. 6. Kyle RA, Rajkumar SV. Criteria for diagnosis, staging, risk stratification and response assessment of multiple myeloma. Leukemia. 2009; 23:3-9. 7. Schwartz RN, Vozniak M. Current and emerging treatments for multiple myeloma. J Manag Care Pharm. 2008;14(7 suppl):12-19. 8. Thalomid [package insert]. Summit, NJ: Celgene Corporation; 2007. 9. Tariman JD, Love G, McCullagh E, Sandifer S; for the IMF Nurse Leadership Board. Peripheral neuropathy associated with novel therapies in patients with multiple myeloma: consensus statement of the IMF Nurse Leadership Board. Clin J Oncol Nurs. 2008;12(3 suppl):29-36. 10. Revlimid [package insert]. Summit, NJ: Celgene Corporation; 2009. 11. Velcade [package insert]. Cambridge, MA: Millennium Pharmaceuticals, Inc; 2009. 12. Palumbo A, Bringhen S, Caravita T, et al; for the Italian Multiple Myeloma Network, GIMEMA. Oral melphalan and prednisone chemotherapy plus thalidomide compared with melphalan and prednisone alone in elderly patients with multiple myeloma: randomised controlled trial. Lancet. 2006;367:825-831. 13. Palumbo A, Bringhen S, Liberati AM, et al.

Oral melphalan, prednisone, and thalidomide in elderly patients with multiple myeloma: updated results of a randomized controlled trial. Blood. 2008;112:3107-3114. 14. Facon T, Mary JY, Hulin C, et al; for the Intergroupe Francophone du Myélome. Melphalan and prednisone plus thalidomide versus melphalan and prednisone alone or reduced-intensity autologous stem cell transplantation in elderly patients with multiple myeloma (IFM 99-06): a randomised trial. Lancet. 2007;370:1209-1218. 15. San Miguel JF, Schlag R, Khuageva NK, et al; for the VISTA Trial Investigators. Bortezomib plus melphalan and prednisone for initial treatment of multiple myeloma. N Engl J Med. 2008;359:906-917. 16. Mateos M-V, Richardson PG, Schlag R, et al. Bortezomib plus melphalan and prednisone compared with melphalan and prednisone in previously untreated multiple myeloma: updated follow-up and impact of subsequent therapy in the phase III VISTA trial. J Clin Oncol. 2010;28:2259-2266. 17. Zonder JA, Crowley J, Hussein MA, et al. Superiority of lenalidomide (len) plus highdose dexamethasone (HD) compared to HD alone as treatment of newly-diagnosed multiple myeloma (NDMM): results of the randomized, double-blinded, placebo-controlled SWOG trial S0232. Blood (ASH Annual Meeting Abstracts). 2007;110:Abstract 77. 18. Rajkumar SV, Jacobus S, Callander N, et al. Randomized trial of lenalidomide plus highdose dexamethasone versus lenalidomide plus

low-dose dexamethasone in newly diagnosed myeloma (E4A03), a trial coordinated by the Eastern Cooperative Oncology Group: analysis of response, survival, and outcome. J Clin Oncol. 2008;26(May 20 suppl):Abstract 8504. 19. Harousseau JL, Mathiot C, Attal M, et al. Velcade/dexamethasone (Vel/D) versus VAD as induction treatment prior to autologous stem cell transplantation (ASCT) in newly diagnosed multiple myeloma (MM): updated results of the IFM 2005/01 trial. Blood (ASH Annual Meeting Abstracts). 2007;110:Abstract 450. 20. Cavo M, Tacchetti P, Patriarca F, et al. Superior complete response rate and progression-free survival after autologous transplantation with up-front Velcade-thalidomide-dexamethasone compared with thalidomide-dexamethasone in newly diagnosed multiple myeloma. Blood (ASH Annual Meeting Abstracts). 2008;112: Abstract 158. 21. Sonneveld P, van der Holt B, Schmidt-Wolf IGH, et al. First analysis of HOVON-65/ GMMG-HD4 randomized phase III trial comparing bortezomib, adriamycine, dexamethasone (PAD) vs VAD as induction treatment prior to high dose melphalan (HDM) in patients with newly diagnosed multiple myeloma (MM). Blood (ASH Annual Meeting Abstracts). 2008;112: Abstract 653. 22. Richardson PG, Sonneveld P, Schuster MW, et al; for the Assessment of Proteasome Inhibition for Extending Remissions (APEX) Investigators. Bortezomib or high-dose dexamethasone for relapsed multiple myeloma. N Engl J Med. 2005;352:2487-2498.

23. Orlowski RZ, Nagler A, Sonneveld P, et al. Randomized phase III study of pegylated liposomal doxorubicin plus bortezomib compared with bortezomib alone in relapsed or refractory multiple myeloma: combination therapy improves time to progression. J Clin Oncol. 2007;25:3892-3901. 24. Dimopoulos M, Spencer A, Attal M, et al; for the Multiple Myeloma (010) Study Investigators. Lenalidomide plus dexamethasone for relapsed or refractory multiple myeloma. N Engl J Med. 2007; 357:2123-2132. 25. Weber DM, Chen C, Niesvizky R, et al; for the Multiple Myeloma (009) Study Investigators. Lenalidomide plus dexamethasone for relapsed multiple myeloma in North America. N Engl J Med. 2007;357:2133-2142. 26. Kettle JK, Finnkbiner KL, Klenke SE, et al. Initial therapy in multiple myeloma: investigating the new treatment paradigm. J Oncol Pharm Pract. 2009;15:131-141. 27. Mateos MV, Garcia-Sanz R, Colado E, et al. Should prophylactic granulocyte-colony stimulating factor be used in multiple myeloma patients developing neutropenia under lenalidomidebased therapy? Br J Haematol. 2008;140:324-326. 28. Palumbo A, Rajkumar SV, Dimopoulos MA, et al; for the International Myeloma Working Group. Prevention of thalidomide- and lenalidomide-associated thrombosis in myeloma. Leukemia. 2008;22:414-423. 29. Kyle RA, Yee GC, Somerfield MR, et al; for the American Society of Clinical Oncology. American Society of Clinical Oncology 2007 clinical practice guideline update on the role of bisphosphonates in multiple myeloma. J Clin Oncol. 2007;25:2464-2472.

SUPPORTIVE CARE

Chemotherapy-induced Nausea and Vomiting: Clinical Updates Continued from page 48 Numerous chemotherapy regimens have been found to be safe and effective without dose modification in the elderly, which suggests that there is a similar risk of CINV in this population as in younger patients. Evaluating the risk of

changes in dexterity in older patients may present problems for self-medication. It may be more beneficial in this instance to administer long-acting IV medication to ensure effective management of CINV.

Prevention strategies that reduce CINV, particularly delayed CINV, and allow effective outpatient management are critical to reducing the costs associated with CINV. CINV in the older adult requires consideration of comorbidities and polypharmacy, self-care capabilities, cost, and diminished renal and hepatic function affecting drug metabolism and excretion.13 Hypertension and cardiovascular disease are common in the elderly, often requiring medications for management, thus increasing the risk for drug–drug interactions. Careful attention to agents that inhibit or induce the CYP450 pathway or those with the potential for prolongation of the QT interval is necessary when considering antiemetic regimens. Oral absorption of drugs may be delayed by the decreased intestinal motility common in the elderly.13 The potential for impaired vision, memory deficits, and

MAY 2010 I VOL 3, NO 3

Financial impact A retrospective analysis of 19,139 patients who received either HEC or MEC and at least one antiemetic agent evaluated the incidence and cost of outpatient and hospital visits associated with CINV-related ICD-9-CM diagnosis codes.14 CINV prophylaxis included a 5HT3 RA (85%), dexamethasone (76%), and an NK1 antagonist (2%). Almost 14% of the patients had a CINV-related visit, most commonly associated with HEC and the majority occurring after the first 24 hours (delayed CINV). The treatment setting affected the costs: inpatient setting (64%, mean cost $7448), outpatient setting (26%, mean cost $1494), and emergency department (10%, mean cost $918). Prevention

strategies that reduce CINV, particularly delayed CINV, and allow effective outpatient management are critical to reducing the costs associated with CINV. Conclusion CINV remains a common problem for patients receiving chemotherapy despite the availability of newer antiemetic agents and the establishment of treatment guidelines. Understanding the complex network of neurotransmitters, receptor sites, pathways, and patterns of CINV is critical to developing effective treatment strategies. Consideration of the unique needs of individual patients based on risk profiles, age, comorbidities, and medications is necessary to reduce potential toxicities. Evidence-based management of CINV can improve patient outcomes, including cost and quality of life. ● References

1. Hesketh PJ. Chemotherapy-induced nausea and vomiting. N Engl J Med. 2008;358:24822494. 2. Kris M, Hesketh P, Somerfeld M, et al; for the American Society of Clinical Oncology. American Society of Clinical Oncology guideline for antiemetics in oncology: update 2006. J Clin Oncol. 2006;24:2932-2947. 3. Jordan K, Sippel C, Schmoll HJ. Guidelines for antiemetic treatment of chemotherapy-induced nausea and vomiting: past, present and future recommendations. Oncologist. 2007;12:1143-1150. 4. National Comprehensive Cancer Network.

Clinical Practice Guidelines in Oncology: Antiemesis. V.1.2010. www.nccn.org/profession als/physician_gls/PDF/antiemesis.pdf. Accessed February 19, 2010. 5. Herrstedt J. Antiemetics: an update and the MASCC guidelines applied in clinical practice. Nat Clin Pract Oncol. 2008;5:32-43. 6. Hawkins R, Grunberg S. Chemotherapyinduced nausea and vomiting: challenges and opportunities for improved patient outcomes. Clin J Oncol Nurs. 2009;13:54-64. 7. Billio A, Morello E, Clarke MJ. Serotonin receptor antagonists for highly emetogenic chemotherapy in adults. Cochrane Database Syst Rev. 2010;(1):CD006272. 8. Sancuso (Granisetron Transdermal System) [package insert]. Bedminster, NJ: ProStrakan Inc; 2008. 9. Blower P, deWit R, Goodin S, Aapro M. Drugdrug interactions in oncology: why are they important and can they be minimized? Crit Rev Oncol Hematol. 2005;55:117-142. 10. Higa GM, Auber M, Altaha R, et al. Concordance between substance P levels and antiemetic guidelines. J Support Oncol. 2009; 7:138-142. 11. Trigg ME, Higa GM. Chemotherapy-induced nausea and vomiting: anti-emetic trials that impact clinical practice. J Oncol Pharm Practice. January 19, 2010. Epub ahead of print. 12. Cancer Facts and Figures, 2009. American Cancer Society. www.cancer.org/downloads/ STT/500809 web.pdf. Accessed February 19, 2010. 13. Jakobsen JN, Herrstedt J. Prevention of chemotherapy-induced nausea and vomiting in elderly cancer patients. Crit Rev Oncol Hematol. 2009;71:214-221. 14. Burke T, Wisniewski T, Ernst F. Resource utilization and costs associated with chemotherapy-induced nausea and vomiting (CINV) following highly or moderately emetogenic chemotherapy administered in the US outpatient hospital setting. Support Care Cancer. January 26, 2010. Epub ahead of print.

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Supportive Care

Patient Navigation: Year in Review 2009-2010 By Sean T. Walsh Executive Director, Academy of Oncology Nurse Navigators, Monroe Township, New Jersey

n the past 12 months, patient navigation, specifically the role of oncology nurse navigators, has become of increased interest in the cancer community. Although the concept of patient navigation dates back to the early 1990s, the most recent surge surrounding this evolving area of patient care, as well as the signing of the Patient Protection and Affordable Care Act into law, has further solidified the growth of this movement in the US healthcare system.

evidenced by the greater number of manuscripts submitted and published in the literature; she also noted, however, that many questions remain unanswered. The three main articles and the Leadership and Professional Development feature all focused on the valuable role that patient navigators play and helped to begin to frame the national dialogue around patient navigation, especially in the oncology nursing community.

Oncology Nursing Society (ONS) Over the past year, ONS has focused more attention on patient navigation. They conducted a joint think tank and released a statement with the Association of Oncology Social Work (AOSW), held a session on the topic at the 10th Annual Institutes of Learning (IOL) meeting in Tampa, Florida, and devoted the first 2010 issue of Oncology Nursing Forum to it.

AOSW In June 2009, representatives from ONS, AOSW, and the National Association of Social Workers (NASW) met to discuss how oncology nurses and social workers should relate themselves to the patient navigation role. The position statement that came from this think tank highlights the integral aspects of patient navigation, including the fact that for optimal patient outcomes there

The first official examination was given in March 2010 at the NCBC annual conference, and more than 200 breast patient navigators were certified. At an ONS IOL session, presenters Lillie D. Shockney, RN, BS, MAS, and Sharon Gentry, RN, BSN, OCN, CBCN, discussed the history of the patient navigator, the various models, and the specific roles that navigators play in the cancer care continuum. Of note is that both presenters described their use of survivor volunteers as an extension of their role in the community. Shockney spoke about The Red Devils (www.thered-devils.org), a Maryland-based nonprofit group that helps improve the quality of life of breast cancer patients and their families by funding services such as meal preparation and delivery, house cleaning, and transportation. Subsequently, Gentry spoke about her program’s recent decision to employ a cancer survivor to help with the administrative tasks that navigators perform, such as providing information about community services to patients. In the January 2010 issue of Oncology Nursing Forum, assistant editor Susan Moore, RN, MSN, ANP, AOCN, wrote an editorial titled “Making Room at the Table,” which highlighted the fact that various organizations have taken interest in patient navigation in cancer care, as

must be a multidisciplinary navigation team consisting of nurses, social workers, and lay navigators. In addition, it clearly lays the groundwork for further research on national standards and appropriate outcomes and metrics to be measured. The release of this joint position represents a major step forward for patient navigation in cancer care and can be read in full at www.ons.org/Publications/ Positions/Navigation. Association of Community Cancer Centers (ACCC) ACCC has championed the role of patient navigation in the community cancer center setting. In March 2009, it released updated Cancer Program Guidelines, which describe the rationale for and characteristics of patient navigation services, including the distinction between nurses and social workers as navigators and between lay navigators and volunteers. Building from this update, it launched a patient navigation section of its website that can be accessed at www.accc-cancer. org/education/education-patientnavi gation.asp. Over the course of its short existence, this section of the site has grown and is a great

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resource for navigators and all those interested in navigation. On June 10, 2009, Tricia Strusowski, RN, MS, led the webinar “ACCC’s Cancer Care Patient Navigation: A Call to Action,” which is available online for continuing education credit until June 30, 2010. During her presentation, Strusowski discussed ACCC’s Patient Navigation Project, the various models of navigation, and a process to develop a program. To further this discussion, ACCC held a Cancer Care Patient Navigation Pre-Conference in Minneapolis, Minnesota, on September 22, 2009. A poster presented at this preconference outlined the various levels of need discussed during the webinar. National Consortium of Breast Centers (NCBC) In 2009, NCBC held its beta year of testing for its Breast Patient Navigator Certification Program, with examinations conducted at their annual National Interdisciplinary Breast Center Conference in Las Vegas, Nevada, in March 2009, as well as at two regional sites in Baltimore, Maryland, and Chicago, Illinois. The first official examination was given in March 2010 at the NCBC annual conference, and more than 200 breast patient navigators were certified. NCBC has three regional examinations planned in 2010 and has also developed a comprehensive navigation matrix. For more information on the certification program, regional examinations, the matrix, and more, visit www.bpnc.org. Academy of Oncology Nurse Navigators (AONN) AONN began in early 2009 with the mission of advancing the role of patient navigation in cancer care and survivorship planning by providing a network for collaboration and development of best practices for the improvement of patient access to care and quality of life. At the 34th ONS Congress in San Antonio, Texas, in May 2009, AONN began to gain national recognition and to increase its membership. For the majority of 2009, AONN provided various online resources through its website at www. AONNonline.org, including blogs written on various subjects relevant to patient navigation by members of its leadership council. In the fall of 2009, at ONS IOL in Tampa, Florida, AONN further engaged the oncology nursing

Sean T. Walsh

community and released its first newsletter, providing the history of nurse navigation for members and nonmembers alike. In addition, two members of the AONN leadership council, Lillie D. Shockney, RN, BS, MAS, and Sharon Gentry, RN, BSN, OCN, CBCN, presented the patient navigation session at this meeting. AONN entered into a partnership with NCBC in mid-2009 to help raise awareness about their Breast Patient Navigator Certification Program. AONN continues to expand its reach in 2010 with the addition of several new leadership council members, the formation of state/regional chapters, and their first annual conference will be held in September. By forming partnerships with other professional and patient advocacy organizations, AONN continues to support navigators and ensure that patients benefit from their services. Finally, AONN has begun to accept manuscripts for a peer-reviewed journal on navigation and survivorship. Other Organizations In addition to the several organizations discussed in this article, many others are actively supporting the navigator community. These organizations include the American Cancer Society, Lance Armstrong Foundation, American College of Oncology Administrators, Association of Cancer Executives, and the National Coalition of Oncology Nurse Navigators. Conclusion Although many questions remain surrounding the optimal role of patient navigators in the cancer care continuum, one thing is certain, there is great momentum behind this movement, as evidenced by the events of 2009 and the continued progress being made in 2010. Patient navigation will continue to be a major area of research and discourse and will take on further significance as navigators become more heavily involved in providing survivorship support and care for cancer patients. ●

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Solid Tumors

Medical Management of Breast Cancer: Update from the San Antonio Breast Cancer Symposium 2009 By Cynthia Frankel, RN, OCN Director, Breast Cancer Research and Development, Memorial Cancer Institute, Hollywood, Florida

he evolving epidemiology statistics relative to breast cancer worldwide are alarming. The cumulative incidence of breast cancer is 6.3% in developed countries compared with 1.0% in undeveloped countries. Western developed areas show increasing rates, with projections of 2 million cases diagnosed annually. Advances in understanding of the causes of breast cancer, epidemiology, risk factors, and both maturing data and new findings on hormonal, cytotoxic, and biological approaches were presented at the 32nd annual San Antonio Breast Cancer Symposium.

Risk factors Kwan and associates reviewed the relationship between alcohol use and breast cancer recurrence and survival in 1898 women with stage I, II, or IIIA breast cancer who participated in the Life After Cancer Epidemiology (LACE) study.1 They found that those who consumed more than 6 g/day of alcohol had a 1.5-fold increase in death and a 1.3fold increase in recurrence. Obesity is also associated with a poor prognosis after breast cancer. A population-based cohort study of almost 19,000 patients showed that although on univariate analysis the risk of local or regional cancer recurrence was not related to body mass index (BMI), the risk of distant metastases increased with increasing BMI.2 The investigators also found that the risk of dying from breast cancer remains elevated for obese women (BMI 25) throughout 30 years of observation. On a more positive note, in a population-based case-control study, the use of bisphosphonates for more than 1 year was shown to lead to a 29% reduction in the risk of postmenopausal breast cancer.3 When tumors did develop in bisphosphonate users, they tended to have a more favorable prognostic factors profile. A head-to-head comparison of denosumab with zoledronic acid in 2048 women revealed an 18% reduction in risk of developing a skeletal-related event in those receiving denosumab.4 A 6% absolute risk reduction and a

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16% relative risk reduction were found in the denosumab group. The findings also showed a 22% reduction in skeletal morbidity rate in the denosumab arm. Compared with zoledronic acid, denosumab significantly delayed the time to first radiation to bone and first on-study skeletal-related event or hypercalcemia of malignancy. The US Food and Drug Administration has not approved denosumab. Results of a subanalysis from the E1199 study revealed that, although black women are one third less likely than women of other races to develop breast cancer, they are 30% more likely to die if they are diagnosed with the disease.5 In this analysis, black race was associated with significantly poorer disease-free survival (DFS) and overall survival (OS). Potential explanations for the disparities noted include poorer adherence to endocrine therapy, obesity and associated hyperinsulinemia, or other factors. Advances in drug therapy The Tamoxifen Exemestane Adjuvant Multinational (TEAM) trial randomized 9775 women with hormone receptor–positive early breast cancer to either 5 years of the aromatase inhibitor (AI) exemestane as initial therapy or 5 years of tamoxifen followed by exemestane.6 The 5-year update showed there was no advantage to switching and 5 years of an AI provided superior efficacy. The Intergroup Exemestane Study (IES) evaluated exemestane taken for 2 to 3 years followed by randomization to either exemestane or tamoxifen for a total of 5 years of adjuvant endocrine therapy.7 The study showed a 2.4% increase in survival in those in the exemestane arm as well as fewer events overall, including second primaries. As determined in the MA17 trial of letrozole versus placebo, extending hormonal therapy in the adjuvant setting beyond 5 years has been found to have a DFS advantage, particularly for those with estrogen receptorpositive disease.8 The role of bevacizumab in the metastatic setting was examined in several studies. In the AVADO trial (a double-blind, placebo-controlled, phase 3 study of bevacizumab plus docetaxel compared with placebo plus docetaxel for the first-line treatment of locally recurrent or metastatic breast cancer),

women who received bevacizumab 15 mg/kg combined with docetaxel had a 33% increase in progression-free survival (PFS) as well as better response rates compared with the group that received placebo. To date, however, no survival advantage with the bevacizumab-docetaxel combination has been demonstrated.9 The RIBBON 2 trial was a phase 3 study of bevacizumab used in combination with chemotherapy in the secondline treatment of human epidermal growth factor receptor type 2 (HER2)negative metastatic breast cancer.10 Patients eligible for this study had previously received one prior cytotoxic treatment. They were randomized to chemotherapy plus placebo or chemotherapy plus bevacizumab—the chemotherapy component being the investigator’s choice (a taxane [304], gemcitabine [160], capecitabine [144], or vinorelbine [76]). PFS, the primary end point of the study, was 7.2 months in the bevacizumab arm compared with 5.1 months in the placebo arm. This was statistically significant and represented a 22% decrease in the risk of relapse. The OS rate of 15 months for bevacizumab versus 16.4 months for placebo was not significantly different between the two groups. The SOLTI-0701 phase 2b trial compared sorafenib/capecitabine with capecitabine alone in the second-line setting.11 The overall response rate of 38.3% (sorafenib/capecitabine) compared with 30% (capecitabine alone) in women with locally advanced or metastatic breast cancer. PFS was 7.6 months compared with 4.1 months, respectively, in the first-line setting and 5.7 months compared with 4.1 months, respectively, in the second-line setting. These improvements, however, were offset by toxicity, which included grade 3 hand-foot syndrome in 45% of the participants. A review of studies in HER2-positive breast cancer included EGF104900, a phase 3 randomized trial.12 The population for this trial included women with HER2-positive metastatic breast cancer who had progressed on prior trastuzumab-containing regimens. The trial compared lapatinib 1500 mg alone with lapatinib 1000 mg combined with trastuzumab. At relapse, patients treated with lapatinib alone were allowed to cross over to the combination arm. In

the intent-to-treat analysis, a 4.5month improvement in OS was demonstrated in the combination arm with a statistically significant hazard ratio of 0.76. PFS was 12 weeks with the combination regimen compared with 8.1 weeks with lapatinib alone. Median survival was 14 months for lapatinib/ trastuzumab compared with 9.5 months for lapatinib alone. There was also a survival benefit, which reflected a 24% reduction in death. Slamon and collegues presented the third planned analysis of BCIRG 006 trial, a multicenter, phase 3, randomized trial comparing doxorubicin/cyclophosphamide followed by docetaxel with doxorubicin/cyclophosphamide followed by docetaxel/trastuzumab (ACTH) and with docetaxel/carboplatin/trastuzumab (TCH) in the adjuvant treatment of node-positive and high-risk, node-negative patients with operable HER2-positive breast cancer.13 With a median follow-up of 65 months, the DFS rates were 84% for the ACTH arm and 81% for the TCH arm compared with 75% for the control arm. OS rates were 92% for the ACTH arm, 91% for the TCH arm, and 87% for the control arm. TCH continued to show efficacy equivalent to ACTH, although the study was not designed to determine equivalence. There were 21 cases of congestive heart failure with the ACTH regimen compared with four with TCH. Also, 194 patients in the ACTH arm had sustained reductions in left ventricular ejection fraction compared with 97 in the TCH arm. These findings suggest that a nonanthracyline-containing regimen is an effective alternative for patients at high risk for anthracyclineassociated cardiac toxicities. Perez and colleagues presented an update to N9831, the only randomized phase 3 trial comparing the safety and efficacy of the addition of trastuzumab to doxorubicin/cyclophosphamide (AC) either following paclitaxel (ACpaclitaxeltrastuzumab) or starting concurrently with paclitaxel (ACpaclitaxel/trastuzumab) in women with stage I to III invasive HER2-positive breast cancer.14 Giving paclitaxel and trastuzumab concurrently was found to be superior to the sequential approach. Five-year DFS was increased from 80% with ACpacli-

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Soild Tumors taxeltrastuzumab to 84% with AC paclitaxel/trastuzumab. These results set the stage for trastuzumab therapy being given concurrently with paclitaxel chemotherapy. Conclusion There continues to be much to learn about breast cancer from an epidemiology standpoint, much more to unravel at the scientific level, and an incalculable need to make available effective therapies without exorbitant costs. Nevertheless, the exciting developments reported in San Antonio attest to the efforts of scientists, clinicians, patients, caregivers, and advocates who participate in clinical trials and work to advance our understanding of breast cancer. ● References

1. Kwan ML, Kushi LH, Weltzien E, et al. Alcohol and breast cancer survival in a prospective cohort study. Presented at: San Antonio Breast Cancer Symposium. December 10, 2009. San Antonio, TX. 2. Ewertz M, Jensen M-B, Gunnarsdottir K, Cold S; for the Danish Breast Cancer Co-operative Group. Effect of obesity on prognosis after early breast cancer. Presented at: San Antonio Breast Cancer Symposium. December 10, 2009. San Antonio, TX. 3. Rennert G, Pinchev M, Rennert HS. Use of bisphosphonates and risk of postmenopausal breast cancer. Presented at: San Antonio Breast Cancer Symposium. December 10, 2009. San Antonio, TX. 4. Stopeck A, de Boer R, Fujiwara Y, et al. A comparison of denosumab versus zoledronic acid for the prevention of skeletal-related events in breast cancer patients with bone metastases. Presented at: San Antonio Breast Cancer Symposium. December 10, 2009. San Antonio, TX. 5. Sparano JA, Wang W, Stearns V, et al; for the Cancer and Leukemia Group B. Black race is associated with a worse outcome in patients with hormone receptor positive, HER2-normal breast cancer treated with adjuvant chemohormonal therapy. Presented at: San Antonio Breast Cancer Symposium. December 11, 2009. San Antonio, TX. 6. Rea D, Hasenburg A, Seynaeve C, et al. Five years of exemestane as initial therapy compared to 5 years of tamoxifen followed by exemestane: the TEAM trial, a prospective, randomized, phase III trial in postmenopausal women with hormonesensitive early breast cancer. Cancer Res. 2009;69(meeting abstract suppl):Abstract nr11. 7. Bliss JM, Kilburn LS, Coleman RE, et al. Disease related outcome with long term followup: an updated analysis of the Intergroup Exemestane Study (IES). Presented at: San Antonio Breast Cancer Symposium. December 10, 2009. San Antonio, TX. 8. Goss PE, Mamounas E, Jakesz R, et al. Aromatase inhibitors vs not after 5 years tamoxifen in postmenopausal breast cancer: meta-analysis of the randomized trials. Presented at: San Antonio Breast Cancer Symposium. December 10, 2009. San Antonio, TX. 9. Miles DW, Chan A, Romieu G, et al. Final overall survival (OS) results from the randomised, double-blind, placebo-controlled, phase III AVADO study of bevacizumab (BV) plus docetaxel (D) compared with placebo (PL) plus D for the first-line treatment of locally recurrent (LR) or metastatic breast cancer (mBC). Presented at: San Antonio Breast Cancer Symposium. December 11, 2009. San Antonio, TX. 10. Brufsky A, Bondarenko IN, Smirnov V, et al. RIBBON-2: a randomized, double-blind, placebo-controlled, phase III trial evaluating the efficacy and safety of bevacizumab in combination with chemotherapy for second-line treatment of HER2negative metastatic breast cancer. Presented at: San Antonio Breast Cancer Symposium.

December 11, 2009. San Antonio, TX. 11. Baselga J, Roché H, Costa F, et al. [SOLTI0701]: a multinational double-blind, randomized phase 2b study evaluating the efficacy and safety of sorafenib compared to placebo when administered in combination with capecitabine in patients with locally advanced or metastatic breast cancer (BC). Presented at: San Antonio Breast Cancer Symposium. December 11, 2009. San Antonio, TX. 12. Blackwell KL, Burstein HJ, Sledge GW, et al. Updated survival analysis of a randomized study

of lapatinib alone or in combination with trastuzumab in women with HER2-positive metastatic breast cancer progressing on trastuzumab therapy. Presented at: San Antonio Breast Cancer Symposium. December 12, 2009. San Antonio, TX. 13. Slamon D, Eiermann W, Robert N, et al; for the BCIRG006 Investigators. Phase III randomized trial comparing doxorubicin and cyclophosphamide followed by docetaxel (ACT) with doxorubicin and cyclophosphamide followed by docetaxel and trastuzumab (ACTH) with

RITUXAN® (Rituximab) Brief summary—Please consult full prescribing information. counts prior to each Rituxan course. During treatment with Rituxan and chemotherapy, obtain CBC and platelet counts at weekly to monthly intervals and more frequently in WARNING: FATAL INFUSION REACTIONS, TUMOR LYSIS SYNDROME (TLS), patients who develop cytopenias. [See Adverse Reactions]. s The duration of cytopenias SEVERE MUCOCUTANEOUS REACTIONS, and PROGRESSIVE MULTIFOCAL caused by Rituxan can extend months beyond the treatment period. ADVERSE LEUKOENCEPHALOPATHY (PML) REACTIONS The most common adverse reactions of Rituxan (incidence ≥25%) Infusion Reactions: Rituxan administration can result in serious, including observed in clinical trials of patients with NHL were infusion reactions, fever, fatal infusion reactions. Deaths within 24 hours of Rituxan infusion have lymphopenia, chills, infection, and asthenia. The most common adverse reactions of occurred. Approximately 80% of fatal infusion reactions occurred in Rituxan (incidence ≥25%) observed in clinical trials of patients with CLL were: infusion association with the first infusion. Carefully monitor patients during reactions and neutropenia. Clinical Trials Experience in Lymphoid Malignancies infusions. Discontinue Rituxan infusion and provide medical treatment for Because clinical trials are conducted under widely varying conditions, adverse reaction Grade 3 or 4 infusion reactions [see Warnings and Precautions, Adverse rates observed in the clinical trials of a drug cannot be directly compared to rates in the Reactions]. s Tumor Lysis Syndrome (TLS): Acute renal failure requiring clinical trials of another drug and may not reflect the rates observed in practice. The data dialysis with instances of fatal outcome can occur in the setting of TLS described below reflect exposure to Rituxan in 2282 patients, with exposures ranging from a single infusion up to 6–8 months. Rituxan was studied in both single-agent and following treatment of non-Hodgkin’s lymphoma (NHL) patients with Rituxan active-controlled trials (n = 356 and n = 1926). The population included 679 patients [see Warnings and Precautions, Adverse Reactions]. s Severe Mucocutaneous with low-grade follicular lymphoma, 927 patients with DLBCL, and 676 patients with Reactions: Severe, including fatal, mucocutaneous reactions can occur in CLL. Most NHL patients received Rituxan as infusion of 375 mg/m2 per infusion, given as patients receiving Rituxan [see Warnings and Precautions, Adverse a single agent weekly for up to 8 doses, in combination with chemotherapy for up to 8 Reactions]. s Progressive Multifocal Leukoencephalopathy (PML): JC virus doses, or following chemotherapy for up to 16 doses. CLL patients received Rituxan 375 infection resulting in PML and death can occur in patients receiving Rituxan mg/m2 as an initial infusion followed by 500 mg/m2 for up to 5 doses, in combination with [see Warnings and Precautions, Adverse Reactions]. s fludarabine and cyclophosphamide. Seventy-one percent of CLL patients received 6 cycles and 90% received at least 3 cycles of Rituxan-based therapy. Infusion INDICATIONS AND USAGE Non-Hodgkin’s Lymphoma (NHL) Rituxan® (rituximab) is Reactionss In the majority of patients with NHL, infusion reactions consisting of fever, indicated for the treatment of patients with: Relapsed or refractory, low-grade or chills/rigors, nausea, pruritus, angioedema, hypotension, headache, bronchospasm, follicular, CD20-positive, B-cell NHL as a single agent; Previously untreated follicular, urticaria, rash, vomiting, myalgia, dizziness, or hypertension occurred during the first CD20-positive, B-cell NHL in combination with CVP chemotherapy; Non-progressing Rituxan infusion. Infusion reactions typically occurred within 30 to 120 minutes of (including stable disease), low-grade, CD20-positive, B-cell NHL, as a single agent, after beginning the first infusion and resolved with slowing or interruption of the Rituxan first-line CVP chemotherapy; Previously untreated diffuse large B-cell, CD20-positive infusion and with supportive care (diphenhydramine, acetaminophen, and intravenous NHL in combination with CHOP or other anthracycline-based chemotherapy regimens. saline). The incidence of infusion reactions was highest during the first infusion (77%) Chronic Lymphocytic Leukemia (CLL) Rituxan® (rituximab) is indicated, in and decreased with each subsequent infusion. [See Boxed Warning, Warnings and combination with fludarabine and cyclophosphamide (FC), for the treatment of patients Precautions.] Infections Serious infections (NCI CTCAE Grade 3 or 4), including sepsis, with previously untreated and previously treated CD20-positive CLL. Limitations of use occurred in less than 5% of patients with NHL in the single-arm studies. The overall Rituxan is not recommended for use in patients with severe, active infections. incidence of infections was 31% (bacterial 19%, viral 10%, unknown 6%, and fungal WARNINGS AND PRECAUTIONS Infusion Reactions Rituxan can cause severe, 1%). [See Warnings and Precautions.] In randomized, controlled studies where Rituxan including fatal, infusion reactions. Severe reactions typically occurred during the first was administered following chemotherapy for the treatment of follicular or low-grade infusion with time to onset of 30–120 minutes. Rituxan-induced infusion reactions and NHL, the rate of infection was higher among patients who received Rituxan. In diffuse sequelae include urticaria, hypotension, angioedema, hypoxia, bronchospasm, large B-cell lymphoma patients, viral infections occurred more frequently in those who pulmonary infiltrates, acute respiratory distress syndrome, myocardial infarction, received Rituxan. Cytopenias and hypogammaglobulinemiaa In patients with NHL ventricular fibrillation, cardiogenic shock, anaphylactoid events, or death. Premedicate receiving rituximab monotherapy, NCI-CTC Grade 3 and 4 cytopenias were reported in patients with an antihistamine and acetaminophen prior to dosing. Institute medical 48% of patients. These included lymphopenia (40%), neutropenia (6%), leukopenia management (e.g. glucocorticoids, epinephrine, bronchodilators, or oxygen) for infusion (4%), anemia (3%), and thrombocytopenia (2%). The median duration of lymphopenia reactions as needed. Depending on the severity of the infusion reaction and the required was 14 days (range, 1–588 days) and of neutropenia was 13 days (range, 2–116 days). interventions, temporarily or permanently discontinue Rituxan. Resume infusion at a A single occurrence of transient aplastic anemia (pure red cell aplasia) and two minimum 50% reduction in rate after symptoms have resolved. Closely monitor the occurrences of hemolytic anemia following Rituxan therapy occurred during the singlefollowing patients: those with pre-existing cardiac or pulmonary conditions, those who arm studies. In studies of monotherapy, Rituxan-induced B-cell depletion occurred in experienced prior cardiopulmonary adverse reactions, and those with high numbers of 70% to 80% of patients with NHL. Decreased IgM and IgG serum levels occurred in 14% circulating malignant cells (≥25,000/mm3). [See Boxed Warning, Warnings and of these patients. Relapsed or Refractory, Low-Grade NHL Adverse reactions in Table 1 Precautions, Adverse Reactions.] Tumor Lysis Syndrome (TLS) Acute renal failure, occurred in 356 patients with relapsed or refractory, low-grade or follicular, CD20-positive, hyperkalemia, hypocalcemia, hyperuricemia, or hyperphosphatemia from tumor lysis, B-cell NHL treated in single-arm studies of Rituxan administered as a single agent. [See some fatal, can occur within 12–24 hours after the first infusion of Rituxan in patients Clinical Studies.] Most patients received Rituxan 375 mg/m2 weekly for 4 doses. with NHL. A high number of circulating malignant cells (≥25,000/mm3) or high tumor burden Table 1 confers a greater risk of TLS. Administer aggressive intravenous hydration and anti- Incidence of Adverse Reactions in ≥5% of Patients with Relapsed or Refractory, Lowhyperuricemic therapy in patients at high risk for TLS. Correct electrolyte abnormalities, Grade or Follicular NHL, Receiving Single-agent Rituxan (N = 356)a,b monitor renal function and fluid balance, and administer supportive care, including dialysis as All Grades (%) Grade 3 and 4 (%) All Grades (%) Grade 3 and 4 (%) indicated. [See Boxed Warning.] Severe Mucocutaneous Reactions Mucocutaneous Any Adverse Events 99 57 Respiratory p y System y 38 4 reactions, some with fatal outcome, can occur in patients treated with Rituxan. These Bodyy as a Whole 86 10 Increased Cough 13 1 Fever 53 1 Rhinitis 12 1 reactions include paraneoplastic pemphigus, Stevens-Johnson syndrome, lichenoid Chills 33 3 Bronchospasm 8 1 dermatitis, vesiculobullous dermatitis, and toxic epidermal necrolysis. The onset of these Infection 31 4 Dyspnea 7 1 Asthenia 26 1 Sinusitis 6 0 reactions has varied from 1–13 weeks following Rituxan exposure. Discontinue Rituxan Headache 19 1 Metabolic and Nutritional in patients who experience a severe mucocutaneous reaction. The safety of Abdominal Pain 14 1 Disorders 38 3 Pain 12 1 Angioedema 11 1 readministration of Rituxan to patients with severe mucocutaneous reactions has not Back Pain 10 1 Hyperglycemia 9 1 been determined. [See Boxed Warning, Adverse Reactions.] Progressive Multifocal Throat Irritation 9 0 Peripheral Edema 8 0 5 0 LDH Increase 7 0 Leukoencephalopathy (PML) JC virus infection resulting in PML and death can occur HemeFlushing and Lymphatic y p System y 67 48 Digestive g System y 37 2 in Rituxan-treated patients with hematologic malignancies or with autoimmune diseases. Lymphopenia 48 40 Nausea 23 1 Leukopenia 14 4 Diarrhea 10 1 The majority of patients with hematologic malignancies diagnosed with PML received Neutropenia 14 6 Vomiting 10 1 Rituxan in combination with chemotherapy or as part of a hematopoietic stem cell Thrombocytopenia 12 2 Nervous System y 32 1 Anemia 8 3 Dizziness 10 1 transplant. The patients with autoimmune diseases had prior or concurrent Skin and Appendages pp g 44 2 Anxiety 5 1 immunosuppressive therapy. Most cases of PML were diagnosed within 12 months of Night Sweats 15 1 Musculoskeletal System y 26 3 Rash 15 1 Myalgia 10 1 their last infusion of Rituxan. Consider the diagnosis of PML in any patient presenting Pruritus 14 1 Arthralgia 10 1 with new-onset neurologic manifestations. Evaluation of PML includes, but is not limited Urticaria 8 1 Cardiovascular System y 25 3 Hypotension 10 1 to, consultation with a neurologist, brain MRI, and lumbar puncture. Discontinue Rituxan Hypertension 6 1 and consider discontinuation or reduction of any concomitant chemotherapy or a b immunosuppressive therapy in patients who develop PML. [See Boxed Warning, Adverse Adverse reactions observed up to 12 months following Rituxan. Adverse reactions graded for severity Reactions.] Hepatitis B Virus (HBV) Reactivation Hepatitis B virus (HBV) reactivation by NCI-CTC criteria. with fulminant hepatitis, hepatic failure, and death can occur in patients with hematologic In these single-arm Rituxan studies, bronchiolitis obliterans occurred during and up to malignancies treated with Rituxan. The median time to the diagnosis of hepatitis was 6 months after Rituxan infusion. Previously Untreated Low-Grade NHL In Study 4, approximately 4 months after the initiation of Rituxan and approximately one month after patients in the R-CVP arm experienced a higher incidence of infusional toxicity and the last dose. Screen patients at high risk of HBV infection before initiation of Rituxan. neutropenia compared to patients in the CVP arm. The following adverse reactions Closely monitor carriers of hepatitis B for clinical and laboratory signs of active HBV occurred more frequently (≥5%) in patients receiving R-CVP compared to CVP alone: infection for several months following Rituxan therapy. Discontinue Rituxan and any rash (17% vs. 5%), cough (15% vs. 6%), flushing (14% vs. 3%), rigors (10% vs. 2%), concomitant chemotherapy in patients who develop viral hepatitis, and institute pruritus (10% vs. 1%), neutropenia (8% vs. 3%), and chest tightness (7% vs. 1%). In appropriate treatment including antiviral therapy. Insufficient data exist regarding the Study 5, the following adverse reactions were reported more frequently (≥5%) in safety of resuming Rituxan in patients who develop hepatitis subsequent to HBV patients receiving Rituxan following CVP compared to patients who received no further reactivation. [See Adverse Reactions.] Infections Serious, including fatal, bacterial, therapy: fatigue (39% vs. 14%), anemia (35% vs. 20%), peripheral sensory fungal, and new or reactivated viral infections can occur during and up to one year neuropathy (30% vs. 18%), infections (19% vs. 9%), pulmonary toxicity (18% vs. following the completion of Rituxan-based therapy. New or reactivated viral infections 10%), hepato-biliary toxicity (17% vs. 7%), rash and/or pruritus (17% vs. 5%), included cytomegalovirus, herpes simplex virus, parvovirus B19, varicella zoster virus, arthralgia (12% vs. 3%), and weight gain (11% vs. 4%). Neutropenia was the only West Nile virus, and hepatitis B and C. Discontinue Rituxan for serious infections and Grade 3 or 4 adverse reaction that occurred more frequently (≥2%) in the Rituxan arm institute appropriate anti-infective therapy. [See Adverse Reactions.] Cardiovascular Discontinue infusions for serious or life-threatening cardiac arrhythmias. Perform compared with those who received no further therapy (4% vs. 1%). [See Clinical Studies.] DLBCLL In Studies 6 and 7, [see Clinical Studies] s the following adverse reactions, 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 regardless of severity, were reported more frequently (≥5%) in patients age ≥60 years Adverse Reactions.] Renal Severe, including fatal, renal toxicity can occur after Rituxan receiving R-CHOP as compared to CHOP alone: pyrexia (56% vs. 46%), lung disorder administration in patients with NHL. Renal toxicity has occurred in patients who (31% vs. 24%), cardiac disorder (29% vs. 21%), and chills (13% vs. 4%). Detailed experience tumor lysis syndrome and in patients with NHL administered concomitant safety data collection in these studies was primarily limited to Grade 3 and 4 adverse cisplatin therapy during clinical trials. The combination of cisplatin and Rituxan is not an reactions and serious adverse reactions. In Study 7, a review of cardiac toxicity approved treatment regimen. Monitor closely for signs of renal failure and discontinue determined that supraventricular arrhythmias or tachycardia accounted for most of Rituxan in patients with a rising serum creatinine or oliguria. Bowel Obstruction and the difference in cardiac disorders (4.5% for R-CHOP vs. 1.0% for CHOP). The Perforation Abdominal pain, bowel obstruction and perforation, in some cases leading following Grade 3 or 4 adverse reactions occurred more frequently among patients in to death, can occur in patients receiving Rituxan in combination with chemotherapy. In the R-CHOP arm compared with those in the CHOP arm: thrombocytopenia (9% vs. postmarketing reports, the mean time to documented gastrointestinal perforation was 6 7%) and lung disorder (6% vs. 3%). Other Grade 3 or 4 adverse reactions occurring (range 1–77) days in patients with NHL. Perform a thorough diagnostic evaluation and more frequently among patients receiving R-CHOP were viral infection (Study 7), institute appropriate treatment for complaints of abdominal pain. [See Adverse neutropenia (Studies 7 and 8), and anemia (Study 8). CLLL The data below reflect Reactions.] Immunization The safety of immunization with live viral vaccines following exposure to Rituxan in combination with fludarabine and cyclophosphamide in 676 s The age range was Rituxan therapy has not been studied and vaccination with live virus vaccines is not patients with CLL in Study 9 or Study 10 [see Clinical Studies]. recommended. Laboratory Monitoring In patients with lymphoid malignancies, during 30–83 years and 71% were men. Detailed safety data collection in Study 9 was limited treatment with Rituxan monotherapy, obtain complete blood counts (CBC) and platelet to Grade 3 and 4 adverse reactions and serious adverse reactions. Infusion-related

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docetaxel, carboplatin and trastuzumab (TCH) in HER2/neu positive early breast cancer patients: BCIRG 006 Study. Presented at: San Antonio Breast Cancer Symposium. December 12, 2009. San Antonio, TX. 14. Perez EA, Suman VJ, Davidson NE, et al. Results of chemotherapy alone, with sequential or concurrent addition of 52 weeks of trastuzumab in the NCCTG N9831 HER2-positive adjuvant breast cancer trial. Presented at: San Antonio Breast Cancer Symposium. December 12, 2009. San Antonio, TX. adverse reactions were defined by any of the following adverse events occurring during or within 24 hours of the start of infusion: nausea, pyrexia, chills, hypotension, vomiting, and dyspnea. In Study 9, the following Grade 3 and 4 adverse reactions occurred more frequently in R-FC–treated patients compared to FC-treated patients: infusion reactions (9% in R-FC arm), neutropenia (30% vs. 19%), febrile neutropenia (9% vs. 6%), leukopenia (23% vs. 12%), and pancytopenia (3% vs. 1%). In Study 10, the following Grade 3 or 4 adverse reactions occurred more frequently in R-FC–treated patients compared to FC-treated patients: infusion reactions (7% in R-FC arm), neutropenia (49% vs. 44%), febrile neutropenia (15% vs. 12%), thrombocytopenia (11% vs. 9%), hypotension (2% vs. 0%), and hepatitis B (2% vs. <1%). Fifty-nine percent of R-FC–treated patients experienced an infusion reaction of any severity. 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, anti-human antichimeric 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 Rituxan-treated patients is unclear. Postmarketing Experience The following adverse reactions have been identified during post-approval 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. In patients with CLL, Rituxan did not alter systemic exposure to fludarabine or cyclophosphamide. 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 breast-feeding. 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, active-controlled trials, 927 patients received Rituxan in combination with chemotherapy. Of these, 396 (43%) were age 65 or greater and 123 (13%) were age 75 or greater. No overall differences in effectiveness were observed between these patients and younger patients. Cardiac adverse reactions, mostly supraventricular arrhythmias, occurred more frequently among elderly patients. Serious pulmonary adverse reactions were also more common among the elderly, including pneumonia and pneumonitis. Low-Grade or Follicular Non-Hodgkin’s Lymphoma Clinical studies of Rituxan in low-grade or follicular, CD20-positive, B-cell NHL did not include sufficient numbers of patients aged 65 and over to determine whether they respond differently from younger subjects. Chronic Lymphocytic Leukemia Among patients with CLL evaluated in two randomized active-controlled trials, 243 of 676 Rituxan-treated patients (36%) were 65 years of age or older; of these, 100 Rituxan-treated patients (15%) were 70 years of age or older. In exploratory analyses defined by age, there was no observed benefit from the addition of Rituxan to fludarabine and cyclophosphamide among patients 70 years of age or older in Study 9 or in Study 10; there was also no observed benefit from the addition of Rituxan to fludarabine and cyclophosphamide among patients 65 years of age or older in Study 10 [see Clinical Studies]. s Patients 70 years or older received lower dose intensity of fludarabine and cyclophosphamide compared to younger patients, regardless of the addition of Rituxan. In Study 9, the dose intensity of Rituxan was similar in older and younger patients, however in Study 10 older patients received a lower dose intensity of Rituxan. The incidence of Grade 3 and 4 adverse reactions was higher among patients receiving R-FC who were 70 years or older compared to younger patients for neutropenia [44% vs. 31% (Study 9); 56% vs. 39% (Study 10)], febrile neutropenia [16% vs. 6% (Study 9)], anemia [5% vs. 2% (Study 9); 21% vs. 10% (Study 10)], thrombocytopenia [19% vs. 8% (Study 10)], pancytopenia [7% vs. 2% (Study 9); 7% vs. 2% (Study 10)] and infections [30% vs. 14% (Study 10)]. OVERDOSAGE There has been no experience with overdosage in human clinical trials. Single doses of up to 500 mg/m2 have been administered in clinical trials. NONCLINICAL TOXICOLOGY Carcinogenesis, Mutagenesis, Impairment of Fertilityy No long-term animal studies have been performed to establish the carcinogenic or mutagenic potential of Rituxan or to determine potential effects on fertility in males or females. PATIENT COUNSELING INFORMATION Patients should be provided the Rituxan Medication Guide and provided an opportunity to read prior to each treatment session. It is important that the patient’s overall health be assessed at each visit and the risks of Rituxan therapy and any questions resulting from the patient’s reading of the Medication Guide be discussed. Rituxan is detectable in serum for up to six months following completion of therapy. Individuals of childbearing potential should use effective contraception during treatment and for 12 months after Rituxan therapy. Revised 02/2010 (4851501) Jointly Marketed by: Biogen Idec Inc. 5200 Research Place San Diego, CA 92122 Genentech USA, Inc. 1 DNA Way South San Francisco, CA 94080-4990 ©2010 Biogen Idec Inc. and Genentech, Inc. 7140919 February 2010

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ACROSS APPROVED CLL AND NHL INDICATIONS

DRIVING PATIENT OUTCOMES Supporting your central role in patient care Resources to support your patients with NHL and CLL Patients can talk to a nurse educator about RITUXAN, CLL, and NHL 24 hours a day, 7 days a week. Call the RITUXAN Support Center at (888) 455-2220. You, your patients, and their caregivers can turn to RITUXAN.com for additional resources and materials.

RITUXAN Access Solutions is committed to connecting your patients to RITUXAN, regardless of their ability to pay; for more information, please visit www.RituxanAccessSolutions.com.

Indications RITUXAN® (Rituximab) is indicated for the treatment of patients with: Previously untreated and previously treated CD20positive CLL in combination with fludarabine and cyclophosphamide (FC) Relapsed or refractory, low-grade or follicular, CD20positive, B-cell NHL as a single agent Weekly ×4 Weekly ×8 Bulky disease Retreatment 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 firstline CVP chemotherapy Previously untreated diffuse large B-cell, CD20-positive NHL in combination with CHOP or other anthracyclinebased chemotherapy regimens RITUXAN is not recommended for use in patients with severe, active infections.

BOXED WARNINGS and Additional Important Safety Information RITUXAN therapy can result in serious, including fatal, adverse reactions. These include infusion reactions, tumor lysis syndrome (TLS), severe mucocutaneous reactions, progressive multifocal leukoencephalopathy (PML), hepatitis B reactivation with fulminant hepatitis, other infections, cardiovascular events, renal toxicity, and bowel obstruction and perforation. The most common adverse reactions of RITUXAN (incidence ≥25%) observed in patients with NHL were infusion reactions, fever, lymphopenia, chills, infection, and asthenia. The most frequent Grade 3 or 4 adverse reactions observed in NHL were cytopenias. The most common adverse reactions of RITUXAN (incidence ≥25%) observed in clinical trials of patients with CLL were infusion reactions and neutropenia. Most patients treated with R-FC experienced at least one Grade 3 or 4 adverse reaction. The most frequently reported Grade 3 or 4 adverse reaction was neutropenia. CLL patients 70 years of age or older who received R-FC had more Grade 3 and 4 adverse reactions compared with younger CLL patients who received the same treatment. For additional safety information, please see following page for brief summary of full prescribing information, including BOXED WARNINGS. Attention Healthcare Provider: Provide Medication Guide to patient prior to RITUXAN infusion.

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