March/April 2009 Vol. 2 No. 2 by The Oncology Pharmacist

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VIEWPOINT Massachusetts healthcare program has lessons for nation

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MARCH/APRIL 2009 • VOL. 2, NO. 2

er d a e L The s and ew in N eting Me age r Cove

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Arsenic Trioxide: A New Addition to Initial Treatment of APL BY 񡑒񡑃񡑖񡑄 񡑃񡑂񡑀 񡑆񡑃񡑖񡑑񡑁񡑀 񡑕񡑥񡑡񡑱񡑨񡑅 CLEVELAND CLINIC, OHIO

cute promyelocytic leukemia (APL) represents a relatively rare subtype of acute myeloid leukemia, occurring in approximately 1500 persons every year. It is characterized by a translocation of chromosomes 15 (promyelocytic leukemia gene) and 17 (retinoic acid receptor alpha). Along with pancytopenia, patients

often present with varying degrees of coagulopathy, which is a major source of morbidity and mortality during initial treatment. Complete response (CR) rates range from 80% to 95% during induction, and, depending on baseline risk factors, disease-free survival (DFS) can exceed 70% to 80%.1,2 Treatment in the 1970s

focused on the sensitivity of cells to chemotherapy, resulting in CR rates of 75%. The chemotherapy regimens used then consisted of an anthracycline and cytarabine. This treatment was complicated by a high rate of mortality due to coagulopathy, and 5-year DFS was only 35% to 45%.3,4 In the 1980s, Continued on page 18

Nilotinib in CP CML: Faster Responses, More with Bcr-Abl Transcripts Undetectable SAN FRANCISCO—Compared with earlier experience with imatinib, patients with early chronic phase (CP) Philadelphia-positive chronic myeloid leukemia (CML) receiving nilotinib achieved cytogenetic responses faster. In addition, stated Jorge Cortes, MD, M.D. Anderson Cancer Center, Houston, Texas, a higher percentage of patients had undetectable Bcr-Abl transcript levels. Earlier experience has shown, Cortes said at the 50th American Society of Hematology Annual Meeting, that standard-dose imatinib induces molecular complete remissions infrequently, that earlier responses Continued on page 19

COMPLIMENTARY CE CREDIT

PHARMACY PRACTICE

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AT WWW.THEONCOLOGYPHARMACIST.COM

Storing Alemtuzumab as Multiple Small Doses Preserves Stability, Reduces Costs

NCCN Updates Guidelines for NSCLC

PROGRAM #CIK10082

lemtuzumab (Campath) is commercially available only as a 30-mg single-use glass vial. A recent study demonstrates, however, that multiple doses can be prepared from a single vial and stored for 28 days without loss of activity. This could improve patient care and substantially reduce costs. Alemtuzumab is indicated for treatment of B-cell

o keep pace with the advances being made in non–small-cell lung cancer (NSCLC), the National Comprehensive Cancer Network (NCCN) recently updated its guidelines. The new guidelines were the topic of a presentation at the NCCN’s 13th annual conference by David S. Ettinger, MD, the Alex Grass Professor of Oncology at the Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins, Baltimore, Maryland. “The future is looking brighter for lung cancer

Continued on page 10

Continued on page 12

Reimbursement for Expensive Cancer Therapies: The Role of Cost-effectiveness Analysis

PAGE 13

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

LEUKINE

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

LEUKINE

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

▲ Reduces the incidence of early death associated with fungal infections, including deaths due to Aspergillus and Candida*1-3 ▲ Reduces the incidence of life-threatening, severe, and fatal infections1,2 ▲ Shortens time to neutrophil recovery1,2 ▲ Adverse event proﬁle similar to placebo1 *During and within 30 days of study completion.2

LEUKINE is indicated for use following induction chemotherapy in older adults with AML to shorten time to neutrophil recovery and to reduce the incidence of severe and life-threatening infections and infections resulting in death.

Important Information In controlled clinical trials across all indications, no signiﬁcant differences were observed between LEUKINE- and placebo-treated patients in the type or frequency of adverse events with the exception of an increase in skin-associated events in the LEUKINE group in the pivotal AML trial. There were occasional reports of ﬂuid retention, dyspnea, supraventricular tachycardia, and laboratory abnormalities (increases in creatinine, bilirubin, and liver enzymes). Other adverse events have been reported; please see full Prescribing Information, which contains a more complete listing of indications, contraindications, warnings, precautions, adverse events, and dosage and administration guidelines. Please see adjacent brief summary of full Prescribing Information.

References: 1. LEUKINE® (sargramostim) [package insert]. Seattle, Wash: Bayer HealthCare Pharmaceuticals Inc.; 2007. 2. Rowe JM, Rubin A, Mazza JJ, et al. Incidence of infections in adult patients (> 55 years) with acute myeloid leukemia treated with yeast-derived GM-CSF (sargramostim): results of a double-blind prospective study by the Eastern Cooperative Oncology Group. In: Hiddemann W, et al, eds. Acute Leukemias V: Experimental Approaches and Management of Refractory Diseases. Berlin, Germany: Springer-Verlag; 1996:178-184. 3. Rowe JM. Treatment of acute myeloid leukemia with cytokines: effect on duration of neutropenia and response to infections. Clin Infect Dis. 1998;26:1290-1294.

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

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BRIEF SUMMARY CONSULT PACKAGE INSERT FOR FULL PRESCRIBING INFORMATION INDICATIONS AND USAGE Use Following Induction Chemotherapy in Acute Myelogenous Leukemia LEUKINE is indicated for use following induction chemotherapy in older adult patients with acute myelogenous leukemia (AML) to shorten time to neutrophil recovery and to reduce the incidence of severe and life-threatening infections and infections resulting in death. The safety and efficacy of LEUKINE have not been assessed in patients with AML under 55 years of age. The term acute myelogenous leukemia, also referred to as acute non-lymphocytic leukemia (ANLL), encompasses a heterogeneous group of leukemias arising from various non-lymphoid cell lines which have been defined morphologically by the French-American-British (FAB) system of classification. Use in Mobilization and Following Transplantation of Autologous Peripheral Blood Progenitor Cells LEUKINE is indicated for the mobilization of hematopoietic progenitor cells into peripheral blood for collection by leukapheresis. Mobilization allows for the collection of increased numbers of progenitor cells capable of engraftment as compared with collection without mobilization. After myeloablative chemotherapy, the transplantation of an increased number of progenitor cells can lead to more rapid engraftment, which may result in a decreased need for supportive care. Myeloid reconstitution is further accelerated by administration of LEUKINE following peripheral blood progenitor cell transplantation. Use in Myeloid Reconstitution After Autologous Bone Marrow Transplantation LEUKINE is indicated for acceleration of myeloid recovery in patients with non-Hodgkin’s lymphoma (NHL), acute lymphoblastic leukemia (ALL) and Hodgkin’s disease undergoing autologous bone marrow transplantation (BMT). After autologous BMT in patients with NHL, ALL, or Hodgkin’s disease, LEUKINE has been found to be safe and effective in accelerating myeloid engraftment, decreasing median duration of antibiotic administration, reducing the median duration of infectious episodes and shortening the median duration of hospitalization. Hematologic response to LEUKINE can be detected by complete blood count (CBC) with differential cell counts performed twice per week. Use in Myeloid Reconstitution After Allogeneic Bone Marrow Transplantation LEUKINE is indicated for acceleration of myeloid recovery in patients undergoing allogeneic BMT from HLA-matched related donors. LEUKINE has been found to be safe and effective in accelerating myeloid engraftment, reducing the incidence of bacteremia and other culture positive infections, and shortening the median duration of hospitalization. Use in Bone Marrow Transplantation Failure or Engraftment Delay LEUKINE is indicated in patients who have undergone allogeneic or autologous bone marrow transplantation (BMT) in whom engraftment is delayed or has failed. LEUKINE has been found to be safe and effective in prolonging survival of patients who are experiencing graft failure or engraftment delay, in the presence or absence of infection, following autologous or allogeneic BMT. Survival benefit may be relatively greater in those patients who demonstrate one or more of the following characteristics: autologous BMT failure or engraftment delay, no previous total body irradiation, malignancy other than leukemia or a multiple organ failure (MOF) score ≤ two (see CLINICAL EXPERIENCE). Hematologic response to LEUKINE can be detected by complete blood count (CBC) with differential performed twice per week. CONTRAINDICATIONS LEUKINE is contraindicated: 1) in patients with excessive leukemic myeloid blasts in the bone marrow or peripheral blood (≥ 10%); 2) in patients with known hypersensitivity to GM-CSF, yeast-derived products or any component of the product; 3) for concomitant use with chemotherapy and radiotherapy. Due to the potential sensitivity of rapidly dividing hematopoietic progenitor cells, LEUKINE should not be administered simultaneously with cytotoxic chemotherapy or radiotherapy or within 24 hours preceding or following chemotherapy or radiotherapy. In one controlled study, patients with small cell lung cancer received LEUKINE and concurrent thoracic radiotherapy and chemotherapy or the identical radiotherapy and chemotherapy without LEUKINE. The patients randomized to LEUKINE had significantly higher incidence of adverse events, including higher mortality and a higher incidence of grade 3 and 4 infections and grade 3 and 4 thrombocytopenia.11 WARNINGS Pediatric Use Benzyl alcohol is a constituent of liquid LEUKINE and Bacteriostatic Water for Injection diluent. Benzyl alcohol has been reported to be associated with a fatal “Gasping Syndrome” in premature infants. Liquid solutions containing benzyl alcohol (including liquid LEUKINE ) or lyophilized LEUKINE reconstituted with Bacteriostatic Water for Injection, USP (0.9% benzyl alcohol) should not be administered to neonates (see PRECAUTIONS and DOSAGE AND ADMINISTRATION). Fluid Retention Edema, capillary leak syndrome, pleural and/or pericardial effusion have been reported in patients after LEUKINE administration. In 156 patients enrolled in placebo-controlled studies using LEUKINE at a dose of 250 mcg/m2/day by 2-hour IV infusion, the reported incidences of fluid retention (LEUKINE vs. placebo) were as follows: peripheral edema, 11% vs. 7%; pleural effusion, 1% vs. 0%; and pericardial effusion, 4% vs. 1%. Capillary leak syndrome was not observed in this limited number of studies; based on other uncontrolled studies and reports from users of marketed LEUKINE, the incidence is estimated to be less than 1%. In patients with preexisting pleural and pericardial effusions, administration of LEUKINE may aggravate fluid retention; however, fluid retention associated with or worsened by LEUKINE has been reversible after interruption or dose reduction of LEUKINE with or without diuretic therapy. LEUKINE should be used with caution in patients with preexisting fluid retention, pulmonary infiltrates or congestive heart failure. Respiratory Symptoms Sequestration of granulocytes in the pulmonary circulation has been documented following LEUKINE infusion12 and dyspnea has been reported occasionally in patients treated with LEUKINE. Special attention should be given to respiratory symptoms during or immediately following LEUKINE infusion, especially in patients with preexisting lung disease. In patients displaying dyspnea during LEUKINE administration, the rate of infusion should be reduced by half. If respiratory symptoms worsen despite infusion rate reduction, the infusion should be discontinued. Subsequent IV infusions may be administered following the standard dose schedule with careful monitoring. LEUKINE should be administered with caution in patients with hypoxia. Cardiovascular Symptoms Occasional transient supraventricular arrhythmia has been reported in uncontrolled studies during LEUKINE administration, particularly in patients with a previous history of cardiac arrhythmia. However, these arrhythmias have been reversible after discontinuation of LEUKINE. LEUKINE should be used with caution in patients with preexisting cardiac disease. Renal and Hepatic Dysfunction In some patients with preexisting renal or hepatic dysfunction enrolled in uncontrolled clinical trials, administration of LEUKINE has induced elevation of serum creatinine or bilirubin and hepatic enzymes. Dose reduction or interruption of LEUKINE administration has resulted in a decrease to pretreatment values. However, in controlled clinical trials the incidences of renal and hepatic dysfunction were comparable between LEUKINE (250 mcg/m2/day by 2-hour IV infusion) and placebotreated patients. Monitoring of renal and hepatic function in patients displaying renal or hepatic dysfunction prior to initiation of treatment is recommended at least every other week during LEUKINE administration. PRECAUTIONS General Parenteral administration of recombinant proteins should be attended by appropriate precautions in case an allergic or untoward reaction occurs. Serious allergic or anaphylactic reactions have been reported. If any serious allergic or anaphylactic reaction occurs, LEUKINE therapy should immediately be discontinued and appropriate therapy initiated. A syndrome characterized by respiratory distress, hypoxia, flushing, hypotension, syncope, and/or tachycardia has been reported following the first administration of LEUKINE in a particular cycle. These signs have resolved with symptomatic treatment and usually do not recur with subsequent doses in the same cycle of treatment. Stimulation of marrow precursors with LEUKINE may result in a rapid rise in white blood cell (WBC) count. If the ANC exceeds 20,000 cells/mm3 or if the platelet count exceeds 500,000/mm3, LEUKINE administration should be interrupted or the dose reduced by half. The decision to reduce the dose or interrupt treatment should be based on the clinical condition of the patient. Excessive blood counts have returned to normal or baseline levels within three to seven days following cessation of LEUKINE therapy. Twice weekly monitoring of CBC with differential (including examination for the presence of blast cells) should be performed to preclude development of excessive counts. Growth Factor Potential LEUKINE is a growth factor that primarily stimulates normal myeloid precursors. However, the possibility that LEUKINE can act as a growth factor for any tumor type, particularly myeloid malignancies, cannot be excluded. Because of the possibility of tumor growth potentiation, precaution should be exercised when using this drug in any malignancy with myeloid characteristics. Should disease progression be detected during LEUKINE treatment, LEUKINE therapy should be discontinued. LEUKINE has been administered to patients with myelodysplastic syndromes (MDS) in uncontrolled studies without evidence of increased relapse rates.13, 14, 15 Controlled studies have not been performed in patients with MDS.

Use in Patients Receiving Purged Bone Marrow LEUKINE is effective in accelerating myeloid recovery in patients receiving bone marrow purged by anti-B lymphocyte monoclonal antibodies. Data obtained from uncontrolled studies suggest that if in vitro marrow purging with chemical agents causes a significant decrease in the number of responsive hematopoietic progenitors, the patient may not respond to LEUKINE. When the bone marrow purging process preserves a sufficient number of progenitors (>1.2 x 104/kg), a beneficial effect of LEUKINE on myeloid engraftment has been reported.16 Use in Patients Previously Exposed to Intensive Chemotherapy/Radiotherapy In patients who before autologous BMT, have received extensive radiotherapy to hematopoietic sites for the treatment of primary disease in the abdomen or chest, or have been exposed to multiple myelotoxic agents (alkylating agents, anthracycline antibiotics and antimetabolites), the effect of LEUKINE on myeloid reconstitution may be limited. Use in Patients with Malignancy Undergoing LEUKINE-Mobilized PBPC Collection When using LEUKINE to mobilize PBPC, the limited in vitro data suggest that tumor cells may be released and reinfused into the patient in the leukapheresis product. The effect of reinfusion of tumor cells has not been well studied and the data are inconclusive. Information for Patients LEUKINE should be used under the guidance and supervision of a health care professional. However, when the physician determines that LEUKINE may be used outside of the hospital or office setting, persons who will be administering LEUKINE should be instructed as to the proper dose, and the method of reconstituting and administering LEUKINE (see DOSAGE AND ADMINISTRATION). If home use is prescribed, patients should be instructed in the importance of proper disposal and cautioned against the reuse of needles, syringes, drug product, and diluent. A puncture resistant container should be used by the patient for the disposal of used needles. Patients should be informed of the serious and most common adverse reactions associated with LEUKINE administration (see ADVERSE REACTIONS). Female patients of childbearing potential should be advised of the possible risks to the fetus of LEUKINE (see PRECAUTIONS, Pregnancy Category C). Laboratory Monitoring LEUKINE can induce variable increases in WBC and/or platelet counts. In order to avoid potential complications of excessive leukocytosis (WBC >50,000 cells/mm3; ANC >20,000 cells/mm3), a CBC is recommended twice per week during LEUKINE therapy. Monitoring of renal and hepatic function in patients displaying renal or hepatic dysfunction prior to initiation of treatment is recommended at least biweekly during LEUKINE administration. Body weight and hydration status should be carefully monitored during LEUKINE administration. Drug Interaction Interactions between LEUKINE and other drugs have not been fully evaluated. Drugs which may potentiate the myeloproliferative effects of LEUKINE, such as lithium and corticosteroids, should be used with caution. Carcinogenesis, Mutagenesis, Impairment of Fertility Animal studies have not been conducted with LEUKINE to evaluate the carcinogenic potential or the effect on fertility. Pregnancy (Category C) Animal reproduction studies have not been conducted with LEUKINE. It is not known whether LEUKINE can cause fetal harm when administered to a pregnant woman or can affect reproductive capability. LEUKINE should be given to a pregnant woman only if clearly needed. Nursing Mothers It is not known whether LEUKINE is excreted in human milk. Because many drugs are excreted in human milk, LEUKINE should be administered to a nursing woman only if clearly needed. Pediatric Use Safety and effectiveness in pediatric patients have not been established; however, available safety data indicate that LEUKINE does not exhibit any greater toxicity in pediatric patients than in adults. A total of 124 pediatric subjects between the ages of 4 months and 18 years have been treated with LEUKINE in clinical trials at doses ranging from 60-1,000 mcg/m2/day intravenously and 4-1,500 mcg/m2/day subcutaneously. In 53 pediatric patients enrolled in controlled studies at a dose of 250 mcg/m2/day by 2hour IV infusion, the type and frequency of adverse events were comparable to those reported for the adult population. Liquid solutions containing benzyl alcohol (including liquid LEUKINE ) or lyophilized LEUKINE reconstituted with Bacteriostatic Water for Injection, USP (0.9% benzyl alcohol) should not be administered to neonates (see WARNINGS). Geriatric Use In the clinical trials, experience in older patients (age ≥65 years), was limited to the acute myelogenous leukemia (AML) study. Of the 52 patients treated with LEUKINE in this randomized study, 22 patients were age 65-70 years and 30 patients were age 55-64 years. The number of placebo patients in each age group were 13 and 33 patients respectively. This was not an adequate database from which determination of differences in efficacy endpoints or safety assessments could be reliably made and this clinical study was not designed to evaluate difference between these two age groups. Analyses of general trends in safety and efficacy were undertaken and demonstrate similar patterns for older (65-70 yrs) vs younger patients (55-64 yrs). Greater sensitivity of some older individuals cannot be ruled out. ADVERSE REACTIONS Autologous and Allogeneic Bone Marrow Transplantation LEUKINE is generally well tolerated. In three placebo-controlled studies enrolling a total of 156 patients after autologous BMT or peripheral blood progenitor cell transplantation, events reported in at least 10% of patients who received IV LEUKINE or placebo were as reported in Table 6. No significant differences were observed between LEUKINE and placebo-treated patients in the type or frequency of laboratory abnormalities, including renal and hepatic parameters. In some patients with preexisting renal or hepatic dysfunction enrolled in uncontrolled clinical trials, administration of LEUKINE has induced elevation of serum creatinine or bilirubin and hepatic enzymes (see WARNINGS). In addition, there was no significant difference in relapse rate and 24 month survival between the LEUKINE and placebotreated patients. In the placebo-controlled trial of 109 patients after allogeneic BMT, events reported in at least 10% of patients who received IV LEUKINE or placebo were as reported in Table 7. There were no significant differences in the incidence or severity of GVHD, relapse rates and survival between the LEUKINE and placebo-treated patients. Adverse events observed for the patients treated with LEUKINE in the historically-controlled BMT failure study were similar to those reported in the placebo-controlled studies. In addition, headache (26%), pericardial effusion (25%), arthralgia (21%) and myalgia (18%) were also reported in patients treated with LEUKINE in the graft failure study. In uncontrolled Phase I/II studies with LEUKINE in 215 patients, the most frequent adverse events were fever, asthenia, headache, bone pain, chills and myalgia. These systemic events were generally mild or moderate and were usually prevented or reversed by the administration of analgesics and antipyretics such as acetaminophen. In these uncontrolled trials, other infrequent events reported were dyspnea, peripheral edema, and rash. Reports of events occurring with marketed LEUKINE include arrhythmia, fainting, eosinophilia, dizziness, hypotension, injection site reactions, pain (including abdominal, back, chest, and joint pain), tachycardia, thrombosis, and transient liver function abnormalities. In patients with preexisting edema, capillary leak syndrome, pleural and/or pericardial effusion, administration of LEUKINE may aggravate fluid retention (see WARNINGS). Body weight and hydration status should be carefully monitored during LEUKINE administration. Adverse events observed in pediatric patients in controlled studies were comparable to those observed in adult patients. Acute Myelogenous Leukemia Adverse events reported in at least 10% of patients who received LEUKINE or placebo were as reported in Table 8. Nearly all patients reported leukopenia, thrombocytopenia and anemia. The frequency and type of adverse events observed following induction were similar between LEUKINE and placebo groups. The only significant difference in the rates of these adverse events was an increase in skin associated events in the LEUKINE group (p=0.002). No significant differences were observed in laboratory results, renal or hepatic toxicity. No significant differences were observed between the LEUKINE and placebo-treated patients for adverse events following consolidation. There was no significant difference in response rate or relapse rate. In a historically-controlled study of 86 patients with acute myelogenous leukemia (AML), the LEUKINE treated group exhibited an increased incidence of weight gain (p=0.007), low serum proteins and prolonged prothrombin time (p=0.02) when compared to the control group. Two LEUKINE treated patients had progressive increase in circulating monocytes and promonocytes and blasts in the marrow which reversed when LEUKINE was discontinued. The historical control group exhibited an increased incidence of cardiac events (p=0.018), liver function abnormalities (p=0.008), and neurocortical hemorrhagic events (p=0.025).15 Antibody Formation Serum samples collected before and after LEUKINE treatment from 214 patients with a variety of underlying diseases have been examined for immunogenicity based on the presence of antibodies. Neutralizing antibodies were detected in five of 214 patients (2.3%) after receiving LEUKINE by continuous IV infusion (three patients) or subcutaneous injection (SC)(two patients) for 28 to 84 days in multiple courses. All five patients had impaired hematopoiesis before the administration of LEUKINE and consequently the effect of the development of anti-GM-CSF antibodies on normal hematopoiesis could not be assessed. Antibody studies of 75 patients with Crohn’s disease receiving LEUKINE by subcutaneous injection with normal hematopoiesis and no other immunosuppressive drugs showed one patient (1.3%) with detectable neutralizing antibodies. The clinical relevance of the presence of these antibodies are unknown. Drug-induced neutropenia, neutralization of endogenous GM-CSF activity and diminution of the therapeutic effect of LEUKINE secondary to formation of neutralizing antibody remain a theoretical possibility. Serious allergic and anaphylactoid reactions have been reported with LEUKINE but the rate of occurrence of antibodies in such patients has not been assessed. Overdosage The maximum amount of LEUKINE that can be safely administered in single or multiple doses has not been determined. Doses up to 100 mcg/kg/day (4,000 mcg/m2/day or 16 times the recommended dose) were administered to four patients in a Phase I uncontrolled clinical study by continuous IV infusion for 7 to 18 days. Increases in WBC up to 200,000 cells/mm3 were observed. Adverse events reported were dyspnea, malaise, nausea, fever, rash, sinus tachycardia, headache and chills. All these events were reversible after discontinuation of LEUKINE. In case of overdosage, LEUKINE therapy should be discontinued and the patient carefully monitored for WBC increase and respiratory symptoms.

Table 6

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

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

Table 7

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

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

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

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

Table 8

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

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

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

REFERENCES 11. Bunn P, Crowley J, Kelly K, et al. Chemoradiotherapy with or without granulocyte-macrophage colonystimulating factor in the treatment of limited-stage small-cell lung cancer: a prospective phase III randomized study of the southwest oncology group. JCO 1995; 13(7):1632-1641. 12. Herrmann F, Schulz G, Lindemann A, et al. Yeast-expressed granulocyte-macrophage colonystimulating factor in cancer patients: A phase Ib clinical study. In Behring Institute Research Communications, Colony Stimulating Factors-CSF. International Symposium, Garmisch-Partenkirchen, West Germany. 1988; 83:107-118. 13. Estey EH, Dixon D, Kantarjian H, et al. Treatment of poor-prognosis, newly diagnosed acute myeloid leukemia with Ara-C and recombinant human granulocyte-macrophage colony-stimulating factor. Blood 1990; 75(9):1766-1769. 14. Vadhan-Raj S, Keating M, LeMaistre A, et al. Effects of recombinant human granulocyte-macrophage colony-stimulating factor in patients with myelodysplastic syndromes. NEJM 1987; 317:1545-1552. 15. Buchner T, Hiddemann W, Koenigsmann M, et al. Recombinant human granulocyte-macrophage colony stimulating factor after chemotherapy in patients with acute myeloid leukemia at higher age or after relapse. Blood 1991; 78(5):1190-1197. 16. Blazar BR, Kersey JH, McGlave PB, et al. In vivo administration of recombinant human granulocyte/macrophage colony-stimulating factor in acute lymphoblastic leukemia patients receiving purged autografts. Blood 1989; 73(3):849-857. © 2008, Bayer HealthCare Pharmaceuticals Inc. All rights reserved. U.S. Patent Nos. 5,391,485; 5,393,870; and 5,229,496. Licensed under Research Corporation Technologies U.S. Patent No. 5,602,007, and under Novartis Corporation U.S. Patent Nos. 5,942,221; 5,908,763; 5,895,646; 5,891,429; and 5,720,952. Manufactured by:

Bayer HealthCare Pharmaceuticals, LLC. Seattle, WA 98101 US License No. 1791

6701801BS

(11981)

Revised April 2008

EDITORS’ LETTER

A Letter from the Editors SUSAN GOODIN, PharmD, FCCP, BCOP

PATRICK MEDINA, PharmD, BCOP

The Rising Costs of Cancer Care

n this issue of The Oncology Pharmacist we are reminded by two articles how the rising cost of cancer care may potentially impact the treatment of patients with cancer. The National Institutes of Health estimated overall annual costs of cancer in 2007 to be $219.2 billion, with approximately 40% of that related to direct medical costs (including drugs). These costs are expected to rise in the future. The March 27 editorial in the Wall Street Journal (see page 8) comments on the Massachusetts plan to reduce healthcare costs in a state with severe budget restraints. The plan, which covers middle-class state residents, would “limit coverage to services that produce the highest value when considering both clinical effectiveness and cost.” The potential impact on cancer patients could be profound, as proving both the clinical and

cost-effectiveness of cancer therapies has been historically difficult. If this plan reaches the national level, cancer patients may be drastically affected, with an increasing burden of costs shifted to them. This potential policy is also in contrast to the American Cancer Society’s position that reducing barriers to cancer care is critical in the fight to eliminate suffering and death due to cancer. The continuing education article by Gary Yee in this issue (page 13) suggests one controversial way to decrease the costs of cancer care through using cost-effectiveness models. As mentioned in the article and the accompanying commentaries, however, determining the level at which a medication becomes “cost-effective” largely depends on one’s point of view. Not surprisingly, patients and healthcare insurers place different values on the cost-effectiveness of a medication.

Coming Soon CE article: Treatment of Advanced Non–Small Cell-Lung Cancer: Gefitinib vs Docetaxel Setting Up a Chemotherapy Prep Area in a Community Practice New Technologies in HER2 Testing Ixabepilone: A New Treatment for Metastatic Breast Cancer Increasing Oncology Patient Participation in Clinical Trials: The Coalition of Cancer Cooperative Groups

EDITORS’ LETTER

Reports from NCCN 14th Annual Conference, Scripps Cancer Center’s 29th Annual Conference on Clinical Hematology and Oncology

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With increasing coinsurance charges, declining lifetime caps, and increasing costs of medications, one in five people with health insurance who are diagnosed with cancer uses all or most of his or her savings because of the financial cost of care. Efforts to decrease, not increase, this number should become a priority. This does not include the impact of those with no or limited medical insurance. Obviously there is no easy answer to these rising healthcare costs, but potentially limiting care to cancer patients may have damaging consequences. Pharmacists should continue to assure that medications are used in the most appropriate manner, assist patients in obtaining medications with the minimal financial impact possible, and continue to be an advocate for cancer patients in the management of their disease.

EDITORIAL CORRESPONDENCE should be addressed to EDITORIAL DIRECTOR, The Oncology Pharmacist®, 241 Forsgate Drive, Suite 205C, Monroe Twp, NJ 08831. E-mail: editorial@greenhillhc.com. YEARLY SUBSCRIPTION RATES: United States and possessions: individuals, $105.00; institutions, $135.00; single issues $17.00. Orders will be billed at individual rate until proof of status is confirmed. Prices are subject to change without notice. Correspondence regarding permission to reprint all or part of any article published in this journal should be addressed to REPRINT PERMISSIONS DEPARTMENT, Green Hill Healthcare Communications, LLC, 241 Forsgate Drive, Suite 205C, Monroe Twp, NJ 08831. The ideas and opinions expressed in The Oncology Pharmacist® do not necessarily reflect those of the Editorial Board, the Editorial Director, or the Publisher. Publication of an advertisement or other product mention in The Oncology Pharmacist® should not be construed as an endorsement of the product or the manufacturer’s claims. Readers are encouraged to contact the manufacturer with questions about the features or limitations of the products mentioned. Neither the Editorial Board nor the Publisher assumes any responsibility for any injury and/or damage to persons or property arising out of or related to any use of the material contained in this periodical. The reader is advised to check the appropriate medical literature and the product information currently provided by the manufacturer of each drug to be administered to verify the dosage, the method and duration of administration, or contraindications. It is the responsibility of the treating physician or other healthcare professional, relying on independent experience and knowledge of the patient, to determine drug dosages and the best treatment for the patient. Every effort has been made to check generic and trade names, and to verify dosages. The ultimate responsibility, however, lies with the prescribing physician. Please convey any errors to the Editorial Director. ISSN #1944-9607. The Oncology Pharmacist® is published 7 times a year by Green Hill Healthcare Communications, LLC, 241 Forsgate Drive, Suite 205C, Monroe Twp, NJ 08831. Telephone: 732.656.7935. Fax: 732.656.7938. Copyright ©2009 by Green Hill Healthcare Communications, LLC. All rights reserved. The Oncology Pharmacist® logo is a registered trademark of Green Hill Healthcare Communications, LLC. No part of this publication may be reproduced or transmitted in any form or by any means now or hereafter known, electronic or mechanical, including photocopy, recording, or any informational storage and retrieval system, without written permission from the Publisher. Printed in the United States of America.

March/April 2009

STRONG. FROM THE START.

FOR A SUCCESSFUL CINV PREVENTION STRATEGY FROM THE FIRST CYCLE When patients experience acute chemotherapy-induced 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®: A single IV dose lasts up to 5 days after MEC4,5* The only IV 5-HT3 antiemetic speciﬁcally approved for prevention of both acute and delayed CINV associated with MEC6* 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. 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 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. Chemotherapyinduced nausea and vomiting: incidence and impact on patient quality of life at community oncology settings. Support Care Cancer. 2007;15:497503. 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

News Notes NEWS NOTES

■ Wristbands Reduce Nausea Associated with Cancer Care Acupressure wristbands are a lowcost, safe, and effective adjunct to standard antiemetic therapy in patients with cancer treatment–related nausea, according to a study by University of Rochester researchers. Joseph A. Roscoe, PhD, and associates ALOXI® (palonosetron HCl) injection BRIEF SUMMARY OF PRESCRIBING INFORMATION INDICATIONS AND USAGE

NEWS NOTES

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-HT3 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.

divided 88 patients who had experienced nausea after previous radiation treatments into three groups. Patients received either standard care (group 1) or standard care plus wristbands with either neutral (group 2) or positive (group 3) information about the bands’ efficacy. Patients in groups 2 and 3 reported a 23.8% decrease in

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.

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nausea compared with a 4.8% decrease in group 1. No significant difference in nausea was found between the two groups that received wristbands (J Pain Symptom Manag. 2009 Mar 27. [Epub ahead of print]).

■ Patient’s Medication Beliefs Influence Adherence Patients’ beliefs about medication, such as their perceptions of medication necessity and concerns about their potential harmful effects, influence their adherence to medication, a new study 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. © 2008 Eisai Inc. All rights reserved. Printed in USA. AL350 10/08

shows. In a survey of 275 inner-city hospital pharmacy patients, Margaret E. Gatti and associates found that 52.7% reported low medication adherence (score of >2 on the Morisky 8-item Medication Adherence Scale). Negative beliefs about medications were significantly associated with low medication adherence. Other factors independently associated with low adherence were age <65 years, low medication self-efficacy scores, and hyperlipidemia. According to the authors, healthcare providers need to address patients’ concerns about medication and educate them about the importance of adherence to prescribed therapies (Am J Health-Syst Pharm. 2009; 66:657-664).

■ ASCO Guide on Managing Costs of Care A new American Society of Clinical Oncology (ASCO) guide, Managing the Cost of Cancer Care, can help patients and clinical staff communicate about the costs of cancer care. The guide can help patients understand what costs to expect. Included in the guide is a list of questions patients can ask their providers about healthcare costs. Information on resources for employment or health insurance problems is also included, along with tips for organizing bills and expenses, a list of financial resources available to people with cancer, and a glossary of cancer treatment and financial terms. The guide can be downloaded at www.cancer.net/ managing costofcare. ■ Survey Shows Rise in Prescription Abandonment, Generic Drug Use New data show an increasing rate of “prescription abandonment” by consumers and greater use of generic drugs. The Wolters Kluwer Health annual analysis of the US pharmaceutical market shows that prescription abandonment (defined as failure of a patient to pick up a prescription submitted to a pharmacy) grew from an average of 5.15% in 2006 to 6.8% in 2008, a 34% increase. Abandonment increased as the copay rose, especially for new prescriptions. The data also show that 60% of all prescriptions filled in 2008 were for generic drugs (www.wolterskluwer health.com). ■ Targeted Therapies Used More Often Among Informed Patients Patients with colorectal cancer who search for health information on the Internet and in the news media are more likely to be aware of and receive targeted therapy. A retrospective analysis by researchers from the NCI Center of Excellence in Cancer Communication Research at the University of Pennsylvania Annenberg School showed a correlation between patient awareness of bevacizumab and cetuximab and use of these drugs. However, patients did not always understand which treatments were appropriate or inappropriate for their condition. The researchers emphasize the importance of exploring patient influence on physician prescribing patterns and understanding the impact of information seeking on cancer outcomes (Cancer. 2009;115:14 24-1434). March/April 2009

March/April 2009

11 Drugs in Development New drugs target hedgehog pathway

Continuing Education

Reimbursement for expensive cancer therapies: the role of cost-effectiveness analysis

19 Conference News

Imatinib plus Peg IFN for chronic phase CML

20 Prostate Cancer

Brachytherapy cost-effective for localized prostate cancer

Editors’ Letter

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March/April 2009

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The University of Texas MD Anderson Cancer Center Houston, TX

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John F. Aforismo, BSc Pharm, RPh, FASCP

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CONTENTS

Vol. 2, No. 2

John M. Valgus, PharmD, BCOP

University of North Carolina Hospitals and Clinics Chapel Hill, NC

New York Presbyterian Hospital/Weill Cornell Medical School New York, NY

Gary C. Yee, PharmD, FCCP, BCOP University of Nebraska College of Pharmacy Omaha, NE

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Medical Minutes MEDICAL MINUTES

BY JOHN SCHIESZER

John Schieszer is an award-winning national journalist and radio broadcaster of The Medical Minute. He can be reached at medminutes@aol.com.

SBRT May Provide Favorable Results in the Treatment of Early-Stage Prostate Cancer Preliminary results suggest that a shortened course of radiation therapy for prostate cancer with stereotactic body radiation therapy (SBRT) may provide good prostate-specific antigen response for early-stage prostate cancer. In addition, this approach has the same side-effect profile as other treatments, according to a new study by researchers at Stanford University. Although external-beam radiation therapy (EBRT) can be very effective and minimally invasive for the treatment of localized prostate cancer, the length of treatment can be burdensome for some patients, particularly those who live far away from a treatment facility. So, investigators have been studying ways to shorten the course of treatment through SBRT. With this method, patients receive a higher dose of radiation every day for 5 days. Growing biological evidence also suggests that delivering radiotherapy in this fashion might be more effective for prostate cancer than conventionally protracted courses. In the current study, researchers from Stanford University treated

41 men with low-risk prostate cancer with SBRT (King CR, et al. Int J Radiat Oncol Biol Phys. 2009;73:1043-1048). After a median followup of 33 months, none of the men in the study had prostate cancer recurrence. Reported side effects, including urinary and rectal problems, were no better or worse than those with other prostate cancer radiation treatments. “There is great enthusiasm for reducing the length of treatment for prostate cancer while also possibly improving its effectiveness, and these early results are very promising for men with early-stage prostate cancer,” said Christopher R. King, MD, PhD, who is an associate professor of radiation oncology at Stanford University School of Medicine, Stanford, California. “However, it can often take as long as 10 years to see late side effects and recurrences, so we will have to monitor these men closely and cautiously pursue these treatments further before we can confidently say that SBRT is as good as other proven prostate cancer treatments, like EBRT, brachytherapy, or surgery.”

Combining Chemotherapy with Radiotherapy May Benefit Glioblastoma Patients Giving patients with glioblastoma temozolomide in combination with radiotherapy (TMZ/RT) may increase survival compared with those patients receiving radiotherapy (RT) alone. These improvements in survival may persist for up to 5 years, according to European researchers. For more than 30 years, postoperative RT has been the standard poor diagnosis (elderly patients and those whose tumor could treatment for glioblastoma. However, it has offered only modest sur- not be surgically removed). In addition, the researchers found vival benefits to patients. The average life expectancy of glioblas- that overall survival data were best in patients being treated with TMZ/RT whose tumors carried an inactivated MGMT toma patients is 9 to 12 months. In 2004, after many disappointing attempts with drug therapy, (0-6-methylguanine-DNA methyltransferase) gene. Almost half the large international phase 3 EORTC-NCIC trial finally of these patients were alive after 2 years, and they showed a pershowed promising results in this difficult setting where use of sistent survival advantage at 3, 4, and 5 years. The authors sugTMZ/RT was found to reduce the risk of dying from glioblastoma gest that testing tumors for the methylation status of the MGMT by 37% compared with RT alone. At 2 years, researchers found gene would allow the selection of patients most likely to benefit that 27% of patients receiving TMZ/RT were alive, compared from this treatment regimen. with just 10% of patients being treated with RT alone. However, whether this survival benefit would persist over time was unknown. In the current study, Roger Stupp, MD, from the University of Lausanne Hospitals, Lausanne, Switzerland, A new study suggests for the first time that group of 282 patients with follicular lymand his colleagues examined the 5-year maintenance therapy with the monoclonal phoma, the corresponding rates were 64% outcomes of patients enrolled in the antibody rituximab following cyclophos- for MR patients and 33% for controls. With study (Stupp R, et al. Lancet Oncol. phamide, vincristine, and prednisone more than 10 years’ follow-up, the patients 2009; Mar 6. Epub ahead of print). (CVP) therapy may improve progression- receiving MR went nearly 5 years on average They sought to determine whether clinical factors and the molecular profree survival in patients with stage III-IV before relapse, compared with 1.9 years for file of the tumors would identify which indolent lymphoma. control subjects. patients may fare best with TMZ/RT. The researchers studied 311 patients with “Low-grade lymphoma is very treatable, The investigators found that 16% of stable or responding disease after CVP ther- with patients living many years on average,” patients receiving TMZ/RT were alive apy. The patients were randomly assigned to said lead study author Howard Hochster, at 3 years compared with just 4% in the observation only or maintenance rituximab MD, who is a professor of medicine and group receiving just RT. At 4 years, the (MR) 375 mg/m2 once per week for 4 weeks pharmacology at New York University overall survival rate was 12.1% in the every 6 months for 2 years (Hochster H, et School of Medicine. “But no one treatment TMZ/RT group compared with just 3% al. J Clin Oncol. 2009; Mar 2. Epub ahead of to date has shown benefit on long-term surfor the RT alone group, and at 5 years, print). An improved disease response was vival. This reasonably nontoxic antibody it was 9.8% and 1.9% for the TMZ/RT seen in 22% of the MR group versus just 7% can improve disease-free survival by several and the RT groups, respectively. of the control subjects. Toxic effects were years and possibly affect overall survival. In The researchers noted that im minimal in both groups. Three-year progres- this group of patients, even 10 years of provement in survival was seen across sion-free survival was also higher in the MR observation is a little too soon to show surall clinical prognostic subgroups, group (68% vs 33% in controls). In the sub- vival benefits, but the trend is present.” even in patients considered to have a

Almost half of these patients were alive after 2 years, and they showed a persistent survival advantage at 3, 4, and 5 years.

Maintenance Rituximab May Be Useful for Advanced Indolent Lymphoma

MEDICAL MINUTES 6

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March/April 2009

NATIONAL SAFE HANDLING awareness month

Furthering education surrounding the safe handling of hazardous drugs

april 2009

It’s not too late to attend the National Safe Handling Awareness Day CE Webcast on April 20th from 1–2pm EST This month we recognize the first-ever National Safe Handling Awareness Month and National Safe Handling Awareness Day. As official sponsor, Carmel Pharma – the maker of PhaSeal® – is proud to provide a complimentary CE webcast detailing the proper handling of hazardous drugs, followed by a live “Ask the Experts” session featuring today’s industry thought leaders. Register now for the webcast or find more information at carmelpharmausa.com/aware or call 866-487-9250.

Protection is Prevention. This program is pending ﬁnal accreditation for 1.0 contact hours of continuing education for pharmacists, nurses and healthcare risk managers.

National Health Preview

The Massachusetts debacle, coming soon to your neighborhood.

VIEWPOINT

raise Mitt Romney. Three years ago, the former Massachusetts Governor had the inadvertent good sense to create the â&#x20AC;&#x153;universalâ&#x20AC;? health-care program that the White House and Congress now want to inflict on the entire country. It is proving to be instructive, as Mr Romneyâ&#x20AC;&#x2122;s foresight previews what President Obama, Max Baucus, Ted Kennedy and Pete Stark are cooking up for everyone else. In Massachusettsâ&#x20AC;&#x2122;s latest crisis, Governor Deval Patrick and his Democratic colleagues are starting to move down the path that government health plans always follow when spending collides with realityâ&#x20AC;&#x201D;ie, price controls. As costs continue to rise, the inevitable results are coverage restrictions and waiting periods. It was only a matter of time. Theyâ&#x20AC;&#x2122;re trying to manage the huge costs of the subsidized middle-class insurance program that is gradually swallowing the state budget. The program provides low- or no-cost coverage to about 165,000 residents, or threefifths of the newly insured, and is budgeted at $880 million for 2010, a 7.3% single-year increase that is likely to be optimistic. The stateâ&#x20AC;&#x2122;s overall costs on health programs have increased by 42% (!) since 2006. Like gamblers doubling down on their losses, Democrats have already hiked the fines for people who donâ&#x20AC;&#x2122;t obtain insurance under the â&#x20AC;&#x153;individual mandate,â&#x20AC;? already increased business penalties, taxed insurers and hospitals, raised premiums, and pumped up the state tobacco levy. Thatâ&#x20AC;&#x2122;s still not enough money. So earlier this year, Mr Patrick appointed a state commission to figure out how to control costs and preserve â&#x20AC;&#x153;this grand experiment.â&#x20AC;? One objective is to change the incentives for preventative care and treatments for chronic disease, but everyone says that. It sometimes results in better health but always more spending. Socalled â&#x20AC;&#x153;pay for performanceâ&#x20AC;? financing models, on the other hand, would do away with fee for serviceâ&#x20AC;&#x201D;but they also tend to reward process, not the better results implied. What are the alternatives? If health planners wonâ&#x20AC;&#x2122;t accept the prices set by the marketplaceâ&#x20AC;&#x201D;thus putting themselves out of workâ&#x20AC;&#x201D;the only other choice is limiting care via politics, much as Canada and most of Europe do today. The Patrick panel is considering one option to â&#x20AC;&#x153;exclude coverage of services of low priority/low value.â&#x20AC;? Another would â&#x20AC;&#x153;limit coverage to services that produce the highest value when considering both clinical effectiveness and cost.â&#x20AC;? (Guess who would determine what is high or low value? Not patients or doctors.) Yet another is â&#x20AC;&#x153;a limitation on the total amount of money available for health care services,â&#x20AC;? ie, an overall spending cap. 8

The Institute for Americaâ&#x20AC;&#x2122;s Futureâ&#x20AC;&#x201D; which is providing the intellectual horsepower (we use the term loosely) for reforms like those in Massachusettsâ&#x20AC;&#x201D;argues that the cost overruns prove the state must cap how

much insurers are allowed to charge consumers and regulate their profits. If Mr Patrick doesnâ&#x20AC;&#x2122;t get there first, that is. He reportedly told insurers and hospitals at a closed meeting this month that if they didnâ&#x20AC;&#x2122;t take steps to hold

down the rate of medical inflation, he would. Even the single-payer cheerleaders at the New York Times have caught on to this rolling catastrophe. In a pageone story this month, the paper

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March/April 2009

and constrain their medical practices, they said.â&#x20AC;? Now they tell us. What really whipped along RomneyCare were claims that health care would be less expensive if everyone were covered. But reducing costs while increasing access are irreconcilable issues. Mr Romney should have known better before signing on to this not-sogrand experiment, especially since the stateâ&#x20AC;&#x2122;s â&#x20AC;&#x153;free marketâ&#x20AC;? reforms that he boasts about have proven to be irrelevant when not fictional. Only

21,000 people have used the â&#x20AC;&#x153;connectorâ&#x20AC;? that was supposed to link individuals to private insurers. Which brings us to Washington, where Mr Obama and Congressional Democrats are about to try their own Bay State bait and switch: First create vast new entitlements that can never be repealed, then later take the less popular step of rationing care when itâ&#x20AC;&#x2122;s their last hope to save the federal fisc. The consequences of that deception will be far worse than those in Mas-

sachusetts, however, given that prior to 2006 the state already had a far smaller percentage of its population uninsured than the national average. The real lesson of Massachusetts is that reform proponents wonâ&#x20AC;&#x2122;t tell Americans the truth about what â&#x20AC;&#x153;universalâ&#x20AC;? coverage really means: Runaway costs followed by price controls and bureaucratic rationing. Reprinted with permission from Opinion Journal, The Wall Street Journal. March 27, 2009.

VIEWPOINT

reported on the â&#x20AC;&#x153;expedient choiceâ&#x20AC;? that Mr Romney and Democrats made to defer â&#x20AC;&#x153;until another day any serious effort to control the stateâ&#x20AC;&#x2122;s runaway health costâ&#x20AC;Ś.Those who led the 2006 effort said it would not have been feasible to enact universal coverage if the legislation had required heavy cost controls. The very stakeholders who were coaxed into the tentâ&#x20AC;&#x201D;doctors, hospitals, insurers and consumer groupsâ&#x20AC;&#x201D;would probably have been driven into opposition by efforts to reduce their revenues

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VIEWPOINT

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March/April 2009

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Storing Alemtuzumab PHARMACY PRACTICE

Continued from cover

chronic lymphocytic leukemia (CLL) and has been used as an induction agent in solid organ transplantation. For CLL, the monoclonal antibody is typically started at a dose of 3 mg and increased to the maintenance dose of 30 mg three times a week. For induction, the ideal dose has not been determined, but

because of the lack of stability data, the preparation of doses smaller than 30 mg often results in waste. To determine whether preparation of small aliquots of alemtuzumab would be practical, Lee C. Vermeulen, RPh, MS, FCCP, and his colleagues conducted a stability study of alemtuzumab activity

in a sterile storage system for up to 28 days. Vermeulen is director, Center for Drug Policy, University of Wisconsin Hospital and Clinics, and clinical associate professor at the University of Wisconsin School of Pharmacy, Madison. “The initial impetus for the study was to show that aliquots of alem-

tuzumab remain stable over the course of a month so they can be used for transplant patients (when organs become available intermittently),” he explained. “The results, however, are equally relevant when trying to reduce waste in an oncology clinic.” Using an aseptic technique, the

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G REEN H ILL H EALTHCARE C OMMUNICATIONS

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March/April 2009

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started), in my clinic, some drug is wasted and even a little is very expensive. Clinic staff hate to have the patient wait a long time between when counts are verified and the infusion is started so doses are sometimes prepared in advance and then not administered if counts donâ&#x20AC;&#x2122;t allow it. Even if that happens rarely, the high cost of this product leads to huge financial losses every time a dose is wasted. I suspect losses could be in the tens of thousands of dollars per year in some clinics,â&#x20AC;? he said. Vermeulen and his colleagues have

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3 % $ # . ) , # ! 2 . ( ( # & -( # " " ( + , ! ! 8< $ ! 8 # ! , 899 E ! 2 . # , & ! ! 9&; # ! 899 E ! 2 . "

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also studied the stability of cetuximab and panitumumab (using ELISA, not flow cytometry) with the same intentâ&#x20AC;&#x201D;to lengthen the expiration date on these products to reduce waste and cost. â&#x20AC;&#x153;There is a real dearth of data on the stability of many biological products, so weâ&#x20AC;&#x2122;re hoping to conduct similar studies on other products (both in oncology and in other areas) in the future,â&#x20AC;? he said. â&#x20AC;&#x201D;Karen Rosenberg

ńĄ&#x2018; ńĄ&#x2018;?ńĄ&#x2018;&#x201C;ńĄ&#x2018;&#x192;ńĄ&#x2018;&#x2018;ńĄ&#x2018;&#x20AC;ńĄ&#x2018;&#x201E;ńĄ&#x2018;&#x2021; ńĄ&#x2018; ńĄ&#x2018;&#x201A;ńĄ&#x2018;&#x201D;ńĄ&#x2018;&#x201A;ńĄ&#x2018;&#x2026;ńĄ&#x2018;&#x2C6;ńĄ&#x2018;&#x2030;ńĄ&#x2018;&#x2020;ńĄ&#x2018;&#x201A;ńĄ&#x2018;&#x2021;ńĄ&#x2018;&#x2019; Hedgehog Hunters: Three Companies Target Cancer Molecular Pathway

arly clinical findings show that inhibiting the hedgehog pathway can result in a high proportion of remissions with low toxicity for certain rare but aggressive cancers. In small clinical studies involving patients with invasive or metastatic basal cell carcinoma (BCC), the development-stage compound GDC-0449 (Genentech) showed good activity and excellent safety. Charles Rudin, MD, PhD, who is associate director for clinical research at Johns Hopkins University in Baltimore, presented a study of 42 patients with solid tumors at the Symposium on Molecular Targets and Cancer Therapeutics in Geneva, Switzerland, in October 2008. Only patients with advanced BCC (n = 13) showed responses, with 10 having partial responses or stable disease, one having progressive disease, and two too early to evaluate. BCC is usually one of the most curable cancers, but rarely, it becomes invasive, aggressive, and metastatic, especially in individuals with Gorlin syndrome, because of a genetic defect in the hedgehog pathway. â&#x20AC;&#x153;This is a tumor type where the vast majority of patients have mutations in the hedgehog signaling pathway that lead to constitutive activation of the pathway,â&#x20AC;? Rudin said, â&#x20AC;&#x153;and in fact we did see significant clinical benefit in almost all basal cell skin cancer patients who were treated in the study.â&#x20AC;? Possibly more significantly, the activity of hedgehog antagonists is a proof of concept that the approach is biologically sound and may have application to other tumors with this specific molecular defect. The hedgehog pathway is normally repressed, but when hedgehog ligand binds to its cell-surface receptor, the pathway is derepressed. Hedgehog genes are then activated, and many of them are involved in cell proliferation, Continued on page 18

March/April 2009

PHARMACY PRACTICE

The ability to prepare multiple doses of alemtuzumab from a single vial could result in substantial cost savings, according to the authors (Am J Transplant. 2009;9:651-652). â&#x20AC;&#x153;Expecations for savings would depend on how much alemtuzumab is used in a particular clinic, and what procedures are in place to avoid waste,â&#x20AC;? Vermeulen told The Oncology Pharmacist. â&#x20AC;&#x153;Given the importance of reducing wait times (the time between when patients arrive in the clinic, have counts verified, and have their infusion

G REEN H ILL H EALTHCARE C OMMUNICATIONS

PHARMACY PRACTICE

researchers injected alemtuzumab into sterile 100-mL minibags of 0.9% sodium chloride injection to a final concentration of 50 Âľg/mL and stored samples at 4Â°C for 28 days. The Gri-fill System was used to ensure sterility of the stored solution. Using a validated flow cytometric method, they found that alemtuzumab concentrations ranging from 0.1 Âľg/mL to 41 Âľg/mL in 0.9% sodium chloride remained stable for 28 days with virtually no loss of activity and no measurable filter adsorption.

Lung Cancer Continued from cover

LUNG CANCER

patients,” said Ettinger, who chairs the NCCN panel on NSCLC. “We have made strides, and I am optimistic we can go further.” The addition of bevacizumab to the armamentarium has increased the median survival of advanced NSCLC to 12+ months. In the European Avastin in Lung (AVAiL) trial (Manegold C, et al. Ann Oncol. 2008;19[suppl 8]:Abstract LBA1), advanced-disease patients who received first-line treatment with bevacizumab in addition to gemcitabine/ cisplatin had significantly improved response rates, duration of response, and progression-free survival (PFS) compared with chemotherapy alone; however, overall survival was not improved. Ettinger estimated that, approximately 20% of eligible patients do not receive bevacizumab because of concerns about side effects. Risks in the elderly were confirmed in a 2008 analysis of the landmark Eastern Cooperative Oncology Group (ECOG) 4599 trial (Ramalingam SS, et al. J Clin Oncol. 2008; 26:60-65). Although elderly patients (񡑀70 years) did have increased response rates with bevacizumab, they also had significantly more toxicity than younger patients and no corresponding increase in median survival, 1-year survival, or PFS, compared with paclitaxel/carboplatin. “The story with bevacizumab is not finished yet,” Ettinger predicted. Activity has also been shown when bevacizumab is combined with pemetrexed and carboplatin. The NCCN guidelines were updated to allow bevacizumab in patients with treated brain metastases and those on blood thinners.

New first-line options For advanced and metastatic disease,

Key Updates • Cetuximab/vinorelbine/cisplatin is a new first-line option for appropriately selected patients • Bevacizumab can be given to patients with treated brain metastases and those on blood thinners • For patients with nonsquamous histology, pemetrexed is an option for first-line treatment, preferably with cisplatin, and for maintenance therapy • The staging system has been revised • A survivorship care section has been added

the guidelines have added information regarding the use of cetuximab and pemetrexed. Specifically, the updated guidelines added cetuximab/vinorelbine/cisplatin and cisplatin/pemetrexed as first-line options for performance status (PS) 0-1 patients, in addition to chemotherapy with or without bevacizumab. The use of cetuximab is dependent upon positive staining for the epidermal growth factor receptor (EGFR), and the use of pemetrexed is dependent upon nonsquamous histology. Cetuximab/vinorelbine/cisplatin is also an option for PS 2 patients with EGFR positivity. Cetuximab/vinorelbine/cisplatin is included in the guidelines based on efficacy shown in the FLEX study, which randomized 1125 patients to cisplatin/vinorelbine with and without cetuximab (Pirker R, et al. J Clin Oncol. 2008;26[20 suppl]:Abstract 3). The use of cetuximab was associated with a 23% reduction in mortality. According to Ettinger, the addition of pemetrexed/cisplatin to the recom-

LUNG CANCER 12

G REEN H ILL H EALTHCARE C OMMUNICATIONS

mended options was based largely on a phase 3 trial comparing pemetrexed/ cisplatin to gemcitabine/cisplatin in 1725 patients (Scagliotti GV, et al. J Clin Oncol. 2008;26:3543-3551). With pemetrexed/cisplatin, median survival was improved, but only in patients with adenocarcinoma and large cellhistologies, and toxicity was worse. The guidelines no longer support the use of gemcitabine/carboplatin, docetaxel/carboplatin, or gemcitabine/ docetaxel in patients who cannot tolerate chemotherapy, he added.

Maintenance therapy As maintenance, the updated guidelines now allow patients with nonsquamous histology to receive single-agent pemetrexed until disease progression. Alternatively, patients responding to chemotherapy can continue chemotherapy for four to six cycles. The use of pemetrexed as maintenance therapy is based on a 2008 study (Ciuleanu T, et al. J Clin Oncol. 2008;26[20 suppl]:Abstract 8011), in which chemotherapy responders were randomized to maintenance with pemetrexed or placebo. Those receiving pemetrexed had a doubling in PFS, from <2 months to 4 months, for a 41% highly significant reduction in risk. Most benefit was seen in patients with nonsquamous and adenomatous tumors. In patients with nonsquamous histology, survival was increased from 9.4 months to 14.4 months. “These studies illustrate the new concept that we must know the histology to select treatment. When we get a pathology report that says ‘carcinoma, not otherwise specified,’ that is now a problem,” Ettinger suggested. The NCCN panel also reiterated the preference for a two-drug regimen, with the exception of threedrug regimens containing bevacizumab and cetuximab. They also indicate that patients having reactions to paclitaxel or docetaxel can be treated with albumin-bound paclitaxel. After disease progression, secondline agents include docetaxel, pemetrexed, and erlotinib for PS 0-2 patients. Best supportive care is suggested for PS 3-4 patients.

Molecular diagnostic studies in NSCLC The presence of EGFR-activating mutations is of true biological relevance for patient selection. There is a significant association between EGFR mutations, especially exon 19 and 21 deletions, and response to tyrosine kinase inhibitors. Mutations in exon 18 are associated with resistance to treatment. And mutations in Kirsten rat sarcoma (KRAS), which is a critical downstream effector of the EGFR pathway, are also associated with intrinsic resistance to tyrosine kinase inhibitors. “In many institutions now, patients are automatically getting tested for EGFR and KRAS status,” Ettinger noted. In patients with an EGFR mutation or gene amplification, or never smokers, clinicians can consider erlotinib with or without chemotherapy, the guidelines state. If the patient has a KRAS mutation, treatment other than erlotinib should be considered. Guidelines for survivorship care The NCCN has recognized the need for structured recommendations on caring for cancer survivors, and these have been incorporated into the NSCLC guidelines. Surveillance recommendations include obtaining a history and physical examination, with a contrast-enhanced chest computed tomography (CT) scan every 4 to 6 months for 2 years, then history and physical examination, with a noncontrast-enhanced chest CT scan annually. Smoking status should be assessed at each visit, with counseling and referral for cessation as needed. Patients should receive annual influenza and pneumococcal vaccinations with revaccination as appropriate. Survivorship care also includes counseling patients regarding health promotion and wellness, additional health monitoring, cancer screenings, and so forth in accordance with recommendations for all cancer survivors. Updates in evaluation and staging The new guidelines have changed all references to positron-emission tomograph (PET) scan to “PET/CT scan,” reflecting the higher resolution and better correlation with this modality, and have added endobronchial ultrasound biopsy to the evaluation of stage IIIB patients. Changes were also made to the staging of NSCLC, especially the T and M descriptors, to better reflect the way that clinicians practice, Ettinger explained. The new staging recognizes the impact of the primary tumor size on prognosis, recognizes the lack of impact of the same lobe nodules (ie, T4 to T3), eliminates “wet 3B,” and adds M1a and M1b to the lexicon. N2 descriptors remain the same (see ST-1 in guidelines). For the complete guidelines go to www.nccn.org. March/April 2009

Complimentary

CONTINUING EDUCATION

AT WWW.THEONCOLOGYPHARMACIST.COM Program #CIK10082 • RELEASE DATE: April 15, 2009 • EXPIRATION DATE: April 14, 2010

Reimbursement for Expensive Cancer Therapies: The Role of Cost-effectiveness Analysis BY 񡑑񡑅񡑗񡑙 񡑇񡑄񡑀񡑙񡑉񡑉񡑃񡑀񡑖񡑥񡑠񡑱񡑨񡑈񡑃񡑀񡑐񡑇񡑇񡑖񡑃񡑀񡑆񡑇񡑕񡑖 College of Pharmacy, University of Nebraska Medical Center, Omaha, Nebraska HOW TO RECEIVE CREDIT To receive continuing education credit, learners must: • Read the article in its entirety • Take the CE self-assessment test and complete the evaluation test: 1. Log on to www.theoncologypharmacist. 2. Click on UNMC logo on homepage. 3. Register to participate. 4. Enter program number #CIK10082. • The learner must answer at least 70% of the questions on the post-test correctly. • The estimated time to complete this activity is 1 hour. Your continuing education certificate can be printed by following the directions online after successful completion of the post-test. DISCLAIMERS The opinions or views expressed in this continuing education activity are those of the faculty and do not necessarily reflect the opinions or recommendations of the University of Nebraska Medical Center (UNMC), Center for Continuing Education. While the University of Nebraska Medical Center, Center for Continuing Education is

ue to changes in the US Food and Drug Administration (FDA) approval process for cancer drugs, many new cancer drugs have been approved over the past 10 to 15 years. Although the availability of these new drugs has improved survival for many cancer patients, there is increasing concern over the cost of these agents.1 The global oncology market is predicted to increase 12% to 15% each year, from $48 billion in 2008 to $75 billion to $80 billion in 2012.2 About 70% of all sales of cancer drugs in North America and the European Union are of agents introduced in the past 10 years. Although purchasers and payers have always been concerned about healthcare costs, recently concerns have been raised by providers (ie, hospitals and oncologists) and patients. In an effort to control the utilization of expensive specialty drugs, many insurers have added a fourth tier to their pharmacy benefit plans.3 In contrast to the modest copayments required for other tiers, the fourth tier usually requires that patients pay a percentage of the drug cost (ie, coinsurance). Coinsurance payments, which generally range from 20% to 33% of the drug cost, can sometimes exceed $10,000 each year. Elderly patients FACULTY/PLANNER DISCLOSURES It is the policy of the University of Nebraska Medical Center, Center for Continuing Education that all planners and faculty participating in continuing education activities provided by the University of Nebraska Medical Center, Center for Continuing Education are to disclose to the audience any real or apparent conflicts of interest with providers of commercial products and/or devices relating to the topics of this educational activity and also disclose discussion of labeled/unapproved uses of drugs or devices discussed in their presentation. The planners and faculty have been advised that this activity must be free from commercial bias and based upon all the available scientifically rigorous data from research that conforms to accepted standards of experimental design, data collection, and analysis.

March/April 2009

an ACPE accredited organization, this does not imply endorsement by the UNMC or ACPE of any commercial products affiliated with this activity. LEARNING OBJECTIVES After completing this activity, the reader should be better able to: • Describe the types of cost analyses used in making decisions about reimbursement for cancer drugs. • Explain the role of cost-effectiveness in reimbursement decisions in the United States compared with the United Kingdom and Canada. • Provide an example of how cost-effectiveness analysis may affect decisions about coverage of a new cancer therapy. TARGET AUDIENCE Registered pharmacists and other interested healthcare professionals, especially those caring for cancer patients. COST This program is complimentary for all learners.

with Medicare coverage who receive their chemotherapy in the clinic setting are subject to similar coinsurance payments. As a result, many patients cannot afford the coinsurance payments.4 With declining reimbursement, private oncology offices and hospital-based clinics are caught in the middle, and many now require up-front payment before chemotherapy administration.5 In a recent survey, 23% of oncologists responded that costs influenced their treatment decisions, and 16% said that they omit discussion of very expensive treatments when they know that cost would place a great strain on patient resources.6 In this review, a recently published cost-effectiveness analysis will be used to illustrate how these types of analyses may be used by policy makers to make reimbursement decisions concerning cancer drugs.

Case study: sunitinib for first-line treatment of metastatic renal cell carcinoma Sunitinib malate is a recently approved, orally administered small molecule with antitumor activity against renal cell carcinoma, gastrointestinal stromal tumors, and other solid tumors. The annual cost

The authors, reviewers, and planning committee members listed below have stated they have no significant or substantial relationship with providers of commercial products and/or devices discussed in this activity and/or with any commercial supporter of this activity. • Carole R. Chambers, BSc (Pharm), MBA • Lois Colburn • Susan Goodin, PharmD, FCCP, BCOP • Dawn Lagrosa • Brenda Ram, CMP • Lara J. Reiman • Karen Rosenberg The following authors have stated that they have the following financial relationships: • Lyssa Friedman, RN, MPA, OCN, is an employee of Veracyte, Inc.

• Gary C. Yee, PharmD, FCCP, BCOP, serves on the utilization management and national pharmacy & therapeutics committees for a large pharmacy benefits manager. ACCREDITATION AND CONTACT HOURS STATEMENT The University of Nebraska Medical Center, Center for Continuing Education is accredited by the Accreditation Council for Pharmacy Education as a provider of continuing pharmacy education. The ACPE provider number is 447-000-09-008-H04-P. To receive the 1 contact hour of continuing education credit, pharmacists should complete the activity requirements and evaluation at the conclusion of the activity. Approval is valid from the initial release date of April 15, 2009. The expiration date is April 14, 2010. A statement of credit will be available for printing online upon completion of the post-test with a score of 70% or better and the evaluation instrument.

EDITORIAL BOARD 񡑇񡑠񡑱񡑰񡑧񡑤񡑀񡑗񡑄񡑀񡑇񡑥񡑠񡑨񡑡񡑤񡑱 񡑃񡑀񡑆񡑘񡑢񡑀񡑁񡑖񡑥񡑠񡑱񡑨񡑂񡑃 񡑓񡑆񡑅 Director of Pharmacy Alberta Cancer Board 1331-29th Street NW Edmonton, Alberta T2N 4 N2 Canada 񡑒∀ 񡑠񡑀񡑐񡑱񡑦񡑤񡑣񡑨񡑠񡑩񡑃񡑀񡑗񡑔񡑃񡑀񡑓񡑖񡑅񡑃񡑀񡑕񡑇񡑔 Senior Director, Clinical Programs Veracyte, Inc. 7000 Shoreline Court South San Francisco, CA 94080 񡑘! 񡑠񡑩񡑀񡑑񡑰񡑰񡑣񡑦񡑩񡑃񡑀񡑖񡑥񡑠񡑱񡑨񡑈񡑃񡑀񡑐񡑇񡑇񡑖񡑃񡑀񡑆񡑇񡑕񡑖 Director, Division of Pharmaceutical Sciences Cancer Institute of New Jersey 195 Little Albany Street New Brunswick, NJ 08903-2681 񡑑񡑠񡑱∀񡑀񡑇񡑄񡑀񡑙񡑤񡑤񡑃񡑀񡑖񡑥񡑠񡑱񡑨񡑈񡑃񡑀񡑐񡑇񡑇񡑖񡑃񡑀񡑆񡑇񡑕񡑖 Professor of Pharmacy Practice College of Pharmacy University of Nebraska Medical Center 986405 Nebraska Medical Center Omaha, NE 68198-6045 PLANNING COMMITTEE Lois Colburn Executive Director Center for Continuing Education University of Nebraska Medical Center 986800 Nebraska Medical Center Omaha, NE 68198-6800 Brenda Ram, CMP Coordinator Center for Continuing Education University of Nebraska Medical Center 986800 Nebraska Medical Center Omaha, NE 68198-6800 Dawn Lagrosa Associate Editor Green Hill Healthcare Communications, LLC 241 Forsgate Drive Monroe Twp, NJ 08831 Lara J. Reiman Managing Editor Green Hill Healthcare Communications, LLC 241 Forsgate Drive Monroe Twp, NJ 08831 Karen Rosenberg Editorial Director Green Hill Healthcare Communications, LLC 241 Forsgate Drive Monroe Twp, NJ 08831

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AT WWW.THEONCOLOGYPHARMACIST.COM Program #CIK10082 • RELEASE DATE: April 15, 2009 • EXPIRATION DATE: April 14, 2010 Table. Cost-effectiveness of Targeted Agents for Renal Cell Carcinoma Treatment

Comparator

Base-Case ICER (Cost [£] per QALY) NICE Manufacturer

First-line treatment, suitable for immunotherapy Sunitinib IFN Bevacizumab plus IFN IFN

71,462 171,301

28,546 74,978

First-line treatment, poor prognosis Temsirolimus IFN

94,385

55,814

Second-line treatment Sorafenib

102,498

90,630

BSC

BSC indicates best supportive care; ICER, incremental cost-effectiveness ratio; IFN, interferon; NICE, National Institute for Health and Clinical Excellence; QALY, qualityadjusted life-year. Adapted with permission from Coon JT, Hoyle M, Green C, et al; Peninsula Technology Assessment Group. Bevacizumab, sorafenib tosylate, sunitinib, and temsirolimus for renal cell carcinoma: a systematic review and economic evaluation. Exeter, UK: Peninsula Medical School; May 2008.

of sunitinib in the United States is $50,000 to $60,000. A recently published large multicenter, randomized, phase 3 trial showed that sunitinib was superior to interferon alfa in patients with previously untreated metastatic renal cell carcinoma.7 Sunitinib-treated

patients had a significantly higher objective response rate (31% vs 6%, P <.001) and longer median progression-free survival (11 vs 5 months, P <.001) than those treated with interferon alfa. In a recent update of that trial, patients in the sunitinib group had longer median

overall survival than those in the interferon alfa group (26.4 vs 21.8 months), although the difference was of borderline significance (P = .051).8 Based on the results of that phase 3 trial, a Pfizer-supported cost-effectiveness analysis was conducted, and the results of that analysis were recently published.9 A Markov model was developed to evaluate the costeffectiveness and cost-utility of sunitinib (as compared with interferon alfa or interleukin-2) in a hypothetical cohort of 1000 patients with metastatic renal cell carcinoma receiving first-line treatment of sunitinib. The analysis was done from a US societal perspective. Model parameters were obtained from trial results, published literature, government sources, and expert opinion. A 10-year time horizon was assumed to represent a lifetime horizon, because the model predicted that fewer than 1% of patients would still be alive at 10 years. Utilities were derived from quality-of-life data collected with the EuroQoL (EQ-5D) instrument in clinical trials. Only direct medical costs were included. Sunitinib was more effective and more costly than interferon alfa. Both sunitinib and interferon alfa dominated interleukin-2 (ie, more effective and less costly). The incremental cost-effectiveness or cost-utility ratio of sunitinib versus interferon alfa was $18,611 per progression-free year gained, $67,215 per life-year gained, or $52,593 per quality-adjusted life-year (QALY) gained (2006 US dollars; costs and outcomes discounted at 5%). A probabilistic sensitivity analysis showed that the

񡑃񡑑񡑉񡑉񡑅񡑐񡑕񡑂񡑓񡑖 Reimbursement for Expensive Cancer Therapies: The Role of Cost-effectiveness Analysis: Implications for Nurses BY 񡑈񡑖񡑔񡑔񡑂 񡑆񡑓񡑇񡑅񡑄񡑉񡑂񡑐񡑁񡑀񡑓񡑐񡑁񡑀񡑉񡑒񡑂񡑁񡑀񡑑񡑃񡑐 Senior Director, Clinical Programs, Veracyte, Inc, South San Francisco, California

he economic news is abysmal. Unemployment has skyrocketed; home values and retirement savings accounts have plummeted. Start saving, the pundits advise; ease spending. Even President Obama counseled, “Our economy is badly weakened, a consequence of greed and irresponsibility on the part of some, but also our collective failure to make hard choices and prepare the nation for a new age.”1 Nowhere is the downturn felt more than in healthcare. According to the Centers for Medicare & Medicaid Services (CMS), total US health expenditures reached $2.2 trillion in 2007, which equals about $7421 per person or 16.2% of the nation’s gross domestic product (GDP).2 In the accompanying article, Yee notes that the United Kingdom controls healthcare costs by using cost-effectiveness to decide which therapies are approved. Britain’s National Institute for Health and Clinical Excellence (NICE), under fire for denying high-cost drugs such as sunitinib for patients with metastatic renal cell carcinoma, has support from health policy experts in countries around the globe, including the United States. Here, however, efforts by CMS to apply such controls meet with considerable backlash and have been unsuccessful.3 “Why does U.S. health care cost so much?” asked Princeton University economist Uwe E. Reinhardt. He noted that although high healthcare costs are common in 14

wealthy countries (as defined by high GDP), healthcare spending is considerably higher per capita in the United States than elsewhere in the developed world. Reinhardt attributed what health services researchers call “excess spending” to several factors, such as4: • Higher prices for healthcare goods and services than those paid in other countries for the same goods and services • Higher administrative overhead costs than those incurred in other countries with simpler health insurance systems • More use of high-cost, high-technology equipment and procedures than are used in other countries • Higher healthcare utilization related to American tort laws, in which tests and procedures are used as a defense against possible future malpractice litigation. Oncology nurses who see themselves as patient advocates may find it difficult to support the NICE model in the United States. The Oncology Nursing Society 20092012 strategic plan lists advocacy as its primary strategic area, with efforts targeted at increasing cancer services reimbursement, promoting legislation to ensure access to care and clinical trials, and advocating for medically underserved populations.5 Health services policy experts may view healthcare at the population level, but in the United States, nurse advocates evaluate healthcare one patient at a time. Yee describes cost-effectiveness and

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cost-utility ratios, which lead to rationing of costly therapies. To nurses, rationing may seem acceptable in the abstract yet untenable when applied to an individual patient or family member. Yee suggests that the United States is at a crossroads; society has postponed the use of cost models to drive reimbursement, yet society can no longer bear cancer care’s rising cost. Perhaps an ethical society cannot justify denying care from an individual, but if healthcare breaks down population-wide, the healthcare system no longer benefits even one person. Perhaps ethically we cannot afford to withhold a single dose of sunitinib; system-wide, however, can we afford not to? References

1. Obama B. Transcript: Barack Obama’s inaugural address. New York Times. January 20, 2009. 2. Centers for Medicare & Medicaid Services. National health expenditures 2007 highlights. www.cms.hhs.gov/NationalHealthExpendData/ downloads/highlights.pdf. Accessed February 9, 2009. 3. Harris G. The evidence gap: British balance benefit vs. cost of latest drugs. New York Times. December 2, 2008. 4. Reinhardt UE. Why does U.S. health care cost so much (part 1)? Economix/New York Times Blog. November 14, 2008. http:// economix.blogs.nytimes.com/2008/11/14/why-does-us-health-carecost-so-much-part-i/?scp=2&sq=health%20care%20cost&st=cse. Accessed February 2, 2009. 5. Oncology Nursing Society strategic plan pillar description document (2009-2012). April 15, 2008. http://onsopcontent.ons.org/Corporate Reports/strategic.shtml. Accessed February 2, 2009.

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AT WWW.THEONCOLOGYPHARMACIST.COM Program #CIK10082 • RELEASE DATE: April 15, 2009 • EXPIRATION DATE: April 14, 2010 model was most sensitive to utility values during treatment, sunitinib cost, and the cost of best supportive care. The authors concluded that sunitinib is a cost-effective alternative to interferon alfa as first-line treatment for metastatic renal cell carcinoma because the costeffectiveness (or cost-utility) ratios were in the range of values that society (in the United States) is willing to pay for health benefits.

NICE declines drugs for metastatic renal cell carcinoma In the United Kingdom, the National Institute for Health and Clinical Excellence (NICE), a government agency, advises the National Health Service (NHS) on coverage for medicines and technologies.10 Details on its appraisal process are available online on the NICE web site (www.nice.org.uk). NICE usually hires an academic group to prepare its appraisals, which include an economic evaluation that estimates the incremental cost-effectiveness (or cost-utility) ratio of the new drug. These appraisals can sometimes take 2 to 3 years after a drug has been approved. The NHS then considers these analyses when it makes decisions concerning reimbursement for that new drug or technology. In August 2008, NICE issued draft guidance that rejected the use of four drugs, including sunitinib, for metastatic renal cell carcinoma.11 Although the report

concluded that the four drugs were effective, NICE rejected them because its analysis showed that they were “not cost-effective use of NHS resources” based on its usual threshold of £30,000 per QALY (Table). It is interesting to note that estimates of the cost-effectiveness ratios of the four drugs from the manufacturers differed considerably from the estimates from the independent academic group hired by NICE. The estimated cost-utility ratio for sunitinib in the setting of first-line treatment in the Pfizer model submitted to NICE was about 25% lower than the value reported in the study published by Remák and associates,9 which is about the same as the difference in sunitinib cost between the United States and Britain. That decision angered patients and physicians, because the drugs are widely available in other European countries. Furthermore, British patients were angered by the NHS guidelines, which state that they would lose all of their NHS benefits if they decided to pay for the cancer drugs with their personal funds. In response to this outcry, the British government announced in November 2008 that it would not withdraw NHS benefits from patients who choose to pay out-of-pocket for cancer drugs and issued new guidelines to NICE that encourage greater flexibility when NICE appraises high-cost drugs for patients with rare and serious conditions. Some reports indicate that NICE will increase the threshold to as high as

£80,000 per QALY for these selected drugs. In a final ruling announced March 25, 2009, NICE recommends sunitinib for the first-line treatment of renal cancer.

Role of cost-effectiveness analysis in reimbursement decisions In the United States, the single largest payer of healthcare for cancer patients is the Centers for Medicare & Medicaid Services. The long-standing Medicare policy is to not consider cost-effectiveness analyses in its reimbursement decisions.12 Private insurers also have been reluctant to formally consider costeffectiveness analyses in its reimbursement decisions. Although cancer drugs usually have been viewed as “off limits” for utilization management strategies, the high cost of these agents has prompted private insurers to apply these strategies to cancer drugs.13,14 Some insurers are limiting the use of these agents to FDAapproved indications, which can be problematic because cancer drugs are often used for “off-label” indications and because some drugs are approved based on limited evidence. Others are applying step-therapy protocols to cancer drugs, which require that patients fail one or more less expensive options before they are eligible to receive the more expensive agent. One innovative approach is a “pay-for-performance” strategy, which means that the manufacturer agrees to lower the price

񡑇񡑓񡑑񡑑񡑈񡑒񡑗񡑅񡑕񡑘 Reimbursement for Expensive Cancer Therapies: The Role of Cost-effectiveness Analysis: A Canadian Pharmacist’s Perspective BY 񡑇񡑅񡑕񡑓񡑐񡑈 񡑕񡑄񡑀񡑇񡑉񡑅񡑑񡑆񡑈񡑕񡑖񡑃񡑀񡑆񡑖񡑇 񡑁񡑔񡑠񡑙񡑢񡑡񡑂񡑃񡑀񡑑񡑆񡑅 Pharmacy Director, Alberta Cancer Board, Edmonton, Alberta

he role of cost-effectiveness analysis in expensive cancer therapies is a timely topic, with the recent release of the updated National Institute for Health and Clinical Excellence (NICE) guidance document for cancer drugs in the United Kingdom and the studies on the new therapies for treating renal cell carcinoma. However, funding decisions continue to challenge us. Although many of the new tyrosine kinase inhibitors (TKIs) for the treatment of renal cell carcinoma have been available for more than 2 years, funding questions have not resolved. The incorporation of cost-effectiveness in the evaluation of new drugs and technologies is anticipated in certain countries, such as Canada.1 Our provincial oncology program annually identifies those cancer agents that consume 80% of the cancer drug program resources. Thirteen agents consumed 80% of the resources for the calendar year 2008; nine (70%) of these agents did not exist in the marketplace 10 years ago. Should we perform economic evaluations as a pharmaceutical is undergoing clinical trials? The National Cancer Institute of Canada (NCIC) Working Group on Economics recommends that at least one of the following criteria be met before an economic analysis is undertaken alongside a clinical trial2: • The new intervention is anticipated to have only a modest therapeutic benefit in a potentially large population • The new therapy is potentially very costly

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• There is a high degree of uncertainty about the economic impact of the treatment of interest • An economic evaluation associated with equivalence trials may yield information of importance in the determination of routine practice • Economic data will assist future economic evaluation of new therapies. Because of the controlled environment of a clinical trial, the result of the economic analysis is the intervention’s cost efficacy; after it is released into the market, we can learn its true cost-effectiveness. A novel idea being discussed in the literature is “coverage with evidence development,” which explores funding approvals for promising technologies and drugs for which the evidence remains uncertain.3,4 One-time decisions regarding funding may become history as evidence continues to accumulate during the early stages of drug market entry, and this new concept provides for earlier access to the new therapy but ongoing scrutiny. Economic evaluation is one of many tools that can be used by decision makers, but it cannot serve alone to make such value-based decisions.5 As Yee explains, NICE came to different conclusions over time. The use of cost-effectiveness by panels such as NICE does not guarantee that similar decisions are made as values are implicitly or explicitly a part of the recommendations for funding. In Canada, we have a Common Drug Review (CDR) for review of all new pharmaceuticals. CDR did not support the use of public funds for

the TKIs in renal cell carcinoma in the spring of 2007. On March l, 2007, a new oncology-focused panel called the Joint Oncology Drug Review (JODR) was formed.6 JODR, which uses both clinical and pharmacoeconomic review tools in its decision-making, is similar to NICE and the new panel under consideration for the United States. JODR has supported the use of sunitinib for renal cell carcinoma as well as sorafenib for second-line therapy. Access to cancer drugs is an evolving area that is not yet resolved and is an important consideration for all those involved in the decision-making process. References

1. Guideline for the Economic Evaluation of Health Technologies: Canada. 3rd ed. Ottawa, ON: Canadian Agency for Drugs and Technologies in Health; 2006. 2. Evans WK, Goyle D, Gafni A, Walker H; NCIC Working Group on Economic Analysis. Which cancer clinical trials should be considered for economic evaluation? Selection criteria from the National Cancer Institute of Canada’s Working Group on Economic Analysis. Chronic Dis Can. 2003;24:102-107. 3. Hutton J, Trueman P, Henshall C. Coverage with evidence development: an examination of conceptual and policy issues. Int J Technol Assess Health Care. 2007;23:425-432. 4. Tunis SR, Pearson SD. Coverage options for promising technologies: Medicare’s ‘coverage with evidence development.’ Health Aff (Millwood). 2006;25:1218-1230. 5. Browman GP, Manns B, Hagen N, et al. 6-STEPPPs: a modular tool to facilitate clinician participation in fair decisions for funding new cancer drugs. J Oncol Pract. 2008;4:2-7. 6. Jeffcott G. New initiatives in managing access to cancer drugs. Provincial Reimbursement Advisor. May 2007:43-48.

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AT WWW.THEONCOLOGYPHARMACIST.COM Program #CIK10082 • RELEASE DATE: April 15, 2009 • EXPIRATION DATE: April 14, 2010 of its drug by providing a rebate if the drug fails to perform.15,16 Several manufacturers have already agreed to that strategy in Britain, and at least one large private insurer in the United States is exploring it. Many policy experts support an expanded role of costeffectiveness analyses in determining reimbursement decisions, including the creation of a new federally funded, independent entity (modeled after NICE) to produce comparative effectiveness and cost-effectiveness information.1,12,17-19 Some argue that payers already make these comparisons, either implicitly or explicitly. Creation of such a formal entity was recently predicted to yield savings of $368 billion to the healthcare system over the next 10 years.19 Although cost-effectiveness analyses can be useful to decision makers, healthcare professionals and the public are skeptical of the use of these types of information and are uncomfortable with efforts to allocate resources based on the economic value of a person’s life.20 Ideally, the public (ie, society) should determine how societal resources are allocated. Private employers, however, are major purchasers of healthcare in the United States. The outcry in Britain over NICE’s decision concerning drugs to treat renal cell carcinoma suggests that the public views cancer drugs differently from other drugs. In response, NICE has adjusted its cost-effectiveness threshold for certain cancer drugs. Similarly, some experts suggest Americans do not want to consider cost when making decisions concerning new cancer treatments.20

Summary The rising cost of cancer drugs is of concern to society, particularly patients with cancer, who often cannot afford the newer agents. Although decision makers have been reluctant to consider cost-effectiveness analyses in reimbursement decisions, there is increasing support for an expanded role of these types of analyses, including the creation of a new federally funded entity to produce these analyses. As illustrated by the experiences in Britain, however, application of cost-effectiveness analyses to reimbursement decisions for cancer drugs can be controversial because of the societal burden of cancer. Disclosure Dr. Yee serves on the utilization management and national pharmacy & therapeutics committees for a large pharmacy benefits manager. References 1. Sinha G. Expensive cancer drugs with modest benefit ignite debate over solutions. J Natl Cancer Inst. 2008;100:1347-1349. 2. Gavel SJ. The oncology pipeline: maturing, competitive, and growing? Oncology Business Review. Sept 2008. www.imshealth.com/im shealth/ Global/Content/Web%20Article/The_Oncology_Pipeline3.pdf. Accessed February 6, 2009. 3. Kolata G. Co-payments soar for drugs with high prices. New York Times. April 14, 2008. 4. Kolata G, Pollack A. Costly cancer drug offers hope, but also a dilemma. New York Times. July 6, 2008. 5. Chase M. Pricey drugs put squeeze on doctors. Wall Street Journal. July 8, 2008.

6. Schrag D, Hanger M. Medical oncologists’ views on communicating with patients about chemotherapy costs: a pilot survey. J Clin Oncol. 2007;25:233-237. 7. Motzer RJ, Hutson TE, Tomczak P, et al. Sunitinib versus interferon alfa in metastatic renal-cell carcinoma. N Engl J Med. 2008;356:115-124. 8. Figlin RA, Hutson TE, Tomczak P, et al. Overall survival with sunitinib versus interferon-alfa as first-line treatment of metastatic renal cell carcinoma [abstract]. J Clin Oncol 2008;26(suppl):Abstract 5024. 9. Remák E, Charbonneau C, Négrier S, et al. Economic evaluation of sunitinib malate for the first-line treatment of metastatic renal cell carcinoma. J Clin Oncol. 2008;26:3995-4000. 10. Steinbrook R. Saying no isn’t NICE—travails of Britain’s National Institute for Health and Clinical Excellence. N Engl J Med. 2008;359:1977-1981. 11. Harris G. British balance benefit vs. cost of latest drugs. New York Times. December 2, 2008. 12. Neumann PJ, Rosen AB, Weinstein MC. Medicare and cost-effectiveness analysis. N Engl J Med. 2005;353:1516-1522. 13. Anand G. As costs rise, new medicines face pushback. Wall Street Journal. September 18, 2007. 14. Chase M. Payers aim to rein in specialty-drug spending. Wall Street Journal. March 20, 2008. 15. Pollack A. Pricing pills by the results. New York Times. July 14, 2007. 16. Garber AM, McClellan MB. Satisfaction guaranteed—”payment by results” for biologic agents. N Engl J Med. 2007;357:1575-1577. 17. Emanuel EJ, Fuchs VR, Garber AM. Essential elements of a technology and outcomes assessment initiative. JAMA. 2007;298:1323-1325. 18. American College of Physicians. Information on cost-effectiveness: an essential product of a national comparative effectiveness program. Ann Intern Med. 2008;148:956-961. 19. Davis K. Slowing the growth of health care costs—learning from international experience. N Engl J Med. 2008;359:1751-1755. 20. Berenson A. Pinning down the money’s value of a person’s life. New York Times. June 11, 2007.

񡑄񡑒񡑐񡑐񡑆񡑑񡑖񡑂񡑔񡑘 Reimbursement for Expensive Cancer Therapies: The Role of Cost-effectiveness Analysis: A US Pharmacist’s Perspective BY 񡑕񡑗񡑕񡑂񡑑 񡑈񡑒񡑒񡑅񡑉񡑑񡑁񡑀񡑓񡑠񡑙񡑢񡑡񡑅񡑁񡑀񡑇񡑄񡑄񡑓񡑁񡑀񡑃񡑄񡑒񡑓 Cancer Institute of New Jersey, New Brunswick

magine if you can, buying your dream home at today’s median price of $198,6001 and then being told you can only live in it 2.4 months of the year, or 20% of the time. We all would understand the ramifications of such a decision and, as long as there were other alternatives, this is not an agreement we would enter into from a financial standpoint. Similarly, although the newest cancer drugs offer improvements over older therapies, they often cost thousands of dollars more a month with response rates around 20%. It is a similar type decision, payers, providers, and patients struggle with every day to decide which drugs are worth the increased costs. While there are patients dying of cancer every minute of every day, we must be smart about drug selection, because the direct medical costs of cancer are $89 billion a year2 and continue to rise. Genetic testing has been shown to boost efficacy in cancer care, and reduce costs, but we are still a long way from having a test to predict for response with every new drug. An example of how this could reduce drugs costs is testing for Kirsten rat sarcoma (KRAS) mutations before prescribing cetuximab, which was approved by the US Food and Administration in 2004. Patients with KRAS mutations do not respond to cetuximab, and it has been estimated that limiting cetuximab to patients without these mutations will save the country up to $604 million a year.3 Putting this savings in perspective, if the lack of a KRAS 16

mutation had been identified at the time of approval as a predictor for the pool of patients who may have benefited from cetuximab, a healthcare savings of approximately $2.4 billion may have occurred. As many of the newly approved agents do not have a biomarker for prediction of response, cost is becoming the “biomarker” used by policy makers for coverage decisions. Yee discusses a recently published cost-effectiveness analysis that could be used in making these policy decisions, instead of the evaluation of these agents based on cost alone. Pharmacists must be familiar with cost-effectiveness analyses that have been performed and the methodology behind their calculations. In addition to understanding the recent literature on cost-effective analyses, pharmacists in the ambulatorycare setting must be familiar with the recent changes to the Centers for Medicare & Medicaid Services (CMS) “off-label” reimbursement and the current compendia for coverage, because cost-effectiveness analyses are not currently a part of the reimbursement decision. At my own institution, a policy has been in place since 1993 that requires the prescribed regimen be a nationally accepted treatment regimen, as defined in standard textbooks or documented in a peer-reviewed publication or multi-institutional trial that is published as an abstract, but the final decision is left with the dispensing pharmacist. This policy was not developed because

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of reimbursement issues but because we support evidence-based care. It has made the transition to the new CMS guidelines easy, because compendia follow similar rules for “off-label” reimbursement. I urge all pharmacists to evaluate their institutional policies regarding “off-label” use and base their decisions on evidence, not solely on reimbursement, whether the payer is CMS or another third-party payer. If we “police” ourselves regarding these decisions, we will not have payers dictating therapy. Healthcare costs, and ultimately payers, eventually will drive down prices of pharmaceuticals, and the pharmaceutical industry will have to be more efficient in drug development and identification of the appropriate patient population. Until this goal is attained, pharmacists must be at the table with the appropriate understanding of cost-effectiveness when making decisions regarding formularies, reimbursement, and patient care. References

1. Freedman R. 2009 economic outlook. January 2009. www.realtor.org/ rmonews_and_commentary/articles/2009/0901_residentialoutlook2009. Accessed February 3, 2009. 2. Schwartz K, Claxton G, Martin K, Schmidt C; Kaiser Family Foundation, American Cancer Society. Spending to Survive. February 2009. www.cancer.org/downloads/accesstocare/Spending_to_Survive. pdf. Accessed February 9, 2009. 3. Gardner A. Researchers zero in on GI cancers. USA Today. January 14, 2009.

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with the use of all-trans retinoic acid (ATRA) in combination with chemotherapy, CR rates reached 95% with a DFS of approximately 80%. Chemotherapy in combination with ATRA also reduced the incidence of differentiation syndrome, a common complication with ATRA treatment during induction therapy.2,5 Standard therapy now consists of an induction, consolidation, and maintenance phase (all consisting of ATRA and chemotherapy).

Safety and efficacy of arsenic trioxide The latest addition to APL therapy is the use of arsenic trioxide, which has been found to be effective in patients with untreated, relapsed, or refractory disease. The proposed mechanism of action includes induction differentiation at lower doses and apoptosis at higher concentrations. Because of its effectiveness, multiple studies have investigated the proper placement and dosing of arsenic trioxide in APL.6-8 A recent Cancer and Leukemia Group B study evaluated adding arsenic trioxide as consolidation therapy to a standard treatment protocol.9 Patients were randomized to receive two courses of arsenic trioxide (0.15 mg/kg/day for 5 days each week for 5 weeks) if they were in remission after induction therapy (ATRA 45

mg/m2/day, daunorubicin 50 mg/ m2 for 4 days, and cytarabine 200 Table. Arsenic Trioxide Induction mg/m2 for 7 days). Both groups and Consolidation Dosing were then given additional conRegimens solidation therapy with daunorubicin (50 mg/m2 IV for 3 days) 񡑆񡑢񡑙񡑦񡑘񡑥񡑠񡑣񡑢񡑁 and ATRA (45 mg/m2 for 7 days). Patients were then randomized to Arsenic trioxide should be administered ATRA (45 mg/m2/day for 7 days intravenously (IV) at a dose of 0.15 every other week), with or withmg/kg/day until bone marrow remission. out 6-mercaptopurine (60 mg/ Total induction dose should not exceed m/day) and methotrexate (20 mg 2 60 doses. /m weekly) for 1 year of maintenance therapy. 񡑂񡑣񡑢񡑤񡑣񡑡񡑠񡑙񡑗񡑥񡑠񡑣񡑢񡑁񡑀 This phase 3 trial enrolled 582 Consolidation treatment should begin 3 to 6 patients, 73% of them between weeks after completion of induction therapy. the ages of 15 and 60 years. At the time of publication, the Arsenic trioxide should be administered IV at median follow-up time was 29 a dose of 0.15 mg/kg/day for 25 doses over months. The CR rate for both a period of up to 5 weeks. groups was 89%. The primary end point of event-free survival (EFS) was 77% in the arsenic arm and 59% in the placebo arm (P = the study is that the outcomes (EFS, .013). Overall survival (OS) was also OS) of the patients who did not improved in the arsenic arm: 86% receive arsenic are lower than that compared with 77% (P = .029) with reported in other APL studies. This placebo. There was an increase in may make the comparison to other studgrade 3 nonhematologic toxicity in the ies less persuasive. arsenic group (43% compared with Nonetheless, this study provides evi28%). All other toxicities were similar dence that the addition of arsenic to between groups. It appears the addition current APL therapy may be beneficial. of arsenic trioxide to consolidation Because of this, more patients will liketherapy increases the EFS and OS of ly receive treatment with arsenic trioxpatients with APL. One criticism of ide, and healthcare professionals must be aware of the dosing and adverse events associated with the drug. Arsenic trioxide has been used in various forms since the late 18th century to treat many different diseases and conditions. It is a recognized poison, and not until the early 1990s was it studied for efficacy in APL. Before a patient is treated with arsenic trioxide, a baseline electrocardiogram (ECG) must be obtained and serum electrolytes must be checked. A serious hyponatremia, and a couple had grade 3 adverse effect of the drug is prolongation fatigue. Perry Ivy, MD, who is senior of the QTc interval. If the QTc interval investigator in the Cancer Therapy is >500 ms, the drug should not be given Evaluation Program at the National until corrective measures are undertaken Cancer Institute in Rockville, Mary- to reduce the QTc interval. Electrolyte land, warned, however, of the likelihood levels and ECG should be done weekly, of teratogenicity when the hedgehog with a goal potassium level of >4 mEq/dL pathway is inhibited. The original and magnesium level of >1.8 mg/dL. If at inhibitor, cyclopamine, was discovered any time during therapy the QTc interval when pregnant ewes grazing on corn lily increases to >500 ms, therapy should be (Veratrum californicum) in the 1950s pro- withheld until it is <460 ms.10 duced cyclopic offspring, that is, having Arsenic trioxide is given intravenousfused orbits containing a single eye. ly over 1 to 2 hours. The induction and While Genentech appears to be consolidation schedules are shown in the farthest along in developing and test- Table. ing its compound, at least two other Side effects include edema, rash, and companies are developing hedgehog headache. Similar to therapy with pathway inhibitors. IPI-926 (Infinity ATRA, a differentiation syndrome can Pharmaceuticals) showed efficacy in occur, especially if patients are being a preclinical animal model against treated with arsenic trioxide during human pancreatic cancer, according induction therapy. Symptoms include to a poster presentation at the sym- fever, dyspnea, sudden weight gain (>2 posium in Geneva, and it has shown pounds in 24 hours), pulmonary infilactivity against medulloblastoma and trates, and effusions. If it is not properly small-cell lung cancer in similar managed, this syndrome can be fatal. models. Bristol-Myers Squibb in part- Treatment includes dexamethasone 10 nership with Exelixis is developing mg IV twice daily for at least 3 days.10 BMS-833923 (XL139), which is in phase 1 trials. Conclusion The historical stigma associated —Daniel M. Keller with arsenic can make patients cau-

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Hedgehog Hunters

Continued from page 11

HEMATOLOGIC CANCERS

survival, and angiogenesis. Mutations in the receptor can result in constitutive pathway activation and have been implicated in several cancers, including BCCs, some medulloblastomas, and colorectal and pancreatic adenocarcinomas. Additional tumors may be small-cell lung cancer, breast, and prostate cancers. Lucio Miele, MD, PhD, who is professor of pathology and pharmacology and director of the Breast Cancer Preclinical Program at the Cardinal Bernardin Cancer Center at Loyola University in Chicago, said, “The biggest promise of agents that are targeted to these developmental pathways like hedgehog…is precisely that they might be able to target not only the bulk tumor cells but also more resistant subpopulations of cells within the tumor that aren’t necessarily targeted by standard chemotherapy. There is some evidence for promise in that area.” Resistant subpopulations may include tumor-initiating or tumor stem cells. According to Rudin, toxicity with GDC-0449 was “remarkably low” with “very few grade 3 and grade 4 toxicities.” One patient had asymptomatic 18

G REEN H ILL H EALTHCARE C OMMUNICATIONS

tious about its use for treatment of APL. Diligent patient consultation about possible side effects and potential drug interactions and the need for weekly laboratory monitoring can offer reassurance about receiving arsenic. This patient education allows for an effective drug to be incorporated into the treatment of APL.

References

1. Avvisati G, Petti MC, Lo Cocco F, et al. The Italian way of treating acute promyelocytic leukemia (APL): final act. Blood. 2003; 102(suppl):142a. Abstract 487. 2. Sanz MA, Martin G, González M, et al. Riskadapted treatment of acute promyelocytic leukemia with all-trans retinoic acid and anthracycline monochemotherapy: a multicenter study by the PETHEMA group. Blood. 2004;103:12371243. 3. Cunningham I, Gee TS, Reich LM, et al. Acute promyelocytic leukemia: results of treatment during a decade at Memorial Hospital. Blood. 1989;73:1116-1122. 4. Fenaux P, Wang ZZ, Degos L. Treatment of acute promyelocytic leukemia by retinoids. Curr Top Microbiol Immunol. 2007;313:101-128. 5. Tallman MS, Anderson JS, Schiffer CA, et al. All-trans retinoic acid in acute promyelocytic leukemia: long-term outcome and prognostic factor analysis from the North American Intergroup protocol. Blood. 2002;100:4298-4302. 6. Zhang P, Wang SY, Hu LH. Arsenic trioxide treated 72 cases of acute promyelocytic leukemia. Chin J Haematol. 1996;17:58-62. 7. Chen GQ, Zhu J, Shi XG, et al. In vitro studies on cellular and molecular mechanisms of arsenic trioxide in the treatment of acute promyelocytic leukemia. Blood. 1996;88:1052-1061. 8. Shen ZX, Chen GQ, Ni JH, et al. Use of arsenic trioxide (As2O3) in the treatment of acute promyelocytic leukemia (APL): II. Clinical efficacy and pharmacokinetics in relapsed patients. Blood. 1997;89:3354-3360. 9. Powell B, Moser B, Stock W, et al. Effect of consolidation with arsenic trioxide (As2O3) on eventfree survival (EFS) and overall survival (OS) among patients with newly diagnosed acute promyelocytic leukemia (APL): North American intergroup C9710. J Clin Oncol. 2007;25(suppl 18S):Abstract 2. 10. Trisenox [package insert]. Frazer, PA: Cephalon, Inc; 2006.

Recent FDA

Approvals • Everolimus for Advanced Renal Cell Cancer

The US Food and Drug Administration has approved everolimus (Affinitor, Novartis) for treatment of advanced renal cell carcinoma after failure of treatment with sunitinib or sorafenib. Approval was based on the results of a phase 3 trial, which showed that compared with placebo, everolimus more than doubled the time without tumor growth or death (4.9 vs 1.9 months) and reduced the risk of disease progression or death by 67%. The trial also showed that approximately 25% of patients had no tumor growth after 10 months of treatment. Everolimus inhibits mammalian target of rapamycin, a protein that controls tumor cell division and blood vessel growth. March/April 2009

Nilotinib in CP CML correlate with improved long-term outcomes, and that outcomes are improved with higher imatinib doses. Among patients with CP CML, standard-dose imatinib induces complete cytogenetic responses (CCyRs) in approximately 80% of patients. Nilotinib is a phenylamino-pyrimidine derivative with increased selectivity against Bcr-Abl that inhibits most imatinib-resistant Bcr-Abl kinase domain mutants (except T3151). Among CP CML patients for whom imatinib therapy fails, treatment with nilotinib induces CCyR in 40%. The toxicity profile is favorable. Cortes’ clinical trial included 53 patients with CP CML (median age, 47 years), nine of whom had received imatinib previously. The primary end point was major molecular response (MMR) at 12 months. Individuals included in the trial had had no previous therapy or < 1 month of interferonalfa or imatinib. Starting doses of imatinib were 400 mg twice daily, 200 mg twice daily, or 200 mg once daily. Major cytogenetic responses were achieved by 90% of patients within 3 months, and responses were sustained at 100% from 30 to 36 months. Best responses included complete hematologic responses (CHRs) among all 47 patients not in CHR at start of treat-

Table. Percent Achieving Major Molecular Response with Nilotinib/Imatinib (Historical) Imatinib 400 mg

Imatinib 800 mg (N = 205)

Nilotinib 800 mg (N = 53)

12 months

18 months

ment, CCyRs in 45 (97%) of 46, and MMRs in 25 (53%) of 47. Ten (21%) patients achieved complete molecular responses (CMRs). Although there were very few molecular responses at 3 months (7%), by 12 months (primary end point), 47% had achieved molecular responses, with CMRs in 7%. The molecular responses increased over time, and at 18 months, MMRs were reported in 65% of patients, among them 30% with CMRs. Event-free survival was 89% at 12 months, and overall survival was 100%. Events were defined as loss of CHR, loss of CCyR, going off treatment because of toxicity, progression to accelerated or blast phase, or death. The most common nonhematologic adverse event was elevated liver enzyme levels (grade 3 to 4, 13%). Rash and fatigue (any grade) were noted in 68% and 61% of patients, respectively, with little higher grade incidence (2% and 4%, respectively).

Adverse events were generally lower than with other therapies, Cortes said. Hematologic adverse events included grade 3 to 4 thrombocytopenia in 9% of patients, neutropenia in 11%, and anemia in 5%. Grade 1 to 2 thrombocytopenia, neutropenia, and anemia were found in 39%, 25%, and 70% of patients, respectively. Cortes emphasized that elevated liver enzymes were transient and that higher grade neutropenia and thrombocytopenia occurred in the first 2 to 3 months and seldom after that. Treatment interruptions were necessary in 40% of patients, with 21% needing more than one. The median dose-interruption duration was 9 days (range 2-63 days). Although dose reductions were needed in 28% of patients, the median dose was 800 mg (range 200-800 mg). Six patients went off study; among those entering the trial in CP, given reasons were liver toxicity, pericarditis/pericardial effu-

sion, fatigue, elevated creatinine, progression to blast phase, and personal reasons. Among three additional patients starting in accelerated phase, progression to blast phase was given as the reason for withdrawal. At 6 months, more patients achieved MMR with nilotinib than has been seen in earlier experience with imatinib (40% vs 0% with imatinib 400 mg and vs 34% with imatinib 800 mg). The pattern persisted over time (Table), although molecular responses at 12 months were similar to those for high-dose imatinib. Cortes noted that cytogenetic responses occurred sooner than with imatinib, and that a high percentage of patients achieved undetectable transcript levels. He concluded, “Nilotinib induced rapid complete cytogenetic responses in most patients and had a favorable toxicity profile.”

CONFERENCE NEWS

Continued from cover

—Walter Alexander

SAN FRANCISCO—The most powerful treatment for patients with chronic myeloid leukemia (CML) in chronic phase (CP) is the combination of imatinib and pegylated interferon (Peg IFN), according to results of the STI571 Prospective International Randomised Trial (SPIRIT). SPIRIT findings were presented by Francois Guilhot, MD, at the 50th American Society of Hematology Annual Meeting. Guilhot, who is with the Department of Oncology, Hematology and Cell Therapy at University Hospital, Poitiers, France, noted that although imatinib at 400 mg/day induces high rates of durable cytogenetic and molecular responses in CP CML patients, higher doses of imatinib or combination therapies may improve response rates and outcomes. Single-arm phase 2 studies have explored imatinib in combination with cytarabine (ara-C) or Peg IFN. SPIRIT is a prospective, four-arm, phase 3 trial of higher doses of imatinib and combination therapies. In the four treatment arms, CP CML patients (N = 636, median age 51 years, 62% male) were randomized (1:1:1:1) to 14 days of imatinib 400 mg/day (N = 159) or 600 mg/day (N = 160), or to imatinib 400 mg/day plus ara-C 20 mg/m2 for 14 days/month (N = 158) or to imatinib 400 mg/day plus Peg IFN alfa-2a 90 µg/week (N = 159). The primary end March/April 2009

point was overall survival. SPIRIT investigators enrolled patients who received their CP CML diagnosis within the preceding 3 months and had had no previous CML therapy except hydroxyurea or anagrelide for 3 months. Median follow-up was 36 months. All results were expressed as Bcr-Abl:Abl ratio in the international scale. The definition for a major molecular response was Bcr-Abl:Abl ratio ≤ 0.1%. Complete hematologic responses at 3 months were achieved by 88% of patients. At 6 months, complete cytogenetic responses (CCyRs) were attained by more patients in the imatinib 600 mg/day arm (68%) than in the other arms (P <.001 vs imatinib 400 mg/day [49%], and P = .03 vs imatinib plus araC [56%] or imatinib plus Peg IFN [56%]). At 12 months, CCyRs were achieved similarly in all arms, in 55% of patients receiving 400 mg/day imatinib and by 62%, 63%, and 65% respectively in the imatinib 600 mg/day, imatinib plus ara-C, and imatinib plus Peg IFN arms. The major molecular response rate (Bcr-Abl:Abl ≤ 0.01%) for the imatinib plus Peg IFN arm was significantly higher than in the imatinib 400 mg/day arm at both 6 months (39%, 20%; P = .0005) and 12 months (57%, 38%; P = .0008). The cumulative incidence of achieving ≤ 0.01% Bcr-Abl:Abl levels within 12 months was significantly higher in the

imatinib plus Peg IFN group (36%) than in the other groups (imatinib 600 mg/day [21%], imatinib plus ara-C [20%], imatinib 400 mg/day [16%]; P = .002). Optimal molecular responses (deep and complete) at 12 months were also more frequent in the imatinib plus Peg IFN arm than in the other arms (30% vs 15%, 18%, 15% for imatinib 400 mg/day, 600 mg/day, imatinib plus ara-C, respectively; P = .0019). Higher rates of grade 3 to 4 toxicities were recorded with higher doses of imatinib and with the combination arms (especially neutropenia and thrombocytopenia). Grade 3 to 4 neutropenia occurred in approximately 50% of patients in the imatinib plus Peg IFN arm, approximately 42% in the imatinib plus ara-C arm, in approximately 15% of the imatinib 600mg/day, and approximately 7% in imatinib 400 mg/day arms. Grade 3 to 4 thrombocytopenia was reported in approximately 30% of imatinib plus ara-C patients, approximately 15% of imatinib plus Peg IFN patients, in approximately 7% of the imatinib 600mg/day patients, and in approximately 4% of the imatinib 400mg/day patients. Although anemia was the most common nonhematologic adverse event, grade 3 to 4 anemia was reported in only about 10% of imatinib plus ara-C patients and in very low percentages in the other trial arms.

Discontinuations were most frequent in the combination arms, with Peg IFN stopped in 115 of 159 patients and ara-C stopped in 139 of158 patients. At 1 year, Peg IFN was stopped by 71 patients (45%) as compared with 62 patients (39%) discontinuing ara-C. Imatinib was discontinued by 7% to 10% of patients (all arms). Most patients were able to tolerate imatinib, with a median dose in the first year of 400 mg/day in the 400 mg/day group, and 590 mg/day in the 600 mg/day group. Median ara-C dose was 24 mg/day, and Peg IFN 54 µg/week. Guilhot emphasized that major molecular responses at 12 months were significantly higher with imatinib plus Peg IFN (57%) than with imatinib alone (38%). Imatinib plus Peg IFN also produced a higher rate of optimal molecular responses in the same period (30% vs 15%). Better responses, however, were at a cost of higher grade 3 to 4 toxicity rates, with both imatinib and the combinations. He concluded, “The combination of imatinib and Peg IFN has been established in this trial as the most powerful treatment for patients with chronic myeloid leukemia in chronic phase.” He commented further that with this combination, patients might be able to stop treatment. —WA

G REEN H ILL H EALTHCARE C OMMUNICATIONS

CONFERENCE NEWS

SPIRIT Shows Imatinib Plus Peg IFN Most Powerful Regimen for Chronic Phase CML

Prostate Cancer PROSTATE CANCER

Brachytherapy May Be More Cost-effective than IMRT for Low-risk Localized Prostate Cancer

Julia Hayes, MD

ORLANDO—Brachytherapy (BT) may be more effective and less costly than intensity-modulated radiation therapy (IMRT) or proton-beam (PB) therapy for men with low-risk, clinically localized prostate cancer, according to a cost-effec-

tiveness analysis presented at the 2009 Genitourinary Cancers Symposium. Julia Hayes, MD, who is a clinical instructor of medicine at Harvard Medical School, Boston, and her colleagues created a cost-effectiveness model simulating

men who were treated with BT, PB therapy, or IMRT. The side effects and costs of each therapy were derived from the medical literature and 2007 Medicare payments. The investigators also estimated the cost-effectiveness of following

Presents The Second Annual 2009 Curriculum for

CONSIDERATIONS IN MULTIPLE MYELOMA A Newsletter Series for Cancer Care Professionals Center of Excellence Media, along with Editor-in-Chief Sagar Lonial, MD, of Emory University, will proudly offer the multidisciplinary cancer team at your center a series of newsletters focusing on the challenges in treating patients with multiple myeloma.

SAGAR LONIAL, MD

Associate Professor of Hematology and Oncology Emory University

★ Earn Continuing Education Credits ★ Eight part newsletter series

• Retreatment Settings • Maintenance Therapy • Do CRs Correlate to a Clinical Benefit?

CLINICAL TOPICS:

• Perspectives on Relevant Endpoints of Clinical Trials • Stem Cell Mobilization • Cytogenic Testing in the MM Patient

• To Transplant or Not to Transplant…That is the Question • Sequencing Strategies in MM: Treatment with Case Studies

Each newsletter will feature:

• Contributions from thought-leading physicians, pharmacists, and nurses

• Continuing Education credits available to physicians, pharmacists, and nurses

TO REQUEST FREE COPIES

Call 732-992-1899 or visit www.coexm.com

Retreatment Settings Newsletter Statement of Need

The purpose of this activity is to enhance knowledge concerning the treatment of patients with relapsed and refractory multiple myeloma (MM).

Target Audience

This activity was developed for physicians, nurses, and pharmacists.

Learning Objectives

PROSTATE CANCER

At the completion of this educational activity, participants should be able to: • Describe how standard therapy may be improved with novel agents and treatment approaches for patients with relapsed and refractory multiple myeloma (MM) • Summarize new data from clinical trials in relapsed/refractory MM as reported at the 2008 American Society of Hematology annual meeting • Review the side effect profiles of novel agents for MM • Identify effective strategies for the management of common toxicities associated with MM therapies

Physician Accreditation

This activity has been planned and implemented in accordance with the Essential Areas and Policies of the Accreditation Council for Continuing Medical Education (ACCME) through the joint sponsorship of Global Education Group (Global) and Medical Learning Institute, Inc. (MLI). Global is accredited by the ACCME to provide continuing medical education for physicians.

Physician Credit Designation

Global designates this educational activity for a maximum of 1.0 AMA PRA Category 1 Credit(s)TM. Physicians should only claim credit commensurate with the extent of their participation in the activity.

Registered Nurse Designation

MLI is accredited as a provider of continuing nursing education by the American Nurses Credentialing Center’s Commission on Accreditation through the California Board of Registered Nursing, Provider #15106. This continuing nursing education activity for 1.0 contact hour is provided by MLI.

Registered Pharmacy Designation

MLI is accredited by the Accreditation Council for Pharmacy Education (ACPE) as a provider of continuing pharmacy education. Completion of this activity provides for 1.0 contact hour (0.1 CEU) of continuing education credit. The universal program number for this activity is 468-999-09-008-H01-P. Estimated time to complete this activity: 1 hour Date of original release: March 31, 2009 Valid for CME credit through: March 31, 2010 This activity is jointly sponsored by

This activity is supported by an educational grant from Millennium Pharmaceuticals, Inc.

men on active surveillance (AS) for 3 years before treatment, and of treating men at diagnosis. In the base case, BT was less costly and more effective than IMRT, providing 13.90 years of quality-adjusted life expectancy (QALE) at a cost of $29,575. This suggested a total cost-savings of $12,016 and an additional 4.7 weeks of QALE. In the model examining AS strategies, BT was more effective than initial BT. It added 2.8 weeks of QALE at an additional cost of $1730 and an incremental costeffectiveness ratio (ICER) of $33,111 relative to BT. In the model that looked at men aged 58 years, BT was the least costly and most effective strategy, at a cost savings of $34,885 and a QALE of 17.73 weeks. These findings translated into a saving of more than $12,300 and a QALE benefit of 5.9 weeks relative to IMRT. “These therapies appear to be equally good at treating the prostate cancer, so this model is designed to capture the difference in side effects and costs between the treatments, to look at the way the treatments affect men’s quality of life, and the cost to the healthcare system. Ours is the first study to evaluate these treatments in this way,” said Hayes. A sensitivity analysis that was specifically sensitive to the probability of side effects at the extremes of tested ranges was included in the investigation. IMRT or PB therapy had ICERs relative to BT of at least $58,000/QALE in all cases. In the probabilistic sensitivity analysis, BT was the least expensive in 89% of 1000 samples and provided the highest QALE in 62% of the samples. In addition, BT provided the highest QALE at the lowest cost in 57% of samples. “The most important takehome message is that based on the data we have in the literature, BT is marginally better tolerated than IMRT or PB therapy, and is less expensive. Until prospective clinical studies comparing these techniques are carried out, models like this one can help us synthesize and understand the data we already have to help us make better decisions, both clinically and for our healthcare system,” explained Hayes. “In this economic climate, we are going to need to make good choices about how to allocate resources. So we need to know where the money is best spent.” —John Schieszer

G REEN H ILL H EALTHCARE C OMMUNICATIONS

March/April 2009

Meetings 12th World Congress on Cancer of the Skin 2009 Wccs2009@kenes.com

JUNE 2009

17-20 MIAMI, FL

HOPA 2009: Hematology/Oncology Pharmacy Association 5th Annual Conference www.hoparx.org

17-20 KOHALA COAST, HI 10th International Lung Cancer Congress www.cancerlearning.com

22-26 KOHALA COAST, HI

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2009 Pan Pacific Lymphoma Conference bram@unmc.edu

24-26 MADRID, SPAIN

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VIII Madrid Breast Cancer Conference www.madridbreastcancer2009.com

25-27 ROME, ITALY

Supportive Care in Cancer MASCC/ISOO 2009 International Symposium www.mascc.org

March/April 2009

13-14 WASHINGTON, DC May 29-June 2

4th Annual Oncology Economics Forum: Access to Innovative Cancer Therapies in 2009 www.conferagroup.com

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

INDICATIONS AND USAGE Non-Hodgkin’s Lymphoma (NHL) Rituxan® (rituximab) is indicated for the treatment of patients with: Relapsed or refractory, low-grade or follicular, CD20-positive, B-cell NHL as a single agent; Previously untreated follicular, CD20-positive, B-cell NHL in combination with CVP chemotherapy; Non-progressing (including stable disease), low-grade, CD20positive B-cell NHL, as a single agent, after first-line CVP chemotherapy; Previously untreated diffuse large B-cell, CD20-positive NHL in combination with CHOP or other anthracycline-based chemotherapy regimens. WARNINGS AND PRECAUTIONS Infusion Reactions Rituxan can cause severe, including fatal, infusion reactions. Severe reactions typically occurred during the first infusion with time to onset of 30–120 minutes. Rituxan-induced infusion reactions and sequelae include urticaria, hypotension, angioedema, hypoxia, bronchospasm, pulmonary infiltrates, acute respiratory distress syndrome, myocardial infarction, ventricular fibrillation, cardiogenic shock, or anaphylactoid events. Premedicate patients with an antihistamine and acetaminophen prior to dosing. Institute medical management (e.g., glucocorticoids, epinephrine, bronchodilators, or oxygen) for infusion reactions as needed. Depending on the severity of the infusion reaction and the required interventions, consider resumption of the infusion at a minimum 50% reduction in rate after symptoms have resolved. Closely monitor the following patients: those with preexisting cardiac or pulmonary conditions, those who experienced prior cardiopulmonary adverse reactions, and those with high numbers of circulating malignant cells (≥25,000/mm3). [See Boxed Warning, Warnings and Precautions, Adverse Reactions.] Tumor Lysis Syndrome (TLS) Rapid reduction in tumor volume followed by acute renal failure, hyperkalemia, hypocalcemia, hyperuricemia, or hyperphosphatemia, can occur within 12–24 hours after the first infusion. Fatal TLS cases have occurred after administration of Rituxan. A high number of circulating malignant cells (≥25,000/mm3) or high tumor burden confers a greater risk of TLS after rituximab. Consider prophylaxis for TLS in patients at high risk. Correct electrolyte abnormalities, monitor renal function and fluid balance, and administer supportive care, including dialysis as indicated. [See Boxed Warning.] Severe Mucocutaneous Reactions Mucocutaneous reactions, some with fatal outcome, can occur in patients treated with Rituxan. These reactions include paraneoplastic pemphigus, Stevens-Johnson syndrome, lichenoid dermatitis, vesiculobullous dermatitis, and toxic epidermal necrolysis. The onset of these reactions has varied from 1–13 weeks following Rituxan exposure. Discontinue Rituxan in patients who experience a severe mucocutaneous reaction. The safety of readministration of Rituxan to patients with severe mucocutaneous reactions has not been determined. [See Boxed Warning, Adverse Reactions.] Progressive Multifocal Leukoencephalopathy (PML) JC virus infection resulting in PML and death can occur in Rituxan-treated patients with hematologic malignancies or with autoimmune diseases. The majority of patients with hematologic malignancies diagnosed with PML received Rituxan in combination with chemotherapy or as part of a hematopoietic stem cell transplant. The patients with autoimmune diseases had prior or concurrent immunosuppressive therapy. Most cases of PML were diagnosed within 12 months of their last infusion of Rituxan. Consider the diagnosis of PML in any patient presenting with new-onset neurologic manifestations. Discontinue Rituxan and consider discontinuation or reduction of any concomitant chemotherapy or immunosuppressive therapy in patients who develop PML. [See Boxed Warning, Adverse Reactions.] Hepatitis B Virus (HBV) Reactivation Hepatitis B Virus (HBV) reactivation with fulminant hepatitis, hepatic failure, and death can occur in patients with hematologic malignancies treated with Rituxan. The median time to the diagnosis of hepatitis was approximately 4 months after the initiation of Rituxan and approximately one month after the last dose. Screen patients at high risk of HBV infection before initiation of Rituxan. Closely monitor carriers of hepatitis B for clinical and laboratory signs of active HBV infection for several months following Rituxan therapy. Discontinue Rituxan and any concomitant chemotherapy in patients who develop viral hepatitis, and institute appropriate treatment including antiviral therapy. Insufficient data exist regarding the safety of resuming Rituxan in patients who develop hepatitis subsequent to HBV reactivation. [See Adverse Reactions.] Other Viral Infections The following additional serious viral infections, either new, reactivated, or exacerbated, have been identified in clinical studies or postmarketing reports. The majority of patients received Rituxan in combination with chemotherapy or as part of a hematopoietic stem cell transplant. These viral infections included cytomegalovirus, herpes simplex virus, parvovirus B19, varicella zoster virus, West Nile virus, and hepatitis C. In some cases, the viral infections occurred as late as one year following discontinuation of Rituxan and have resulted in death. [See Adverse Reactions.] Cardiovascular Discontinue infusions for serious or life-threatening cardiac arrhythmias. Perform cardiac monitoring during and after all infusions of Rituxan for patients who develop clinically significant arrhythmias or who have a history of arrhythmia or angina. [See Adverse Reactions.] Renal Severe, including fatal, renal toxicity can occur after Rituxan administration in patients with hematologic malignancies. Renal toxicity has occurred in patients with high numbers of circulating malignant cells (≥25,000/mm3) or high tumor burden who experience tumor lysis syndrome and in patients with NHL administered concomitant cisplatin therapy during clinical trials. The combination of cisplatin and Rituxan is not an approved treatment regimen. Use extreme caution if this non-approved combination is used in clinical trials and monitor closely for signs of renal failure. Consider discontinuation of Rituxan for patients with a rising serum creatinine or oliguria. Bowel Obstruction and Perforation Abdominal pain, bowel obstruction and perforation, in some

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cases leading to death, can occur in patients receiving Rituxan in combination with chemotherapy. In postmarketing reports, the mean time to documented gastrointestinal perforation was 6 (range 1–77) days in patients with NHL. Perform a thorough diagnostic evaluation and institute appropriate treatment for complaints of abdominal pain, especially early in the course of Rituxan therapy. [See Adverse Reactions.] Immunization The safety of immunization with live viral vaccines following Rituxan therapy has not been studied and vaccination with live virus vaccines is not recommended. For NHL patients, the benefits of primary or booster vaccinations should be weighted against the risks of delay in initiation of Rituxan therapy. Laboratory Monitoring Because Rituxan binds to all CD20positive B lymphocytes (malignant and non-malignant), obtain complete blood counts (CBC) and platelet counts at regular intervals during Rituxan therapy and more frequently in patients who develop cytopenias [see Adverse Reactions]. The duration of cytopenias caused by Rituxan can extend months beyond the treatment period. ADVERSE REACTIONS The most common adverse reactions of Rituxan (incidence ≥25%) observed in patients with NHL are infusion reactions, fever, chills, infection, asthenia, and lymphopenia. The most important serious adverse reactions of Rituxan are infusion reactions, tumor lysis syndrome, mucocutaneous toxicities, hepatitis B reactivation with fulminant hepatitis, PML, other viral infections, cardiac arrhythmias, renal toxicity, and bowel obstruction and perforation. Clinical Trials Experience Non-Hodgkin’s Lymphoma Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice. The data described below reflect exposure to Rituxan in 1606 patients, with exposures ranging from a single infusion up to 6–8 months. Rituxan was studied in both single-agent and active-controlled trials (n = 356 and n = 1250). These data were obtained in adults with low-grade, follicular, or DLBCL NHL. Most patients received Rituxan as an infusion of 375 mg/m2 per infusion, given as a single agent weekly for up to 8 doses, in combination with chemotherapy for up to 8 doses, or following chemotherapy for up to 16 doses. Infusion Reactions In the majority of patients with NHL, infusion reactions consisting of fever, chills/rigors, nausea, pruritus, angioedema, hypotension, headache, bronchospasm, urticaria, rash, vomiting, myalgia, dizziness, or hypertension occurred during the first Rituxan infusion. Infusion reactions typically occurred within 30 to 120 minutes of beginning the first infusion and resolved with slowing or interruption of the Rituxan infusion and with supportive care (diphenhydramine, acetaminophen, and intravenous saline). The incidence of infusion reactions was highest during the first infusion (77%) and decreased with each subsequent infusion. [See Boxed Warning, Warnings and Precautions.] Infections Serious infections (NCI CTCAE Grade 3 or 4), including sepsis, occurred in less than 5% of patients with NHL in the single-arm studies. The overall incidence of infections was 31% (bacterial 19%, viral 10%, unknown 6%, and fungal 1%). [See Warnings and Precautions.] In randomized, controlled studies where Rituxan was administered following chemotherapy for the treatment of follicular or low-grade NHL, the rate of infection was higher among patients who received Rituxan. In diffuse large B-cell lymphoma patients, viral infections occurred more frequently in those who received Rituxan. Cytopenias and hypogammaglobulinemia In patients with NHL receiving rituximab monotherapy, NCI-CTC Grade 3 and 4 cytopenias were reported in 48% of patients. These included lymphopenia (40%), neutropenia (6%), leukopenia (4%), anemia (3%), and thrombocytopenia (2%). The median duration of lymphopenia was 14 days (range, 1–588 days) and of neutropenia was 13 days (range, 2–116 days). A single occurrence of transient aplastic anemia (pure red cell aplasia) and two occurrences of hemolytic anemia following Rituxan therapy occurred during the single-arm studies. In studies of monotherapy, Rituxan-induced B-cell depletion occurred in 70% to 80% of patients with NHL. Decreased IgM and IgG serum levels occurred in 14% of these patients. Single-Agent Rituxan Adverse reactions in Table 1 occurred in 356 patients with relapsed or refractory, lowgrade or follicular, CD20-positive, B-cell NHL treated in single-arm studies of Rituxan administered as a single agent. Most patients received Rituxan 375 mg/m2 weekly for 4 doses. Table 1 Incidence of Adverse Events in ≥5% of Patients with Relapsed or Refractory, LowGrade or Follicular NHL, Receiving Single-agent Rituxan (N = 356)a,b

Chemotherapy for DLBCL In Studies 6 and 7, the following adverse reactions, regardless of severity, were reported more frequently (≥5%) in patients age ≥60 years receiving R-CHOP as compared to CHOP alone: pyrexia (56% vs. 46%), lung disorder (31% vs. 24%), cardiac disorder (29% vs. 21%), and chills (13% vs. 4%). Detailed safety data collection in these studies was primarily limited to Grade 3 and 4 adverse reactions and serious adverse reactions. In Study 7, a review of cardiac toxicity determined that supraventricular arrhythmias or tachycardia accounted for most of the difference in cardiac disorders (4.5% for R-CHOP vs. 1.0% for CHOP). The following Grade 3 or 4 adverse reactions occurred more frequently among patients in the R-CHOP arm compared with those in the CHOP arm: thrombocytopenia (9% vs. 7%) and lung disorder (6% vs. 3%). Other Grade 3 or 4 adverse reactions occurring more frequently among patients receiving R-CHOP were viral infection (Study 7), neutropenia (Studies 7 and 8), and anemia (Study 8). Immunogenicity As with all therapeutic proteins, there is a potential for immunogenicity. The observed incidence of antibody (including neutralizing antibody) positivity in an assay is highly dependent on several factors including assay sensitivity and specificity, assay methodology, sample handling, timing of sample collection, concomitant medications, and underlying disease. For these reasons, comparison of the incidence of antibodies to Rituxan with the incidence of antibodies to other products may be misleading. Using an ELISA assay, antihuman anti-chimeric antibody (HACA) was detected in 4 of 356 (1.1%) patients with low-grade or follicular NHL receiving single-agent Rituxan. Three of the four patients had an objective clinical response. The clinical relevance of HACA formation in rituximab treated patients is unclear. Postmarketing Experience The following adverse reactions have been identified during postapproval use of Rituxan in hematologic malignancies. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure. Decisions to include these reactions in labeling are typically based on one or more of the following factors: (1) seriousness of the reaction, (2) frequency of reporting, or (3) strength of causal connection to Rituxan. Hematologic: prolonged pancytopenia, marrow hypoplasia, and late-onset neutropenia, hyperviscosity syndrome in Waldenstrom’s macroglobulinemia. Cardiac: fatal cardiac failure. Immune/Autoimmune Events: uveitis, optic neuritis, systemic vasculitis, pleuritis, lupus-like syndrome, serum sickness, polyarticular arthritis, and vasculitis with rash. Infection: viral infections, including progressive multifocal leukoencephalopathy (PML), increase in fatal infections in HIV-associated lymphoma, and a reported increased incidence of Grade 3 and 4 infections in patients with previously treated lymphoma without known HIV infection. Neoplasia: disease progression of Kaposi’s sarcoma. Skin: severe mucocutaneous reactions. Gastrointestinal: bowel obstruction and perforation. Pulmonary: fatal bronchiolitis obliterans and pneumonitis (including interstitial pneumonitis). DRUG INTERACTIONS Formal drug interaction studies have not been performed with Rituxan. USE IN SPECIFIC POPULATIONS Pregnancy Category C: There are no adequate and well-controlled studies of rituximab in pregnant women. Postmarketing data indicate that B-cell lymphocytopenia generally lasting less than six months can occur in infants exposed to rituximab in-utero. Rituximab was detected postnatally in the serum of infants exposed in-utero. Non-Hodgkin’s lymphoma is a serious condition that requires treatment. Rituximab should be used during pregnancy only if the potential benefit to the mother justifies the potential risk to the fetus. Reproduction studies in cynomolgus monkeys at maternal exposures similar to human therapeutic exposures showed no evidence of teratogenic effects. However, B-cell lymphoid tissue was reduced in the offspring of treated dams. The B-cell counts returned to normal levels, and immunologic function was restored within 6 months of birth. Nursing Mothers It is not known whether Rituxan is secreted into human milk. However, Rituxan is secreted in the milk of lactating cynomolgus monkeys, and IgG is excreted in human milk. Published data suggest that antibodies in breast milk do not enter the neonatal and infant circulations in substantial amounts. The unknown risks to the infant from oral ingestion of Rituxan should be weighed against the known benefits of breastfeeding. Pediatric Use The safety and effectiveness of Rituxan in pediatric patients have not been established. Geriatric Use Diffuse Large B-Cell NHL Among patients with DLBCL evaluated in three randomized, activecontrolled trials, 927 patients received Rituxan in combination with chemotherapy. Of these, 396 (43%) were age 65 or greater and 123 (13%) were age 75 or All Grades (%) Grade 3 and 4 (%) All Grades (%) Grade 3 and 4 (%) greater. No overall differences in effectiveness were observed between these Any Adverse Events 99 57 Respiratory System 38 4 patients and younger patients. Cardiac adverse reactions, mostly supraventricular Body as a Whole 86 10 Increased Cough 13 1 arrhythmias, occurred more frequently among elderly patients. Serious pulmonary Fever 53 1 Rhinitis 12 1 Chills 33 3 Bronchospasm 8 1 adverse reactions were also more common among the elderly, including Infection 31 4 Dyspnea 7 1 Asthenia 26 1 Sinusitis 6 0 pneumonia and pneumonitis. Low-Grade or Follicular Non-Hodgkin’s Headache 19 1 Metabolic and Nutritional Lymphoma Clinical studies of Rituxan in low-grade or follicular, CD20-positive, Abdominal Pain 14 1 3 Disorders 38 Pain 12 1 Angioedema 11 1 B-cell NHL did not include sufficient numbers of patients aged 65 and over to Back Pain 10 1 Hyperglycemia 9 1 Throat Irritation 9 0 Peripheral Edema 8 0 determine whether they respond differently from younger subjects. Flushing 5 0 LDH Increase 7 0 OVERDOSAGE There has been no experience with overdosage in human clinical Heme and Lymphatic System 67 48 Digestive System 2 37 Lymphopenia 48 40 Nausea 23 1 trials. Single doses of up to 500 mg/m2 have been given in dose-escalation Leukopenia 14 4 Diarrhea 10 1 Neutropenia 14 6 Vomiting 10 1 clinical trials. NONCLINICAL TOXICOLOGY Carcinogenesis, Mutagenesis, Thrombocytopenia 12 2 Nervous System 32 1 Impairment of Fertility No long term animal studies have been performed to Anemia 8 3 Dizziness 10 1 Skin and Appendages 44 2 Anxiety 5 1 establish the carcinogenic or mutagenic potential of Rituxan or to determine Night Sweats 15 1 Musculoskeletal System 26 3 Rash 15 1 Myalgia 10 1 potential effects on fertility in males or females. PATIENT COUNSELING Pruritus 14 1 Arthralgia 10 1 INFORMATION Patients should be provided the Rituxan Medication Guide and Urticaria 8 1 25 3 Cardiovascular System Hypotension 10 1 provided an opportunity to read prior to each treatment session. Because caution Hypertension 6 1 should be exercised in administering Rituxan to patients with active infections, it is a Adverse reactions observed up to 12 months following Rituxan. bAdverse reactions graded for severity by important that the patient’s overall health be assessed at each visit and any NCI-CTC criteria. questions resulting from the patient’s reading of the Medication Guide be In these single-arm Rituxan studies, bronchiolitis obliterans occurred during and discussed. Rituxan is detectable in serum for up to six months following up to 6 months after Rituxan infusion. Rituxan in Combination With completion of therapy. Individuals of childbearing potential should use effective Chemotherapy Adverse reactions information below is based on 1250 patients contraception during treatment and for 12 months after Rituxan therapy. who received Rituxan in combination with chemotherapy or following chemotherapy. Rituxan in Combination With Chemotherapy for Low-Grade NHL In Study 4, patients in the R-CVP arm experienced a higher incidence of infusional toxicity and neutropenia compared to patients in the CVP arm. The following adverse reactions occurred more frequently (≥5%) in patients receiving R-CVP compared to CVP alone: rash (17% vs. 5%), cough (15% vs. 6%), flushing (14% vs. 3%), rigors (10% vs. 2%), pruritus (10% vs. 1%), neutropenia (8% vs. 3%), and chest tightness (7% vs. 1%). In Study 5, the following adverse reactions Revised 9/2008 (4835505) were reported more frequently (≥5%) in patients receiving Rituxan following CVP Jointly Marketed by: compared to patients who received no further therapy: fatigue (39% vs. 14%), Biogen Idec Inc. 5200 Research Place San Diego, CA 92122 anemia (35% vs. 20%), peripheral sensory neuropathy (30% vs. 18%), infections Genentech USA, Inc. 1 DNA Way South San Francisco, CA 94080-4990 (19% vs. 9%), pulmonary toxicity (18% vs. 10%), hepato-biliary toxicity (17% vs. 7%), rash and/or pruritus (17% vs. 5%), arthralgia (12% vs. 3%), and weight gain (11% vs. 4%). Neutropenia was the only Grade 3 or 4 adverse reaction that occurred more frequently (≥2%) in the Rituxan arm compared with those who received no further therapy (4% vs. 1%). Rituxan in Combination With ©2008 Biogen Idec Inc. and Genentech, Inc. 7140917 October 2008

G REEN H ILL H EALTHCARE C OMMUNICATIONS

MEETINGS

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3-6 TEL AVIV, ISRAEL

MEETINGS

MAY 2009

For previously untreated diffuse large B-cell, CD20-positive NHL in combination with CHOP or other anthracycline-based chemotherapy regimens

When planning a treatment course for DLBCL

Take the essential path toward improved survival

Cumulative Cumulative Proportion Proportion Surviving Surviving

RITUXAN+CHOP is proven to prolong survival in DLBCL

47% INCREASE

1.0

in 7-year OS in GELA* trial 1,2

0.8 0.6 0.4 R-CHOP (n=202) CHOP† (n=197) p =0.0004

0.2 0 0 Years

• At 7 years, 8 cycles of RITUXAN+ CHOP increased overall survival (OS) from 36% to 53% compared with CHOP alone1 • At 5 years, 8 cycles of RITUXAN+ CHOP increased OS from 46% to 58% compared with CHOP alone5

BOXED WARNINGS and Additional Important Safety Information

The most important serious adverse reactions of RITUXAN are fatal infusion reactions, tumor lysis syndrome (TLS), severe mucocutaneous reactions, progressive multifocal leukoencephalopathy (PML), hepatitis B reactivation with fulminant hepatitis, other viral infections, cardiovascular events, renal toxicity, and bowel obstruction and perforation. The most common adverse reactions of RITUXAN (incidence ≥25%) observed in patients with NHL are infusion reactions, fever, chills, infection, asthenia, and lymphopenia.5

RITUXAN in Combination with CHOP Chemotherapy for DLBCL: The following adverse reactions, regardless of severity, were reported more frequently (≥5%) in patients age ≥60 years receiving R-CHOP as compared to CHOP alone: pyrexia (56% vs 46%), lung disorder (31% vs 24%), cardiac disorder (29% vs 21%), and chills (13% vs 4%). In the GELA LNH 98-5 study, a review of cardiac toxicity determined that supraventricular arrhythmias or tachycardia accounted for most of the difference in cardiac disorders (4.5% for R-CHOP vs 1.0% for CHOP).5 The following Grade 3 or 4 adverse reactions occurred more frequently among patients in the R-CHOP arm compared with those in the CHOP arm: thrombocytopenia (9% vs 7%) and lung disorder (6% vs 3%). Other Grade 3 or 4 adverse reactions reported more frequently among patients receiving R-CHOP were viral infection (GELA LNH 98-5 study), neutropenia (GELA LNH 98-5 and MInT studies), and anemia (MInT study).5

Please see brief summary of prescribing information on adjacent page. Attention Healthcare Provider: Provide Medication Guide to patient prior to RITUXAN infusion. *GELA (Groupe d’Etude des Lymphomes de l’Adulte) LNH 98-5 trial: A Phase III trial of 399 previously untreated elderly (age ≥60 years) DLBCL patients.3,4 †CHOP: Cyclophosphamide, doxorubicin, vincristine, and prednisone.

References: 1. Coiffier B, Feugier P, Mounier N, et al. Long-term results of the GELA study comparing R-CHOP and CHOP chemotherapy in older patients with diffuse large B-cell lymphoma show good survival in poor-risk patients. J Clin Oncol. 2007;25(suppl 18S):443s. Abstract 8009. 2. Coiffier B, Feugier P, Mounier N, et al. Long-term results of the GELA study comparing R-CHOP and CHOP chemotherapy in older patients with diffuse large B-cell lymphoma show good survival in poor-risk patients. Paper presented at: 43rd American Society of Clinical Oncology Annual Meeting; June 1-5, 2007; Chicago, Ill. Abstract 8009. 3. Coiffier B, Lepage E, Brière J, et al. CHOP chemotherapy plus rituximab compared with CHOP alone in elderly patients with diffuse large-B-cell lymphoma. N Engl J Med. 2002;346:235-242. 4. Data on file, Genentech, Inc. 5. RITUXAN® (Rituximab) full prescribing information, Genentech, Inc., 2008.

PROVE N. POWE R FU L.